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Insulin

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insulin

Dr. Ben Bikman: How To Reverse Insulin Resistance Through Diet, Exercise, & Sleep

Posted on July 11th 2025 (about 7 hours)

rhonda
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Q&A #52 with Dr. Rhonda Patrick (10/7/23)

Posted on October 11th 2023 (over 1 year)

Dr. Rhonda Patrick explores supplemental tyrosine, lion's mane, cordyceps, aging tests, and sunscreen's efficacy and safety in a Q&A.

exercise

Increasing metabolism — Is high-intensity interval training better? | Dr. Martin Gibala

Posted on September 28th 2023 (almost 2 years)

In this clip, Dr. Martin Gibala discusses the 'afterburn effect' and its impact on post-workout metabolism.

Topic Pages

  • Sugar-sweetened beverages (SSBs)

    SSB-derived rapid glucose absorption acutely stimulates pancreatic β-cell insulin secretion, while chronic intake promotes insulin resistance and hyperinsulinemia.

  • Ultra-processed Foods (UPFs)

    UPFs, high in rapidly digestible, low-fiber carbohydrates, provoke postprandial hyperglycemia that amplifies insulin secretion and promotes resistance.

News & Publications

  • Nearly half of people with type 2 diabetes have multiple micronutrient deficiencies—the most common being vitamin D. nutrition.bmj.com
    Vitamin D Diabetes Micronutrients Magnesium Vitamin B12 Insulin Metformin

    Micronutrient deficiencies contribute to insulin resistance, a key driver of type 2 diabetes, but researchers still don’t fully understand their role in the disease’s progression. A recent study found that nearly half of people with type 2 diabetes suffer from multiple micronutrient deficiencies, with vitamin D being the most prevalent.

    Researchers analyzed data from studies investigating links between micronutrient deficiencies and type 2 diabetes. Their analysis included 132 studies and more than 52,000 participants.

    They found that 45% of people with type 2 diabetes had multiple micronutrient deficiencies. Women with the disease were more likely to have deficiencies, with 48% affected compared to 41% of men. Vitamin D deficiency was the most common, affecting 60% of participants, followed by magnesium (42%) and vitamin B12 (28%)—the latter being especially prevalent among people with type 2 diabetes who were taking metformin. The prevalence of deficiencies also varied by region.

    These findings suggest that micronutrient deficiencies are widespread in people with type 2 diabetes, particularly among women. Check out our many resources on micronutrients, including vitamin D and magnesium, and the long-term health consequences of deficiencies.

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  • Even a brief five-day junk food binge can disrupt the brain's insulin function, potentially impairing memory and influencing eating decisions over the long term. www.nature.com
    Brain Diet Insulin

    Study link:

    Indulging in a junk food binge can have lasting effects on your brain, even after you return to your usual eating habits. A recent study found that five days of overeating high-calorie, nutrient-poor foods temporarily boosted brain insulin sensitivity but caused a drop in responsiveness once participants switched back to a healthier diet.

    Researchers assigned 29 healthy-weight men, ages 19 to 27, to one of two groups: One followed a junk food diet for five days, while the other stuck to their regular eating habits. They measured participants' brain insulin activity through imaging techniques and insulin administration before and after the binge.

    At the peak of the junk food binge, researchers observed heightened insulin activity in key brain regions. However, just one week after returning to their usual diet, participants who had overindulged experienced lower brain insulin sensitivity, particularly in areas associated with memory and food-related reward, such as the hippocampus and fusiform gyrus. Interestingly, while the junk food group showed increased liver fat, there were no noticeable changes in weight or peripheral insulin sensitivity.

    These findings suggest that the effects of overeating go beyond immediate metabolic changes, potentially contributing to cognitive decline and influencing eating behaviors over time. They also underscore how even a brief junk food binge can disrupt insulin function in the brain, impairing areas critical to memory and decision-making. Behavioral strategies like mindfulness can help curb overeating. Learn more in this clip featuring Dr. Ashley Mason.

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  • Aspartame, a popular artificial sweetener, provokes a sharp increase in insulin secretion and fosters atherosclerosis in animal models, potentially elevating cardiovascular risks. https://www.cell.com/cell-metabolism/fulltext/S1550-4131\(25\)00006-3
    Diet Insulin

    Scientists have long debated whether artificial sweeteners influence insulin levels and cardiovascular risk. A recent study found that consuming aspartame, a popular artificial sweetener, sharply increased insulin secretion in mice and monkeys, a process driven by parasympathetic nervous system activation.

    Researchers fed mice a diet containing 0.15% aspartame and measured changes in blood insulin levels. They also surgically severed the vagus nerve in some animals to assess whether parasympathetic activation was involved. To examine insulin’s role in atherosclerosis, they implanted slow-release insulin pumps in mice to mimic chronically elevated insulin levels. Finally, they tested aspartame’s effects in Cynomolgus monkeys, which are metabolically similar to humans.

    They found that mice that consumed aspartame experienced a sharp increase in insulin secretion, an effect eliminated after severing the vagus nerve. Long-term aspartame consumption worsened atherosclerosis, and implanting insulin pumps had a similar effect. In monkeys, aspartame triggered an insulin spike comparable to the effects of sucrose. However, instead of raising blood sugar, it lowered it, potentially driving insulin resistance, inflammation, and increased risk of atherosclerosis. Further analysis revealed that aspartame-induced insulin secretion activated cell signaling pathways linked to arterial inflammation and plaque formation.

    These findings suggest that aspartame consumption worsens cardiovascular risk by increasing insulin secretion, altering glucose metabolism, and promoting inflammation and plaque buildup in the arteries. Notably, the aspartame dose used in the experiment greatly exceeds what most humans consume. While the study provides insight into biological effects, its relevance to typical human intake is unclear due to the high exposure levels. Learn more about artificial sweeteners and other sugar substitutes in Aliquot #66: Sugar substitutes: Risks and benefits

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  • Ketones may protect against cognitive decline by mitigating insulin resistance-induced neuronal damage. www.futurity.org
    Brain Aging Insulin Resistance Memory Insulin Ketogenic Diet

    Insulin regulates many processes involved in memory and cognitive function. However, age-related insulin resistance in the brain disrupts neuronal synaptic activity and contributes to cognitive decline. A recent study found that ketones may protect the brain from age-related insulin resistance in the brain.

    Researchers induced acute insulin resistance in mouse hippocampal tissue and determined its effects on neuronal function. Then, they administered beta-hydroxybutyrate, a type of ketone, to the tissues and evaluated the outcomes.

    They found that insulin resistance adversely affected aspects of neuronal communication, including synaptic activity, axonal conduction, network synchronization, synaptic plasticity, and action potential properties. However, ketones restored these functions.

    These findings suggest that ketones rescue the brain from the deleterious effects of acute insulin resistance. The high blood glucose levels associated with insulin resistance induce glucotoxicity, which causes structural damage and functional impairments of neuronal cells. Learn more about the effects of insulin resistance in the brain in this clip featuring Dr. Dale Bredesen.

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  • Individualized responses to macronutrients influence metabolic health, with consequences for people with type 2 diabetes. www.sciencedaily.com
    Diet Diabetes Fat Insulin Protein Carbohydrates

    Carbohydrates are the principal driver of insulin secretion, facilitating the uptake and metabolism of this macronutrient. However, a recent study found that fats and proteins also stimulate insulin secretion, potentially affecting people with type 2 diabetes.

    Researchers collected pancreatic islet cells responsible for insulin secretion from 140 donors after their deaths. About half of the donors had type 2 diabetes. They exposed the cells to carbohydrates, fats, and proteins and assessed insulin secretion.

    They found that most donors' islet cells exhibited a robust insulin response to carbohydrates, a moderate response to protein, and a low response to fat. However, some donors' cells elicited responses to protein (9%) and fat (8%) greater than their response to carbohydrates. Cells from donors with type 2 diabetes exhibited diminished responses to carbohydrates and fats, but their protein response was preserved.

    These findings suggest that insulin responses to macronutrients differ among individuals, with some preferentially responding to proteins and fats over carbohydrates. They also suggest that higher protein diets could benefit people with type 2 diabetes. Some evidence suggests that current guidelines for protein intake are too low, with implications for people more responsive to protein. Learn more about protein requirements in this clip featuring Dr. Stuart Philips.

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  • Moderate to high nighttime light exposure increases type 2 diabetes risk by up to 53 percent, comparable to genetic factors. t.co
    Metabolism Diabetes Circadian Rhythm Insulin Blue Light

    Circadian rhythms regulate metabolic processes, including glucose metabolism and insulin sensitivity. Disruptions in circadian rhythms can lead to metabolic impairments, increasing the risk of obesity, type 2 diabetes, and metabolic syndrome. A recent study found that personal light exposure patterns predict the risk of developing type 2 diabetes.

    Researchers assessed the light exposure patterns of more than 84,000 UK Biobank participants. Participants wore light sensors for one week to record their day and night light exposure. The researchers tracked the incidence of type 2 diabetes among the participants over an average follow-up period of nearly eight years.

    They found that diabetes risk increased as night light exposure increased. Compared to low light exposure, the risk of diabetes increased by - 29 percent with moderate light exposure. - 39 percent with high-moderate light exposure. - 53 percent with high light exposure. The increased risk associated with night light exposure was comparable to the difference between people with low and moderate genetic risk for diabetes.

    These findings suggest that nighttime light exposure is a risk factor for developing type 2 diabetes, comparable to genetic risk factors. Interestingly, low solar angle light – as in the early morning or late evening – resets the body’s circadian rhythms, improving metabolic health and mood. Learn more about low solar angle light exposure in this episode featuring Dr. Andrew Huberman.

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  • Daily cinnamon supplementation averaging 2,100 milligrams – roughly a teaspoon – shows promise in managing type 2 diabetes. pubmed.ncbi.nlm.nih.gov
    Diet Diabetes Insulin Resistance Insulin Polyphenol

    Cinnamon is one of the most consumed spices in the world, popular in both sweet and savory dishes in many cuisines. Evidence suggests cinnamon improves lipid profiles and protects against damage induced by oxidative stress. A recent systematic review and meta-analysis found that cinnamon helps maintain healthy blood glucose levels and reduces insulin resistance in people with type 2 diabetes.

    Researchers analyzed the findings of 24 clinical trials investigating the effects of cinnamon supplementation on blood glucose levels. The various trials included more than 1,800 participants from 11 nations.

    The analysis revealed that cinnamon supplementation reduced fasting blood glucose levels, hemoglobin A1c concentrations, and insulin resistance (without lowering insulin) in people with type 2 diabetes. The trials varied in duration from six to 16 weeks, and daily cinnamon doses ranged from 120 to 6,000 milligrams, averaging 2,100 milligrams – roughly a teaspoon.

    These findings suggest that cinnamon improves symptoms of type 2 diabetes and may be a valuable adjunct to traditional therapies. Cinnamon is rich in polyphenols, a broad class of plant bioactive compounds. Learn more about polyphenols in our overview article.

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  • Morning exercise outperforms afternoon workouts in enhancing cardiometabolic health in people with metabolic syndrome. physoc.onlinelibrary.wiley.com
    Exercise Metabolism Diabetes Insulin Metabolic Syndrome Cardiovascular

    The idea that exercise benefits metabolic health is widely accepted. But whether the benefits of exercise are greater depending on when one exercises – morning versus afternoon – is a matter of considerable debate. A recent study shows that morning exercise reduces blood pressure, fasting insulin, and insulin resistance better than afternoon exercise in people with metabolic syndrome.

    Metabolic syndrome is a constellation of conditions characterized by abdominal (central) obesity, elevated blood pressure, elevated fasting plasma glucose, high serum triglycerides, and low high-density lipoproteins. Having metabolic syndrome increases a person’s risk of cardiovascular disease and type 2 diabetes. Roughly one-third of adults between the ages of 20 and 60 have metabolic syndrome.

    The study involved 139 adults with metabolic syndrome who agreed to participate in three supervised high-intensity interval training sessions every week for 16 weeks. About a third of the participants performed their exercise in the morning, a third did so in the afternoon, and a third didn’t engage in any exercise. Researchers measured the participants' body composition, cardiorespiratory fitness, maximal fat oxidation, blood pressure, and blood metabolites before and after the intervention.

    They found that both exercise groups demonstrated greater body fat loss, reduced waist circumference (nearly an inch), and lower diastolic blood pressure than those who didn’t exercise. However, when comparing the morning exercise group to the afternoon group, they found that morning exercise was more effective at reducing systolic blood pressure (4 percent drop vs. 1 percent), lowering fasting insulin (12 percent drop vs. 5 percent), and decreasing insulin resistance (14 percent drop vs. 4 percent).

    These findings suggest that morning exercise boosts cardiometabolic health better than afternoon exercise. The investigators posited that these effects may be related to circadian rhythms, which influence the body’s response to exercise and dietary intake.

    Finding the time or motivation to exercise in the morning may be challenging for many. Fortunately, most experts agree that some exercise is better than none, as long as it’s not too close to bedtime. Learn more in this clip featuring Dr. Rhonda Patrick.

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  • Vegan diets linked to cardiovascular and metabolic benefits, with marked improvements in body weight, LDL cholesterol, and fasting insulin. www.ncbi.nlm.nih.gov
    Diet Metabolism Insulin Vegetarian Cardiovascular

    Plant-based dietary patterns are typically higher in fiber, vitamins, minerals, and phytonutrients than other dietary patterns. Consequently, they may confer health benefits that reduce the risk of cardiovascular and metabolic disorders. A recent study found that a vegan diet reduced body weight, LDL (“bad”) cholesterol, and fasting insulin in healthy adults.

    To negate any genetic influences that diet might have on cardiometabolic fitness, researchers recruited 22 pairs of female twins to participate in the study. Within each twin pair, one twin followed a healthy vegan diet for eight weeks, and the other followed a healthy omnivorous diet. The researchers measured the twins' cardiometabolic markers before and after the intervention.

    They found that compared to twins who ate an omnivorous diet, twins who followed a vegan diet experienced reduced body weight, LDL cholesterol, and fasting insulin. Participants following a vegan diet had a lower protein, dietary cholesterol, and vitamin B12 intake and a higher vegetable and dietary iron intake than those on the omnivorous diet. They also reported lower satisfaction with their dietary options.

    The findings from this small study suggest that following a vegan diet confers cardiometabolic benefits in healthy young women, aligning with previous research demonstrating that vegan diets reduce the risk of cardiometabolic disease. They also underscore the considerable influence that diet has on cardiometabolic health. Learn how to avoid dietary deficiencies when following a vegan diet in this clip featuring Rich Roll.

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  • Long-term nutritional ketosis improves metabolism and reduces inflammatory markers in women. www.mdpi.com
    Diet Metabolism Ketosis Inflammation Insulin Ketogenic Diet

    Nutritional ketosis is a powerful tool for managing weight and moderating inflammation. However, most studies on ketosis have been conducted in men and have only assessed short-term effects. A recent study found that nutritional ketosis reduces blood glucose, insulin, and inflammatory markers in healthy women practicing long-term ketosis.

    Researchers asked ten healthy young women who had been maintaining nutritional ketosis for more than a year to alter their dietary habits to suppress ketosis. The study involved three one-week phases: nutritional ketosis, suppressed ketosis, and return to nutritional ketosis. The researchers measured the women’s ketone levels daily; at the end of each phase, they took their women’s body measurements and assessed their metabolic and inflammatory biomarkers.

    They found that when the women suppressed ketosis, their insulin, IGF-1, glucose, and pro-inflammatory markers increased. However, when they returned to ketosis, those markers returned to baseline levels.

    These findings suggest that nutritional ketosis maintains healthy metabolism and suppresses inflammation without altering metabolic flexibility. Other evidence demonstrates that a ketogenic diet promotes weight loss and reduces cancer risk. Learn how to design the optimal ketogenic diet in this episode featuring Dr. Dominic D'Agostino

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  • Supplemental vitamin K2 improves diabetes markers and glycemic control. pubmed.ncbi.nlm.nih.gov
    Metabolism Diabetes Insulin Resistance Vitamin K Insulin

    Vitamin K2 – a form of vitamin K produced in the gut – plays important roles in blood clotting, bone mass maintenance, and blood vessel contractility. But new research shows that supplemental vitamin K2 also improves diabetes markers. People with type 2 diabetes who took supplemental vitamin K2 had better markers of glycemic control than those who took a placebo.

    Researchers performed a three-part study in humans and mice. First, they conducted a randomized controlled trial involving 60 adults who had type 2 diabetes. Half of the participants took vitamin K2 every day for six months, while the other half took a placebo. Then the researchers transplanted gut microbes from vitamin K2-supplemented mice into obese mice. Finally, they analyzed the gut microbial composition and their metabolites in both humans and mice.

    They found that the participants who received supplemental vitamin K2 experienced marked reductions in levels of fasting blood glucose (13.4 percent), insulin (28.3 percent), and HbA1c (7.4 percent), indicating improved glycemic control. Similarly, the mice demonstrated improved glucose tolerance after receiving the gut microbe transplants. Lastly, the researchers found that certain metabolites that play roles in glucose metabolism, including bile acids and short-chain fatty acids, increased in the feces of both groups. Furthermore, they identified a specific type of bacteria that was responsible for producing these metabolites.

    Vitamin K is a fat-soluble vitamin. The body has limited vitamin K storage capacity, so the body recycles it in a vitamin K redox cycle and reuses it multiple times. Naturally occurring forms of vitamin K include phylloquinone (vitamin K1) and a family of molecules called menaquinones (vitamin K2). Vitamin K1 is synthesized by plants and is the major form found in the diet. Vitamin K2 molecules are synthesized by the gut microbiota and found in fermented foods and some animal products (especially liver).

    These findings suggest that vitamin K2 participates in maintaining glycemic control in people with type 2 diabetes. They also underscore the role of the gut microbiota in this process. Learn about other roles for the gut microbiota in this episode featuring Dr. Eran Elinav.

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  • Omega-3s improve metabolic markers in women with gestational diabetes. www.sciencedirect.com
    Diabetes Insulin Resistance Omega-3 Inflammation Pregnancy Insulin

    Omega-3s improve metabolic markers in women with gestational diabetes.

    Gestational diabetes, a form of diabetes that occurs only during pregnancy, carries many health concerns for women, including an increased risk of developing type 2 diabetes in later life. A new study shows that omega-3 fatty acids may improve metabolic markers associated with gestational diabetes. Women who took omega-3s during their pregnancies had healthier blood glucose, triglyceride, and cholesterol levels than those who didn’t.

    Researchers analyzed the findings of six randomized controlled trials that investigated the effects of omega-3s in women with gestational diabetes. The studies included more than 330 pregnant women, and the duration of the various trials was six weeks. Omega-3 doses ranged from 1 to 2 grams per day.

    They found that across the six studies, markers of glucose metabolism (fasting glucose, fasting insulin, and insulin resistance), lipid metabolism (triglycerides and very low-density lipoprotein cholesterol), and inflammation (C-reactive protein) were lower among women who took omega-3s than those who took a placebo. Levels of high-density lipoprotein cholesterol – often referred to as “good” cholesterol – increased.

    This analysis suggests that omega-3 fatty acids, which are perhaps best known for their cardioprotective and neuroprotective properties, positively influence metabolism in pregnant women. It also aligns with the findings of a previous analysis, which found that compared to women who took a placebo, those who took supplemental omega-3s had considerably lower fasting blood sugar levels and insulin resistance. Learn about other health benefits associated with omega-3s in our comprehensive overview article.

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  • Estrogen may improve insulin sensitivity and suppress gluconeogenesis via Foxo1, mouse study suggests. (2019) www.sciencedaily.com
    Hormones Diabetes Estrogen Insulin Blood Sugar

    From the article:

    “Premenopausal women exhibit enhanced insulin sensitivity and reduced incidence of Type 2 diabetes compared with age-equivalent men,” he explained. “But this advantage disappears after menopause with disrupted glucose homeostasis, in part owing to a reduction in circulating estrogen.”

    […]

    “We wanted to understand the mechanism by which estrogen regulates gluconeogenesis by means of interaction with hepatic Foxo1,” he explained. “Foxo1 has an important role in the regulation of glucose production through insulin signaling. It is an important component of insulin-signaling cascades regulating cellular growth, differentiation and metabolism.”

    He said in both male and ovariectomized female control mice, a subcutaneous estrogen implant improved insulin sensitivity and suppressed gluconeogenesis. However, the estrogen had no effect on the liver-specific Foxo1 knockout mice of both sexes.

    “This suggests Foxo1 is required for estrogen to be effective in suppressing gluconeogenesis,” he said.

    “We further demonstrated that estrogen suppresses hepatic glucose production through activation of estrogen receptor signaling, which can be independent of insulin receptor substrates Irs1 and Irs2. This reveals an important mechanism for estrogen in the regulation of glucose homeostasis.”

    Guo said study results support the hypothesis that improvement of glucose homeostasis by estrogen is regulated by hepatic Foxo1-mediated gluconeogenesis rather than by promoting muscle glucose uptake.

    […]

    Guo also noted some foods, such as soybeans, contain a certain amount of phytoestrogens, which can function in a similar way to that of estrogen, regulating bodily glucose metabolism and insulin sensitivity.

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  • Testosterone treatment of older men didn`t affect functional status or cognition but increased lean body mass and had mixed metabolic effects. (2008) www.sciencedaily.com
    Hormones Cholesterol Testosterone Muscle Bone Insulin Weight Loss Cardiovascular

    From the article:

    Marielle H. Emmelot-Vonk, M.D., of University Medical Center Utrecht, the Netherlands, and colleagues conducted a randomized, placebo-controlled study to assess the effects of testosterone supplementation on functional mobility, cognition, bone mineral density, body composition, lipids, quality of life, and safety parameters in older men with testosterone levels less than 13.7 nmol/L (less than the average level in this age group) during a period of six months. The trial, conducted from January 2004 to April 2005, included 207 men between the ages of 60 and 80 years. Participants were randomly assigned to receive 80 mg of testosterone undecenoate or a matching placebo twice daily for six months.

    The researchers found that during the study, lean body mass increased and fat mass decreased in the testosterone group compared with the placebo group but these factors were not accompanied by an increase of functional mobility or muscle strength. Cognitive function and bone mineral density did not change. Insulin sensitivity improved but high-density lipoprotein cholesterol (the “good” cholesterol) decreased. By the end of the study, 47.8 percent in the testosterone group vs. 35.5 percent in the placebo group had the metabolic syndrome (a strong risk factor for cardiovascular disease and type 2 diabetes, a group of several metabolic components in one individual including obesity and dyslipidemia). This difference was not statistically significant.

    Quality-of-life measures did not differ aside from hormone-related quality of life in the testosterone group. Adverse events were not significantly different in the two groups. Testosterone supplementation was associated with an increase in the concentrations of blood creatinine, a measure of kidney function, and hemoglobin and hematocrit, two red blood cell measures. No negative effects on prostate safety were detected (some reports have suggested that testosterone therapy could increase the risk of development or progression of prostate disease or cancer).

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  • Testosterone therapy increased tissue glucose uptake by 32% in response to insulin in men with type 2 diabetes and low testosterone (2015) www.sciencedaily.com
    Hormones Diabetes Insulin Resistance Testosterone Insulin

    From the article:

    The current study included 94 men with Type 2 diabetes. Prior to being treated, the 44 men in the study with low testosterone levels expressed significantly lower levels of insulin signaling genes and, thus, diminished insulin sensitivity. These men were randomized to receive a testosterone injection or a placebo every week for 24 weeks.

    The study found that while there was no change in body weight, testosterone treatment produced a reduction in total body fat of 3 kilograms (more than six pounds) while increasing muscle mass by the same amount.

    “Most importantly, we saw a dramatic increase in insulin sensitivity, demonstrated by a 32 percent increase in the uptake of glucose by tissues in response to insulin,” Dandona said. At the same time, there was a similar increase in the expression of the major genes that mediate insulin signaling.

    While patients' hemoglobin A1C (HbA1c) levels did not go down, a necessary indicator that testosterone can help control diabetes, Dandona noted that fasting glucose levels had diminished significantly, by 12 milligrams per deciliter. He said that a significant improvement in HbA1c may eventually be seen when longer term studies are carried out.

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  • Men with low testosterone are at greater risk for developing type 2 diabetes. (2016) www.sciencedaily.com
    Hormones Diabetes Testosterone Insulin

    From the article:

    Doctors have long known that men with low testosterone are at greater risk for developing type 2 diabetes. For the first time, researchers have identified how testosterone helps men regulate blood sugar by triggering key signaling mechanisms in islets, clusters of cells within the pancreas that produce insulin.

    […]

    “Our study shows that testosterone is an anti-diabetic hormone in men. If we can modulate its action without side effects, it is a therapeutic avenue for type 2 diabetes.”

    Researchers used specially bred male mice with pancreatic beta cells lacking the receptor to testosterone (the androgen receptor). They fed them a Western diet rich in fats and sugar and tested their response to glucose. The mice without androgen receptors all developed lower insulin secretion, leading to glucose intolerance compared with normal mice in the control group.

    To better understand how testosterone interacted with insulin production within the pancreas, researchers administered testosterone and glucose directly to human islet cells treated with an androgen receptor inhibitor and islets cells harvested from mice without androgen receptors. In both cases the islet cells showed decreased insulin production compared to islet cells whose receptor to testosterone was not inhibited or missing.

    Further experiments in cultured mouse and human islet cells showed the insulin-producing effect of testosterone could be abolished by inhibiting glucagon-like peptide-1 (GLP-1), a hormone the body produces after a meal. The study suggests that testosterone amplifies the islet impact of the hormone, which is currently used as a diabetes treatment.

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  • Visceral fat may be less circadian than (healthier) subcutaneous fat: only subcutaneous showed circadian rhythmicity in insulin sensitivity www.sciencedaily.com
    Obesity Insulin Resistance Circadian Rhythm Insulin Metabolic Syndrome Visceral Fat

    From the article:

    Using samples of adipose tissue from both visceral fat and subcutaneous fat from 18 people who underwent gastric bypass surgery, researchers found that subcutaneous fat has an intrinsic circadian rhythm in insulin sensitivity. Insulin sensitivity reached its maximum around noon, and was more than 50 percent higher than at midnight. Interestingly, the rhythm was not observed in visceral fat.

    […]

    “Our study demonstrates that subcutaneous human fat tissue has an internal clock that is able to regulate insulin sensitivity even when outside of the body. This tissue rhythm matches well with what has been observed in humans overall when examining how people cope with a meal or sugar load,”

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  • Vitamin D protects against high glucose-induced pancreatic β-cell dysfunction via AMPK- NLRP3 inflammasome pathway pubmed.ncbi.nlm.nih.gov
    Vitamin D Insulin

    Vitamin D protects pancreatic beta cells in type 2 diabetes.

    Chronic inflammation is a principal driver of many of the pathological processes that accompany type 2 diabetes, a metabolic disorder characterized by hyperglycemia (high blood glucose) and subsequent pancreatic beta cell dysfunction. Findings from a recent study suggest that vitamin D blocks activation of the NLRP3 inflammasome, preventing inflammation-driven impairment of pancreatic beta cells.

    The NLRP3 inflammasome is a large, intracellular complex that plays critical roles in immune function. Its activation triggers the release of the proinflammatory proteins interleukin (IL)-1 beta and IL-18, promoting inflammation and cell death. People who have type 2 diabetes exhibit upregulated NLRP3 inflammasome activation. However, AMP-activated protein kinase (AMPK), an enzyme that participates in metabolic regulation, blocks NLRP3 activation.

    The investigators conducted a three-part study. First, they evaluated the vitamin D status of 399 adults with type 2 diabetes and 78 healthy adults. There was no significant difference in vitamin D status between the two groups. Although males tended to have higher vitamin D concentrations than females, vitamin D deficiency was common among both sexes, with approximately 80 percent of males deficient and 91 percent of females deficient. The investigators then assessed the participants' beta cell function following a meal. They found that higher vitamin D concentrations were associated with greater beta cell function, but this correlation was seen in males only.

    In a second experiment, the investigators fed rats either a normal diet or a high-glucose diet (designed to induce beta cell dysfunction) for five weeks. They supplemented half of the rats in both diet groups with vitamin D. At the end of five weeks, they found that among rats that ate the high-glucose diet, those that received vitamin D had lower blood glucose levels than those that did not. The rats that received vitamin D also had greater insulin secretion – an indicator of healthy beta cell function.

    Finally, they conducted an in vitro experiment to evaluate the effects of vitamin D on INS1e cells, a well-established model for studies of pancreatic islet beta cell function. They found that vitamin D inhibited hyperglycemia-induced NLRP3 activation and IL-1 beta production, leading to lower levels of inflammation. Further investigation revealed that vitamin D upregulated AMPK production in the cells, which likely contributed to the reduction of inflammation.

    These findings suggest that vitamin D inhibits NLRP3 activation via enhanced AMPK production, thereby reducing inflammation due to high blood sugar in mice with type 2 diabetes. Learn more about the beneficial effects of vitamin D in our overview article.

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  • Insulin improves dopamine signaling in regions of the brain associated with eating behavior. www.sciencedaily.com
    Obesity Insulin Dopamine

    Insulin signaling in the brain influences behavior, weight regulation, motivation, and cognition. Previous research demonstrates that insulin resistance reduces brain volume and cognitive function in middle-aged adults. Results of a new study demonstrate that insulin interacts with dopamine to modulate reward-based behavior and whole-body metabolism.

    Dopamine is a neurotransmitter that regulates activity of the mesocorticolimbic system, a region of the brain involved in reward-based learning. Mesocorticolimbic circuits transmit information from the midbrain to the ventral and dorsal striatum, prefrontal cortex, amygdala, and hippocampus to coordinate emotions, memories, and impulses involved in eating and other rewarding behaviors. Previous research has demonstrated that insulin interacts with dopamine, altering activity of the mesocorticolimbic systems, inducing feelings of satiety and decreasing high-calorie food seeking. However, much of the existing research has been conducted in mice, using very high levels of insulin, making translation to humans difficult.

    The investigators assigned ten male participants (average age, 27 years) with a normal BMI (average BMI, 24) to receive either intranasal insulin or a placebo and undergo a combined PET and MRI scan after having fasted overnight. The researchers gave participants an injection of a radioactive marker called [11C]-raclopride that binds to dopamine receptors so they could measure dopamine-related brain activity during the scan. Participants also completed surveys to assess eating behavior and provided a blood sample for measurement of insulin and other hormones.

    Following administration of intranasal insulin, [11C]-raclopride synaptic binding potential increased in the ventral and dorsal striatum, suggesting an increase in the number of dopamine receptors in these regions. Accordingly, synaptic dopamine concentrations (dopamine that has not bound to a receptor and internalized by the neuron) decreased. Ultimately, this increase in dopamine signaling reduced resting-state activity in the ventral and dorsal striatum and improved functioning of mesocorticolimbic circuits 15 to 45 minutes after insulin exposure. As the participants' response to insulin exposure increased, so did their scores on tests of subjective wellbeing and cognitive control.

    This study, which demonstrated the effects of intranasal insulin on dopamine activity in the mesocorticolimbic system, has important implications for reward-based learning, eating behavior, and obesity. Future research should include participants with insulin resistance to gain a better understanding of the effects of obesity and metabolic disease on the brain.

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  • Allulose reduces blood sugar and insulin levels. drc.bmj.com
    Diabetes Sugar Insulin Blood Sugar

    Foods with a high glycemic index, such as sugar-sweetened soft drinks, desserts, and white bread products, contain sugars that are rapidly absorbed into the bloodstream, causing hyperglycemia (high blood glucose). Regular consumption of high glycemic foods may lead to insulin resistance, type 2 diabetes, and obesity. Low-calorie sweeteners (i.e., artificial sweeteners) such as allulose have a low glycemic index and can be used in place of sugar to reduce the intake of calories and high-glycemic carbohydrates; however, the effects of allulose in addition to sugar require further investigation. Findings published in a new report show that allulose significantly reduces glucose and insulin levels following sugar consumption.

    Allulose is a rare sugar that can be found in small amounts in some fruits and grains and is sold as a low-calorie sweetener. Allulose is an epimer of fructose, meaning its chemical structure is very similar to fructose, giving it a nearly identical taste and texture; however, allulose provides only 0.4 calories per gram, compared to 4 calories per gram of fructose. A meta-analysis of previous research found that small doses of allulose improved glucose and insulin regulation; however, additional randomized controlled trials are needed, especially in Western populations and in people without type 2 diabetes.

    The researchers recruited 30 participants (average age, 33 years) without type 2 diabetes and asked them to follow an individualized diet plan that provided 50 to 65 percent of calories from carbohydrates for up to eight weeks. Participants completed five study visits with one to two weeks between visits. At each visit, the researchers gave participants a beverage containing 50 grams of fructose (the amount in about 16 ounces of sugar-sweetened soda) with escalating doses of allulose (0, 2.5, 5, 7.5, or 10 grams). They measured glucose and insulin levels in the blood 0, 30, 60, 90, and 120 minutes after beverage consumption.

    Allulose consumption reduced plasma glucose levels among participants in a dose-dependent manner, meaning as the dose of allulose increased from 0 to 10 grams, glucose levels at each time point decreased. The relationship between allulose and lower glucose levels was statistically significant at the 30-minute time point when either 7.5 or 10 grams of allulose was added to the fructose beverage. Compared to consuming a fructose beverage with no added allulose, the 10-gram dose of allulose also significantly decreased insulin levels 30 minutes after beverage consumption.

    These findings demonstrate that allulose decreased glucose and insulin levels when added to a high-sugar beverage in healthy young people without diabetes. The authors suggested that future studies explore more of the mechanisms underlying these results.

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  • Brain aging emerges in the late 40's but dietary ketosis increases overall brain activity and stabilizes functional networks. news.stonybrook.edu
    Brain Aging Ketosis Insulin Time-Restricted Eating Carbohydrates Ketogenic Diet

    Insulin resistance and poor blood glucose control – defining characteristics of type 2 diabetes – drive changes associated with brain aging and cognitive decline. A growing body of evidence suggests that dementia is the manifestation of insulin resistance and altered metabolism in the brain. A recent study suggests that dietary patterns that promote ketosis improve brain metabolism and function.

    Ketosis is a metabolic state that results in the body’s production and use of ketones (byproducts of fatty acid metabolism). It occurs under conditions of fasting, starvation, and low carbohydrate intake. Ketones induce physiological and metabolic responses to promote brain health.

    The study had multiple components. First, the authors of the study investigated the time course of human brain aging. Using functional MRI (fMRI) data from more than 900 people between the ages of 18 and 88 years, they determined that neural network stability is a biomarker of brain aging, and the loss of network stability manifests as early as the fifth decade of life (average age, 47 years). They found that the greatest changes in the brain occur around the age of 60 years.

    Then they performed fMRI scans on 12 young adults (average age, 28 years) to assess how different energy sources – glucose versus ketones – alter brain function. Each participant underwent three scans under different dietary conditions: a normal diet without fasting, a normal diet with overnight fasting, or a ketogenic diet for one week. They performed fMRI scans on 30 young adults (average age 29 years) 30 minutes after they took an oral bolus of either glucose or ketones or after following their normal diet with overnight fasting. The authors of the study measured the participants' blood glucose and ketone levels before and after each of the scans.

    The fMRI scans revealed that ketones increased overall brain activity and stabilized functional networks, but glucose had the opposite effect, regardless of whether the ketones were produced endogenously or supplied from exogenous sources. These findings suggest that dietary interventions that increase ketone production may be useful in mitigating the harmful effects of glucose on the brain.

    Certain dietary patterns promote ketosis. For example, the Ketoflex 12/3 diet, a form of time-restrictive eating that limits the period during which a person eats to a 12-hour window at least three hours before bedtime, promotes the production of ketones. Watch this clip in which Dr. Dale Bredesen describes this novel dietary protocol and how it improves cognitive function.

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  • Consuming diet drinks along with carbohydrates may have negative effects on the brain and metabolic health. www.inverse.com
    Brain Insulin Carbohydrates Weight Loss

    Low-calorie sweeteners – also known as non-nutritive sweeteners, artificial sweeteners, or sugar substitutes – contain few, if any, calories but deliver a greater intensity of sweetness than sweeteners with calories. They are ubiquitous in the Western diet, appearing in beverages, baked goods, frozen desserts, chewing gum, and many other foods. A new study demonstrates that consuming low-calorie sweeteners in tandem with carbohydrate-rich foods alters brain function and impairs metabolism.

    The health effects of consuming low-calorie sweeteners are not well understood. Whereas some evidence suggests that substituting sugar-sweetened beverages with low-calorie sweeteners can aid in weight loss, other studies suggest that low-calorie sweeteners may contribute to weight gain and diabetes risk, especially in men.

    This study involved 45 healthy adults who did not regularly consume low-calorie sweeteners. Over a period of 10 days, each of the participants drank seven 12-ounce beverages that contained sucralose (a low-calorie sweetener), sugar, or a combination of sucralose and maltodextrin (a polysaccharide produced from grain starch). Before and after the study period, participants underwent oral glucose tolerance tests, sensory tests, and neuroimaging to assess insulin sensitivity, taste perception, and brain response to taste, respectively.

    The authors of the study found that drinking the beverage sweetened with the sucralose-maltodextrin combination reduced the participants' insulin sensitivity and altered their brain responses to sweet tastes. These findings suggest that consuming low-calorie sweeteners while eating or drinking high carbohydrate foods or beverages may have negative effects on metabolism.

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  • Dietary olive oil may improve healthspan and delay aging by switching on the activity of sirtuins. www.sciencedaily.com
    Aging Insulin Monounsaturated Fat Protein

    Olive oil, the principal fat consumed in the Mediterranean diet, is widely consumed for its flavor, versatility, and health-promoting attributes. A recent study demonstrates that the monounsaturated fats (MUFAs) in olive oil may extend lifespan by switching on the activity of key cellular proteins called sirtuins.

    Monounsaturated fats are dietary fats found in plant foods, such as nuts, avocados, and vegetable oils, especially olive oil, which contains approximately 75 percent of the MUFA known as oleic acid. The body stores MUFAs in lipid droplets – intracellular fat storage depots that facilitate the movement and signaling activities of fatty acids. During times of increased energy demand (such as during exercise) or decreased energy supply (such as during fasting), the fatty acids stored in lipid droplets can be released for the body’s use.

    Sirtuins are highly conserved enzymes that play key roles in healthspan and longevity in multiple organisms. Sirtuin 1 (SIRT1) is linked to the regulation of a variety of metabolic processes, including the release of insulin, mobilization of lipids, response to stress, and modulation of lifespan.

    The authors of the study first investigated the role of perilipin 5 (PLIN5), a protein found in lipid droplets that regulates fatty acid oxidation in oxidative tissues. They found that PLIN5 binds to lipid droplet MUFAs and delivers them to the cell nucleus, where they modulate the activity of SIRT1.

    Then they studied the effects of MUFA consumption in mice. They fed the mice a control diet rich in lard and soybean oil or a diet rich in olive oil for 12 weeks. The mice that ate the olive oil-rich diet lost weight and had higher energy expenditure than mice fed the control diet. These effects were attributed to activation of SIRT1.

    These findings suggest that the health-promoting benefits associated with the Mediterranean diet may be attributable to the diet’s high olive oil content. In addition, olive oil as part of a healthy eating pattern such as the Mediterranean diet may increase healthspan and longevity.

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  • Sulforaphane from broccoli sprout extract improves fasting glucose and HbA1c in obese patients with dysregulated type 2 diabetes. www.sciencedaily.com
    Diabetes Sulforaphane Insulin Isothiocyanates Blood Sugar NRF2

    Type 2 diabetes is a metabolic disorder characterized by high blood sugar and insulin resistance. Long-term complications from poorly controlled type 2 diabetes include heart disease, stroke, diabetic retinopathy (and subsequent blindness), kidney failure, and diminished peripheral blood flow, which may lead to amputations. An estimated 500 million people worldwide are living with type 2 diabetes. A 2017 study suggests that sulforaphane may be beneficial in treating the symptoms of type 2 diabetes.

    Sulforaphane is an isothiocyanate compound derived from cruciferous vegetables such as broccoli, Brussels sprouts, and mustard. Sulforaphane is produced when the cruciferous plant is damaged by insects or eaten by humans. The compound activates cytoprotective mechanisms within cells in a hormetic-type response and has demonstrated beneficial effects against several chronic health conditions, including autism, cancer, cardiovascular disease, and others.

    The authors of the study identified sulforaphane out of more than 3,800 drugs and natural products as a potential therapeutic for type 2 diabetes based on statistical analysis that showed that sulforaphane’s protective effects (called a drug signature) had the potential to counteract diabetes’ harmful effects (called a disease signature).

    They then conducted a randomized double-blind placebo-controlled study involving 97 adults with type 2 diabetes. All the participants were of Scandinavian ethnicity and had diabetes for less than 10 years. Sixty of the participants had well-controlled diabetes; the remaining 37 had poorly controlled diabetes. Of those with poorly controlled diabetes, 17 were obese, and 20 were not obese.

    After undergoing blood tests to check their fasting blood sugar and HbA1c (a measure of long-term blood sugar control) and taking an oral glucose challenge, the participants took either a placebo or powdered broccoli sprout extract (containing 150 µmol sulforaphane per dose) every day for 12 weeks.

    At the end of the study period, the blood tests and the oral glucose challenge were repeated. The participants who took broccoli sprout extract and whose diabetes was well-controlled experienced no changes in their fasting blood sugar or HbA1c levels. The participants who were heaviest and had poorly controlled diabetes saw the greatest benefits from the broccoli sprout extract. After 12 weeks of treatment, obese participants’ fasting blood sugar levels and HbA1c levels decreased, but the participants who received a placebo experienced slightly increased blood sugar and HbA1c levels.

    The researchers also measured the amount of sulforaphane in the participants’ blood and noted that the levels varied from person to person. The higher the blood concentration, however, the greater the change in the participants’ fasting blood sugar.

    Although very few of the participants experienced any negative effects after taking the broccoli sprout extracts, the authors of the study cautioned against prescribing it to patients because more testing needs to be done to understand how sulforaphane works and who would benefit most from it.

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  • Alterations in gut microbial fermentation modulate the efficacy of exercise for diabetes prevention and management. www.cell.com
    Exercise Microbiome Insulin Carbohydrates

    Public health officials and healthcare providers commonly recommend exercise as a strategy to prevent or manage the symptoms of type 2 diabetes, but the cardiometabolic response to exercise is variable. Whereas exercise improves insulin sensitivity and promotes cardiovascular health in most adults (responders), exercise exerts a paradoxical effect in which metabolic health is compromised in as many as 69 percent of adults (non-responders). Findings from a recent study suggest the variable effects of exercise in people with prediabetes may be due to alterations in gut microbial fermentation.

    Microbial fermentation is the process by which gut bacteria break down and utilize carbohydrates in the gut. The metabolites produced during microbial fermentation include short-chain fatty acids and branched-chain amino acids, which are absorbed and used by the host. Short-chain fatty acids improve symptoms of diabetes, but branched-chain amino acids have the converse effect

    The study involved both humans and mice. The human study included 39 overweight or obese men with prediabetes who were between the ages of 20 and 60 years. Participants were randomized to engage in either sedentary activities or supervised exercise training for 12 weeks. They maintained their usual diet throughout the study period. At the end of the 12-week period, fecal microbial samples from two of the participants (responders and non-responders) were transplanted into obese mice.

    The results demonstrated that the responders' microbiota displayed increased production of short-chain fatty acids, whereas those of the non-responders displayed increased production of brain-chain amino acids. Fecal microbial transplantation from responders mimicked the effects of exercise on alleviation of insulin resistance in the mice, but fecal transplants from the non-responders did not. These findings may augment and facilitate clinical management of symptoms of diabetes.

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  • Decreasing the insulin signaling pathway and the TOR pathway increased lifespan of worms by 500 percent. www.eurekalert.org
    Aging Depression Insulin Protein

    The insulin and insulin-like signaling (IIS) pathways and the target of rapamycin (TOR) pathway are critical elements of the aging process. Findings from a new study suggest that decreasing the activity of these highly conserved pathways markedly increases the lifespan of worms.

    The IIS pathways are involved in maintaining glucose homeostasis. They facilitate the uptake of glucose into fat and muscle cells while inhibiting gluconeogenesis – the production of glucose in the liver. These pathways are dysregulated in obesity and type 2 diabetes.

    The TOR pathway senses amino acid concentrations and regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis, autophagy, and transcription. It integrates other pathways including insulin, growth factors (such as IGF-1), and amino acids and plays a key role in mammalian metabolism and physiology. The pathway is dysregulated in many human diseases, such as diabetes, obesity, depression, and certain cancers.

    The study focused on altering the activity of orthologs of these pathways (called DAF-2 and RSKS-1) in C. elegans, a type of nematode worm, which is often used in aging studies. The authors of the study introduced double mutations in the worms to block the activities of DAF-2 and RSKS-1 and conducted genome-wide translational state analysis to identify genes associated with the worms' lifespan.

    Knocking DAF-2 and RSK-1 elicited a synergistic effect that increased the lifespan of the worms by 500 percent, suggesting that regulation of these two pathways is integral to the aging process in worms. Watch this clip for learn more about the evidence that altered growth hormone and insulin signaling may improve healthspan in humans, too.

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  • Supplementation with Akkermansia muciniphila improves metabolic parameters in overweight and obese people. www.nature.com
    Insulin Dairy

    The worldwide prevalence of cardiometabolic disorders is increasing with the global obesity epidemic. Evidence from a new study suggests that supplementation with Akkermansia muciniphila (A. muciniphila) may reduce the risk of developing several aspects of cardiometabolic disorders in overweight and obese people.

    A. muciniphila is one of the most abundant microbial species in the human gut, comprising as much as 5 percent of the total bacteria. Its presence in the human gut is associated with reduced risk of obesity, cardiometabolic disorders, and chronic, low-grade inflammation.

    The randomized, double-blind, placebo-controlled pilot study involved 32 overweight or obese adults who were insulin-resistant, a risk factor for type 2 diabetes. The participants were randomized to receive either live A. muciniphila (1010 bacteria per day), pasteurized A. muciniphila (1010 bacteria per day), or a placebo daily for three months.

    At the end of the study period, participants who took pasteurized A. muciniphila experienced improved insulin sensitivity and reduced insulinemia, total cholesterol, and body weight compared to their baseline assessments and the placebo group. The findings from this pilot study demonstrate that A. muciniphila improves metabolic parameters in overweight or obese people and may have promise as a preventive therapy for various cardiometabolic disorders.

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  • Obese adolescents have decreased white matter in a brain region that connects the right and left hemispheres of the brain (compared to healthy teens). www.sciencedaily.com
    Brain Obesity Inflammation Insulin

    Obese adolescents have decreased white matter in a brain region that connects the right and left hemispheres of the brain (compared to healthy teens). These changes correlated with markers of inflammation and insulin resistance.

    Approximately 20 percent of teens living in the United States are obese. Obesity negatively affects multiple organ systems, including the nervous system. Findings from a new study indicate that the white matter in the brains of obese teens is lower than that of healthy teens.

    Obesity is associated with chronic low-grade inflammation, which can drive many disease processes. A specialized magnetic resonance imaging technique, called diffusion tensor imaging (DTI), can measure this inflammation in the brain.

    A study involving 59 obese adolescents and 61 normal weight adolescents between the ages of 12 and 16 years used DTI to measure damage to the white matter in the teens' brains. The imaging results revealed that areas of the corpus callosum, a bundle of nerve fibers that connects the left and right hemispheres of the brain, as well as areas of the middle orbitofrontal gyrus, an area responsible for emotional control and reward circuits, were diminished in the obese teens' brains. Damage in these areas was correlated with altered levels of insulin, inflammatory markers, and leptin, a key regulator of appetite, and insulin.

    Future research with DTI imaging techniques may reveal whether these changes in the structure of obese teens' brains are reversible.

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  • Study demonstrates that exercising before eating breakfast burns more fat, improves insulin sensitivity, & increases glucose uptake into muscle. www.sciencedaily.com
    Exercise Fasting Insulin Time-Restricted Eating Carbohydrates

    Exercise promotes the uptake of glucose into muscle cells and increases insulin sensitivity. Other physical adaptations occur during exercise, as well, including increased muscle mass, decreased fat mass, and improved mitochondrial function. Previous research has demonstrated that training in the fasted state promotes greater glucose tolerance and insulin sensitivity and induces higher fatty acid oxidation compared to training in the fed state. A recent study bolsters these findings, demonstrating that exercising before eating breakfast may enhance some of the beneficial effects of exercise.

    The six-week, single-blind, randomized, controlled trial involved 30 overweight or obese men who engaged in moderate-intensity cycling either before or after eating a high-carbohydrate, mixed-macronutrient breakfast. The men exercised for three, 30-minute sessions the first week and progressed to three, 50-minute sessions over the remaining weeks.

    The men who exercised before eating had nearly 2-fold higher whole-body lipid utilization rates as well as decreased carbohydrate utilization compared to the men who exercised after eating. The effects were sustained throughout the entire six-week study period. These findings suggest that exercising before eating breakfast burns more fat, improves insulin sensitivity, and increases glucose uptake into muscle tissue compared to exercising after eating breakfast. Exercising after eating may blunt these effects, however.

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  • Metformin supplementation prevented gains in lean muscle mass in healthy people 65 years and older who engaged in resistance training. onlinelibrary.wiley.com
    Exercise Aging Muscle Insulin Dairy Metformin

    Age-related skeletal muscle mass and strength is a leading cause of the functional decline and loss of independence in older adults. Resistance training exercise is a highly effective strategy for maintaining or building muscle mass. A new study suggests that metformin, a drug commonly used to treat type 2 diabetes, blunts the effects of resistance training.

    Metformin is in a class of drugs called biguanides, which act by decreasing liver gluconeogenesis (the production of glucose in the liver), decreasing glucose uptake in the gut, and increasing overall glucose utilization by improving insulin sensitivity in skeletal muscle and fat tissue. Scientific evidence suggests that metformin modulates aging processes to improve healthspan and extend lifespan in multiple organisms.

    The present study involved 94 healthy men and women aged 65 years and older who were randomized to take either a 1,700-milligram dose of metformin daily (a typical dose prescribed for diabetes and prediabetes) or a placebo for 14 weeks. The participants also performed supervised resistance training for the duration of the study. At the end of the study, participants who took the placebo exhibited greater gains in lean body mass and thigh muscle mass than those who took metformin.

    Although metformin is a safe and effective treatment for type 2 diabetes, these findings underscore concerns about the possible negative effects of metformin use in healthy older adults.

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  • Obesity can break down our protective blood brain barrier resulting in problems with learning and memory: overactivity of adenosine in obesity www.sciencedaily.com
    Brain Alzheimer's Obesity Diabetes Coffee Insulin Blood Sugar Blood-Brain Barrier Lipopolysaccharide

    Diet-induced insulin resistance caused blood vessels to become leaky which impaired blood and oxygen flow to a brain region involved in learning and memory (animal evidence).

    Obesity and insulin resistance are associated with a leaky blood-brain barrier. This new animal study found that a high-sugar combined with a high-fat diet caused shrinkage of the tight junctions between endothelial cells that make up the blood-brain barrier and actual holes in those cells.

    Obesity is known to increase toll-like receptor activation through a variety of mechanisms. One of the mechanisms is through through associated increases of circulating of lipopolysaccharide. Another mechanism is the leaking of fatty acids from fatty acids, triggering toll-like receptors through the recognition of damage-associated molecular patterns (DAMPs). (See “obesity” section of toll-like receptor article.)

    Furthermore, LPS challenge in animal studies induces microglia in the brain to attack and damage the blood-brain barrier.

    Blocking adenosine may play a role in preventing impairment of the blood-brain barrier by diet-induced obesity

    However, adenosine, which helps us sleep and helps regulate our blood pressure and is blocked by caffeine may play a role in preventing some of the damaging effects obesity has on the blood-brain barrier, which promotes dementia.

    From the article:

    They knew that chronic activation of the receptor Adora2a [an adenosine receptor] on the endothelial cells that line this important barrier in our brain can let factors from the blood enter the brain and affect the function of our neurons.

    Now Medical College of Georgia scientists have shown that when they block Adora2a in a model of diet-induced obesity, this important barrier function is maintained.

    […]

    In the brain, adenosine is a neurotransmitter that helps us sleep and helps regulate our blood pressure; in the body it’s also a component of the cell fuel adenosine triphosphate, or ATP. Adenosine also activates receptors Adora1a and Adora2a on endothelial cells, which normally supports healthy relationships between brain activity and blood flow.

    Problems arise with chronic activation, particularly in the brain, which is what happens with obesity, says Stranahan.

    People who have obesity and diabetes have higher rates of cognitive impairment as they age and most of the related structural changes are in the hippocampus, a center of learning and memory and Stranahan’s focus of study. Fat is a source of inflammation and there is evidence that reducing chronic inflammation in the brain helps prevent obesity-related memory loss.

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  • Time-restricted eating, a ketogenic diet, and exercise improved cognitive function and markers of metabolism in a woman with ApoE4 and Alzheimer's . www.sciencedirect.com
    Alzheimer's Ketosis Fasting Insulin Triglycerides Time-Restricted Eating Metabolic Syndrome Ketogenic Diet

    Time-restricted eating (TRE), a ketogenic diet, and exercise improved cognitive function and markers of metabolism including triglycerides, VLDL, and HbA1c in a 71-year-old woman with ApoE4 that has mild Alzheimer’s disease and metabolic syndrome (case study).

    This is an interesting proof of principle study showing that implementing a nutrition protocol purposed at raising plasma ketones through fasting (TRE) a ketogenic diet and physical exercises can compensate for insulin resistance and the ApoE4 gene in a mild Alzheimer’s patient experiencing cognitive impairment.

    The APOE4 gene is the largest risk factor for Alzheimer’s disease besides age itself.

    To learn more check out this episode highlight of Dr. Dale Bredesen talking about time-restricted eating and a ketogenic diet in the context of Alzheimer’s disease in people with and without ApoE4.

    Episode: https://youtu.be/PWZbeq6MCKU

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  • Insulin Sensitivity and Glucose Tolerance Are Altered by Maintenance on a Ketogenic Diet (2010) academic.oup.com
    Ketosis Insulin Carbohydrates Ketogenic Diet

    Low-carbohydrate, ketogenic diets (KD) are frequently implemented in efforts to reduce or maintain body weight, although the metabolic effects of long-term exposure to this type of diet remain controversial. This study assessed the responsivity to peripheral and central insulin, glucose tolerance, and meal-induced effects of consuming a KD in the rat. After 8 wk of consuming chow or KD, caloric intake after peripheral or central insulin and insulin and glucose levels after a glucose challenge were assessed. In a separate group of rats, glucose and insulin responses to either a low- or high-carbohydrate test meal were measured. Finally, rats maintained on KD were switched back to a chow diet, and insulin sensitivity and glucose tolerance were evaluated to determine whether the effects of KD were reversible. Maintenance on KD resulted in decreased sensitivity to peripheral insulin and impaired glucose tolerance. Furthermore, consumption of a high-carbohydrate meal in rats that habitually consumed KD induced significantly greater insulin and glucose levels for an extended period of time, as compared with chow-fed controls. Responsivity to central insulin was heightened in KD rats and associated with increased expression levels of insulin receptor mRNA. Finally, returning to a chow diet rapidly reversed the effects of KD on insulin sensitivity and glucose tolerance. These data suggest that maintenance on KD negatively affects glucose homeostasis, an effect that is rapidly reversed upon cessation of the diet.

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  • Nutrient-induced Mitochondrial Activation (NiMA): A Novel Lysosome-to-Mitochondria Signaling Pathway Disrupted by Amyloid-β Oligomers papers.ssrn.com
    Nutrition Alzheimer's Metabolism Mitochondria Neuron Insulin Neurons Protein

    The mechanisms of mitochondrial dysfunction in Alzheimer’s Disease (AD) are incompletely understood. We show that activation of lysosomal mechanistic target of rapamycin complex 1 (mTORC1) by insulin or amino acids stimulates mitochondrial activity and regulates mitochondrial DNA synthesis in neurons. Amyloid-β oligomers, which are precursors of amyloid plaques in AD brain and stimulate mTORC1 protein kinase activity at the plasma membrane, but not at lysosomes, block this nutrient-induced mitochondrial activity (NiMA) by a mechanism dependent on tau, which forms neurofibrillary tangles in AD brain. NiMA was also disrupted in fibroblasts derived from a patient with tuberous sclerosis complex, a genetic disorder that causes dysregulation of lysosomal mTORC1. Thus, lysosomal mTORC1 couples nutrient availability to mitochondrial activity, and links mitochondrial dysfunction to AD by a mechanism dependent on soluble building blocks of plaques and tangles. https://ssrn.com/abstract=3188445

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  • Food Additives Causing Harm, Reforms Urgently Needed, AAP Says www.medscape.com
    Brain Cancer Gut Hormones Pregnancy Neurotransmitter Insulin

    The Worst Offenders:

    The statement addresses 2 broad categories of additives: direct and indirect. Indirect additives refers to substances in “food contact materials,” such as “adhesives, dyes, coatings, paper, paperboard, plastic, and other polymers,” the authors of the policy statement explain. Direct food additives include chemicals such as colorings, flavorings, and preservatives added to food during processing. Within those two categories the authors identified six types of additives of most concern, based on accumulating evidence summarized in the report and in an accompanying press release:

    Bisphenols: Used to manufacture plastic containers and food and beverage cans, these compounds have been associated with endocrine and neurodevelopmental disruption and obesogenic activity, with alterations in the timing of puberty, reduced fertility, and impaired neurological and immunological development. One bisphenol, bisphenol A, has already been banned from baby bottles and sippy cups.

Phthalates: As components of plastic wrap and plastic tubing and containers, phthalates similarly have been implicated in endocrine disruption and obesogenic activity. "A robust literature" shows that these chemicals adversely affect male sexual development, may contribute to childhood obesity and insulin resistance, and may also contribute to cardiovascular disease.

Perfluoroalkyl chemicals: These chemicals are used in the manufacture of greaseproof paper and cardboard packaging. They have been associated with immunosuppression, endocrine disruption such as impaired thyroid function, and decreased birth weight.

Perchlorate: Often added to plastic packaging for dry foods to control static electricity, perchlorate has been shown to disrupt production of thyroid hormone, with implications for subsequent cognitive function. Of particular concern is exposure among pregnant women, "given that the developing fetus is entirely reliant on the maternal thyroid hormone during the first trimester of pregnancy," the authors write in the technical report. They suggest that perchlorate "may be contributing to the increase in neonatal hypothyroidism and other thyroid system perturbations that have been documented in the United States."

Nitrates and nitrites: As direct food additives, these compounds are used as preservatives and color enhancers in cured and processed meats, fish, and cheese. There has been "longstanding concern" over their use, the authors write, because of an association with cancers of the nervous and gastrointestinal systems, and methemoglobinemia in infants. They were classified as "probable human carcinogens" in 2006 by the International Agency for Research on Cancer.

Artificial food colors: Often added to products that appeal to children, such as juice drinks, artificial food colors have been associated in some studies with an increased risk for attention-deficit hyperactivity disorder. Although their mechanisms of action are not yet completely understood, and the research "should be interpreted with caution," the authors recommend "a thorough reassessment" of artificial food colors to ensure they are safe.
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  • Suppression of insulin with a ketogenic diet improves the efficacy of cancer drugs known as PI3K inhibitors and shrinks tumors in mice. www.nature.com
    Cancer Ketosis Insulin Ketogenic Diet

    Suppression of insulin with a ketogenic diet improves the efficacy of cancer drugs known as PI3K inhibitors and shrinks tumors in several different animal models of cancer.

    Insulin activates the PI3K pathway is usually which then leads to cell proliferation and tumor growth. Drugs inhibiting the PI3K pathway have not been very effective due to an insulin feedback response. A ketogenic diet lowered the insulin response and made the drugs more effective.

    The researchers point out that this study doesn’t suggest a ketogenic diet alone would treat cancer. Their data showed in a leukemia model, the ketogenic diet seemed to make cancer more aggressive in mice who were not also given a PI3K inhibiting drug. However, the combination of a PI3K inhibitor and ketogenic diet showed efficacy in many different cancer types (in mice).

    Talk of a pilot clinical study in humans is underway.

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  • Exercise causes acute elevation of IL-6 which reduces postprandial blood glucose levels and insulin secretion by delaying gastric emptying. www.cell.com
    Exercise Diabetes Inflammation Insulin IL-6

    Exercise causes acute elevation of IL-6 which reduces postprandial blood glucose levels and insulin secretion by delaying gastric emptying in men with type 2 diabetes.

    IL-6 is a cytokine with both negative and positive effects. Chronic elevation of IL-6 reflects ongoing inflammation and is linked to type 2 diabetes and atherosclerosis. In contrast, acute elevation of IL-6 from exercise inhibits inflammatory cytokines and stimulates the production of anti-inflammatory cytokines in humans.

    To learn more about the role of exercise-induced IL-6, the postprandial inflammatory response and their effects on the brain…check out my interview with Dr. Charles Raison. This episode has a timeline, transcript, summary, and glossary to help find and understand the talking points.

    Charles Raison, MD podcast: https://www.foundmyfitness.com/episodes/charles-raison

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  • Early Time-Restricted Feeding Improves Insulin Sensitivity, Blood Pressure, and Oxidative Stress Even without Weight Loss in Men with Prediabetes www.cell.com
    Insulin Resistance Fasting Insulin Time-Restricted Eating Blood Pressure Weight Loss

    A small randomized controlled clinical trial finds time-restricted eating within a 6-hour window (fasting for 18 hours) without reducing calories or losing weight improves insulin sensitivity, beta cell function, blood pressure, oxidative stress and reduces evening appetite.

    All eating was supervised and approached metabolic ward rigor. The improvements in metabolism were independent of weight loss and the reduction in blood pressure was so significant that it was comparable to the standard of care blood pressure medication (ACE inhibitors).

    The time-restricted eating they started early with the first meal at 8 am and dinner before 3 pm. The importance of time of day for this type of intermittent fasting is still an interesting open question, especially since there’s a lot of advocacy for late eating among 16:8 advocates, however, insulin sensitivity usually declines later in the day (and is exacerbated by the production of melatonin, which has an effect of shutting off insulin secretion). Interestingly, Dr. Satchin Panda has been gathering data via his mobile app (my circadian clock) that suggests an eating window later in the day may be comparable to an early eating window.

    To learn more about time-restricted eating and intermittent fasting check out the two separate podcasts I did with Dr. Satchin Panda. The episodes have summaries, timelines, and transcripts!

    Round 2 episode: https://www.foundmyfitness.com/episodes/satchin-round-2

    Round 1 episode: https://www.foundmyfitness.com/episodes/satchin-panda

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  • Genetically lowering plasma insulin levels by 25% extended median lifespan by 11% in female mice fed a low-calorie, high-carb low-fat diet. www.cell.com
    Diet Aging Insulin Resistance Insulin Protein Carbohydrates

    Genetically lowering plasma insulin levels by 25% extended median lifespan by 11% in female mice fed a low-calorie/high-carb/low-fat diet and by 3% in female mice fed a high-calorie/high-fat/low-carb diet.

    This study looked at the effects of genetically lowering insulin levels in older mice. Unfortunately, the male mice did not have lower plasma levels of insulin despite genetically lowering insulin-genes and so the effect on lifespan could not be determined in male mice.

    The female mice were fed two diets: (diet A: moderate-energy diet of 4.68 kcal/g, with 20% of calories from protein, 25% from fat, and 55% from carbohydrate; diet B: high-energy diet of 5.56 kcal/g, with 16% of calories from protein, 58% from fat, and 26% from carbohydrate).

    Interestingly, the lowering of circulating insulin through gene manipulation had a more profound effect on median lifespan in female mice fed the low-calorie/high-carb/low-fat diet (11% extension) versus the high-calorie/low-carb/high-fat diet (3% extension). It is important to note that diets A and B were not matched for the type of fat content, protein levels, or micronutrient composition, so there are numerous potential factors that could have impacted diet-dependent outcomes.

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  • Type 2 diabetics given broccoli sprout extract containing 150 μmol sulforaphane for 12 weeks lowered blood glucose levels by 10% compared to placebo. www.newscientist.com
    Diet Diabetes Insulin Resistance Sulforaphane Insulin NRF2 Metformin

    Broccoli sprout extract reduced HbA1c by 7.04% in obese patients with dysregulated type 2 diabetes. It has been demonstrated that a 1% decrease of HbA1c corresponds to 37% reduced risk of microvascular complications.

    Sulforaphane reduces glucose by suppressing liver enzymes that otherwise stimulate the production of glucose.

    In animals, sulforaphane also attenuated exaggerated glucose production and glucose intolerance by a magnitude similar to that of metformin.

    Further investigations showed that while both metformin and sulphoraphane cut blood glucose, they do it in different ways. Metformin makes cells more sensitive to insulin, so they sponge more surplus glucose out of the bloodstream. Sulphoraphane reduces glucose by suppressing liver enzymes that otherwise stimulate the production of glucose. For this reason, Rosengren thinks the broccoli extract is complementary to metformin, not competitive."

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  • VSL#3 improved HDL, insulin sensitivity, LDL, atherogenic factors, and inflammation www.ncbi.nlm.nih.gov
    Gut Obesity Microbiome Insulin Resistance Cholesterol Omega-3 Inflammation Microbes VSL#3 Insulin Triglycerides

    FTA

    … a clinical trial in 60 overweight (BMI > 25), healthy adults, aged 40-60 years. After initial screening, the subjects were randomized into four groups with 15 per group. The four groups received, respectively, placebo, omega-3 fatty acid, probiotic VSL#3, or both omega-3 and probiotic, for 6 weeks. […] The probiotic (VSL#3) supplemented group had a significant reduction in total cholesterol, triglyceride, LDL, and VLDL and had increased HDL (P < 0.05) value. VSL#3 improved insulin sensitivity (P < 0.01), decreased hsCRP and favorably affected the composition of gut microbiota. Omega-3 had a significant effect on insulin sensitivity and hsCRP but had no effect on gut microbiota. The addition of omega-3 fatty acid with VSL#3 had a more pronounced effect on HDL, insulin sensitivity and hsCRP. Table showing statistics of the study.

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  • Late-night eating increases weight gain, raised insulin, fasting glucose, cholesterol & triglycerides in small trial. www.sciencedaily.com
    Insulin Resistance Fasting Circadian Rhythm Fat Insulin Triglycerides Time-Restricted Eating

    A small clinical trial finds that eating later in the day (12 pm to 11 pm) increased weight gain, raised insulin, fasting glucose, cholesterol, and triglyceride levels compared to eating earlier in the day (8 am to 7 pm).

    In the small study, each of the nine healthy weight adults underwent each of the two conditions: daytime eating (three meals and two snacks between 8 a.m. and 7 p.m.) for eight weeks and delayed eating (the same three meals and two snacks eating from noon to 11 p.m.) for eight weeks after a 2-week washout period. This is a small trial and needs to be repeated but is in line with another study that showed when healthy adults eat meals that are identical for breakfast, lunch, or dinner, the postprandial glucose increase is lowest after breakfast and highest after dinner even though the meals were 100% identical.

    For more on meal timing and time-restricted eating…check out my podcasts with the experts, Dr. Satchin Panda and Dr. Ruth Patterson on youtube and iTunes.

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  • Supplemental probiotics for 12 weeks improved cognition in Alzheimer's patients & also lowered inflammatory markers. www.sciencedaily.com
    Brain Alzheimer's Gut Microbiome Inflammation Probiotics Behavior Insulin Triglycerides Dopamine Norepinephrine Acetylcholine

    The probiotics also lowered triglycerides, VLDL, and markers of insulin resistance. There was no cognitive improvement in the placebo group.

    The participants took 2 billion Bifidobacterium bacteria per day, which is a pretty small quantity of probiotics. It is likely that the probiotics are working through multiple mechanisms such as lowering inflammation and increasing neurotransmitters. Other studies have shown that gut bacteria are able to modulate the levels of GABA, norepinephrine, serotonin, dopamine, and acetylcholine through the gut-brain axis.

    I spoke with the gut experts, Drs. Justin and Erica Sonnenburg, about the importance of the gut microbiome in human health and the various foods (ie. fermentable fiber and other prebiotics) that provide our gut bacteria with the food they need to thrive. Here is the interview (also available on iTunes and Sticher): https://www.youtube.com/watch?v=gOZcbNw7sng

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  • Unraveling Alzheimer’s: Making Sense of the Relationship between Diabetes and Alzheimer’s Disease1 www.drperlmutter.com
    Alzheimer's Diabetes Insulin Resistance Insulin

    Abstract. Numerous studies have documented a strong association between diabetes and Alzheimer’s disease (AD). The nature of the relationship, however, has remained a puzzle, in part because of seemingly incongruent findings. For example, some studies have concluded that insulin deficiency is primarily at fault, suggesting that intranasal insulin or inhibiting the insulin-degrading enzyme (IDE) could be beneficial. Other research has concluded that hyperinsulinemia is to blame, which implies that intranasal insulin or the inhibition of IDE would exacerbate the disease. Such antithetical conclusions pose a serious obstacle to making progress on treatments. However, careful integration of multiple strands of research, with attention to the methods used in different studies, makes it possible to disentangle the research on AD. This integration suggests that there is an important relationship between insulin, IDE, and AD that yields multiple pathways to AD depending on the where deficiency or excess in the cycle occurs. I review evidence for each of these pathways here. The results suggest that avoiding excess insulin, and supporting robust IDE levels, could be important ways of preventing and lessening the impact of AD. I also describe what further tests need to be conducted to verify the arguments made in the paper, and their implications for treating AD

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  • [TIMELINE] Joe Rogan Experience #502 with Dr. Rhonda Patrick www.foundmyfitness.com
    Omega-3 Depression Insulin Fatty Liver Vitamin A Isothiocyanates Antioxidant Protein Dairy Blood Sugar Metabolic Syndrome Myrosinase

    This is the full minute-by-minute timeline for JRE #502. Click here to watch the video on YouTube.

    • 00:02:42 - Starts off by talking about kappa opioids and dynorphin and how you feel stress right before important events
    • 00:04:24 - Joe talks about how great you feel after a competition (fight)
    • 00:05:35 - Talks about how capsaicin in spicy food also induces a release of endorphins via dynorphin agonization
    • 00:06:22 - Briefly mentions sauna/hyperthermic conditioning article featured on 4-Hour Workweek
    • 00:06:45 - Description of hormesis and how this is part of the mechanism of action for things like EGCGs in green tea and polyphenols in fruit.
    • 00:07:50 - Joe brings up that Rhonda suggested mycotoxin might be hormetic previously, Rhonda clarifies this was entirely and highly speculative. Includes jazz hands.
    • 00:08:45 - Joe mentions that his best decisions are made after a good workout. He does not trust his judgment if he has not got a good workout in.
    • 00:09:15 - Discussion of exercise and how it grows new brain cells (neurogenesis) via the BDNF pathway and how the growth of new brain cells allows you to forget other memories.
    • 00:11:20 - Joe mentions how people in highschool that never left your small hometown sometimes remember stuff you don’t. Get out of the small town, highschool friends. Make new memories.
    • 00:12:00 - Talks about how amygdala activation from either extreme excitement or fear increases episodic memory.
    • 00:12:15 - Talks about her new paper and how serotonin plays a role in brain function/dysfunction, behavior, and episodic memory.
    • 00:13:38 - Joe brings up MDMA burnout and suggests serotonin’s role in episodic memory may be why the MDMA/roller burnout stereotype exists
    • 00:15:00 - Explanation of what receptor down-regulation is and why it adds enormous complexity to understanding the effects of drugs, like SSRIs.
    • 00:16:27 - Discussion of “Serotonin Syndrome.”
    • 00:17:22 - Most serotonin is actually made in the gut, not the brain.
    • 00:17:44 - Discussion of how the genes that convert tryptophan to serotonin found in the gut (TPH1) and in the brain (TPH2) are show a characteristic nucleotide sequence known as a “Vitamin D Response Element” that seems to indicate, for the most part, that Vitamin D represses the production of serotonin in the gut (TPH1) and increases serotonin in the brain (TPH2). This is the subject of Rhonda’s most recent academic paper: “Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.”
    • 00:18:45 - Serotonin made in the gut has been shown to cause gastrointestinal inflammation by activating T cells and causing them to proliferate. Knocking out TPH1 in a mouse model of colitis ameliorates the inflammation associated with the disorder.
    • 00:21:55 - Theoretical vitamin D mechanism may play a role in the development of autism by depriving developing foetus of serotonin that serves as an “early brain morphogen” when mothers are deficient in vitamin D.
    • 00:23:45 - Autism appears to be developing early in utero (during pregnancy) and seems to show indications of being at least partially related to environment.
    • 00:24:00 - Estrogen can activate TPH2 in lieu of Vitamin D and thus may explain why autism is predominantly found in males.
    • 00:24:30 - Gut inflammation is common among autistics.
    • 00:24:45 - Explains 5-HTP bypasses the normal tryptophan hydroxylase (TPH) conversion, and because of that it can be converted into serotonin more rapidly… but (hypothetically) too soon and in the gut instead of the brain.
    • 00:25:35 - Tryptophan gets transported into the brain in order to be converted into serotonin by tryptophan hydroxylase (TPH2) but competes with BCAAs for transport into the brain, which are transported preferentially.
    • 00:25:55 - Tryptophan is less abundant of an amino acid than branch chain amino acids like leucine in protein.
    • 00:26:55 - Joe asks Rhonda if T cell activation/proliferation in the context of TPH1 has relevance for AIDS.
    • 00:28:00 - Joe relates how “New Mood” (Onnit’s product) was originally called “Roll Off.”
    • 00:30:30 - Joe quips that it was recently experimentally validated in mice that DMT is produced in the pineal glands of mice during sleep, goes on to talk about speculation that near death experiences relating to altered perception from endogenous DMT release.
    • 00:35:10 - Plays a video of a jaguar eating hallucinogenic plants.
    • 00:37:20 - Talks about monoamine oxidase
    • 00:38:40 - Merits of “theoretical papers” (like “Vitamin D hormone regulates serotonin synthesis. Part 1: relevance for autism.”)
    • 00:39:37 - 70% of population is vitamin d deficient. Segways to awesome infographic created by @tjasonwright which covers a ton of the basic facts about vitamin D.
    • 00:43:02 - BaadBobby’s Dad turned Joe onto TA-65. TA-65 has been shown to increase telomere length, but theres a guy who sued the company producing it. Anecdotally, BaadBobby’s dad had improvements in eyesight.
    • 00:45:00 - Explanation of what telomeres are.
    • 00:48:50 - Special enzyme telomerase rebuilds telomeres, but it’s found mostly only in stem cells… and more importantly: cancer cells. Cancer cells hijack this telomerase normally reserved for stem cells to live forever. Strangely… Mice, unlike humans, actually express telomerase in all of their cells and don’t have telomere shortening.
    • 00:50:10 - Werner’s syndrome involves excessive telomere shortening.
    • 00:53:33 - Explains how aging is a function of DNA damage and discusses DNA damage assay (test) that Rhonda performs.
    • 00:55:30 - Obesity link to increased DNA damage.
    • 00:56:50 - Talks about TA-65’s active ingredient in a study was shown to genuinely increase telomerase activity and length of telomeres.
    • 00:58:22 - TA-65 study showed a 40% increase in telomere length in white blood cells in some humans studied.
    • 00:58:44 - Second study on TA-65 using special mouse model from well-known lab also showed re-activation of telomerase, and even began reversing aging of their tissues. Mice notably did not get cancer. Reinforces findings of first study.
    • 01:01:30 - Still concerned TA-65 could encourage the growth of pre-cancerous cells.
    • 01:02:00 - Joe brings up alkalizing diet for cancer prevention (he’s a skeptic).
    • 01:03:05 - Bad bacteria in gut is affected by pH.
    • 01:06:20 - Joe brings up argument that sugar consumption affects growth of cancer.
    • 01:07:50 - Explains because cancer cells become glycolytic which is why people fixate on sugar as a potential cancer cell.
    • 01:08:40 - Rhonda mentions that taking away glucose, but allowing continued presence of glutamine allowed cancer cells to keep growing in vitro.
    • 01:09:50 - Folic acid needed in the absence of cancer because you need it to build new DNA – but this is a problem if you do have a cancer because it can be a bad thing for the same reasons (folic acid needs to produce DNA because cancer cells are highly proliferative).
    • 01:12:00 - Glucosinolates are cleaved into isothiocyanates by myrosinase which is de-activated by heat. Isothiocyanates are potent anti-cancer agents. Recent anti-kale stuff is, in a way, anti-isothiocyanates. Additionally, if you boil kale and de-activate myrosinase you’re actually decreasing the amount of isothiocynates by removing myrosinase.
    • 01:14:00 - Kale thyroid stuff is probably only relevant if you’re very deficient in iodine – probably better to continue getting your isothiocyanates for cancer preventative reasons rather than sweating this stuff.
    • 01:16:35 - Rhonda mentions tumor suppressor genes, which are activated by hormesis (good stress triggered by things like isothiocyanates).
    • 01:19:20 - Joe brings up Dave Asprey’s take on boiling kale to remove oxalic acid.
    • 01:20:10 - Spinach that was either raw, boiled, fried, or frizzled and found that raw and boiling doesn’t affect absorption, but it did very modestly affect minerals in kidneys if raw… didn’t seem to cause kidneys stones (in mice). Probably requires absurd amounts of spinach to cause kidney stones. Just not convinced that it’s bad to eat spinach or kale raw.
    • 01:20:20 - Vegetables do make compounds that are sort of “bad for you” but have a net positive effect because they induce hormesis.
    • 01:24:33 - JRE consensus of #502 –eating raw spinach and kale is good for you.
    • 01:25:10 - Joe throws a curveball by bringing up a documented case of presumed oxalate induced nephropathy (kidney disease) from 1985 to 2010 – only 36 patients documented by paper. Only three patients really suspected that it was caused by raw juicing.
    • 01:27:30 - Discussion of vegetable smoothies begins here – specifically using these powerful blenders which leave the fiber in, not juicing.
    • 01:28:45 - Brock Lesnar allegedly ate nothing but meat, got diverticulitis.
    • 01:29:07 - Putrefying bacteria make nasty smelling hydrogen sulfide farts, use sulfate as source of energy. Needs heme from red meat as a cofactor for creating hydrogen sulfide. Hydrogen sulfide prevents human gut cells from making energy (ATP), and thus causes break-down of gut-mucus barrier.
    • 01:32:25 - Brings up episode with Dr. Offitt on Bryan Callen’s podcast. Offitt claims vitamins and antioxidants cause cancer.
    • 01:35:20 - Beginning of general debunking of Offitt’s claims.
    • 01:36:05 - Randomized double-blind placebo controlled trials are awesome, but using them for nutrition research and expecting the design to perform as effectively is misguided.
    • 01:37:30 - Everyone has different levels of vitamins & minerals in their body, but baseline for drugs is always the same: zero. This is an important fundamental difference.
    • 01:42:20 - Years of research has to be published even if results aren’t great, and this requires salesmanship. This affects some of the misleading presentation of research.
    • 01:43:04 - Joe brings up highly publicized and contentious “Enough is Enough” editorial which was covered at length in podcast #459.
    • 01:46:28 - Begin discussion of Vitamin E prostate cancer study (the SELECT trial).
    • 01:47:35 - Comparison of Alpha Tocopherol & Gamma Tocopherol forms of vitamin E. Alpha tocopherol serves predominantly as an antioxidant, gamma tocopherol serves as an anti-inflammatory agent by reducing reactive nitrogen species (also an anti-oxidant activity). Alpha tocopherol doesn’t serve the same anti-inflammatory behavior, and this is important because inflammation is a cancer initiator (among other things), and excessive alpha tocopherol consumption depletes gamma tocopherol from tissues.
    • 01:50:45 - Study on prostate cancer found that alpha tocopherol and selenium didn’t affect cancer incidence at 5-year followup but at 7.5 year follow-up cancer risk for prostate cancer shot up from taking 400 IU of alpha tocopherol (vitamin E) per day. Importantly, what was found at the 5-year followup was that (relative to baseline) gamma tocopherol was depleted from the tissues. Those who weren’t deficient selenium (& were supplementing) that took the 400 IU of alpha tocopherol didn’t experience the increase in prostate cancer incidence.
    • 01:52:05 - One of the proteins selenium is for is important for preventing damage from reactive nitration products. Nitration damage can cause cancer. This is an interesting novel mechanism by which a depletion of gamma tocopherol through a combination of inflammation and an increase in reactive nitratition products might be responsible for the increase cancer incidence found in this study.
    • 01:54:00 - Discussion of vegetable smoothie as a good source of vitamin E, and also natural magnesium (from chlorophyll molecules – this was mentioned in JRE #459)
    • 01:54:45 - Mixed tocopherol Vitamin E supplements exist which aren’t quite as high dose as 10x the RDA (400 IU) like used in those studies.
    • 02:01:18 - RDA for Vitamin D is 600 IU a day. One study showed that 4,000 IU was more appropriate for actually adequately fixing without toxicity in deficient populations. 2000 to 4000 IU of vitamin D is probably a good range except for in cases of severe deficiency.
    • 02:03:18 - Offit lumped omega-3 in with “antioxidants that cause cancer”, but this is misleading given the fact that randomized controlled trials have shown that omega-3 supplementation actually reduces all-cause mortality.
    • 02:03:39 - 1500 IU of vitamin D a day has been correlated to a 17% reduced cancer risk (overall).
    • 02:04:15 - Study based off of self-reported questionaire found that women who took vitamins (supplements) - on a daily basis had the longest telomeres.
    • 02:05:45 - She tries to get all her micronutrients, as much as she can, from her diet including vegetable smoothies, fish, etc. However, in addition to her diet she takes: omega-3 fatty acids, vitamin D, a multi-vitamin which has selenium and other trace elements, iodine, B-complex.
    • 02:06:30 - B vitamin deficiency is less common due to fortification. However, she supplements B vitamins anyway because changes in mitochondrial membrane rigidity that occurs with age alters the binding affinity (as represented by the constant kM) of important proteins needed to generate energy in the form of ATP which are embedded in the mitochondrial membrane. The Ames lab has partly demonstrated, however, that increasing the concentration of B vitamins compensates for these age related changes caused by changes in the confirmation (shape) of the proteins.
    • 02:08:00 - Rhonda increasingly prefers Swanson brand vitamins, but gets omega-3 from nordic naturals.
    • 02:10:00 - B vitamins are probably less dangerous because they’re water soluble (excess is more readily excreted, similar to Vitamin C)
    • 02:11:00 - Plant form of omega-3, ALA, converts to EPA (normally found in fish) fairly inefficiently at a rate of about 5%.
    • 02:12:13 - Microalgae oil is a good alternative to flaxseed oil if you’re trying to meet EPA/DHA needs and avoiding fish oil for one reason or another.
    • 02:13:30 - Omega-3 EPA is a potent anti-inflammatory, and DHA is a really component of your cell membranes – and makes up about 40% of the brain.
    • 02:13:54 - She takes about 6 pills of her omega-3, which amounts to ~3 “servings” of 800mg of EPA, and 600mg of DHA. (2400 and 1800 mg respectively)
    • 02:15:28 - Omega-3 EPA, which can be bought more concentrated for its particular effects, interacts with the arachnidonic acid pathway to reduce inflammation. The arachnicdonic acid pathway is responsible for creating prostaglandins which activate the COX pathway.
    • 02:16:05 - 2 grams of EPA per day has been shown to reduce C-reactive protein (CRP), which is a generalized systemic marker for inflammation but is most well known for its use to asses risk of cardiovascular disease.
    • 02:17:45 - Omega-3 fatty acids are prone to oxidation. Refrigeration helps with this, however. Also check if they go rancid by smell, if smell bad then probably rancid.
    • 02:20:00 - Talks about krill oil. Joe lists off a bunch of points from a Mercola article, and Rhonda points out it’s talking about ordinary effects of omega-3 and suggesting they may not be unique to krill oil.
    • 02:27:29 - Recommends Linus Pauling Institute for good, objective source of supplemental micronutrient reviews.
    • 02:28:35 - Brief mention of WellnessFX as a useful tool for getting a broad spectrum blood test checking for relevant markers for vitamins, minerals, inflammation, etc.
    • 02:31:00 - Whackiness of homepathy discussed. Homeopathy makes use of official sounding measuring system that measures an absurd amount of dilution that actually guarantees that what you’re taking doesn’t actually include the active ingredient the supplement is being marketed for.
    • 02:33:25 - Discusses how emerging research showing wisdom teeth has dental pulp stem cells in them and they offer promise for eventually being used as a source of cells that can be differentiated into things like brain cells. You can bank children’s teeth or adult wisdom teeth. Usually like $625 to “process” a tooth, and around $125/year to store it.
    • 02:36:16 - They can now take fibroblast cells from skin, the sort that you slough off everyday, and add transcription factors to turn them into “pluripotent” stem cells which can turn into brain cells or liver cells.
    • 02:37:35 - Joe brings up study where they took blood of young mice, injected it into old mice, and found the older mice experienced tissue regeneration. Inverse was also true: injecting young mice with old mouse blood increased rate of aging.
    • 02:38:54 - Human “methylome” now being studied which is revealing a specific pattern of methylation in DNA that can be used to actually identify the chronological age of people. Since epigenetics is obviously playing an important role in age, this is another promising area of new inquiry that may eventually reveal how to reprogram our cells to “be younger”. Cancer cells show a methylation pattern that is ordinarily associated with old age and are clustered around areas related to DNA repair, mitochondrial metabolism, antioxidant genes (all areas associated with aging).
    • 02:43:12 - Scientists are now able to take renal cells excreted in urine and turn them into pluripotent stem cells
    • 02:43:45 - Rant about lack of funding in science reducing room for creativity/moonshots.
    • 02:48:40 - Joe brings up new studies showing its possible to create artificial blood for transplant.
    • 02:50:06 - Inactivating insulin growth factor in c. elegans worms doubles their lifespan from about 15 to 30 days.
    • 02:52:40 - Joe asserts (reasonably so) that by age 200 he will most likely be a wizard.
    • 02:55:42 - Joe relates the fact that he’s actually been evacuated twice due to large fires in his neck of the woods of L.A.
    • 02:57:45 - Rhonda begins plug of iPhone app, website, Twitter, and podcast.
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