Protocols by Charles Sieg

Heart and metabolism

Blood sugar and diabetes

How insulin resistance and type 2 diabetes develop, the diagnostic cutoffs, and what the trials show prevents or reverses it.

Overall evidence Strong41 sourcesReviewed November 5, 2026

Several large randomized trials with decades of follow-up show lifestyle change delays type 2 diabetes, but remission, low-carb diets, glucose monitoring in healthy people, and the newer drugs rest on thinner or shorter evidence.

The short version

  • Prediabetes and diabetes are diagnosed on A1C, fasting glucose, or a 2-hour glucose tolerance test against fixed cutoffs; diabetes starts at an A1C of 6.5% or a fasting glucose of 126 mg/dL1.
  • It matters well beyond sugar: diabetes roughly doubled coronary heart disease risk in a pooled analysis of 102 prospective studies (hazard ratio 2.00)2.
  • Lifestyle change is the best-proven prevention. In the Diabetes Prevention Program it cut new diabetes 58% over an average of 2.8 years3, and in the Da Qing study a 6-year program was still paying off at 30 years4.
  • Remission is real but takes large, sustained weight loss: 36% in remission at 2 years in DiRECT, and 13% at 5 years among the 85 people followed that long5,6.
  • I follow keto, train, and take retatrutide, and I haven't published my own numbers.

The numbers: how diabetes is diagnosed

These are the standard diagnostic thresholds for adults, as a 2018 Stanford study stated them1. The American Diabetes Association reviews its criteria every year in its Standards of Care7.

TestPrediabetesDiabetes
A1Cbetween 5.7% and 6.5%6.5% or higher
Fasting glucose100 to 125 mg/dL126 mg/dL or higher
2-hour glucose after a 75 g oral glucose tolerance test140 to 199 mg/dL200 mg/dL or higher

One high reading isn't always the last word: in the Diabetes Prevention Program's follow-up study, a high fasting or 2-hour glucose had to be confirmed by a repeat test within 6 weeks before it counted as diabetes8. None of these tests measures insulin1, which matters for the next section.

How it develops

The two core defects are insulin resistance (cells respond poorly to insulin) and not enough insulin secretion; obesity, poor diet, inactivity, and genetics all feed in, and at least six other abnormalities contribute9. In the HOMA model, fasting glucose and insulin sit in a feedback loop, which is how fasting values can be used to estimate resistance and beta-cell function10. Ben Bikman, a guest on Rhonda Patrick's podcast, argues the practical consequence: early insulin resistance is high insulin with normal glucose, because the body compensates by making more insulin, so measuring glucose alone can miss it11. That is his view in an interview, not a trial result.

Sleep is one lever that moves it fast. After a single night of 4 hours of sleep in nine healthy adults, glucose production during an insulin clamp rose and glucose disposal fell, so the glucose infusion needed to hold blood sugar steady dropped about 25%12.

The protocol: what the trials used

This is what the research tested, not a prescription. Doses are the trials' own.

LeverWhat the trials used
Weight lossA 7% goal in the DPP3; in DiRECT, 86% of people who lost 15 kg or more were in remission at 12 months13
Exercise150 minutes a week in the DPP3; aerobic plus resistance training 3 times a week for 22 weeks in Sigal's trial14; the WHO range is 150 to 300 minutes of moderate activity a week plus muscle-strengthening15
After-meal walking10 minutes after each main meal, in 2-week periods, in people with type 2 diabetes16
Diet patternMediterranean diet with extra-virgin olive oil, no calorie limit17; carbohydrate under 26% of energy in the low-carb trials18
DrugsMetformin 850 mg twice daily in the DPP3; tirzepatide 5, 10, or 15 mg weekly in SURMOUNT-119

What the research says

Prevention by lifestyle

Strong The Diabetes Prevention Program randomized 3,234 adults with elevated glucose to placebo, metformin, or a lifestyle program (7% weight loss, 150 minutes of activity a week). Over an average of 2.8 years, incidence was 4.8 cases per 100 person-years with lifestyle versus 7.8 with metformin and 11.0 with placebo, a 58% reduction for lifestyle (95% CI 48 to 66) versus 31% for metformin3. The Finnish Diabetes Prevention Study randomized 522 overweight adults with impaired glucose tolerance to diet and activity counseling or a control group, and 11% versus 23% had diabetes at four years20. The DPP follow-up found the benefit persisted: 34% lower incidence at 10 years21 and 27% lower at 15 years (HR 0.73), though cumulative incidence at year 15 was still 55% versus 62% on placebo, and microvascular complications did not differ overall8. Da Qing followed 577 adults with impaired glucose tolerance for up to 30 years: the intervention delayed diabetes by a median 3.96 years and was linked to fewer cardiovascular events (HR 0.74), fewer all-cause deaths (HR 0.74), and 1.44 more years of life expectancy4. Bottom line: lifestyle delays diabetes by years, but it does not make anyone immune.

Remission by weight loss

Moderate DiRECT randomized 49 UK primary care practices (149 people per group analyzed). At 12 months, 46% of the program group were in remission, defined as an HbA1c under 6.5% after at least 2 months off all diabetes drugs, versus 4% of controls13. At 24 months, it was 36% versus 3%, and in a post hoc look, 64% of those who kept off at least 10 kg were in remission5. In the five-year extension, 13% of the 85 people with five-year data were in remission, and 26% of those in remission at year 2 were still there6. The program was total diet replacement with a formula diet of 825 to 853 kcal a day for 12 to 20 weeks, then stepped food reintroduction, and it enrolled adults diagnosed within the past 6 years who were not on insulin6. Remission followed weight loss, and it was most common in the people who lost the most13,5.

Exercise

Moderate In a 251-person trial in type 2 diabetes, aerobic training lowered HbA1c 0.51 points and resistance training 0.38 versus control, and the combination was a further 0.46 below aerobic alone14. In a second trial, of 262 adults, only the combination reached significance (-0.34 points)22. In both, combining the two did best. Muscle-strengthening activity also tracked with a 10% to 17% lower risk of several diseases, diabetes included, across 16 cohort studies, which is observational23. The training page has more on the exercise research.

Walking after meals

Early The trials agree, but all of them were short. A meta-analysis of seven one-day randomized crossover trials found light-intensity walking breaks lowered post-meal glucose and insulin versus sitting24. In 41 adults with type 2 diabetes, advice to walk 10 minutes after each main meal lowered post-meal glucose (measured over 3 hours) more than advice to walk 30 minutes once a day (ratio 0.88), especially after the evening meal (0.78)16. These are glucose readings over hours or weeks, not proof that it prevents diabetes.

Diet pattern

Moderate In a PREDIMED subgroup analysis of 3,541 adults without diabetes at high cardiovascular risk, a Mediterranean diet with extra-virgin olive oil had a diabetes hazard ratio of 0.60 versus a low-fat diet, and the nut version, 0.82, was not significant17. PREDIMED's main 2013 report was later withdrawn and republished with revised estimates after the investigators found randomization problems, including at two of its 11 sites25, and I did not confirm whether this diabetes analysis was redone.

Low-carb and keto

Mixed A meta-analysis of 23 trials found that in the eight reporting remission (264 people), 57% on low-carb diets were in remission at six months (HbA1c under 6.5%) versus 31% on control diets. The evidence was moderate to low certainty, 12-month remission data were sparse, and the gains in weight, triglycerides, and insulin sensitivity diminished by 12 months26. Another meta-analysis, of 25 trials, found carbohydrate under 26% of energy lowered HbA1c 0.47 points at 3 months and 0.36 at 6, with no significant difference at 12 or 24 months18. The Virta program, open-label and not randomized, cut HbA1c from 7.6% to 6.3% at 1 year27, and diabetes medication use was still down at 2 years28. The National Lipid Association found low-carb diets may help appetite, triglycerides, and diabetes medication use but have minimal data on efficacy and safety beyond 2 years29. Read together: it works short term, and the edge is not clearly kept over years. My keto page has the LDL question.

Sleep

Early The one controlled result here is the nine-person clamp study above12. It shows a mechanism after one night, not what months of short sleep do.

Drugs: tirzepatide and retatrutide

Moderate for tirzepatide. SURMOUNT-1 followed 1,032 people with obesity and prediabetes for 176 weeks: type 2 diabetes was diagnosed in 1.3% on tirzepatide versus 13.3% on placebo (HR 0.07), and 2.4% versus 13.7% after 17 weeks off treatment (HR 0.12). Mean weight change was -12.3% to -19.7% versus -1.3%. Eli Lilly funded it19.

Early for retatrutide. A phase 2 trial in 281 people with type 2 diabetes lowered HbA1c 0.43% to 2.02% at 24 weeks versus 0.01% on placebo and 1.41% on dulaglutide, with mild to moderate GI events in 35% and no severe hypoglycemia30. As of November 2026, the latest status I have is a July 23, 2026 Lilly press release (a company announcement, not peer-reviewed), which calls retatrutide investigational and says Lilly plans to submit it to the FDA in the first quarter of 2027. The release reported topline TRIUMPH-2 results in 1,152 people with type 2 diabetes and obesity or overweight: at 80 weeks, weight loss of 12.7% to 20.8% versus 4.0% on placebo, A1C changes of -1.4% to -1.6% from a 7.7% baseline versus -0.2%, and diarrhea in 27.4% to 33.6% versus 13.2%31. My retatrutide page covers the drug in more detail. This site gives no dose or source for it; those are questions for a prescriber.

Supplements

Early I take "NAD" (form unknown), and the trials below are of its precursors, which are not NAD itself; my NAD page has the rest. Nicotinamide mononucleotide raised muscle insulin sensitivity on a clamp test in a 10-week trial of 25 postmenopausal women with prediabetes who were overweight or obese, while placebo did not32. Nicotinamide riboside, at 2,000 mg a day for 12 weeks, did not improve insulin sensitivity in 40 obese men33. A 6-month blueberry trial's primary outcome, insulin resistance, did not move34.

Glucose monitors in people without diabetes

Early A continuous glucose monitor (CGM) is a wearable that reads glucose in real time35. In 153 healthy, nonobese children and adults (ages 7 to 80), median time between 70 and 140 mg/dL was 96%, with a mean glucose of 98 to 99 mg/dL (104 over age 60)36. In a Stanford study of 57 people without a diabetes diagnosis, even those who looked normal on standard tests reached the prediabetic range 15% of the time and the diabetic range 2% of the time, which the authors read as glucose problems being more common than standard tests show1. What a CGM can't do: it reads glucose, and Bikman's point is that early insulin resistance shows up as high insulin with normal glucose11. And I did not find a trial showing that wearing one prevents diabetes in healthy people.

HOMA-IR

HOMA-IR estimates insulin resistance from fasting glucose and fasting insulin. The original paper correlated it with the clamp at Rs = 0.88 but reported a 31% coefficient of variation and said that low precision limits its use10. In 65 studies of adults without diabetes, the highest HOMA-IR group had 64% higher coronary heart disease risk (RR 1.64), while fasting insulin alone was not significant (RR 1.12); these are observational37. The standard diagnostic thresholds use glucose and A1C, not insulin1, so a single HOMA-IR value is a rough estimate, not a diagnosis.

Rhonda Patrick on blood sugar

These are conversations and her own observations, not trials, and they don't mean she endorses this site.

  • Ben Bikman, 2025: his view that insulin resistance sits at the root of most modern health problems, why measuring insulin can catch it early, and sleep, meal timing, and glucose monitors11.
  • Eran Elinav, 2022: he is cautious about proposing that every person wear a CGM but supports measuring one's own food responses; she describes wearing one for almost three years35.
  • Sleep and glucose, 2026: she says sleep loss can temporarily reduce insulin sensitivity and describes brief, intense exercise after a poor night, plus what her own CGM showed during a stretch of broken sleep, as a personal observation38.

How I use it

I follow keto, I train, I take retatrutide, and I do a 3-day water and broth fast once a month (fasting page). That's the extent of what I've shared here.

Cautions

  • Not a diagnosis. This page reports research; a diagnosis takes lab tests and a clinician, and a high result may need a repeat test to confirm it8.
  • Drugs that lower glucose. The FDA label for tirzepatide, a related drug, says taking it with insulin or a secretagogue such as a sulfonylurea can raise the risk of hypoglycemia, including severe hypoglycemia; in its type 2 diabetes trial, hypoglycemia below 54 mg/dL ran 10.3% with a sulfonylurea versus 2.1% without39. Dose changes are for a prescriber.
  • SGLT2 inhibitors. In a case series of nine people, these diabetes drugs were tied to ketoacidosis even without very high blood glucose40.
  • Fasting. A 72-hour water fast lowered glucose and caused frequent hypoglycemic episodes on a monitor in six healthy men41; more on my fasting page.
  • Retatrutide is investigational per Lilly's July 2026 release, so there is no FDA label for it yet31.

References

  1. Hall H, Perelman D, Breschi A, Limcaoco P, Kellogg R, McLaughlin T, et al. Glucotypes reveal new patterns of glucose dysregulation. PLoS Biology. 2018;16(7):e2005143.Cohort studyPubMed 30040822 · DOI

    What it found: Continuous glucose monitoring study that grouped people into 'glucotypes' by their glucose dynamics after an identical nutrient challenge. Even people normoglycemic by standard measures showed high variability, with glucose reaching prediabetic ranges 15% of the time and diabetic ranges 2% of the time.

    Limits: A research framework from a small, mostly short monitoring study; it describes patterns and does not show that any glucotype predicts diabetes or that acting on one changes outcomes.

  2. Emerging Risk Factors Collaboration, Sarwar N, Gao P, Seshasai SR, Gobin R, Kaptoge S, et al. Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of 102 prospective studies. Lancet (London, England). 2010;375(9733):2215-2222.Meta-analysisPubMed 20609967 · DOI

    What it found: Collaborative analysis of 102 prospective studies (698,782 people, 52,765 vascular outcomes). Diabetes roughly doubled coronary heart disease risk (HR 2.00, 95% CI 1.83 to 2.19) and raised ischemic stroke risk (2.27); fasting glucose showed no significant link to risk between 3.90 and 5.59 mmol/L but risk rose above that.

    Limits: Observational; it tracks diabetes and glucose as risk markers and cannot separate their effect from related factors like weight and blood pressure.

  3. Knowler WC, Barrett-Connor E, Fowler SE, Hamman RF, Lachin JM, Walker EA, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. The New England Journal of Medicine. 2002;346(6):393-403.Randomized trialPubMed 11832527 · DOI

    What it found: Diabetes Prevention Program: 3,234 nondiabetic adults with elevated fasting and post-load glucose (mean BMI 34.0) were randomized to placebo, metformin 850 mg twice daily, or a lifestyle program aiming for 7% weight loss and 150 minutes of activity a week, with mean follow-up 2.8 years. Diabetes incidence was 11.0, 7.8, and 4.8 cases per 100 person-years; lifestyle cut incidence 58% (95% CI 48 to 66) and metformin 31% (17 to 43) versus placebo.

    Limits: A high-risk group followed for under 3 years, so it shows prevention or delay in that window and not how long it lasts; the follow-up papers cover that.

  4. Gong Q, Zhang P, Wang J, Ma J, An Y, Chen Y, et al. Morbidity and mortality after lifestyle intervention for people with impaired glucose tolerance: 30-year results of the Da Qing Diabetes Prevention Outcome Study. The Lancet Diabetes & Endocrinology. 2019;7(6):452-461.Randomized trialPubMed 31036503 · DOI

    What it found: Cluster-randomized trial begun in 1986: 33 clinics in Da Qing, China assigned 577 adults with impaired glucose tolerance to control or 6 years of diet, exercise, or both, with follow-up up to 30 years (540 of 576 assessed). The combined intervention delayed diabetes by a median 3.96 years and lowered cardiovascular events (HR 0.74, 95% CI 0.59 to 0.92), microvascular complications (0.65), cardiovascular deaths (0.67), and all-cause deaths (0.74), with an average 1.44 years more life expectancy.

    Limits: One Chinese city, clinics rather than individuals randomized, 6 years of intervention followed by observational years, and not every participant was reached.

  5. Lean MEJ, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Durability of a primary care-led weight-management intervention for remission of type 2 diabetes: 2-year results of the DiRECT open-label, cluster-randomised trial. The Lancet Diabetes & Endocrinology. 2019;7(5):344-355.Randomized trialPubMed 30852132 · DOI

    What it found: Two-year results of DiRECT (149 per group). Diabetes remission was 53 (36%) in the intervention group versus 5 (3%) in controls (adjusted OR 25.82, 95% CI 8.25 to 80.84), weight loss of 15 kg or more occurred in 17 (11%) versus 3 (2%), and post hoc 29 (64%) of 45 who kept off at least 10 kg were in remission.

    Limits: Remission fell from 46% at one year to 36% at two, and the 10 kg analysis was post hoc.

  6. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. 5-year follow-up of the randomised Diabetes Remission Clinical Trial (DiRECT) of continued support for weight loss maintenance in the UK: an extension study. The Lancet Diabetes & Endocrinology. 2024;12(4):233-246.Randomized trialPubMed 38423026 · DOI

    What it found: Five-year extension of a UK primary-care trial in which 149 people with type 2 diabetes of under 6 years were assigned to a diet-replacement weight program and 149 to usual care; at 2 years 36% of participants in the program were in remission. At 5 years 11 of 85 (13%) extension participants who kept low-intensity support were in remission versus 5 of 93 (5%) original controls, and 26% of those in remission at year 2 remained in remission; the original program group was in remission at 27% of visits versus 4% for controls.

    Limits: The 5-year data come from an extension with a smaller, self-selected group, and remission was tied to keeping the weight off.

  7. American Diabetes Association Professional Practice Committee for Diabetes. 2. Diagnosis and Classification of Diabetes: Standards of Care in Diabetes-2026. Diabetes Care. 2026;49(Supplement_1):S27-S49.GuidelinePubMed 41358893 · DOI

    What it found: The American Diabetes Association's 2026 Standards of Care chapter on the diagnosis and classification of diabetes; the ADA's Professional Practice Committee updates the Standards of Care every year.

    Limits: I could not read the chapter's text or tables (the cached PMC copy is front matter only), so no ADA cutoff is quoted from it.

  8. Diabetes Prevention Program Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up: the Diabetes Prevention Program Outcomes Study. The Lancet Diabetes & Endocrinology. 2015;3(11):866-875.Cohort studyPubMed 26377054 · DOI

    What it found: Mean 15-year follow-up of the Diabetes Prevention Program cohort. Diabetes incidence was 27% lower with lifestyle intervention (HR 0.73, 95% CI 0.65 to 0.83) and 18% lower with metformin (HR 0.82, 0.72 to 0.93) than placebo; cumulative incidence at year 15 was 55%, 56%, and 62%, and microvascular prevalence did not differ significantly (11.3% lifestyle, 13.0% metformin, 12.4% placebo).

    Limits: The effect is a delay, not an escape (more than half of every group had diabetes by year 15), and the microvascular result was null overall.

  9. DeFronzo RA, Ferrannini E, Groop L, Henry RR, Herman WH, Holst JJ, et al. Type 2 diabetes mellitus. Nature Reviews Disease Primers. 2015;1:15019.ReviewPubMed 27189025 · DOI

    What it found: Primer describing type 2 diabetes as closely tied to obesity, with obesity, poor diet, inactivity, and genetics all contributing, insulin resistance and insufficient insulin secretion as the core defects, and at least six other abnormalities also involved; higher risks of microvascular and macrovascular complications follow.

    Limits: A 2015 narrative primer with no new data, so newer drug and remission evidence is not in it.

  10. Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985;28(7):412-419.Lab or mechanistic studyPubMed 3899825 · DOI

    What it found: The paper that introduced HOMA: a computer model of the glucose-insulin feedback loop used to estimate insulin resistance and beta-cell function from fasting glucose and insulin. The insulin-resistance estimate correlated with the euglycemic clamp (Rs = 0.88, p < 0.0001), and precision was limited, with coefficients of variation of 31% for insulin resistance and 32% for beta-cell deficit.

    Limits: A 1985 validation in small samples against clamps; the abstract gives no diagnostic cutoff, and a single fasting estimate varies by about a third.

  11. Patrick R, Bikman B. #104 Dr. Ben Bikman: How To Reverse Insulin Resistance Through Diet, Exercise, & Sleep. FoundMyFitness, July 14, 2025.PodcastListen

    What it found: Rhonda Patrick interviews Ben Bikman (Brigham Young University) on insulin resistance; the notes say normal glucose can hide high insulin, that he favors measuring insulin and wider access to glucose monitors, and that poor sleep can raise cortisol and liver glucose output and reduce insulin sensitivity.

    Limits: An interview whose detailed notes are partly behind a premium preview, so I report topics and the guest's views, not trial evidence, and the guest argues a specific view of insulin.

  12. Donga E, van Dijk M, van Dijk JG, Biermasz NR, Lammers GJ, van Kralingen KW, et al. A single night of partial sleep deprivation induces insulin resistance in multiple metabolic pathways in healthy subjects. The Journal of Clinical Endocrinology and Metabolism. 2010;95(6):2963-2968.Randomized trialPubMed 20371664 · DOI

    What it found: Nine healthy adults were studied after normal sleep and after 4 hours of sleep (about 226 versus 454 minutes). After one short night, insulin-clamp glucose production rose (4.4 versus 3.6 umol/kg lean mass/min, P=0.017), glucose disposal fell (32.5 versus 40.7), and the glucose infusion rate needed fell about 25% (P=0.001); basal glucose and insulin did not differ.

    Limits: Nine people, a single night, and a lab clamp study, so it shows a short-term mechanism and not what months of short sleep do.

  13. Lean ME, Leslie WS, Barnes AC, Brosnahan N, Thom G, McCombie L, et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet (London, England). 2018;391(10120):541-551.Randomized trialPubMed 29221645 · DOI

    What it found: DiRECT: 306 people recruited from 49 UK primary care practices (149 per group analyzed). At 12 months, diabetes remission off drugs occurred in 68 (46%) of the intervention group versus 6 (4%) of controls (odds ratio 19.7, 95% CI 7.8 to 49.8), mean weight fell 10.0 kg versus 1.0 kg, and 31 (86%) of 36 who lost 15 kg or more were in remission.

    Limits: Open-label, in people recently diagnosed, and it tested one structured low-calorie program, so it says nothing about keto or fasting and little about long-standing diabetes.

  14. Sigal RJ, Kenny GP, Boulé NG, Wells GA, Prud'homme D, Fortier M, et al. Effects of aerobic training, resistance training, or both on glycemic control in type 2 diabetes: a randomized trial. Annals of Internal Medicine. 2007;147(6):357-369.Randomized trialPubMed 17876019 · DOI

    What it found: Randomized trial in 8 community facilities: 251 adults aged 39 to 70 with type 2 diabetes did aerobic training, resistance training, both, or nothing, 3 times a week for 22 weeks. Versus control, HbA1c fell 0.51 percentage points with aerobic (95% CI -0.87 to -0.14) and 0.38 with resistance training, and combined training lowered it a further 0.46 below aerobic alone and 0.59 below resistance alone.

    Limits: Not blinded, the combined group exercised for more total time, and results may not hold for people who do not stick with the program.

  15. Bull FC, Al-Ansari SS, Biddle S, Borodulin K, Buman MP, Cardon G, et al. World Health Organization 2020 guidelines on physical activity and sedentary behaviour. British Journal of Sports Medicine. 2020;54(24):1451-1462.GuidelinePubMed 33239350 · DOI

    What it found: WHO guideline for adults: 150 to 300 minutes a week of moderate activity, or 75 to 150 minutes of vigorous activity, or an equivalent mix, plus regular muscle-strengthening and less sedentary time.

    Limits: A population guideline for general health, not a plan for building an athlete, and the evidence was too thin to set a sitting-time limit.

  16. Reynolds AN, Mann JI, Williams S, Venn BJ. Advice to walk after meals is more effective for lowering postprandial glycaemia in type 2 diabetes mellitus than advice that does not specify timing: a randomised crossover study. Diabetologia. 2016;59(12):2572-2578.Randomized trialPubMed 27747394 · DOI

    What it found: Randomized crossover study of 41 adults with type 2 diabetes (mean age 60) comparing 2-week periods of advice to walk 30 minutes a day with advice to walk 10 minutes after each main meal, with 5-minute continuous glucose monitoring. The 3-hour post-meal glucose area was lower with after-meal walking (ratio of geometric means 0.88, 95% CI 0.78 to 0.99), and lower still after the evening meal (0.78, 0.67 to 0.91).

    Limits: Forty-one people with type 2 diabetes and two-week periods, so it shows after-meal glucose in diabetes, not prevention in people without it.

  17. Salas-Salvadó J, Bulló M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N, et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of a randomized trial. Annals of Internal Medicine. 2014;160(1):1-10.Randomized trialPubMed 24573661 · DOI

    What it found: PREDIMED subgroup analysis of 3,541 Spanish adults aged 55 to 80 without diabetes at high cardiovascular risk, assigned a Mediterranean diet with extra-virgin olive oil, one with nuts, or a low-fat control diet, with no calorie restriction or activity program. Over a median 4.1 years, new diabetes was 16.0, 18.7, and 23.6 per 1,000 person-years; the hazard ratio was 0.60 (95% CI 0.43 to 0.85) for olive oil and 0.82 (0.61 to 1.10, not significant) for nuts.

    Limits: A subgroup analysis in older, high-risk adults, with higher withdrawals in the control group; the main PREDIMED report was later withdrawn and republished, and I did not confirm whether this analysis was redone.

  18. Sainsbury E, Kizirian NV, Partridge SR, Gill T, Colagiuri S, Gibson AA. Effect of dietary carbohydrate restriction on glycemic control in adults with diabetes: A systematic review and meta-analysis. Diabetes Research and Clinical Practice. 2018;139:239-252.Meta-analysisPubMed 29522789 · DOI

    What it found: Meta-analysis of 25 randomized trials with 2,412 participants with diabetes. Diets restricting carbohydrate to under 26% of energy lowered HbA1c more than higher-carbohydrate diets at 3 months (weighted mean difference -0.47%, 95% CI -0.71 to -0.23) and 6 months (-0.36%, -0.62 to -0.09), with no significant difference at 12 or 24 months; moderate restriction (26 to 45% of energy) showed no difference.

    Limits: Evidence quality is limited, and the benefit faded by one year, so the diet's edge is mostly early.

  19. Jastreboff AM, le Roux CW, Stefanski A, Aronne LJ, Halpern B, Wharton S, et al. Tirzepatide for Obesity Treatment and Diabetes Prevention. The New England Journal of Medicine. 2025;392(10):958-971.Randomized trialPubMed 39536238 · DOI

    What it found: SURMOUNT-1: 2,539 adults with obesity, 1,032 of them with prediabetes, were randomized to weekly tirzepatide 5, 10, or 15 mg or placebo; the prediabetes group was followed 176 weeks plus 17 weeks off treatment. Weight change was -12.3%, -18.7%, and -19.7% versus -1.3%, and type 2 diabetes was diagnosed in 1.3% on tirzepatide versus 13.3% on placebo (HR 0.07), or 2.4% versus 13.7% after the off-treatment period (HR 0.12). Funded by Eli Lilly.

    Limits: Funded by the maker, and the diabetes-prevention result comes from the prediabetes subset of people with obesity, so it does not show benefit for lean people or for years after stopping the drug.

  20. Tuomilehto J, Lindström J, Eriksson JG, Valle TT, Hämäläinen H, Ilanne-Parikka P, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. The New England Journal of Medicine. 2001;344(18):1343-1350.Randomized trialPubMed 11333990 · DOI

    What it found: Finnish Diabetes Prevention Study: 522 middle-aged overweight adults with impaired glucose tolerance were randomized to individualized counseling (weight loss, less total and saturated fat, more fiber, more activity) or a control group, mean follow-up 3.2 years. Weight fell 4.2 kg versus 0.8 kg at year 1, four-year cumulative diabetes incidence was 11% versus 23%, and risk fell 58% (P<0.001).

    Limits: Overweight Finnish adults with impaired glucose tolerance followed about 3 years, and the result depends on people actually making the changes.

  21. Diabetes Prevention Program Research Group, Knowler WC, Fowler SE, Hamman RF, Christophi CA, Hoffman HJ, et al. 10-year follow-up of diabetes incidence and weight loss in the Diabetes Prevention Program Outcomes Study. Lancet (London, England). 2009;374(9702):1677-1686.Cohort studyPubMed 19878986 · DOI

    What it found: Follow-up of the Diabetes Prevention Program cohort. During the 2.8-year trial, incidence was 4.8 (lifestyle), 7.8 (metformin), and 11.0 (placebo) per 100 person-years; afterward it was similar across groups (5.9, 4.9, and 5.6). Over 10 years, diabetes incidence was 34% lower with lifestyle and 18% lower with metformin than placebo, and the lifestyle group lost then partly regained weight.

    Limits: The years after the randomized phase are observational follow-up, so later comparisons are not a clean randomized contest.

  22. Church TS, Blair SN, Cocreham S, Johannsen N, Johnson W, Kramer K, et al. Effects of aerobic and resistance training on hemoglobin A1c levels in patients with type 2 diabetes: a randomized controlled trial. JAMA. 2010;304(20):2253-2262.Randomized trialPubMed 21098771 · DOI

    What it found: HART-D randomized adults with type 2 diabetes (mean age 55.8, baseline HbA1c 7.7%) to aerobic, resistance, or combined training or a control group. Versus control, HbA1c fell 0.34 percentage points with combined training (95% CI -0.64 to -0.03, P = .03) but not significantly with aerobic (-0.24) or resistance training alone (-0.16).

    Limits: Only the combined group reached significance, and the HbA1c change is modest, so it supports combining exercise types more than any single type.

  23. Momma H, Kawakami R, Honda T, Sawada SS. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies. British Journal of Sports Medicine. 2022;56(13):755-763.Meta-analysisPubMed 35228201 · DOI

    What it found: Systematic review and meta-analysis of 16 prospective cohort studies. Muscle-strengthening activity went with a 10 to 17% lower risk of all-cause mortality, cardiovascular disease, total cancer, diabetes, and lung cancer, with the largest reduction (about 10 to 20%) at roughly 30 to 60 minutes per week for all-cause mortality, cardiovascular disease, and total cancer.

    Limits: Observational cohorts, so it cannot show that lifting caused the lower risk; no association was found for colon, kidney, bladder, or pancreatic cancer, and the abstract gives no participant total.

  24. Buffey AJ, Herring MP, Langley CK, Donnelly AE, Carson BP. The Acute Effects of Interrupting Prolonged Sitting Time in Adults with Standing and Light-Intensity Walking on Biomarkers of Cardiometabolic Health in Adults: A Systematic Review and Meta-analysis. Sports Medicine. 2022;52(8):1765-1787.Meta-analysisPubMed 35147898 · DOI

    What it found: Meta-analysis of seven randomized crossover trials of adults, mostly overweight or with obesity. Light-intensity walking breaks lowered postprandial glucose (effect -0.72, 95% CI -1.03 to -0.41) and insulin (-0.83, -1.18 to -0.48) versus continued sitting; standing breaks lowered glucose (-0.31) but not insulin, and walking beat standing for both.

    Limits: Acute, single-day crossover trials, so it shows glucose after a meal or a sitting day, not long-term diabetes risk.

  25. Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Arós F, et al. Primary Prevention of Cardiovascular Disease with a Mediterranean Diet Supplemented with Extra-Virgin Olive Oil or Nuts. The New England Journal of Medicine. 2018;378(25):e34.Randomized trialPubMed 29897866 · DOI

    What it found: PREDIMED, republished in 2018: 7,447 Spanish adults aged 55 to 80 at high cardiovascular risk were assigned a Mediterranean diet with extra-virgin olive oil, a Mediterranean diet with mixed nuts, or a low-fat control diet. Over a median 4.8 years, major cardiovascular events had HR 0.69 (95% CI 0.53 to 0.91) with olive oil and HR 0.72 (0.54 to 0.95) with nuts versus control.

    Limits: The original 2013 report was withdrawn after protocol deviations in randomization at some sites, and the trial tests a whole Mediterranean pattern with olive oil or nuts, not olive oil alone.

  26. Goldenberg JZ, Day A, Brinkworth GD, Sato J, Yamada S, Jönsson T, et al. Efficacy and safety of low and very low carbohydrate diets for type 2 diabetes remission: systematic review and meta-analysis of published and unpublished randomized trial data. BMJ (Clinical research ed.). 2021;372:m4743.Meta-analysisPubMed 33441384 · DOI

    What it found: Meta-analysis of 23 randomized trials with 1,357 participants lasting at least 12 weeks. At six months remission (HbA1c under 6.5% or fasting glucose under 7.0 mmol/L, with or without medication) occurred in 76 of 133 (57%) on low-carbohydrate diets versus 41 of 131 (31%) on control diets (risk difference 0.32, 95% CI 0.17 to 0.47); at 12 months remission data were sparse and weight, triglyceride, and insulin-sensitivity gains diminished. Evidence was moderate to low certainty.

    Limits: Remission here counts people still on medication in some analyses, only eight studies had six-month remission data, and the 12-month picture is thin.

  27. Hallberg SJ, McKenzie AL, Williams PT, Bhanpuri NH, Peters AL, Campbell WW, et al. Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study. Diabetes Therapy. 2018;9(2):583-612.Cohort studyPubMed 29417495 · DOI

    What it found: Virta trial: 349 adults with type 2 diabetes (262 in a continuous remote care program with nutritional ketosis, 87 in usual care); 83% of the program group stayed to 1 year. HbA1c fell from 7.6% to 6.3%, weight fell 13.8 kg, insulin was reduced or stopped in 94% of users, and LDL cholesterol rose 10%; usual care showed no significant change.

    Limits: Open-label and non-randomized, and the program bundled coaching, monitoring, and medication changes with the diet, so the diet's own effect cannot be isolated.

  28. Athinarayanan SJ, Adams RN, Hallberg SJ, McKenzie AL, Bhanpuri NH, Campbell WW, et al. Long-Term Effects of a Novel Continuous Remote Care Intervention Including Nutritional Ketosis for the Management of Type 2 Diabetes: A 2-Year Non-randomized Clinical Trial. Frontiers in Endocrinology. 2019;10:348.Cohort studyPubMed 31231311 · DOI

    What it found: Two-year follow-up of the same Virta cohort (262 in the program, 87 in usual care): glycemic medication other than metformin fell from 55.7% to 26.8% of users, insulin use fell 62%, diabetes reversal was reported in 53.5% and remission in 17.6% of the program group (none in usual care), and spine bone density was unchanged.

    Limits: Non-randomized and open-label, and the abstract does not give numeric HbA1c, weight, or LDL changes for year 2.

  29. Kirkpatrick CF, Bolick JP, Kris-Etherton PM, Sikand G, Aspry KE, Soffer DE, et al. Review of current evidence and clinical recommendations on the effects of low-carbohydrate and very-low-carbohydrate (including ketogenic) diets for the management of body weight and other cardiometabolic risk factors: A scientific statement from the National Lipid Association Nutrition and Lifestyle Task Force. Journal of Clinical Lipidology. 2019;13(5):689-711.e1.Position standPubMed 31611148 · DOI

    What it found: National Lipid Association scientific statement concluding that low-carb and very-low-carb diets are not superior to other diets for weight loss, may help appetite, triglycerides, and medication use in type 2 diabetes, have mixed effects on LDL cholesterol (some studies show an increase), and lack long-term (more than 2 years) safety data.

    Limits: A 2019 expert review, so it predates the KETO-CTA study and the longer Virta follow-up, and the abstract gives no pooled numbers.

  30. Rosenstock J, Frias J, Jastreboff AM, Du Y, Lou J, Gurbuz S, et al. Retatrutide, a GIP, GLP-1 and glucagon receptor agonist, for people with type 2 diabetes: a randomised, double-blind, placebo and active-controlled, parallel-group, phase 2 trial conducted in the USA. Lancet (London, England). 2023;402(10401):529-544.Randomized trialPubMed 37385280 · DOI

    What it found: Phase 2 trial of 281 adults with type 2 diabetes at 42 US centers given weekly retatrutide, placebo, or dulaglutide 1.5 mg. At 24 weeks HbA1c fell 0.43% to 2.02% on retatrutide versus 0.01% on placebo and 1.41% on dulaglutide, weight fell 3.19% to 16.94% at 36 weeks, gastrointestinal events were mild to moderate in 35% (67 of 190), and no severe hypoglycemia or deaths were reported.

    Limits: A phase 2 dose-finding trial of 24 to 36 weeks, funded by the drug's developer, so it cannot show long-term safety or hard outcomes.

  31. Eli Lilly and Company. Lilly's triple agonist, retatrutide, successful in two additional Phase 3 obesity trials, delivering significant improvements in weight and A1C. Eli Lilly and Company press release (PR Newswire); copy read on BioSpace, July 23, 2026.ArticleRead

    What it found: Company press release, not peer-reviewed: Lilly calls retatrutide an investigational once-weekly triple hormone receptor agonist and says it plans to submit a Biologics License Application to the FDA in Q1 2027. TRIUMPH-2 (1,152 people with type 2 diabetes and obesity or overweight, 80 weeks) reported weight loss of 12.7% to 20.8% versus 4.0% on placebo and A1C changes of -1.4% to -1.6% from a 7.7% baseline versus -0.2%; diarrhea ran 27.4% to 33.6% versus 13.2% on placebo and dysesthesia 4.5% to 7.3% versus 0.7%.

    Limits: A company topline release with the efficacy estimand and no peer review; Lilly's own investor page answered 403 to our checks, so the link goes to the same release as reposted on BioSpace.

  32. Yoshino M, Yoshino J, Kayser BD, Patti GJ, Franczyk MP, Mills KF, et al. Nicotinamide mononucleotide increases muscle insulin sensitivity in prediabetic women. Science. 2021;372(6547):1224-1229.Randomized trialPubMed 33888596 · DOI

    What it found: Ten-week randomized, double-blind, placebo-controlled trial of 250 mg/day NMN in 25 postmenopausal women with prediabetes who were overweight or obese (13 NMN, 12 placebo). Insulin-stimulated glucose disposal rose 25 +/- 7 percent per kg fat-free mass (p < 0.01); body weight, fat, blood sugar, and lipids did not change and muscle NAD+ was unchanged.

    Limits: Twenty-five women, 10 weeks, one dose, and women with prediabetes only; some authors disclose NMN patent interests and the capsules came from a supplier.

  33. Dollerup OL, Christensen B, Svart M, Schmidt MS, Sulek K, Ringgaard S, et al. A randomized placebo-controlled clinical trial of nicotinamide riboside in obese men: safety, insulin-sensitivity, and lipid-mobilizing effects. American Journal of Clinical Nutrition. 2018;108(2):343-353.Randomized trialPubMed 29992272 · DOI

    What it found: Randomized, double-blind, placebo-controlled parallel trial in 40 sedentary men aged 40 to 70 with BMI above 30, taking 1,000 mg NR twice daily (2,000 mg/day) for 12 weeks. NR did not improve insulin sensitivity, glucose metabolism, energy expenditure, lipolysis, or body composition, and no serious adverse events occurred.

    Limits: A null result in 40 obese men at one dose for 12 weeks, so it cannot rule out effects in other groups.

  34. Curtis PJ, van der Velpen V, Berends L, Jennings A, Feelisch M, Umpleby AM, et al. Blueberries improve biomarkers of cardiometabolic function in participants with metabolic syndrome: results from a 6-month, double-blind, randomized controlled trial. The American Journal of Clinical Nutrition. 2019;109(6):1535-1545.Randomized trialPubMed 31136659 · DOI

    What it found: Double-blind trial of 115 adults with metabolic syndrome given 75 g or 150 g of blueberries a day or a matched placebo for 6 months. At 150 g, flow-mediated dilatation improved by 1.45% (95% CI 0.83 to 2.1) and augmentation index fell 2.24%; the primary outcome, insulin resistance, did not change, nor did blood pressure, and 75 g had no effect.

    Limits: The primary endpoint was null, the benefits were in secondary markers of artery function, and it ran 6 months in people with metabolic syndrome.

  35. Patrick R, Elinav E. Should healthy people use a continuous glucose monitor? | Dr. Eran Elinav. FoundMyFitness, February 21, 2022.PodcastListen

    What it found: A short clip from Rhonda Patrick's interview with Eran Elinav: he is cautious about proposing that every person wear a continuous glucose monitor but supports measuring personal food responses, and Patrick describes her own multi-year use and that some clinicians worry glucose monitors may steer people away from healthy foods like fruit.

    Limits: A clip page, not a study; it gives no normal ranges or thresholds and does not discuss accuracy, cost, or who should avoid monitors.

  36. Shah VN, DuBose SN, Li Z, Beck RW, Peters AL, Weinstock RS, et al. Continuous Glucose Monitoring Profiles in Healthy Nondiabetic Participants: A Multicenter Prospective Study. The Journal of Clinical Endocrinology and Metabolism. 2019;104(10):4356-4364.Cohort studyPubMed 31127824 · DOI

    What it found: Prospective multicenter study of 153 nonpregnant, nonobese people aged 7 to 80 who wore a blinded Dexcom G6 for up to 10 days. Mean glucose was 98 to 99 mg/dL in most age groups (104 over age 60), median time between 70 and 140 mg/dL was 96%, median time above 140 was 2.1%, and median time below 70 was 1.1%.

    Limits: A short wear period in a small, selected group of healthy people with one sensor model, so it gives reference ranges and not a diagnostic cutoff.

  37. Gast KB, Tjeerdema N, Stijnen T, Smit JWA, Dekkers OM. Insulin resistance and risk of incident cardiovascular events in adults without diabetes: meta-analysis. PLoS One. 2012;7(12):e52036.Meta-analysisPubMed 23300589 · DOI

    What it found: Meta-analysis of 65 studies (516,325 participants without diabetes). Highest versus lowest HOMA-IR carried a coronary heart disease RR of 1.64 (95% CI 1.35 to 2.00); fasting insulin alone gave RR 1.12 (0.92 to 1.37), which was not significant.

    Limits: Pooled observational studies, so the numbers are associations, and the fasting-insulin result had a confidence interval that crossed 1.

  38. Patrick R. How Exercise Affects Glucose After Sleep Loss. FoundMyFitness, July 8, 2026.PodcastListen

    What it found: A clip page from Rhonda Patrick's conversation on More Plates More Dates: sleep loss can temporarily reduce insulin sensitivity, working muscle clears glucose through pathways partly independent of insulin, and she describes a short vigorous workout after a bad night, with her own continuous glucose monitor readings as a personal observation, not a controlled experiment.

    Limits: A clip page whose reference list looked mismatched in places, so I treat it as her framing and personal experience, not as a source for the studies it names.

  39. Eli Lilly and Company (FDA-approved prescribing information). ZEPBOUND (tirzepatide) injection, solution; ZEPBOUND KWIKPEN (tirzepatide) injection, solution. DailyMed, National Library of Medicine, August 28, 2026.Regulatory noticeRead

    What it found: Current FDA label for tirzepatide, a related GIP and GLP-1 drug (label revised August 2026). Its warnings include severe gastrointestinal adverse reactions (section 5.2), acute kidney injury due to volume depletion (5.3), and hypoglycemia when combined with insulin secretagogues such as sulfonylureas (5.7), where hypoglycemia was 10.3% versus 2.1% without a sulfonylurea.

    Limits: The label is for tirzepatide, not retatrutide, which is investigational and adds a glucagon receptor effect, so it shows what a neighboring drug warns about and not what retatrutide's label would say.

  40. Peters AL, Buschur EO, Buse JB, Cohan P, Diner JC, Hirsch IB. Euglycemic Diabetic Ketoacidosis: A Potential Complication of Treatment With Sodium-Glucose Cotransporter 2 Inhibition. Diabetes Care, 2015.ArticlePubMed 26078479 · DOI

    What it found: Case series of 13 episodes of ketoacidosis or ketosis in nine people taking SGLT-2 inhibitors (seven with type 1 diabetes, two with type 2); blood glucose was not markedly high, so recognition was slow. The authors advise testing ketones in anyone on these drugs who is nauseated, vomiting, or unwell, and extreme caution in type 1 diabetes.

    Limits: A small case series identified incidentally, so it cannot give how often this happens and does not test a keto diet itself.

  41. McDougal DH, Darpolor MM, DuVall MA, Sutton EF, Morrison CD, Gadde KM, et al. Glial acetate metabolism is increased following a 72-h fast in metabolically healthy men and correlates with susceptibility to hypoglycemia. Acta Diabetologica. 2018;55(10):1029-1036.Lab or mechanistic studyPubMed 29931424 · DOI

    What it found: Six metabolically healthy men aged 18 to 40 stayed 4 days at a research center and fasted 72 hours on water while wearing continuous glucose monitors. The fast lowered blood glucose and caused frequent hypoglycemic episodes, and brain glial acetate metabolism rose from 53.5% to 61.9% (p = 0.005). The glucose, free fatty acid, ketone, and insulin values on the page come from Table 2 and the results text of the full text.

    Limits: Six men in one lab fast, designed to study the brain and hypoglycemia rather than health outcomes; the metabolite table is in the full text, not the abstract.