The Science MD
Section oneNos. 01–12

Metabolic Health

Insulin resistance and everything downstream of it — fatty liver, type 2 diabetes, hunger regulation, weight, PCOS and gout — ending with the syndrome that ties them together.

No. 01

Insulin Resistance

The foundation for almost everything else on this channel. What insulin actually does, what it means for cells to stop responding to it, and why this single process sits underneath fatty liver, type 2 diabetes, PCOS and more.

References 18

Insulin Physiology & Resistance Mechanisms

  • Kahn BB, Flier JS. Obesity and insulin resistance. J Clin Invest. 2000;106(4):473–481. PubMed
  • Saltiel AR, Kahn CR. Insulin signalling and the regulation of glucose and lipid metabolism. Nature. 2001;414(6865):799–806. PubMed
  • Reaven GM. Banting Lecture 1988: Role of insulin resistance in human disease. Diabetes. 1988;37(12):1595–1607. PubMed

Hyperinsulinemia & Chronic Insulin Exposure

  • Shanik MH, Xu Y, Škrha J, et al. Insulin resistance and hyperinsulinemia: is hyperinsulinemia the cart or the horse? Diabetes Care. 2008;31(Suppl 2):S262–S268. PubMed
  • Corkey BE. Banting Lecture 2011: Hyperinsulinemia: cause or consequence? Diabetes. 2012;61(1):4–13. PubMed

Evolutionary & Thrifty Metabolism

  • Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet. 1962;14(4):353–362. PubMed
  • Speakman JR. Thrifty genes for obesity and the metabolic syndrome — time to call off the search? Diab Vasc Dis Res. 2006;3(1):7–11. PubMed
  • Wells JCK. Thrifty phenotype hypothesis. Int J Epidemiol. 2007;36(2):226–228.

Insulin Resistance & Metabolic Consequences

  • Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997;46(1):3–10. PubMed
  • DeFronzo RA, Ferrannini E. Insulin resistance: a multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991;14(3):173–194. PubMed

Beta Cell Compensation & Progression to Type 2 Diabetes

  • Weir GC, Bonner-Weir S. Five stages of evolving beta-cell dysfunction during progression to diabetes. Diabetes. 2004;53(Suppl 3):S16–S21. PubMed
  • Kahn SE. The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of type 2 diabetes. Diabetologia. 2003;46(1):3–19. PubMed

Lifestyle Interventions & Reversibility

  • Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. PubMed
  • Tuomilehto J, Lindström J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344(18):1343–1350. PubMed

Resistance Training & Insulin Sensitivity

  • Ivy JL. Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus. Sports Med. 1997;24(5):321–336. PubMed
  • Holten MK, Zacho M, Gaster M, et al. Strength training increases insulin-mediated glucose uptake, GLUT4 content, and insulin signaling in skeletal muscle in patients with type 2 diabetes. Diabetes. 2004;53(2):294–305. PubMed

Sleep & Stress

  • Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet. 1999;354(9188):1435–1439. PubMed
  • Björntorp P. Do stress reactions cause abdominal obesity and comorbidities? Obes Rev. 2001;2(2):73–86. PubMed
No. 02
Part 1 of 2

Fatty Liver — Part 1

How fat ends up stored in the liver in the first place, and why a condition with no symptoms became one of the most common liver problems in the world.

References 9
  • Rinella ME et al. A multisociety Delphi consensus statement on new fatty liver disease nomenclature. Hepatology. 2023;78(6):1966–1986. doi:10.1097/HEP.0000000000000520. PMID: 37363821. DOI
  • Zeng J et al. The burden of NAFLD (now referred to as MASLD)-related chronic liver disease and cirrhosis from 1990 to 2021 with projections to 2036: a comparative study of global China, the United States and India. Lipids Health Dis. 2025;24:298. doi:10.1186/s12944-025-02750-z. PMID: 41024003. DOI
  • Donnelly KL et al. Sources of fatty acids stored in liver and secreted via lipoproteins in patients with nonalcoholic fatty liver disease. J Clin Invest. 2005;115(5):1343–1351. doi:10.1172/JCI23621. PMID: 15864352. DOI
  • Sanders FW, Griffin JL. De novo lipogenesis in the liver in health and disease: more than just a shunting yard for glucose. Biol Rev Camb Philos Soc. 2016;91(2):452–468. PubMed
  • Samuel VT, Shulman GI. The pathogenesis of insulin resistance: integrating signaling pathways and substrate flux. J Clin Invest. 2016;126(1):12–22. PubMed
  • Chan WK et al. Metabolic dysfunction-associated steatotic liver disease (MASLD): a state-of-the-art review. J Obes Metab Syndr. 2023;32(3):197–213. PubMed
  • National Institute on Alcohol Abuse and Alcoholism (NIAAA). Drinking levels defined. National Institutes of Health. Available at: https://w ww.niaaa.nih.gov/alcohol-health/overview-alcohol-consumption/moderate-binge-drinking
  • Canadian Centre on Substance Use and Addiction (CCSA). Canada's Guidance on Alcohol and Health. Ottawa, ON: CCSA; 2023. Available at: https://w ww.ccsa.ca/canadas-guidance-alcohol-and-health
  • Rinella ME et al. AASLD practice guidance on the clinical assessment and management of nonalcoholic fatty liver disease. Hepatology. 2023;77(5):1797–1835. PubMed
No. 03
Part 2 of 2

Fatty Liver — Part 2

What happens as fatty liver progresses, what the evidence says about reversing it, and which interventions actually have data behind them.

References 16
  • Koch, M et al. Dietary patterns and fatty liver disease. Current Opinion in Lipidology. 2015 Feb;26(1):35-41. doi: 10.1097 PubMed
  • Assy, N. Nutritional recommendations for patients with non-alcoholic fatty liver diseases. World Journal of Gastroenterology. 2019;11(9):2164.
  • Softic S, Cohen DE, Kahn CR. Role of Dietary Fructose and Hepatic de novo Lipogenesis in Fatty Liver Disease. Dig Dis Sci. 2016;61(5):1282–1293. doi:10.1007/s10620-016-4054-0. PMID: 26856717. DOI
  • Heeren J, Scheja L. Metabolic-associated fatty liver disease and lipoprotein metabolism. Molecular Metabolism. 2021;50:101238. doi:10.1016/j.molmet.2021.101238. DOI
  • Vilar-Gomez E et al. Weight loss through lifestyle modification significantly reduces features of nonalcoholic steatohepatitis. Gastroenterology. 2015;149(2):367–378. PubMed
  • Promrat K et al. Randomized controlled trial testing the effects of weight loss on nonalcoholic steatohepatitis. Hepatology. 2010;51(1):121–129. PubMed
  • Wei X et al. Effects of Time-Restricted Eating on Nonalcoholic Fatty Liver Disease: The TREATY-FLD Randomized Clinical Trial. JAMA Netw Open. 2023;6(3):e233513. doi:10.1001/jamanetworkopen.2023.3513. DOI
  • Anton SD et al. Flipping the metabolic switch: understanding and applying the health benefits of fasting. Obesity (Silver Spring). 2018;26(2):254–268. doi:10.1002/oby.22065. DOI
  • Hallsworth K et al. Resistance exercise reduces liver fat and its mediators in non-alcoholic fatty liver disease independent of weight loss. Gut. 2011;60(9):1278–1283. doi:10.1136/gut.2011.242073. PMID: 21708823. DOI
  • Bacchi E et al. Metabolic effects of aerobic training and resistance training in type 2 diabetic subjects: a randomized controlled trial (the RAED2 study). Diabetes Care. 2012;35(4):676–682. PubMed
  • Brouwers B et al. Effects of exercise training on intrahepatic lipid content in humans. Diabetologia. 2016;59(10):2068–2079. doi:10.1007/s00125-016-4037-x. PMID: 27393135. DOI
  • Ajmera V et al. Among patients with nonalcoholic fatty liver disease, modest alcohol use is associated with less improvement in histologic steatosis and steatohepatitis. Clin Gastroenterol Hepatol. 2018;16(9):1511–1520.e5. doi:10.1016/j.cgh.2018.01.026. PMID: 29378307. DOI
  • Carr RM, Correnti J. Insulin resistance in clinical and experimental alcoholic liver disease. Ann N Y Acad Sci. 2015;1353(1):1–20. doi:10.1111/nyas.12787. PMID: 25998863. DOI
  • Newsome PN et al. A placebo-controlled trial of subcutaneous semaglutide in nonalcoholic steatohepatitis. N Engl J Med. 2021;384(12):1113–1124. doi:10.1056/NEJMoa2028395. DOI
  • Sanyal AJ et al. Phase 3 trial of semaglutide in metabolic dysfunction-associated steatohepatitis. N Engl J Med. 2025;392(21):2089–2099. doi:10.1056/NEJMoa2413258. PMID: 40305708. DOI
  • Chalasani N et al. The diagnosis and management of nonalcoholic fatty liver disease: practice guidance from the American Association for the Study of Liver Diseases. Hepatology. 2018;67(1):328–357. doi:10.1002/hep.29367. PMID: 28714183. DOI
No. 04

Type 2 Diabetes

What is actually happening in type 2 diabetes beyond high blood sugar — the mechanism, how it develops over years before diagnosis, and why it is better understood as the end of a long process than a sudden event.

References 12
  • American Diabetes Association. Standards of Care in Diabetes. Diabetes Care. 2024.
  • Diabetes Canada. Clinical Practice Guidelines. Updated 2024.
  • DeFronzo RA. Banting Lecture. From the triumvirate to the ominous octet: a new paradigm for the treatment of type 2 diabetes mellitus. Diabetes. 2009;58(4):773–95. PubMed
  • Tabák AG et al. Prediabetes: a high-risk state for diabetes development. Lancet. 2012;379(9833):2279–90. PubMed
  • UK Prospective Diabetes Study (UKPDS) Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). Lancet. 1998;352(9131):837–53. PubMed
  • Lean MEJ et al. Primary care-led weight management for remission of type 2 diabetes (DiRECT): an open-label, cluster-randomised trial. Lancet. 2018;391(10120):541–551. PubMed
  • Holman RR et al. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med. 2008;359:1577–1589. PubMed
  • Butler AE et al. Beta-cell deficit and increased beta-cell apoptosis in humans with type 2 diabetes. Diabetes. 2003;52(1):102–10. PubMed
  • Stumvoll M et al. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005;365(9467):1333–46. PubMed
  • Knowler WC et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346(6):393–403. PubMed
  • Davies MJ et al. Management of hyperglycemia in type 2 diabetes, 2022. A consensus report by the American Diabetes Association (ADA) and the
  • European Association for the Study of Diabetes (EASD). Diabetes Care. 2022;45(11):2753–2786. PubMed
No. 05

Hunger Hormones

Leptin, ghrelin and the signalling system that decides when you feel hungry and when you feel full — and why that system is far less under conscious control than most people assume.

References 15

Hunger Hormone Physiology (Ghrelin & Leptin)

  • Sumithran P et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597–1604. doi:10.1056/NEJMoa1105816 DOI
  • Cummings DE et al. Plasma ghrelin levels after diet-induced weight loss or gastric bypass surgery. N Engl J Med. 2002;346(21):1623–1630. doi:10.1056/NEJMoa012908 DOI
  • Schwartz MW et al. Obesity pathogenesis: An Endocrine Society Scientific Statement. Endocr Rev. 2017;38(4):267–296. doi:10.1210/er.2017-00111 DOI

Hypothalamic Appetite Regulation

  • Morton GJ et al. Central nervous system control of food intake and body weight. Nature. 2006;443(7109):289–295. doi:10.1038/nature05026 DOI
  • Grill HJ et al. Hindbrain neurons as an essential hub in the neuroanatomically distributed control of energy balance. Cell Metab. 2012;16(3):296–309. doi:10.1016/j.cmet.2012.06.015 DOI

Satiety Hormones (GLP-1, PYY, CCK)

  • Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439. doi:10.1152/physrev.00034.2006 DOI
  • Batterham RL et al. Gut hormone PYY(3-36) physiologically inhibits food intake. Nature. 2002;418(6898):650–654. doi:10.1038/nature00887 DOI

Leptin Resistance & Set Point

  • Flier JS. Obesity wars: molecular progress confronts an expanding epidemic. Cell. 2004;116(2):337–350. doi:10.1016/s0092-8674(03)01081-x DOI
  • Myers MG et al. Mechanisms of leptin action and leptin resistance. Annu Rev Physiol. 2008;70:537–556. doi:10.1146/annurev.physiol.70.113006.100707 DOI

Adaptive Thermogenesis & Metabolic Response to Weight Loss

  • Rosenbaum M et al. Adaptive thermogenesis in humans. Int J Obes (Lond). 2010;34 Suppl 1:S47–S55. doi:10.1038/ijo.2010.184 DOI
  • Fothergill E et al. Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity (Silver Spring). 2016;24(8):1612–1619. doi:10.1002/oby.21538 DOI

Evolutionary Perspective

  • Speakman JR. Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints. Annu Rev Nutr. 2013;33:289–317. doi:10.1146/annurev-nutr-071811-150711 DOI
  • Wells JCK. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother? J Theor Biol. 2003;221(1):143–161. doi:10.1006/jtbi.2003.3183 DOI

GLP-1 Receptor Agonists

  • van Can J et al. Effects of the once-daily GLP-1 analog liraglutide on gastric emptying, glycemic parameters, appetite and energy metabolism in obese, non-diabetic adults. Int J Obes (Lond). 2014;38(6):784–793. doi:10.1038/ijo.2013.162 DOI
  • Müller TD et al. Glucagon-like peptide 1 (GLP-1). Mol Metab. 2019;30:72–130. doi:10.1016/j.molmet.2019.09.010 DOI
No. 06
Part 1 of 2

Weight Loss — Part 1

The physiology of losing weight, and what the body does in response — the part of the story that gets left out of most advice.

References 14

Energy Balance & Weight Regulation

  • Hall KD et al. Energy balance and its components: implications for body weight regulation. Am J Clin Nutr. 2012;95(4):989-994. doi:10.3945/ajcn.112.036350 DOI
  • Hall KD et al. Quantification of the effect of energy imbalance on bodyweight. Lancet. 2011;378(9793):826-837. doi:10.1016/S0140-6736(11)60812-X DOI
  • Pontzer H et al.Pontzer H et al. The evidence for constrained total energy expenditure in humans and other animals. Curr Biol. 2026;36(4):1013-1025.e4. doi:10.1016/j.cub.2026.01.025 DOI

Adaptive Thermogenesis

  • Rosenbaum M et al. Adaptive thermogenesis in humans. Int J Obes (Lond). 2010;34 Suppl 1:S47-55. doi:10.1038/ijo.2010.184 DOI
  • Fothergill E et al. Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity (Silver Spring). 2016;24(8):1612-1619. doi:10.1002/oby.21538 DOI

Hormonal Changes With Weight Loss

  • Sumithran P et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597-1604. doi:10.1056/NEJMoa1105816 DOI

Lipolysis & Insulin Physiology

  • Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002;45(9):1201-1210. doi:10.1007/s00125-002-0873-y DOI
  • Boden G. Free fatty acids-the link between obesity and insulin resistance. Endocr Pract. 2001;7(1):44-51. doi:10.4158/EP.7.1.44 DOI
  • Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997;46(1):3-10. PubMed

Protein & Resistance Training

  • Phillips SM et al. Dietary protein for athletes: from requirements to optimum adaptation. J Sports Sci. 2011;29 Suppl 1:S29-38. doi:10.1080/02640414.2011.619204 DOI
  • Morton RW et al. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018;52(6):376-384. doi:10.1136/bjsports-2017-097608 DOI

Sleep & Appetite Hormones

  • Spiegel K et al. Brief communication: Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846-850. doi:10.7326/0003-4819-141-11-200412070-00008 DOI

Evolutionary Perspective

  • Speakman JR. Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints. Annu Rev Nutr. 2013;33:289-317. doi:10.1146/annurev-nutr-071811-150711 DOI
  • Wells JCK. The thrifty phenotype hypothesis: thrifty offspring or thrifty mother? J Theor Biol. 2003;221(1):143-161. doi:10.1006/jtbi.2003.3183 DOI
No. 07
Part 2 of 2

Weight Loss — Part 2

Why weight regain is the rule rather than the exception, what the long-term data actually shows, and what that means for how to approach it.

References 13

Energy Balance & Weight Regulation

  • Hall KD et al. Energy balance and its components: implications for body weight regulation. Am J Clin Nutr. 2012;95(4):989–994. doi:10.3945/ajcn.112.036350 DOI
  • Hall KD et al. Quantification of the effect of energy imbalance on bodyweight. Lancet. 2011;378(9793):826–837. doi:10.1016/S0140-6736(11)60812-X DOI
  • Hall KD et al. The energy balance model of obesity: beyond calories in, calories out. Am J Clin Nutr. 2022;115(5):1243–1254. doi:10.1093/ajcn/nqac031 DOI

Adaptive Thermogenesis

  • Rosenbaum M et al. Adaptive thermogenesis in humans. Int J Obes (Lond). 2010;34 Suppl 1:S47–55. doi:10.1038/ijo.2010.184 DOI
  • Fothergill E et al. Persistent metabolic adaptation 6 years after "The Biggest Loser" competition. Obesity (Silver Spring). 2016;24(8):1612–1619. doi:10.1002/oby.21538 DOI

Hormonal Changes With Weight Loss

  • Sumithran P et al. Long-term persistence of hormonal adaptations to weight loss. N Engl J Med. 2011;365(17):1597–1604. doi:10.1056/NEJMoa1105816 DOI

Lipolysis & Insulin Physiology

  • Frayn KN. Adipose tissue as a buffer for daily lipid flux. Diabetologia. 2002;45(9):1201–1210. doi:10.1007/s00125-002-0873-y DOI

Protein & Resistance Training

  • Phillips SM et al. Dietary protein for athletes: from requirements to optimum adaptation. J Sports Sci. 2011;29 Suppl 1:S29–38. doi:10.1080/02640414.2011.619204 DOI
  • Morton RW et al. A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults. Br J Sports Med. 2018;52(6):376–384. doi:10.1136/bjsports-2017-097608 DOI

Sleep & Appetite Hormones

  • Spiegel K et al. Sleep curtailment in healthy young men is associated with decreased leptin levels, elevated ghrelin levels, and increased hunger and appetite. Ann Intern Med. 2004;141(11):846–850. doi:10.7326/0003-4819-141-11-200412070-00008 DOI
  • Liu S et al. Sleep deprivation and central appetite regulation. Nutrients. 2022;14(24):5196. doi:10.3390/nu14245196 DOI

Evolutionary Perspective

  • Speakman JR. Evolutionary perspectives on the obesity epidemic: adaptive, maladaptive, and neutral viewpoints. Annu Rev Nutr. 2013;33:289–317. doi:10.1146/annurev-nutr-071811-150711 DOI

Glucagon-Like Peptide-1 (GLP-1) Receptor Agonists

  • Collins L et al. Glucagon-like peptide-1 receptor agonists. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2026 Jan–. Updated 2024 Feb 29. PMID: 31855395. PubMed
No. 08
Part 1 of 2

GLP-1 Medications — Part 1

How GLP-1 receptor agonists actually work, what they do beyond appetite, and what the trial evidence shows — separated from the noise surrounding them.

References 12

Semaglutide — weight management (STEP 1 Trial)

  • Wilding JPH, et al. Once-weekly semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2021;384(11):989–1002. doi:10.1056/NEJMoa2032183. DOI

Semaglutide — cardiovascular outcomes (SELECT Trial)

  • Lincoff AM, et al. Semaglutide and cardiovascular outcomes in obesity without diabetes. New England Journal of Medicine. 2023;389(24):2221–2232. doi:10.1056/NEJMoa2307563. DOI

Semaglutide — renal outcomes (FLOW)

  • Perkovic V, et al. Effects of semaglutide on chronic kidney disease in patients with type 2 diabetes. New England Journal of Medicine. 2024;391(2):109–121. doi:10.1056/NEJMoa2403347. DOI

Semaglutide — MASH / liver

  • Sanyal AJ, et al. Phase 3 trial of semaglutide in metabolic dysfunction–associated steatohepatitis. New England Journal of Medicine. 2025;392(21):2089–2099. doi:10.1056/NEJMoa2413258. DOI

Tirzepatide — weight management (SURMOUNT-1)

  • Jastreboff AM, et al. Tirzepatide once weekly for the treatment of obesity. New England Journal of Medicine. 2022;387(3):205–216. doi:10.1056/NEJMoa2206038. DOI

Thyroid

  • Mayo Clinic Endocrinology. GLP-1RA and thyroid cancer: new study suggests detection bias, not causation. Mayo Clinic Medical Professionals. August 21, 2025. https://www.mayoclinic.org/medical-professionals/endocrinology/news/glp-1ra-and-thyroid-cancer-new-study-suggests-detection-bias-not-causation/mac-20587812 Source
  • Brito JP, et al. GLP-1RA use and thyroid cancer risk. JAMA Otolaryngology–Head & Neck Surgery. 2025;151(3):243–252. doi:10.1001/jamaoto.2024.4852. DOI

Body composition / lean mass (25–40% range)

  • Neeland IJ, et al.Neeland IJ, et al. Changes in lean body mass with glucagon-like peptide-1-based therapies and mitigation strategies. Diabetes, Obesity and Metabolism. 2024;26(Suppl 4):16–27. doi:10.1111/dom.15728. DOI
  • Soundararajan S, et al. Greater lean-body-mass decline with tirzepatide than semaglutide in routine care, revealed by body-composition digital phenotyping. medRxiv [preprint]. 2026. doi:10.64898/2026.04.11.26350687. DOI

Orforglipron

  • Wharton S, et al. Orforglipron, an oral small-molecule GLP-1 receptor agonist for obesity treatment. New England Journal of Medicine. 2025;393(18):1796–1806. doi:10.1056/NEJMoa2511774. DOI

Retatrutide (Phase 2 Trials)

  • Jastreboff AM, et al. Triple–hormone-receptor agonist retatrutide for obesity — a phase 2 trial. New England Journal of Medicine. 2023;389(6):514–526. doi:10.1056/NEJMoa2301972. DOI

CagriSema (REDEFINE Trial)

  • Garvey WT, et al. Coadministered cagrilintide and semaglutide in adults with overweight or obesity. New England Journal of Medicine. 2025;393(7):635–647. doi:10.1056/NEJMoa2502081. DOI
No. 09
Part 2 of 2

GLP-1 Medications — Part 2

The side effects, why they happen mechanistically, and what actually helps — the practical follow-up to Part 1.

References 10
  • Drucker DJ. Mechanisms of Action and Therapeutic Application of Glucagon-like Peptide-1. Cell Metab. 2018;27(4):740–756. https://doi.org/10.1016/j.cmet.2018.03.001 DOI
  • Holst JJ. The physiology of glucagon-like peptide 1. Physiol Rev. 2007;87(4):1409–1439. https://doi.org/10.1152/physrev.00034.2006 DOI
  • Wilding JPH et al. Once-Weekly Semaglutide in Adults with Overweight or Obesity (STEP 1). N Engl J Med. 2021;384(11):989–1002. https://doi.org/10.1056/NEJMoa2032183 DOI
  • Jastreboff AM et al. Tirzepatide Once Weekly for the Treatment of Obesity (SURMOUNT-1). N Engl J Med. 2022;387(3):205–216. https://doi.org/10.1056/NEJMoa2206038 DOI
  • Bellavance D et al. Gastrointestinal Motility Effects of GLP-1 Receptor Agonists. Curr Gastroenterol Rep. 2025;27(1):49. https://doi.org/10.1007/s11894-025-00995-3 DOI
  • Chiang CH et al. Glucagon-Like Peptide-1 Receptor Agonists and Gastrointestinal Adverse Events: A Systematic Review and Meta-Analysis. Gastroenterology. 2025;169(6):1268–1281. https://doi.org/10.1053/j.gastro.2025.06.003 DOI
  • He L et al. Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases: A Systematic Review and Meta-analysis of Randomized Clinical Trials. JAMA Intern Med. 2022;182(5):513–519. https://doi.org/10.1001/jamainternmed.2022.0338 DOI
  • Takrori E et al. Gastrointestinal Adverse Effects of Anti-Obesity Medications in Non-Diabetic Adults: A Systematic Review. Medicina (Kaunas). 2025;61(11):1987. https://doi.org/10.3390/medicina61111987 DOI
  • Camilleri M, Jencks KJ. Pharmacologic treatments for gastroparesis. Pharmacol Rev. 2024;77(2):100019. https://doi.org/10.1016/j.pharmr.2024.100019 DOI
  • Chang MG et al. A Scoping Review of GLP-1 Receptor Agonists: Are They Associated with Increased Gastric Contents, Regurgitation, and Aspiration Events? J Clin Med. 2024;13(21):6336. https://doi.org/10.3390/jcm13216336 DOI
No. 10

Gout

Uric acid, the kidneys, and the metabolic connection that the rich food and red wine explanation misses entirely.

References 7

Insulin & Renal Urate Handling

  • Facchini F, et al. Relationship between resistance to insulin-mediated glucose uptake, urinary uric acid clearance, and plasma uric acid concentration. JAMA. 1991;266(21):3008-3011. PubMed

Fructose & Uric Acid Mechanism of Action

  • Johnson RJ, et al.Johnson RJ, et al. The fructose survival hypothesis for obesity. Philos Trans R Soc Lond B Biol Sci. 2023;378(1885):20220230. PubMed
  • Johnson RJ, et al. The effect of fructose on renal biology and disease. J Am Soc Nephrol. 2010;21(12):2036-2039. PubMed

Uricase Loss / Evolutionary Hypothesis

  • Kratzer JT, et al. Evolutionary history and metabolic insights of ancient mammalian uricases. PNAS. 2014;111(10):3763-3768. PubMed

Gout & Metabolic Syndrome Prevalence

  • Choi HK, et al.Choi HK, et al. Prevalence of the metabolic syndrome in patients with gout: the Third National Health and Nutrition Examination Survey. Arthritis Rheum. 2007;57(1):109-115. PubMed

Sugar-Sweetened Beverages & Gout Risk

  • Choi HK, et al. Soft drinks, fructose consumption, and the risk of gout in men: prospective cohort study. BMJ. 2008;336(7639):309-312. PubMed

Dietary Purines vs Metabolic Drivers Effects on Uric Acid Levels

  • Major TJ, et al. Evaluation of the diet wide contribution to serum urate levels: meta-analysis of population based cohorts. BMJ. 2018;363:k3951. PubMed
No. 11

PCOS

Why polycystic ovary syndrome makes far more sense as a metabolic condition than a purely reproductive one, and where insulin fits into the picture.

References 12

Diagnosis, prevalence, and management framework

  • Tay CT et al. 2023 International Evidence-Based Polycystic Ovary Syndrome Guideline Update: Insights From a Systematic Review and Meta-Analysis on Elevated Clinical Cardiovascular Disease in Polycystic Ovary Syndrome. Journal of the American Heart Association, 2024, 13(16):e033572. DOI: 10.1161/JAHA.123.033572 DOI
  • Teede HJ et al. Recommendations from the 2023 International Evidence-based Guideline for the Assessment and Management of Polycystic Ovary Syndrome. Fertility and Sterility, 2023, 120(4):767–793. DOI: 10.1016/j.fertnstert.2023.07.025 DOI

Insulin resistance, androgens, and SHBG mechanism

  • Diamanti-Kandarakis E et al. Insulin resistance and the polycystic ovary syndrome revisited: an update on mechanisms and implications. Endocrine Reviews, 2012, 33(6):981–1030. DOI: 10.1210/er.2011-1034 DOI

Metabolic consequences (T2DM, dyslipidemia, NAFLD)

  • Arvanitakis K et al. Metabolic Dysfunction-Associated Steatotic Liver Disease and Polycystic Ovary Syndrome: A Complex Interplay. Journal of Clinical Medicine, 2024, 13(14):4243. DOI: 10.3390/jcm13144243 DOI
  • Wang ET et al. Polycystic Ovary Syndrome and Risk for Long-Term Diabetes and Dyslipidemia. Obstetrics & Gynecology, 2011, 117(1):6–13. DOI: 10.1097/AOG.0b013e31820209bb DOI
  • Liu Q et al. Dyslipidemia involvement in the development of polycystic ovary syndrome. Taiwanese Journal of Obstetrics and Gynecology, 2019, 58(4):447–453. DOI: 10.1016/j.tjog.2019.05.003 DOI

Management evidence

  • Jarrett BY et al. Impact of hypocaloric dietary intervention on ovulation in obese women with PCOS. Reproduction, 2017, 153(1):R15–R27. DOI: 10.1530/REP-16-0385 DOI
  • Mahoney A et al. Treatment Options for Managing Anovulation in Women with PCOS: An Extensive Literature Review of Evidence-Based Recommendations for Future Directions. Life (Basel), 2025, 15(6):863. DOI: 10.3390/life15060863 DOI
  • Szczesnowicz A et al. Do GLP-1 Analogs Have a Place in the Treatment of PCOS? New Insights and Promising Therapies. Journal of Clinical Medicine, 2023, 12(18):5915. DOI: 10.3390/jcm12185915 DOI

Evolutionary hypotheses / Thrifty metabolism

  • Fessler DMT et al. Evolutionary determinants of polycystic ovary syndrome: part 2. Fertility and Sterility, 2016, 106(1):42–47. DOI: 10.1016/j.fertnstert.2016.05.013 DOI
  • Holte J. Polycystic ovary syndrome and insulin resistance: thrifty genes struggling with over-feeding and sedentary life style? Journal of Endocrinological Investigation, 1998, 21(9):589–601. DOI: 10.1007/BF03350784 DOI
  • Dumesic DA et al. An Evolutionary Model for the Ancient Origins of Polycystic Ovary Syndrome. Journal of Clinical Medicine, 2023, 12(19):6120. DOI: 10.3390/jcm12196120 DOI
No. 12

Metabolic Syndrome

The capstone. How blood pressure, blood sugar, triglycerides and waist circumference stop looking like separate problems once you see the process underneath them.

References 12
  • Alberti KGMM et al. Harmonizing the metabolic syndrome: a joint interim statement of the International Diabetes Federation Task Force on Epidemiology and Prevention; National Heart, Lung, and Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation, 2009;120(16):1640–1645. doi:10.1161/CIRCULATIONAHA.109.192644 DOI
  • Saklayen MG. The global epidemic of the metabolic syndrome. Curr Hypertens Rep, 2018;20(2):12. doi:10.1007/s11906-018-0812-z DOI
  • Reaven GM. Banting lecture 1988. Role of insulin resistance in human disease. Diabetes, 1988;37(12):1595–1607. doi:10.2337/diab.37.12.1595 DOI
  • Tchernof A et al. Pathophysiology of human visceral obesity: an update. Physiol Rev, 2013;93(1):359–404. doi:10.1152/physrev.00033.2011 DOI
  • Rashid S et al. The mechanism of HDL lowering in hypertriglyceridemic, insulin-resistant states. J Diabetes Complications, 2002;16(1):24–28. doi:10.1016/s1056-8727(01)00191-x DOI
  • Hall JE et al. Obesity-induced hypertension: interaction of neurohumoral and renal mechanisms. Circ Res, 2015;116(6):991–1006. doi:10.1161/CIRCRESAHA.116.305697 DOI
  • Mottillo S et al. The metabolic syndrome and cardiovascular risk: a systematic review and meta-analysis. J Am Coll Cardiol, 2010;56(14):1113–1132. doi:10.1016/j.jacc.2010.05.034 DOI
  • Ford ES et al. Metabolic syndrome and incident diabetes: current state of the evidence. Diabetes Care, 2008;31(9):1898–1904. doi:10.2337/dc08-0423 DOI
  • Magkos F et al. Effects of moderate and subsequent progressive weight loss on metabolic function and adipose tissue biology in humans with obesity. Cell Metab, 2016;23(4):591–601. doi:10.1016/j.cmet.2016.02.005 DOI
  • Buxton OM et al. Sleep restriction for 1 week reduces insulin sensitivity in healthy men. Diabetes, 2010;59(9):2126–2133. doi:10.2337/db09-0699 DOI
  • Neel JV. Diabetes mellitus: a "thrifty" genotype rendered detrimental by "progress"? Am J Hum Genet, 1962;14(4):353–362. PubMed
  • Peters A et al. The selfish brain: competition for energy resources. Neurosci Biobehav Rev, 2004;28(2):143–180. doi:10.1016/j.neubiorev.2004.03.002 DOI
Section twoNo. 13 onward

Cardiovascular Health

Where the metabolic story leads next. Cholesterol and the lipid panel first, then blood pressure, then how arterial disease actually develops.

No. 13
Part 1 of 3

Cholesterol — Part 1

Total cholesterol is probably the least useful number on your lab report, and the one that predicts risk best usually is not printed on it at all. What LDL and HDL actually are, why the particle count matters more than the cargo, and what changed in the 2026 guidelines.

References 15

LDL Causality & Lipoprotein Biology

  • Ference BA, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. Eur Heart J. 2017;38(32):2459-2472. PMID 28444290 PubMed
  • Carson JAS, et al. Dietary Cholesterol and Cardiovascular Risk: AHA Science Advisory. Circulation. 2020;141(3):e39-e53. PMID 31838890 PubMed
  • Luo J, Yang H, Song BL. Mechanisms and regulation of cholesterol homeostasis. Nat Rev Mol Cell Biol. 2020;21(4):225-245. PMID 31848472. doi:10.1038/s41580-019-0190-7 DOI

ApoB & Particle Number

  • Glavinovic T, et al. Physiological Bases for the Superiority of Apolipoprotein B. J Am Heart Assoc. 2022;11(20):e025858. PMID 36216435 PubMed
  • De Oliveira-Gomes D, et al. Apolipoprotein B: Bridging the Gap Between Evidence and Clinical Practice. Circulation. 2024;150(1):62-79. PMID 38950110 PubMed
  • Johannesen CDL, et al. Discordance analyses comparing LDL cholesterol, non-HDL cholesterol, and apolipoprotein B. Atherosclerosis. 2025;403:119139. PMID 40073776 PubMed

Cholesterol Conservation & Evolutionary Background

  • Jenkins DJA, et al. The Garden of Eden — plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century. Comp Biochem Physiol A Mol Integr Physiol. 2003;136(1):141-151. PMID 14527636. doi:10.1016/S1095-6433(02)00345-8 DOI
  • Eaton SB. Humans, lipids and evolution. Lipids. 1992;27(10):814-820. PMID 1435101. doi:10.1007/BF02535856 DOI
  • Eaton SB. The ancestral human diet: what was it and should it be a paradigm for contemporary nutrition? Proc Nutr Soc. 2006;65(1):1-6. PMID 16441938. doi:10.1079/PNS2005471 DOI
  • Yu XH, Tang CK. ABCA1, ABCG1, and cholesterol homeostasis. Adv Exp Med Biol. 2022;1377:95-107. PMID 35575923. doi:10.1007/978-981-19-1592-5_7 DOI
  • Kunst RF, et al. Targeting the four pillars of enterohepatic bile salt cycling; lessons from genetics and pharmacology. Hepatology. 2021;73(6):2577-2585. PMID 33222321. doi:10.1002/hep.31651 DOI
  • Pellicoro A, Faber KN. Proteins involved in bile salt biosynthesis and transport. Aliment Pharmacol Ther. 2007. doi:10.1111/j.1365-2036.2007.03522.x DOI

HDL-Raising Outcome Trials

  • Niacin: AIM-HIGH (2011), HPS2-THRIVE (2014)
  • CETP inhibitors: ILLUMINATE (2007), dal-OUTCOMES (2012), ACCELERATE (2017), REVEAL (2017)

Guidelines

  • Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA Guideline on the Management of Dyslipidemia. J Am Coll Cardiol. 2026;87(19):2624-2757. doi:10.1016/j.jacc.2025.11.016 DOI
No. 14
Part 2 of 3

Cholesterol — Part 2

In a 2003 trial, a diet lowered LDL by almost 30 percent — about the same as the statin group in the same study. So why is anyone still taking the drug? What actually lowers LDL and by how much, what barely moves it, the Portfolio diet and why its real-world results are half its trial results, and how far realistic lifestyle change gets you compared with a statin.

References 17

Portfolio Diet

  • Jenkins DJA, Kendall CWC, Marchie A, et al. Effects of a dietary portfolio of cholesterol-lowering foods vs lovastatin on serum lipids and C-reactive protein. JAMA. 2003;290(4):502-510. PMID 12876093. doi:10.1001/jama.290.4.502 DOI
  • Jenkins DJA, Jones PJH, Lamarche B, et al. Effect of a dietary portfolio of cholesterol-lowering foods given at 2 levels of intensity of dietary advice on serum lipids in hyperlipidemia: a randomized controlled trial. JAMA. 2011;306(8):831-839. PMID 21862744. doi:10.1001/jama.2011.1202 DOI
  • Chiavaroli L, Nishi SK, Khan TA, et al. Portfolio Dietary Pattern and Cardiovascular Disease: A Systematic Review and Meta-analysis of Controlled Trials. Prog Cardiovasc Dis. 2018;61(1):43-53. PMID 29807048. doi:10.1016/j.pcad.2018.05.004 DOI

Individual Dietary Components

  • Mozaffarian D, Micha R, Wallace S. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. 2010;7(3):e1000252. PMID 20351774. doi:10.1371/journal.pmed.1000252 DOI
  • Vafeiadou K, Weech M, Altowaijri H, et al. Replacement of saturated with unsaturated fats had no impact on vascular function but beneficial effects on lipid biomarkers, E-selectin, and blood pressure: results from the randomized, controlled Dietary Intervention and VAScular function (DIVAS) study. Am J Clin Nutr. 2015;102(1):40-48. PMID 26016869. doi:10.3945/ajcn.114.097089 DOI
  • Jovanovski E, Yashpal S, Komishon A, et al. Effect of psyllium (Plantago ovata) fiber on LDL cholesterol and alternative lipid targets, non-HDL cholesterol and apolipoprotein B: a systematic review and meta-analysis of randomized controlled trials. Am J Clin Nutr. 2018;108(5):922-932. PMID 30239559. doi:10.1093/ajcn/nqy115 DOI
  • Ras RT, Geleijnse JM, Trautwein EA. LDL-cholesterol-lowering effect of plant sterols and stanols across different dose ranges: a meta-analysis of randomised controlled studies. Br J Nutr. 2014;112(2):214-219. PMID 24780090. doi:10.1017/S0007114514000750 DOI
  • Del Gobbo LC, Falk MC, Feldman R, Lewis K, Mozaffarian D. Effects of tree nuts on blood lipids, apolipoproteins, and blood pressure: systematic review, meta-analysis, and dose-response of 61 controlled intervention trials. Am J Clin Nutr. 2015;102(6):1347-1356. PMID 26561616. doi:10.3945/ajcn.115.110965 DOI
  • Blanco Mejia S, Messina M, Li SS, et al. A Meta-Analysis of 46 Studies Identified by the FDA Demonstrates that Soy Protein Decreases Circulating LDL and Total Cholesterol Concentrations in Adults. J Nutr. 2019;149(6):968-981. PMID 31006811. doi:10.1093/jn/nxz020 DOI

Exercise, Weight Loss and Dietary Cholesterol

  • Kelley GA, Kelley KS, Roberts S, Haskell W. Comparison of aerobic exercise, diet or both on lipids and lipoproteins in adults: a meta-analysis of randomized controlled trials. Clin Nutr. 2012;31(2):156-167. PMID 22154987. doi:10.1016/j.clnu.2011.11.011 DOI
  • Dattilo AM, Kris-Etherton PM. Effects of weight reduction on blood lipids and lipoproteins: a meta-analysis. Am J Clin Nutr. 1992;56(2):320-328. PMID 1386186. doi:10.1093/ajcn/56.2.320 DOI
  • Carson JAS, Lichtenstein AH, Anderson CAM, et al. Dietary Cholesterol and Cardiovascular Risk: A Science Advisory From the American Heart Association. Circulation. 2020;141(3):e39-e53. PMID 31838890. doi:10.1161/CIR.0000000000000743 DOI

Evolutionary Background

  • Jenkins DJA, Kendall CWC, Marchie A, et al. The Garden of Eden — plant based diets, the genetic drive to conserve cholesterol and its implications for heart disease in the 21st century. Comp Biochem Physiol A Mol Integr Physiol. 2003;136(1):141-151. PMID 14527636. doi:10.1016/s1095-6433(02)00345-8 DOI
  • O'Keefe JH Jr, Cordain L, Harris CH, Moe RM, Vogel R. Optimal low-density lipoprotein is 50 to 70 mg/dl: lower is better and physiologically normal. J Am Coll Cardiol. 2004;43(11):2142-2146. PMID 15172426. doi:10.1016/j.jacc.2004.03.046 DOI

Guidelines — Treatment Thresholds and Targets

  • Blumenthal RS, Morris PB, Gaudino M, et al. 2026 ACC/AHA Guideline on the Management of Dyslipidemia. J Am Coll Cardiol. 2026;87(19):2624-2757. doi:10.1016/j.jacc.2025.11.016 DOI
  • Pearson GJ, Thanassoulis G, Anderson TJ, et al. 2021 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in Adults. Can J Cardiol. 2021;37(8):1129-1150. PMID 33781847. doi:10.1016/j.cjca.2021.03.016 DOI
  • Anderson TJ, Grégoire J, Pearson GJ, et al. 2016 Canadian Cardiovascular Society Guidelines for the Management of Dyslipidemia for the Prevention of Cardiovascular Disease in the Adult. Can J Cardiol. 2016;32(11):1263-1282. PMID 27712954. doi:10.1016/j.cjca.2016.07.510 DOI
Coming nextOn the schedule

Cardiovascular health

Part 3 of the cholesterol series looks at statins and what the blinded trials say about their side effects. After that: blood pressure, then how arterial disease actually develops. Subscribe on YouTube or by email to know when each one lands.

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