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AHS13 Stephan Guyenet Insulin and Obesity: Reconciling Conflicting Evidence

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The pancreatic hormone insulin regulates the trafficking and metabolism of carbohydrate and fat. Since insulin influences fatty acid flux in fat tissue, and manipulating insulin can influence body fatness, this has raised the possibility that insulin plays a role in common obesity. Two competing hypotheses propose that 1) elevated insulin is a compensatory response to insulin resistance that develops with fat gain, or 2) elevated insulin outpaces insulin resistance and favors fat gain. Each hypothesis appears to be supported by a large amount of evidence. This presentation will outline a framework capable of reconciling this seemingly conflicting evidence.

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AHS13 Stephan Guyenet Insulin and Obesity: Reconciling Conflicting Evidence

  1. 1. Insulin and Obesity: Reconciling Conflicting Evidence Stephan J. Guyenet, Ph.D. Ancestral Health Symposium 2013
  2. 2. The contents of this presentation do not represent the views of the University of Washington or Dr. Michael W. Schwartz Man digging potatoes, undated
  3. 3. 0 40 80 120 160 200 22 25 28 31 34 Fastinginsulin(pmol/L) Body Mass Index Obesity is Associated with Elevated Insulin Folsom et al. Diabetes Care 20:935. 1997 lean overweight obese
  4. 4. Two Hypotheses Obesity Elevated insulin Obesity Elevated insulin
  5. 5. How to Test a Hypothesis A hypothesis is a model of reality Good hypotheses make testable predictions Testing a hypothesis means doing experiments to see how well it predicts outcomes In many cases, hypotheses can be tested using existing data
  6. 6. Insulin biology
  7. 7. Insulin is an Energy Traffic Cop INSULIN Carbohydrate Protein Burn Less Fat Burn More Carb/Protein
  8. 8. Blood Glucose and FFA Changes Following a Meal Time (hrs) Concentration Based on Frayn. Metabolic Regulation. 2010 GLU FFA INS Meal 1 2 3 4
  9. 9. Adipocyte Insulin Biology TAG LPL VLDL chylo GLUT4 DNL G-3-P esterification Based on Frayn. Metabolic Regulation. 2010 HSL
  10. 10. Adipocyte Insulin Biology TAG LPL VLDL chylo GLUT4 DNL G-3-P esterification HSL INSULIN INSULIN INSULIN INSULIN INSULIN INSULIN INSULIN Based on Frayn. Metabolic Regulation. 2010
  11. 11. Lean Cultures With High-Carbohydrate Diets: Past and Present
  12. 12. CHO FAT PRO CHO FAT PRO Insulin and Fuel Selection #1 KcalsExpended Time meal (carb/pro) meal (fat) #2 KcalsExpended Δ FAT
  13. 13. Insulin Makes You Burn What You Eat 500 kcal of fat in 100 kcal of CHO in -500 kcal of fat out 100 kcal of CHO out = 0 change in body fat content 100 kcal of fat in 500 kcal of CHO in 100 kcal of fat out 500 kcal of CHO out = 0 change in body fat content- Insulin
  14. 14. Basic predictions
  15. 15. Changing Adiposity Should Change Insulin 1. Does fat gain increase fasting insulin? Sims 1968: 3-5 months of intense overfeeding; 26% weight gain. “As in spontaneous obesity [fasting] serum insulin as well as the ratio of insulin to glucose is increased in experimental obesity.” Erdmann 2007: 4.5 months of moderate overfeeding; 13.6 lbs of weight gain. Fasting insulin +118% 2. Does fat loss decrease fasting insulin? YES YES 0 20 40 60 80 100 0 10 20 30 40 50 60 70 0 3 6 9 12 Fastinginsulin(pmol/L) FatMass(kg) Time (months) insulin fat massPolyzogopoulou 2003: Bariatric surgery Major fat loss
  16. 16. Changing Insulin Levels Should Change Adiposity - insulin + insulin “insulin lipohypertrophy” NEJM Image Challenge. 2012. Mehran et al. Cell Metab 16:723. 2012 Bluher et al. Dev Cell 3:25. 2002
  17. 17. Study Follow-up (yrs) Association Swinburn 3.5 None Valdez 8 Partial inverse Hoag 4.3 Inverse Schwartz >3 Inverse Hodge 5 None Boyko 5 Inverse Sigal 16.7 Positive Lazarus 3-3.7 Pos and neg Zavaroni 14 Positive Folsom 7 None Folsom 6 Inverse Gould 4.4 Partial inverse Lakka 4 None Masuo 5 None Sandhu 4.5 None Odeleye 9.3 Positive Srinivasan 3 None Byrnes 1 None Johnson 3-6 Positive Salbe 5 Inverse Maffeis 14 Partial inverse Savoye 2.5 Partial positive Elevated Insulin Should Predict Future Fat Gain Hivert et al. Int J Obesity 31:731. 2007. Higher insulin predicts more fat gain: Higher insulin predicts less fat gain: No association: 5 8 9
  18. 18. Insulin Action insulin Carbohydrate Lipid Protein Metabolism insulin insulin insulin insulin insulin
  19. 19. Insulin Action insulin Carbohydrate Lipid Protein Metabolism insulin insulin insulin insulin insulin
  20. 20. Is Insulin Action Actually Increased in Obesity? Ins SI Action LowNormalHigh Lean healthy Ins SI Action LowNormalHigh Uncontrolled type 1 Diabetes Ins SI Action LowNormalHigh Insulin lipohypertrophy Ins SI Action LowNormalHigh Obesity ?? ??
  21. 21. Glucose Metabolism in Obesity 0 40 80 120 160 0 40 80 120 160 22 25 28 31 34 Fastingglucose(mg/dL) Fastinginsulin(pmol/L) BMI insulin glucose? Folsom et al. Diabetes Care 20:935. 1997
  22. 22. Glucose Metabolism in Obesity 0 40 80 120 160 0 40 80 120 160 22 25 28 31 34 Fastingglucose(mg/dL) Fastinginsulin(pmol/L) BMI insulin glucose Folsom et al. Diabetes Care 20:935. 1997
  23. 23. Insulin SI Action LowNormalHigh ?? ?? Glucose Metabolism in Obesity Insulin action on glucose metabolism is normal or reduced in obesity
  24. 24. Fat Metabolism in Obesity 0 100 200 300 400 500 10 15 20 25 30 35 FastingFFA(umol/L) Fat mass (kg) Karpe et al. Diabetes 60:2441. 2011 insulin FFA?
  25. 25. Fat Metabolism in Obesity 0 100 200 300 400 500 10 15 20 25 30 35 FastingFFA(umol/L) Fat mass (kg) Karpe et al. Diabetes 60:2441. 2011 insulin FFA
  26. 26. Fat Metabolism in Obesity Mittendorfer et al. Obesity 17:1872. 2009 Higher fat mass = Higher FFA release
  27. 27. Fat Metabolism in Obesity Insulin action on adipocyte fatty acid flux is normal or reduced in obesity Insulin SI Action LowNormalHigh ?? ??
  28. 28. Insulin Action on Glucose and Fatty Acid Trafficking is Normal or Reduced in Obesity Obesity Elevated insulin Obesity Elevated insulinX
  29. 29. Advanced predictions
  30. 30. Preserving Lean-type Insulin Signaling Should Prevent Obesity Ins SI Action LowNormalHigh Lean healthy Ins SI Action LowNormalHigh Obese Ins SI Action LowNormalHigh ??? Obesity -> insulin: mice should become obese Insulin -> obesity: mice should remain lean
  31. 31. Chow HFD Inflammation and Insulin Resistance Inflammation Insulin resistance Elevated insulin Han et al. Science 339:218. 2012
  32. 32. Chow HFD Inflammation and Insulin Resistance Han et al. Science 339:218. 2012 mutant Inflammation Insulin resistance Elevated insulin
  33. 33. Preserving Lean-type Insulin Signaling Should Prevent Fat Gain Weight and fat gain are normal despite the preservation of lean-type insulin signaling Elevated insulin and obesity are readily uncoupled Han et al. Science 339:218. 2012 Bodyweight(g) Chow HFD Fatmass(g) Chow HFD
  34. 34. Preserving Lean-type Insulin Signaling Should Prevent Fat Gain Similar findings have been reported in: TNFα KO mice (Uysal 1997) Clonidine-treated dogs (Rocchini 1999) Myeloid IR KO mice (Mauer 2010) NLRP3 KO mice (Vandanmagsar 2011) aP2 KO mice (Hotamisligil 1996) Hepatic PTP1B KO mice (Delibegovic 2008) Muscle PTP1B KO mice (Delibegovic 2007) Adipose JNK1 KO mice (Sabio 2008)
  35. 35. Preserving Lean-type Insulin Signaling Should Prevent Fat Gain BMI = 45.2 Kloting et al. Am J Physiol Endo Metab. 299:E506. 2010 Insulin sensitive Low fasting insulin Insulin resistant High fasting insulin
  36. 36. Preserving Lean-type Insulin Signaling Should Prevent Fat Gain Obesity Elevated insulin Obesity Elevated insulinX
  37. 37. Perspective
  38. 38. How do We Reconcile ‘Conflicting’ Evidence? By adopting a model that is able to explain all observations
  39. 39. A Unifying Model Insulin action is what matters - insulin + insulin = NEJM Image Challenge. 2012.
  40. 40. A Unifying Model Insulin SI Action LowNormalHigh Lean, healthy Insulin sensitive Overweight Overeating Poor diet Inactivity Smoking
  41. 41. A Unifying Model Insulin SI Action LowNormalHigh Overweight Overeating Poor diet Inactivity Smoking Somewhat insulin resistant
  42. 42. A Unifying Model Insulin SI Action LowNormalHigh Somewhat insulin resistant Overweight Overeating Poor diet Inactivity Smoking
  43. 43. A Unifying Model Insulin SI Action LowNormalHigh Very insulin resistant Obesity Overeating Poor diet Inactivity Smoking
  44. 44. A Unifying Model Insulin SI Action LowNormalHigh Very insulin resistant Obesity Overeating Poor diet Inactivity Smoking
  45. 45. Type 2 Diabetes: Failure of Compensation 0 10 20 30 40 50 Relativeriskofdiabetes BMI Chan et al. Diabetes Care 17:961. 1994
  46. 46. Two Hypotheses Obesity Elevated insulin Obesity Elevated insulin
  47. 47. Two Hypotheses Obesity Elevated insulin Obesity Elevated insulin Inactivity Poor diet
  48. 48. Implications Preventing obesity reduces the risk of metabolic disturbances that contribute to many modern disorders Diabetes Cardiovascular disease Dementia Cancer Suppressing insulin secretion in the obese using drugs is unlikely to be beneficial because it may further impair metabolic control
  49. 49. Thanks Researchers who made this talk possible Keith Frayn Whole Health Source www.wholehealthsource.org
  50. 50. Implications In obesity, elevated insulin secretion is attempting to compensate for reduced insulin sensitivity Compensation is often incomplete, resulting in insufficient insulin action In susceptible people, compensation can eventually fail, leading to diabetes
  51. 51. • Show graph of relationship between insulin sensitivity and fasting insulin • Make point that they increase in parallel • Does that also occur in fat tissue? • Graph of FFA vs. fat mass from Frayn paper • Graph of FFA Ra vs fat mass • Excel file of graphs and refs in talk folder • RQ is inversely associated with fasting insulin (Ravussin paper in Endo folder)
  52. 52. • Fasting insulin and insulin resistance are closely related (Olefsky 1973 in Endo folder) with graph • 2 of 3 conclusions of the paper: • “Increases in fasting insulin levels and increase in resistance to insulin mediated glucose uptake are closely related” • “The increases in fasting insulin levels which we have observed appear to be compensatory attempts to overcome the resistance to glucose uptake”
  53. 53. Outline • Obesity and insulin association • Cause or effect of obesity? Two hypotheses • Each hypothesis makes testable predictions, many have already been tested. Use this as framework. • Insulin biology – Fasting and postprandial • Data supporting fattening effect – Diabetes and insulin therapy (T1DM photos in Frayn book) – Man with lipoma belly – FIRKO and Ins +/- – But what we really want to know is insulin’s effect in common obesity • Data supporting hypothesis that insulin resistance causes hyperinsulinemia – Defects in a number of points in the insulin signaling pathway causes hyperinsulinemia. – Blocking insulin resistance blocks hyperinsulinemia. • Testing the hypothesis in common obesity – Prospective data – 20+% of obese have normal insulin level – Glucose and fatty acid data for obese – Animal models w suppressed insulin resistance (ap2, TNF, iNOS, myeloid JNK (2012 Science paper Han et al), myeloid insulin receptor, CCR2 KO, clonidine dogs, MCP-1 KO, MHCII, liver-specific PTP1B KO) – Animal models of hyperinsulinemia (glucose vs. fructose, LIKK mouse, LIRKO mouse, hepatic JNK overexpression, three studies where insulin caused weight loss in rodents, also discuss those that caused wt gain and hypoglycemia) – This supports standing hypothesis • Many of the complications of obesity are due to a combination of insulin deficiency and excess (hyperglycemia, diabetes risk, hyperlipidemia, hypertension) • Conclusions

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