Insulin and Obesity:
Reconciling Conflicting
Evidence
Stephan J. Guyenet, Ph.D.
Ancestral Health Symposium 2013
The contents of this presentation do not represent the views
of the University of Washington or Dr. Michael W. Schwartz
Ma...
0
40
80
120
160
200
22 25 28 31 34
Fastinginsulin(pmol/L)
Body Mass Index
Obesity is Associated with Elevated Insulin
Fols...
Two Hypotheses
Obesity
Elevated
insulin
Obesity
Elevated
insulin
How to Test a Hypothesis
A hypothesis is a model of reality
Good hypotheses make testable predictions
Testing a hypothesis...
Insulin biology
Insulin is an Energy Traffic Cop
INSULIN
Carbohydrate
Protein
Burn Less Fat
Burn More Carb/Protein
Blood Glucose and FFA Changes
Following a Meal
Time (hrs)
Concentration
Based on Frayn. Metabolic Regulation. 2010
GLU
FFA...
Adipocyte Insulin Biology
TAG
LPL
VLDL
chylo
GLUT4
DNL
G-3-P
esterification
Based on Frayn. Metabolic Regulation. 2010
HSL
Adipocyte Insulin Biology
TAG
LPL
VLDL
chylo
GLUT4
DNL
G-3-P
esterification
HSL
INSULIN
INSULIN
INSULIN
INSULIN
INSULIN
IN...
Lean Cultures With High-Carbohydrate Diets:
Past and Present
CHO
FAT
PRO
CHO
FAT
PRO
Insulin and Fuel Selection
#1
KcalsExpended
Time
meal (carb/pro)
meal (fat)
#2
KcalsExpended
Δ FAT
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 cha...
Basic predictions
Changing Adiposity Should Change Insulin
1. Does fat gain increase fasting insulin?
Sims 1968: 3-5 months of intense overf...
Changing Insulin Levels Should
Change Adiposity
- insulin + insulin “insulin lipohypertrophy”
NEJM Image Challenge. 2012.
...
Study Follow-up (yrs) Association
Swinburn 3.5 None
Valdez 8 Partial inverse
Hoag 4.3 Inverse
Schwartz >3 Inverse
Hodge 5 ...
Insulin Action
insulin
Carbohydrate
Lipid
Protein
Metabolism
insulin
insulin
insulin
insulin
insulin
Insulin Action
insulin
Carbohydrate
Lipid
Protein
Metabolism
insulin
insulin
insulin
insulin
insulin
Is Insulin Action Actually Increased in Obesity?
Ins SI Action
LowNormalHigh
Lean healthy
Ins SI Action
LowNormalHigh
Unco...
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)
...
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)
...
Insulin SI Action
LowNormalHigh
?? ??
Glucose Metabolism in Obesity
Insulin action on glucose metabolism
is normal or redu...
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 6...
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 6...
Fat Metabolism in Obesity
Mittendorfer et al. Obesity 17:1872. 2009
Higher fat mass =
Higher FFA release
Fat Metabolism in Obesity
Insulin action on adipocyte fatty acid flux
is normal or reduced in obesity
Insulin SI Action
Lo...
Insulin Action on Glucose and Fatty Acid
Trafficking is Normal or Reduced in Obesity
Obesity
Elevated
insulin
Obesity
Elev...
Advanced predictions
Preserving Lean-type Insulin Signaling Should
Prevent Obesity
Ins SI Action
LowNormalHigh
Lean healthy
Ins SI Action
LowNo...
Chow HFD
Inflammation and Insulin Resistance
Inflammation
Insulin
resistance
Elevated
insulin
Han et al. Science 339:218. ...
Chow HFD
Inflammation and Insulin Resistance
Han et al. Science 339:218. 2012
mutant
Inflammation
Insulin
resistance
Eleva...
Preserving Lean-type Insulin Signaling
Should Prevent Fat Gain
Weight and fat gain are normal despite the preservation of
...
Preserving Lean-type Insulin Signaling
Should Prevent Fat Gain
Similar findings have been reported in:
TNFα KO mice (Uysal...
Preserving Lean-type Insulin Signaling
Should Prevent Fat Gain
BMI = 45.2
Kloting et al. Am J Physiol Endo Metab. 299:E506...
Preserving Lean-type Insulin Signaling
Should Prevent Fat Gain
Obesity
Elevated
insulin
Obesity
Elevated
insulinX
Perspective
How do We Reconcile ‘Conflicting’ Evidence?
By adopting a model that is able to
explain all observations
A Unifying Model
Insulin action is what matters
- insulin + insulin
=
NEJM Image Challenge. 2012.
A Unifying Model
Insulin SI Action
LowNormalHigh
Lean, healthy
Insulin sensitive
Overweight
Overeating
Poor diet
Inactivit...
A Unifying Model
Insulin SI Action
LowNormalHigh
Overweight
Overeating
Poor diet
Inactivity
Smoking
Somewhat insulin resis...
A Unifying Model
Insulin SI Action
LowNormalHigh
Somewhat insulin resistant
Overweight
Overeating
Poor diet
Inactivity
Smo...
A Unifying Model
Insulin SI Action
LowNormalHigh
Very insulin resistant
Obesity
Overeating
Poor diet
Inactivity
Smoking
A Unifying Model
Insulin SI Action
LowNormalHigh
Very insulin resistant
Obesity
Overeating
Poor diet
Inactivity
Smoking
Type 2 Diabetes: Failure of Compensation
0
10
20
30
40
50
Relativeriskofdiabetes
BMI
Chan et al. Diabetes Care 17:961. 1994
Two Hypotheses
Obesity
Elevated
insulin
Obesity
Elevated
insulin
Two Hypotheses
Obesity
Elevated
insulin
Obesity
Elevated
insulin
Inactivity
Poor diet
Implications
Preventing obesity reduces the risk of
metabolic disturbances that
contribute to many modern disorders
Diabet...
Thanks
Researchers who made this talk possible
Keith Frayn
Whole Health Source
www.wholehealthsource.org
Implications
In obesity, elevated insulin secretion is attempting to
compensate for reduced insulin sensitivity
Compensati...
• Show graph of relationship between insulin
sensitivity and fasting insulin
• Make point that they increase in parallel
•...
• Fasting insulin and insulin resistance are closely
related (Olefsky 1973 in Endo folder) with graph
• 2 of 3 conclusions...
Outline
• Obesity and insulin association
• Cause or effect of obesity? Two hypotheses
• Each hypothesis makes testable pr...
AHS13 Stephan Guyenet Insulin and Obesity: Reconciling Conflicting Evidence
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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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  • The two most widely recognized hypotheses to explain this association are that… These two are not mutually exclusive
  • What is a hypothesis? It says “this is how I think XYZworks”. So that’s what we’re going to try to do here today.
  • Insulin plays many roles in the body, but its central role is as an energy traffic cop.
  • And if we look in the blood after a mixed meal, glucose and insulin increase after a mixed meal, and free fatty acids decline. FFAs are the body’s main circulating fat fuel. Why do FFAs go down in response to insulin? To understand that, we need to examine the biology of the fat cell, or adipocyte.
  • There’s no denying that insulin causes the adipocyte to shut down whole-body fatty acid delivery.
  • In sum, insulin INCREASES the activity of the pathways that put fat into fat cells, and DECREASES the activity of pathways that take it out. If obesity is about fat going into and out of fat cells, this seems like something we should care about. You can see this process in action following a meal containing carbohydrate or protein, the two macronutrients that stimulate insulin release the most.
  • Kitavans, Bantu, Kuna, Okinawan, mainland Japanese, Chinese, Indian, Maori, New Guinea highlander, Maya, Pima, 1920s potato farmers in Minnesota
  • Insulin is the main factor that coordinates between these two scenarios in response to carbohydrate and protein availability. However, if you eat excess calories of any of the macronutrients, it spares fat burning beyond your metabolic rate and net fat storage is positive. This occurs whether you are overeating carbohydrate or fat.
  • Sims 1968. Prisoners overfed for 3-5 months, gained 26% of body weight. Bariatric surgery was Roux en Y plus biliopancreatic diversion
  • Mention FIRKO, INS+/-. T1DM man after 31 years of insulin injection into the same spot. OK, so we’ve shown that insulin can influence fat mass in the context of disease and pharmacology, but what about in the context of obesity?
  • Well that’s strange. Maybe it’s time to go back to the drawing board and examine our assumptions.
  • Hyperinsulinemia should not be dissociable from obesity
  • It’s well established that inflammation is a key mechanism in the development of insulin resistance, and that insulin resistance leads to elevated insulin. When animals are genetically unable to activate inflammatory pathways, they often don’t develop insulin resistance with age or on fattening diets. In one recent example of this, researchers made a mouse that lacks the critical inflammatory proteins Jun kinase 1 and 2 specifically in key immune cells called macrophages. These mice are unable to mount a normal inflammatory response. When fed a fattening diet, a normal mouse develops insulin resistance and elevated insulin. When these mice are fed a fattening diet, they develop neither.
  • It’s well established that inflammation is a key mechanism in the development of insulin resistance, and that insulin resistance leads to elevated insulin. When animals are genetically unable to activate inflammatory pathways, they often don’t develop insulin resistance with age or on fattening diets. In one recent example of this, researchers made a mouse that lacks the critical inflammatory proteins Jun kinase 1 and 2 specifically in key immune cells called macrophages. These mice are unable to mount a normal inflammatory response. When fed a fattening diet, a normal mouse develops insulin resistance and elevated insulin. When these mice are fed a fattening diet, they develop neither.
  • In fact, we see that insulin levels and fat gain are readily uncoupled.
  • Either preventing or attenuating the development of the insulin resistance-hyperinsulinemia complex has little or no effect on body fat gain.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • If we manipulate insulin action in extreme ways, we can get big effects on body fatness.. But that’s not what happens in common obesity.
  • 42-fold increased risk. All types of diabetes. 5-year follow-up.
  • The two most widely recognized hypotheses to explain this association are that… These two are not mutually exclusive
  • The two most widely recognized hypotheses to explain this association are that… These two are not mutually exclusive
  • 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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