ahs13 stephan guyenet insulin and obesity: reconciling conflicting evidence
DESCRIPTION
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.TRANSCRIPT
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
Man digging potatoes, undated
22 25 28 31 340
40
80
120
160
200
Body Mass Index
Fasti
ng in
sulin
(pm
ol/L
)Obesity is Associated with Elevated Insulin
Folsom et al. Diabetes Care 20:935. 1997
lean overweight obese
Two Hypotheses
Obesity Elevated insulin
ObesityElevated
insulin
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
Insulin biology
Insulin is an Energy Traffic Cop
INSULINCarbohydrate
Protein
Burn Less FatBurn More Carb/Protein
Blood Glucose and FFA Changes Following a Meal
Time (hrs)
Conc
entr
ation
Based on Frayn. Metabolic Regulation. 2010
GLU
FFA
INS
Meal 1 2 3 4
Adipocyte Insulin Biology
TAGLPL
VLDL
chylo
GLUT4
DNL
G-3-P
esterification
Based on Frayn. Metabolic Regulation. 2010
HSL
Adipocyte Insulin Biology
TAGLPL
VLDL
chylo
GLUT4
DNL
G-3-P
esterificationHSL
INSULIN
INSULIN
INSULIN
INSULIN
INSULIN
INSULIN
INSULIN
Based on Frayn. Metabolic Regulation. 2010
Lean Cultures With High-Carbohydrate Diets: Past and Present
CHO
FAT
PRO
CHO
FAT
PRO
Insulin and Fuel Selection
#1
Kcal
s Ex
pend
ed
Time
meal (carb/pro)
meal (fat)
#2
Kcal
s Ex
pend
ed
Δ FAT
Insulin Makes You Burn What You Eat
500 kcal of fat in100 kcal of CHO in-500 kcal of fat out
100 kcal of CHO out
= 0 change in bodyfat content
100 kcal of fat in500 kcal of CHO in
100 kcal of fat out500 kcal of CHO out
= 0 change in bodyfat content-
Insulin
Basic predictions
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 3 6 9 120
10
20
30
40
50
60
70
0
20
40
60
80
100
Time (months)
Fat M
ass
(kg)
Fasti
ng in
sulin
(pm
ol/L
)
insulin
fat massPolyzogopoulou 2003:
Bariatric surgeryMajor fat loss
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
Study Follow-up (yrs) AssociationSwinburn 3.5 NoneValdez 8 Partial inverseHoag 4.3 InverseSchwartz >3 InverseHodge 5 NoneBoyko 5 InverseSigal 16.7 PositiveLazarus 3-3.7 Pos and negZavaroni 14 PositiveFolsom 7 NoneFolsom 6 InverseGould 4.4 Partial inverseLakka 4 NoneMasuo 5 NoneSandhu 4.5 NoneOdeleye 9.3 PositiveSrinivasan 3 NoneByrnes 1 NoneJohnson 3-6 PositiveSalbe 5 InverseMaffeis 14 Partial inverseSavoye 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
Insulin Action
insulin
CarbohydrateLipid ProteinMetabolism
insulin
insulin
insulin
insulin
insulin
insu
lin
insulin
insulin
Insulin Action
insulin
CarbohydrateLipid ProteinMetabolism
insulin
insulin
insulin
insulin
insulin
insu
lin
insulin
insulin
Is Insulin Action Actually Increased in Obesity?
Ins SI Action
Low
Nor
mal
Hig
h
Lean healthy
Ins SI Action
Low
Nor
mal
Hig
h
Uncontrolled type 1 Diabetes
Ins SI Action
Low
Nor
mal
Hig
h
Insulin lipohypertrophy
Ins SI Action
Low
Nor
mal
Hig
h
Obesity
?? ??
Glucose Metabolism in Obesity
22 25 28 31 340
40
80
120
160
0
40
80
120
160
BMI
Fasti
ng in
sulin
(pm
ol/L
)
Fasti
ng g
luco
se (m
g/dL
)
insulin
glucose?
Folsom et al. Diabetes Care 20:935. 1997
Glucose Metabolism in Obesity
22 25 28 31 340
40
80
120
160
0
40
80
120
160
BMI
Fasti
ng in
sulin
(pm
ol/L
)
Fasti
ng g
luco
se (m
g/dL
)
insulin
glucose
Folsom et al. Diabetes Care 20:935. 1997
Insulin SI Action
Low
Nor
mal
Hig
h
?? ??
Glucose Metabolism in Obesity
Insulin action on glucose metabolism is normal or reduced in obesity
Fat Metabolism in Obesity
10 15 20 25 30 350
100
200
300
400
500
Fat mass (kg)
Fasti
ng F
FA (u
mol
/L)
Karpe et al. Diabetes 60:2441. 2011
insulin
FFA?
Fat Metabolism in Obesity
10 15 20 25 30 350
100
200
300
400
500
Fat mass (kg)
Fasti
ng F
FA (u
mol
/L)
Karpe et al. Diabetes 60:2441. 2011
insulin
FFA
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 fluxis normal or reduced in obesity
Insulin SI Action
Low
Nor
mal
Hig
h
?? ??
Insulin Action on Glucose and Fatty Acid Trafficking is Normal or Reduced in Obesity
Obesity Elevated insulin
ObesityElevated
insulinX
Advanced predictions
Preserving Lean-type Insulin Signaling Should Prevent Obesity
Ins SI Action
Low
Nor
mal
Hig
h
Lean healthy
Ins SI Action
Low
Nor
mal
Hig
h
Obese
Ins SI Action
Low
Nor
mal
Hig
h
???
Obesity -> insulin: mice should become obese
Insulin -> obesity: mice should remain lean
Chow HFD
Inflammation and Insulin Resistance
Inflammation Insulinresistance
Elevatedinsulin
Han et al. Science 339:218. 2012
Chow HFD
Inflammation and Insulin Resistance
Han et al. Science 339:218. 2012
mutant
Inflammation Insulinresistance
Elevatedinsulin
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
Body
wei
ght (
g)
Chow
HFD
Fat m
ass
(g)
Chow HFD
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)
Preserving Lean-type Insulin Signaling Should Prevent Fat Gain
BMI = 45.2
Kloting et al. Am J Physiol Endo Metab. 299:E506. 2010
Insulin sensitiveLow fasting insulin
Insulin resistantHigh fasting insulin
Preserving Lean-type Insulin Signaling Should Prevent Fat Gain
Obesity Elevated insulin
ObesityElevated
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
Low
Nor
mal
Hig
h
Lean, healthyInsulin sensitive
Overweight
Overeating
Poor diet
Inactivity
Smoking
A Unifying Model
Insulin SI Action
Low
Nor
mal
Hig
hOverweight
Overeating
Poor diet
Inactivity
Smoking
Somewhat insulin resistant
A Unifying Model
Insulin SI Action
Low
Nor
mal
Hig
h
Somewhat insulin resistant
Overweight
Overeating
Poor diet
Inactivity
Smoking
A Unifying Model
Insulin SI Action
Low
Nor
mal
Hig
h
Very insulin resistant
Obesity
Overeating
Poor diet
Inactivity
Smoking
A Unifying Model
Insulin SI Action
Low
Nor
mal
Hig
h
Very insulin resistant
Obesity
Overeating
Poor diet
Inactivity
Smoking
Type 2 Diabetes: Failure of Compensation
<23 23.0-23.9
24.0-24.9
25.0-26.9
27.0-28.9
29.0-30.9
31.0-32.9
33.0-34.9
>350
10
20
30
40
50
BMI
Rela
tive r
isk o
f dia
bete
s
Chan et al. Diabetes Care 17:961. 1994
Two Hypotheses
Obesity Elevated insulin
ObesityElevated
insulin
Two Hypotheses
Obesity Elevated insulin
ObesityElevated
insulin
Inactivity
Poor diet
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
Thanks
Researchers who made this talk possible
Keith Frayn
Whole Health Sourcewww.wholehealthsource.org
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
• 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)
• 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”
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