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.
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. 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
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
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
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. 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. 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
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
?? ??
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. Chow HFD
Inflammation and Insulin Resistance
Inflammation
Insulin
resistance
Elevated
insulin
Han et al. Science 339:218. 2012
32. Chow HFD
Inflammation and Insulin Resistance
Han et al. Science 339:218. 2012
mutant
Inflammation
Insulin
resistance
Elevated
insulin
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. 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. 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. Preserving Lean-type Insulin Signaling
Should Prevent Fat Gain
Obesity
Elevated
insulin
Obesity
Elevated
insulinX
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
51. 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
52. • 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)
53. • 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”
54. 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
Editor's Notes
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