Body Weight and Insulin Sensitivity

• Negative Correlation • Insulin resistance

may have evolved to prevent excessive weight gain

BMI by County Type II Diabetes by County

Abbasi et al, J. Am. Col. Card. 2002 CDC, 2012

Chang et alDiabetes Care, 1994

How Does Insulin Resistance Lead to Type II Diabetes

Food

CirculatingNutrients (Glucose)

InsulinSecretion

Glucose Production

Glucose Disposal

Nutrient Storage

Insulin Resistance

Not All Obese People Get Insulin Resistance or Type II Diabetes

• About a third of obese people are not insulin resistant or hyperlipidemic. They are known as Metabolically Healthy Obese people

• What mechanism underlies this is unclear

Weight Fluctuations in Bears

The Question at Hand

• Bears seem to be able to cycle between fat accumulation and release on regular intervals

• What are the effects on insulin sensitivity that are associated with these massive fluctuations in weights?

“Patient” Characteristics

May

OctoberJanuary

Insulin and Glucose Levels are Unchanged in “Obese” Bears

Normally with elevated fat mass you would expect a big increase in insulin resistance

These are therefore a model of massive weight gain without increased diabetes

May

OctoberJanuary

Changes in Insulin Sensitivity

More obese in October, but far more insulin sensitive.

May

OctoberJanuary

Key Questions

1. Why are lean(-ish) mid-hibernating bears insulin resistant

2. Why are obese pre-hibernating bears insulin sensitive

Are These Changes Due to Inflammation?

May

OctoberJanuary

Relationship Between Lipolysis and Insulin Sensitivity

AdiposeTriglycerides

Serum FFA

Lipolysis InsulinResistance

MitochondrialStress

Insulin

Basic Monoamines

Rate Limiting Steps in Lipolysis are HSL and CGI-58 Phosphorylation

Increased Lipolysis in Hibernating Bears

May

OctoberJanuary

WHY ARE OBESE, PRE-HIBERNATING BEARS INSULIN SENSITIVE?

Functionally

• Need to store a lot of weight without side effects of hyperglycemia

• Some signal must occur to mediate this transition

• But what is the mechanism underlying this?• What tissue is the originator of this effect?

PI3K Dependent Insulin Signaling

PTEN Phosphorylation

PTEN

PhosphorylationOn Serine 308

InsulinSensitizationDue to ElevatedPIP3/Akt Signaling

Measuring Protein Phosphorylation

Measured both total protein and phosphorylated protein, the ratio is presented here

PI3K Signaling Enhanced Adipose Gastroc

Liver

May

OctoberJanuary

Insulin Responsiveness in WAT

May

OctoberJanuary

HibernatingBear WAT ModestEffects of Insulin

Non-hibernatingBear WAT DramaticEffects of Insulin

Cause or Effect?

Insulin Promotes Weight Gain

• You need insulin to promote lipid accumulation into fat tissue.

• Possibly PTEN mediated insulin sensitization of fat tissue is causing the weight gain but does not cause sensitization of other tissues.

• Where is the knockout grizzly????

Adipose PTEN as a Regulator of Insulin Sensitivity

Confounders and Questions?

• Big changes in energy usage rate in hibernating bears?

• Is it PTEN or PTEN phosphorylation that’s changing. What is the signal?

• What stimulates the lipid breakdown in the hibernating bears?

Conclusion