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Insulin Resistance and Type 2 Diabetes

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Slide 1 :

Insulin Resistance and Type 2 Diabetes Eric Ravussin, Ph.D., RavussE@pbrc.edu Pennington Biomedical Research Center Baton Rouge, Louisiana HUEC 7004 - Molecular and Clinical Nutrition October 1, 2007; 3.10 – 5.00 pm Type 2 diabetes mellitus: facing an epidemic Risk factors for type 2 diabetes mellitus (Pima Indians) Relationship between obesity and insulin resistance Ectopic fat storage syndrome Fat cells: a new endocrine paradigm

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What is Diabetes Mellitus? Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels resulting from defects in insulin secretion, insulin action or both. The chronic high blood glucose levels are associated with long-term tissue damage, dysfunction and failure of various organs especially the eyes, kidneys, nerves, heart and blood vessels.

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Diabetes Mellitus Over the years, better phenotyping (e.g. introduction of assay for insulin, glucose clamp) and recently, genetic studies have shown that diabetes is a phenotypically and genetically heterogeneous disorder.

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Genetics of Diabetes Mellitus Monogenic forms (MODY) Inherit diabetes per se. Mutation in a single gene is sufficient to cause diabetes. Polygenic forms (Type 1 and Type 2 diabetes) Inherit susceptibility to diabetes. Diabetes develops in genetically susceptible individuals but only in the presence of nongenetic risk factors.

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Diabetes Mellitus in 2006 Type 2 Type 2 Type 1 Type 1 MODY 1 (HNF4a) MIDD (Mitochonchrial DNA) Insulinopathies (Preproinsulin) Syndromes of extreme insulin (Insulin resistance receptor) Other Other MODY 2 (Glucokinase) MODY 3 (HNF1a) MODY 4 (IPF1) MODY 5 (HNF1b) FPLD (Lamin A/C) CGL (g3-like protein, AGPAT2) MODY 6 (Beta2/NeuroD)

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Dr David Satcher, The Surgeon General of the United States, December 2001* "..overweight and obesity may soon cause as much preventable disease and death as cigarette smoking." Overweight and Obesity Threatens U.S. Health Gains' Press release from US Dept of Health and Human Services, 13 December 2001

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Medical Complications of Obesity Coronary heart disease Pulmonary disease: Abnormal PFTs Obstructive sleep apnea Hypoventilation syndrome Gall bladder disease Gynecological abnormalities: Abnormal menses Infertility PCOS Gout Stroke Diabetes Osteoarthritis Cancer: Breast, uterus, cervix Colon, esophagus, pancreas Kidney Prostate Liver disease: Steatosis NASH Cirrhosis Hypertension Dyslipidemia Phlebitis Cataracts Skin Borrowed from S. Klein

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Time, September 4, 2000 Newsweek, September 4, 2000

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Marx. Science, Vol 296;26 April 2002 The “Darkening Scene” of Diabetes Mellitus in the US 1990 2000

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Diabetes: A Global Problem and Epidemic Estimated number of people with type 2 diabetes worldwide 118 221 0 50 100 150 200 250 1997 2000 2010 Year People with diabetes (millions) Amos AF, McCarty DJ, Zimmet P. Diabetic Med 1997;14(Suppl 5):S7.

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GLOBAL PROJECTIONS FOR THE DIABETES EPIDEMIC: 1995-2010 14.2 17.5 23% 15.6 22.5 44% 26.5 32.9 24% 1.0 1.3 33% 9.4 14.1 50% World 2000 = 151 million 2010 = 221 million Increase 46% 84.5 132.3 57%

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Purposes of Longitudinal Study of Diabetes in Pima Indians Identify metabolic predictors of diabetes Determine the sequence of metabolic events during the transition from normal glucose tolerance to diabetes To asses cellular determinants of insulin resistance and obesity

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Prospective and Longitudinal Study of Diabetes in Pima Indians Metabolic Studies Yearly 1982-1998 Body composition Oral glucose tolerance Acute insulin response to IV glucose Mixed meal test Two step hyperinsulinemic, euglycemic clamp Muscle and adipose tissue biopsies

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Metabolic Abnormalities in Type 2 Diabetes Mellitus Obesity Insulin Resistance Abnormal Insulin Secretion Excess Glucose Production

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Metabolic Predictors of Type 2 Diabetes Mellitus Obesity Insulin Resistance Abnormal Insulin Secretion Excess Glucose Production

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8 Year Cumulative Incidence (%) of Type 2 Diabetes in Pima Indians 317 NGT/62 Diabetics AIR M

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Early Insulin Secretion vs Insulin Action NGT IGT DIA N=17 N=31 Adapted from Weyer et al, 1999 NGT NGT NGT

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Question What are the pathophysiologic mechanisms by which the diabetic uterine environment and early onset of parental diabetes increase susceptibility to diabetes?

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Insulin Secretion and Action in NGT Offspring Yes No *p<0.05 AIR (uU/ml) N=8 N=41 M (mg/kg-EMBS/min) Yes No Mother’s Diabetes During Pregnancy

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Parental Diabetes and Insulin Secretion Geometric means – adj. Age, sex, %fat, M Parental Age of Onset of Diabetes N=18 N=58 N=30

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Conclusions from Studies in Pima Indians Obesity is a major risk factor for diabetes Independent of obesity, insulin resistance is a risk factor for diabetes At equal insulin sensitivity, those with impaired insulin secretion are at higher risk for diabetes A hyperglycemic-hyperinsulinemic in utero environment causes impaired insulin secretion Early onset diabetes in parents is associated with impaired insulin secretion

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Preventing Type 2 Diabetes Three Levels of Opportunity

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Obesity - Diabetes: Where to break the Cycle ? Obesity Diabetes Diet + Lifestyle Genetics

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“Randle” + Visceral-portal hypothesis Ectopic fat storage syndrome Impaired adipogenesis Endocrine Paradigm The Role of Fat Deposition in the Development of Insulin Resistance

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Glucose/Fatty Acid Cycle (Randle et al 1963) glucose glucose FA TG FA CO 2 G-6-P TG LCACoA pyruvate acetylCoA pyruvate NEFA glut ACS PDH F-1,6-diP LCACoA LCACoA PDK Lipid oxidation leads to increased acetyl CoA and activation of PDH Kinase (PDK). glycogen Adapted from Cooney

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glucose glucose FA TG FA CO 2 G-6-P TG LCACoA pyruvate acetylCoA pyruvate NEFA glut ACS PDH F-1,6-diP LCACoA LCACoA PDK Lipid oxidation leads to increased acetyl CoA and activation of PDH Kinase (PDK). PDK phosphorylates and inactivates PDH. glycogen Glucose/Fatty Acid Cycle (Randle et al 1963) Adapted from Cooney

Slide 28 :

glucose glucose FA TG FA CO 2 G-6-P TG LCACoA pyruvate acetylCoA pyruvate NEFA citrate citrate OAA glut ACS PDH F-1,6-diP LCACoA LCACoA PDK glycogen Lipid oxidation leads to increased acetyl CoA and activation of PDH Kinase (PDK). PDK phosphorylates and inactivates PDH. Citrate increases in the cytosol which inhibits PFK leading to increased G-6-P and inhibition of HK and glucose uptake. Glucose/Fatty Acid Cycle (Randle et al 1963) Adapted from Cooney

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Slide 31 :

Sympathetic input Visceral fat FFA +TNF-?, IL-6, RESISTIN, ADIPONECTIN? INSULIN INSULIN From RN Bergman Visceral-Hepatic Axis “VHA”

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Flux of FFA to the liver Increased visceral adiposity Extreme insulin resistance of central adipocytes Sympathetic activation Sympathetic input Visceral fat FFA +TNF-?, IL-6. Resistin, Adiponectin From RN Bergman

Slide 33 :

“Randle” + Visceral-portal hypothesis Ectopic fat storage syndrome Impaired adipogenesis Endocrine Paradigm The Role of Fat Deposition in the Development of Insulin Resistance

Slide 34 :

Borrowed from R Unger Many “Survival” Genes (Fat Storage Genes) Have Evolved During Mankind History

Slide 35 :

Causes of Ectopic Fat Feposition Increased dietary fat intake Impaired fat oxidation (low EE, High RQ) Impaired adipogenesis

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Modern Environment and Energy Balance

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Pima Indians living in Different Environment 6% Prevalence of diabetes 55% 40% 15% % of calories from fat USA Mexico

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NONADIPOCYTES NATURAL HISTORY OF DIET-INDUCED OBESITY ADIPOCYTES SREBP-1c VLDL INSULIN R Unger & L. Orci, FASEB 2001

Slide 42 :

Nonalcoholic Fatty Liver Disease (NAFLD) (another disease of affluence) and the Risk of Type 2 DM in the US Data from the NHANES III survey (population based survey of 13 000 adults) NAFLD if liver enzymes elevated above normal and no evidence for hepatitis or other liver disease or excessive alcohol consumption Prevalence of NAFLD 23 % Likelihood of diabetes 2.4-fold increased in those with NAFLD after adjusting for BMI, age, gender and race (CI 1.76-2.73)

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0 10 20 30 40 Basal LCACoAs (nmol/g) * * * * * Fat-fed +WY14643 +Pioglit Long chain acyl CoA concentration in muscle from fat-fed rats treated with PPARalpha and PPARgamma agonists Ye et al (2001) Diabetes 50: 411-417 R = -0.74 P < 0.001 0 5 10 15 20 Muscle LCACoAs (nmol/g) 30 60 90 0 Muscle glucose uptake (Rg’) total 18:2 16:0 18:1 18:0

Slide 45 :

1H Spectroscopic Imaging 32x32 matrix 16cm x 16cm FOV Use of Spectral Magnetic Resonance for Determination of Intra-Myocellular Lipids

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Glucose Disposal Rate during a “Clamp” in Individuals with NGT, or Type 2 Diabetes vs.. Intra-Myocellular Lipids McGarry JD, Diabetes 51; 7-18; 2002

Slide 48 :

Greco et al, Diabetes 51; 144-51; 2002 Lipid Droplets in Skeletal Muscle before and after 6-month Treatment: Biliopancreatic Diversion (left), Diet

Slide 49 :

Greco et al, Diabetes 51; 144-51; 2002 Skeletal Muscle GLUT4 Expression before and 6-mo after Biliopancreatic Diversion

Slide 50 :

Simultaneous Quantitative Assessment of Intrahepatic Triglycerides (IHTG) and Intramyocellular Lipids (IMCL) IHTG correlates with IMCL in the soleus (r=0.6; p<.05) IHTG correlates inversely with whole body glucose uptake during a euglycemic hyperinsulinemic clamp (r=-0.89; p<.02) Longitudinal measures of IHTG and IMCL in subjects at risk for type 2 Diabetes will shed light on the etiology of the disease Hwang JH, Stein DT et al; Proc Intl Soc Mag Rson Med 10, 2002

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Slide 53 :

Visceral-portal hypothesis + “Randle” Ectopic fat storage syndrome Impaired adipogenesis Endocrine Paradigm The Role of Fat Deposition in the Development of Insulin Resistance

Slide 54 :

Moitra, J. et al. (1998) Life without fat: a transgenic mouse. Genes Dev. 7:1318-1324 Shimomura, I. et al. (1998) Insulin resistance and diabetes mellitus in transgenic mice expressing nuclear SREBP-1c in adipose tissue: model for congenital generalized lipodystrophy. Genes Dev. 12:3182-3194 Fatless mice are diabetic

Slide 55 :

J Clin Invest 2000 Feb;105(3):271-8

Slide 56 :

Hypothesized Sequence of Events towards Insulin Resistance and Type 2 Diabetes Fat cells become “full” a) increase triglycerides/fat metabolites in muscle and liver causing a worsening of insulin resistance b) endocrine and paracrine effects of larger fat cells Failure of fat cell proliferation and differentiation

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Slide 58 :

+ PPAR-g Triglyceride Free-fatty acid Insulin — + Liver Muscle Normal Fat Partitioning Adapted from AD Attie

Slide 59 :

Triglyceride Free-fatty acid Liver Muscle Hypertrophic Obesity insulin resistance Muscle Adapted from AD Attie

Slide 60 :

Fat Cell Size and Insulin Sensitivity Weyer C et al, Diabetologia 43, 1498-1506, 2000

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Predictive Effect of Fat Cell Size on the Development of Diabetes in Pima Indians Weyer C et al, Diabetologia 43, 1498-1506, 2000

Slide 62 :

Visceral-portal hypothesis + “Randle” Ectopic fat storage syndrome Impaired adipogenesis Endocrine Paradigm The Role of Fat Deposition in the Development of Insulin Resistance

Slide 63 :

Adipose Tissue Unknown Factors Agouti protein Retinol PAI-1 Leptin ASP Angiotensin ANG-II Adiponectin Adipsin Resistin Bone Morphogenic Protein IGF-1 IGFBP TNF-? Interleukins TGF ? FGF EGF Fatty acids Lysophospholipid Lactate Adenosine Prostaglandins Glutamine Estrogen Adipose Secretions

Slide 64 :

Saltiel, A.R. Nat Med. 2001. Model for the Secretion and Action of Adiponectin TZDs Overfeeding Decreases IMCL Decreased FFA and improved hepatic insulin sensitivity

Slide 65 :

Berg AH, et al. Nat Med. 2001. Effect of Lon-Term Caloric Restriction in C57Bl/6J and Thiazolidinedione in db/db mice on Circulating Adiponectin Concentration C57Bl/6J db/db

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0 0.25 0.5 0.75 1 1.25 1.5 Waist Fasting insulin 2 hour glucose Fasting glucose Adiponectin Adiponectin Protects Against Later Type 2 Diabetes: Nested Case-Control study (with matching of BMI) in the Pima Longitudinal Study Lindsay et al, Lancet ,in press, Krakoff ADA 116 OR Incidence Rate Ratio of Diabetes [95%CI]

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Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels resulting from more Diabetes mellitus is a metabolic disorder characterized by high blood glucose levels resulting from defects in insulin secretion, insulin action or both. ... less