Natural History of Type 2 Diabetes Obesity IFG

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Natural History of Type 2 Diabetes Obesity IFG* Diabetes Uncontrolled Hyperglycemia 350 Glucose (mg/d.

Natural History of Type 2 Diabetes Obesity IFG* Diabetes Uncontrolled Hyperglycemia 350 Glucose (mg/d. L) 300 Post-meal Glucose 250 200 Fasting Glucose 150 100 50 Relative Function (%) 250 Insulin Resistance 200 150 100 50 Insulin Level -cell Failure -10 *IFG = impaired fasting glucose -5 0 5 10 15 20 Years of Diabetes Adapted from International Diabetes Center (IDC), Minneapolis, Minnesota. 25 30

Natural History of T 2 DM Mean Plasma Insulin During OGTT (µU/ml) Mean Plasma

Natural History of T 2 DM Mean Plasma Insulin During OGTT (µU/ml) Mean Plasma Glucose During OGTT (mg/dl) 300 140 250 100 200 60 150 20 400 100 300 200 100 De. Fronzo & Felber Diabetes 37: 667 -687, 1988 Metabolism 39: 1068 -75, 1990 LEAN OB NGT OB- OBIGT DIAB Hi INS Lo INS Insulin. Mediated Glucose Uptake (mg/m 2 • min)

Abnormal Insulin Secretion in T 2 DM • • • Early responses during meals/OGTT

Abnormal Insulin Secretion in T 2 DM • • • Early responses during meals/OGTT First and second phase insulin responses Pulsatile insulin release Responses to non-glucose stimuli Proinsulin: insulin ratios

NATURAL HISTORY OF BETA CELL FAILURE IN T 2 DM Beta cell failure occurs

NATURAL HISTORY OF BETA CELL FAILURE IN T 2 DM Beta cell failure occurs much earlier in the natural history of type 2 diabetes and is more severe than previously appreciated

Belfast Diet Study-Bi-phasic Loss of B-Cell FUNCTION 2% /yr decline 18%/yr decline DX DM

Belfast Diet Study-Bi-phasic Loss of B-Cell FUNCTION 2% /yr decline 18%/yr decline DX DM Deteriorating beta-cell function in type 2 diabetes: a long-term model. Bagust A, Beale S. QJM. 2003 Apr; 96(4): 281 -8

A model of long-term metabolic progression of type 2 diabetes mellitus for evaluating treatment

A model of long-term metabolic progression of type 2 diabetes mellitus for evaluating treatment strategies. Bagust A, Evans M, Beale S, Home PD, Perry AS, Stewart M. Pharmacoeconomics. 2006; 24 Suppl 1: 5 -19.

Potential Causes of Beta Cell Dysfunction • • Unknown Genetic Factors Intrauterine Nutrition Glucose

Potential Causes of Beta Cell Dysfunction • • Unknown Genetic Factors Intrauterine Nutrition Glucose Toxicity Lipotoxicity Amyloid Cytokines Insulin Resistance

Glucose AUC (mmol/L 120 min) 0 12 8 8 4 4 IGT 0 CON

Glucose AUC (mmol/L 120 min) 0 12 8 8 4 4 IGT 0 CON <160 <180 <200 Q 1 Q 2 Q 3 Q 4 T 2 DM Insulin AUC (pmol/L 120 min) CON <160 <180 <200 Q 1 Q 2 Q 3 Q 4 PLASMA GLUCOSE AND INSULIN AUC 12 IGT T 2 DM

INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT 30 Lean 20 10 Obese

INSULIN SECRETION / INSULIN RESISTANCE (DISPOSITION) INDEX DURING OGTT 30 Lean 20 10 Obese 0 <1 00 <1 2 <1 0 4 <1 0 60 <1 80 <2 00 <2 40 <2 80 <3 20 <3 60 <4 00 >4 00 ∆ INS/ ∆ GLU ÷ IR 40 NGT IGT T 2 DM 2 -Hour PG (mg/dl)

Log Normalization of the Relationship Between 2 -Hour Plasma Glucose and Insulin Secretion /

Log Normalization of the Relationship Between 2 -Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index Ln ∆I/ ∆G ÷ IR (ml/min • kg. FFM) 6 NGT IGT T 2 DM 4 2 0 -2 -4 4. 0 r = 0. 91 p < 0. 00001 4. 5 5. 0 5. 5 Ln 2 h-PG (mg/dl) 6. 0 6. 5

Log Normalization of the Relationship Between 2 -Hour Plasma Glucose and Insulin Secretion /

Log Normalization of the Relationship Between 2 -Hour Plasma Glucose and Insulin Secretion / Insulin Resistance Index Ln ∆I/ ∆G ÷ IR (ml/min • kg. FFM) 6 NGT IGT T 2 DM 4 2 0 -2 -4 4. 0 r = 0. 91 p < 0. 00001 4. 5 5. 0 5. 5 Ln 2 h-PG (mg/dl) 6. 0 6. 5

FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH

FASTING PLASMA GLUCOSE (FPG) CONCENTRATION AND RELATIVE BETA CELL VOLUME IN OBESE SUBJECTS WITH NGT, IFG, & T 2 DM 250 FPG (mg/dl) p<0. 001 200 p<0. 01 150 100 ß-cell Volume (%) 50 NGT IFG T 2 DM 4 3 p<0. 01 2 p<0. 001 1 0 NGT Butler et al, Diabetes 52: 102 -110, 2003 IFG T 2 DM

SUMMARY Individuals with IGT: ● Are maximally/near-maximally insulin resistant ● Have lost ~80% of

SUMMARY Individuals with IGT: ● Are maximally/near-maximally insulin resistant ● Have lost ~80% of their beta cell function (De. Fronzo) ● Have lost significant beta cell mass (Butler) ● Have an incidence of diabetic retinopathy of ~10%