The document discusses beta cell dysfunction and failure in type 2 diabetes. It begins by presenting hypothetical relationships that determine glucose tolerance categories. It then discusses how beta cell adaptation and failure leads to the progression from normal glucose tolerance to impaired glucose tolerance to type 2 diabetes. The document also examines the progressive loss of beta cell function over time as type 2 diabetes develops and worsens.
2. -Cell Adaptation and Failure: Opportunities for Prevention and Treatment of Type 2 Diabetes
3.
4. Hypothetical Relationships Determine Categories of Glucose Tolerance Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. Type 2 Diabetes Insulin sensitivity index (x10 -5 min -1 /pmol/L) AIRglucose (pmol/L) IGT Normal 0 500 1,000 1,500 95th 75th 50th 25th 5th 0 2 4 6 8 10
5. Hypothetical Outcomes of Interventions to Treat Type 2 Diabetes Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. Type 2 Diabetes IGT Insulin sensitivity index (x10 -5 min -1 /pmol/L) Increased Insulin Secretion Normal Increased Insulin Sensitivity 0 500 1,000 1,500 95th 75th 50th 25th 5th 0 2 4 6 8 10 AIRglucose (pmol/L)
6. Hypothetical Outcomes of Interventions to Prevent Type 2 Diabetes Adapted from Kahn SE et al. Diabetes . 1993;42:1663-1672. 0 0 2 4 6 8 10 Type 2 Diabetes 95th 75th 50th 25th 5th 500 1,000 1,500 IGT Insulin sensitivity index (x10 -5 min -1 /pmol/L) Increased Insulin Sensitivity Increased Insulin Secretion Normal AIRglucose (pmol/L)
7.
8.
9. Decreased -Cell Function in Groups With Diabetes and at High Risk Insulin sensitivity index ( S i ; x10 -5 min -1 /pmol/L) Vidal J, Kahn SE. In: Lowe WL Jr, ed. Genetics of Diabetes Mellitus . 2001:109-131. 0 1 2 3 4 5 6 7 0 100 200 300 400 500 600 700 50th 25th 75th 5th Relatives of Patients With Type 2 Diabetes PCOS Women Former GDMs IGT Type 2 Diabetes Older Subjects AIRglucose (pmol/L)
12. Declining -Cell Function: Best Correlation of Progression Acute insulin response ( U/mL) Weyer C et al. J Clin Invest . 1999;104:787-794. EMBS=estimated metabolic body size 500 400 300 200 100 0 0 1 2 3 4 5 Measure of insulin resistance (mg/kg EMBS/min) Nonprogressors Progressors DIA IGT NGT NGT NGT NGT
13. Loss of -Cell Function in People Who Develop Type 2 Diabetes: Longitudinal Data Insulin Action Insulin Secretion M-low (mg/kg EMBS/min) 0 1 2 3 4 NGT IGT Diabetes * AIR ( U/mL) * 0 50 100 150 200 250 300 NGT Diabetes † IGT * P <0.05; † P <0.01 Adapted from Weyer C et al. J Clin Invest . 1999;104:787-794. EMBS=estimated metabolic body size
14. Changing Glucose: Different Rates at Different Clinical Stages Ferrannini E et al. Diabetes. 2004;53:160-165. Fasting plasma glucose (mmol/L) Baseline 3.25 years 7 years 10 NGT NGT NGT NGT D D NGT NGT D IGT D D IGT IGT D 9 8 7 6 5 4 3
15.
16.
17. UKPDS: Progressive Deterioration in -Cell Function Over Time Holman RR. Diabetes Res Clin Pract . 1998;40(suppl):S21-S25. -Cell function (%) Years from diagnosis 100 80 60 40 20 0 -12 -10 -8 -6 -4 -2 0 2 4 6
18. Insulin and Glucose Patterns: Normal and Type 2 Diabetes Polonsky KS et al. N Engl J Med. 1988;318:1231-1239. 100 200 300 400 0600 1000 1800 1400 0200 2200 0600 Time of day 0600 1000 1800 1400 0200 2200 0600 Time of day 20 40 60 80 100 120 B L S B L S Normal Type 2 diabetes Glucose (mg/dL) Insulin ( U/mL) (meals) (meals)
23. Decreases in Insulin Response r=-0.58; P =0.07 Røder ME et al. J Clin Endocrinol Metab . 1998;83:604-608. AIR max (pmol/L) Fasting glucose (mmol/L) 0 4 8 12 16 20 0 200 400 600 800 1,000 Type 2 diabetes=9 Healthy subjects=10
24. Disproportionate Increase in Proinsulin in Patients With Type 2 Diabetes Ward WK et al. Diabetologia . 1987;30:698-702. Basal (%) PI IRI Controls (n=28) Type 2 diabetes (n=22) P <0.001 0 10 20 30 40 50 60 70
25.
26. -Cell Mass in Normal Patients and Patients With Diabetes: Autopsy Study -Cell volume (%) Normal Impaired Diabetes Normal Diabetes Obese Lean 0 1 2 3 4 - 41% - 40% -63% * * † * P <0.05; † P <0.01 Butler AE et al. Diabetes. 2003;52:102-110.
27. Altered -Cell Mass and Function in Islets From Subjects With Type 2 Diabetes 0 1,000 2,000 3,000 4,000 5,000 6,000 7,000 8,000 9,000 Control (n=14) Type 2 diabetes (n=14) Islet mass (IEq/g pancreas) GSIR=glucose-stimulated insulin release Deng S et al. Diabetes. 2004;53:624-632. 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0 Control (n=14) Type 2 diabetes (n=14) GSIR (ng/min/100 islets) -Cell Mass -Cell Function * P <0.001; † P <0.05 * †
28.
29.
30.
31. Amyloid Deposits in Pancreatic Islets in Type 2 Diabetes Verchere CB et al. Proc Natl Acad Sci USA . 1996;93:3492-3496. Amyloid deposits in pancreatic islets of human with type 2 diabetes 50 m
Editor's Notes
Pancreatic -Cells and Insulin Secretion in Type 2 Diabetes This section focuses on the pathophysiology of -cells in type 2 diabetes.