Glucose Homeostasis. Liver. Glucose. Muscle, Fat. Pancreatic Islet. Glucose utilization. Glucose production, storage Insulin Glucagon

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2 Glucose Homeostasis Liver Glucose Glucose utilization Glucose production, storage Insulin Glucagon Muscle, Fat Pancreatic Islet

3 Classification of Diabetes Type 1 diabetes Type 2 diabetes Other types of diabetes Gestational diabetes mellitus (GDM)

4 IDDM, JODM Usually < 30 Common Non-Obese 0.5% Insulin NIDDM, AODM Usually > 30 Uncommon Obese (80%) 2-5% Diet, Oral Agents, Insulin

5 Classification of Diabetes Type 1 diabetes Immune-mediated Idiopathic

6 Glucose Flux in Type 1 Diabetes Liver Glucose Glucose utilization Glucose production, storage Insulin Glucagon X Pancreatic Islet Muscle, Fat

7 Incidence of Chronic Diseases in US Children (age <16 years)

8 Humoral and Cellular Autoimmunity in Type 1 Diabetes

9 Geographic Differences in Type 1 Diabetes CMAJ 175:165, 2006

10 Temporal Model of Type 1 Diabetes

11 Classification of Diabetes Type 1 diabetes Immune-mediated Idiopathic Type 2 diabetes

12 Glucose Flux in Type 2 Diabetes Liver Reduced glucose utilization Glucose Insulin resistance Increased glucose production Insulin Glucagon Pancreatic Islet Muscle, Fat Impaired insulin secretion

13 Normal Populations Have a Range of Glucose Sensitivity

14 Relationship of Insulin Secretion and Insulin Sensitivity Harrisonʼs, Principles of Internal Medicine, 2005

15 Classification of Diabetes Type 1 diabetes Type 2 diabetes Other types of diabetes Genetic defects of beta cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies acromegaly, Cushing's syndrome, glucagonoma Drug- or chemical-induced - glucocorticoids, clozapine

16 Features of Monogenic Diabetes Gene Mutation MODY 3 TCF1/HNF-1α MODY 2 Glucokinase MODY 1 HNF-4α MODY 4 Pdx-1/IPF1 MODY 5 TCF2/HNF-1β Phenotype Progressive; may require insulin; respond to SU Mild fasting hyperglycemia (stable); rarely have complications; diet Respond to SU Pancreatic agenesis Renal (cysts, dysplasia), uterine, and GU disorders Pediatric Diabetes 7:352, 2006 MODY = Maturity Onset Diabetes of Young

17 MODY and Type 2 Diabetes are Different

18 MODY and Type 1 Diabetes are Different Characteristic MODY Type 1 Diabetes Age of Onset Family history Adolescence, young adult 80-90% (dominant pattern) Childhood, adolescence, young adult < 25% Body habitus Not obese Not obese Autoimmunity Absent Antibodies + Insulin deficiency Partial (no DKA) Almost complete Pediatric Diabetes 7:352, 2006

19 MODY and Type 2 Diabetes are Different Characteristic MODY Type 2 Diabetes Inheritance Monogenic Polygenic Age of Onset Childhood, adolescence, young adult Usually age years Penetrance 80-90% Variable (10-40%) Body habitus Not obese Obese (80%) Features of Metabolic Syndrome Absent Often present NEJM 345:971, 2001

20 Fauci AS, et al. : Harrison s Principles of Internal Medicine, 17 th Edition

21 Neonatal Diabetes Occurs in first six months of life Due to gain-of-function mutations in SUR or Kir6.2 subunits of ATP-sensitive potassium channel (Kir6.2 > SUR1). Mutations prevent ATP from closing channel so glucose does not stimulate insulin secretion. Phenotypically looks like type 1 diabetes (insulin deficiency).

22 K Channel Mutations and Neonatal Diabetes Yellow shows site of mutations on the intracellular side of the Kir6.2 protein Some of these mutations are inherited; some are sporadic. NEJM 350:1838, 2006

23 Neonatal Diabetes Sometimes neonatal diabetes can be treated with a sulfonylureas. Closes the ATP-sensitive potassium channel or alters sensitivity to closure by ATP generated by glucose metabolism.

24 Neonatal Diabetes Sulfonylureas (glyburide, glipizide) Drugs used to treat type 2 diabetes Not effective in type 1 diabetes because beta cells have been destroyed Bind to SUR (sulfonylurea receptor) part of the ATP-sensitive potassium channel. Binding closes ATP-sensitive potassium channel and leads to insulin secretion.

25 from Human to Mouse

26 Differences between Human and Mouse Islets Architecture Cell composition Proliferative capacity Susceptibility to injury Expression of heat-shock proteins, antioxidant enzymes Expression of principal glucose transporter, GLUT-1 vs GLUT-2

27 Optical Sectioning of Whole Mount Islets β Cy2 α Cy3 δ Cy5 Islets attached to Mat-Tek dishes Fixed and permeabilized Labeled with antibodies to islet hormones 1 µm Optically sectioned with confocal laser scanning microscope z y x Brissova et al. J Histochem Cytochem (2005) vol. 53 (9) pp

28 Interspecies Differences in Islet Architecture Mouse 45 µm 55 µm 65 µm 75 µm 3-D 36 µm 44 µm 52 µm 60 µm 3-D 45 µm 55 µm 65 µm 75 µm 3-D Non-human primate Human Brissova et al., J Histochem Cytochem (2005) vol. 53 (9) pp

29 Adult Human Islets Have Fewer Cells and are Heterogeneous in Composition Human islet Mouse islet Brissova et al., J Histochem Cytochem (2005) vol. 53 (9) pp

30 Human Islets Release Less Insulin in Response to Glucose Than Mouse Islets

31 Phenotypic Characterization of MODY-4 Hyperglycemic clamp NM - subjects with Pdx1 mutation NN - subjects without Pdx1 mutation

32 Impaired Glucose Tolerance in Pdx1 +/- Mice 8 wk wk Brissova et al., JBC, 2002

33 Islet Genes Regulated by Pdx1 Insulin GLUT2 Islet amyloid polypeptide (IAPP) Glukokinase Somatostatin

34 β Cell Genes Have Differential Sensitivity to Level of Pdx1 Activity A Insulin Content/ Pancreatic Protein µg/mg Glucagon Content/ Pancreatic Protein ng/mg IAPP Content/ Pancreatic Protein ng/mg Pdx1+/ ± 1.6 (n = 9) 365 ± 31 (n = 13) 411 ± 46 (n = 14) Pdx1+/ ± 3.5 (n = 12) 470 ± 40a (n = 10) 278 ± 33a (n = 15) ap < 0.05 compared with Pdx1+/+ Brissova et al., JBC, 2002

35 Effect of Reduced Pdx1 Expression on β Cell Function

36 Fauci AS, et al. : Harrison s Principles of Internal Medicine, 17 th Edition

37 Insulin Secretory Responses of in situ Perfused Pancreas Reduced responses to glucose, KIC and KCl pointed to defects in mitochondrial function and/or intracellular calcium levels. Preserved insulin response to GLP-1 suggested that insulin exocytosis is normal in Pdx1 +/- β cells. Brissova et al., JBC, 2002

38 Perifusion of Isolated Pdx1+/- Islets