1. Diabetes Mellitus 101 for Medical Professionals An Aggressive Pathophysiologic Approach to Cardiometabolic Therapy for Type 2 Diabetes: Stanley Schwartz MD, FACE, FACP Emeritus, Clinical Associate Professor of Medicine University of Pennsylvania Affiliate, Main Line Health System Wynnewood, Pa. Part 4

2. Pioglitazone  ADVANTAGES-  Improves insulin resistance (fat/muscle), decreases insulin conc., improves endothelial dysfunction, dysfibrinolysis, BP, decreased microalbumin, improved beta-cell function, treats PCOS and steatohepatitis Lipids (GLIA study) Advantage to pio - decrease TG, decreased # of buoyant LDL particles, decrease non-HDL chol. May use in renal insufficiency  No hypoglycemia used alone or with metformin, incretin mimetics  Potential to delay or prevent DM and progression; lower secondary failure rate than SU/met  Pio decreased prospective composite endpoint (MI,CVA, death) 16% in PROactive trial (Can’t assume class effect), dec. risk second MI/ ACS, decreased risk second stroke 47%

3. Pioglitazone in Dysmetabolic Syndrome, Prediabetes, Type 2 Diabetes  Safety  No liver toxicity- issue off label  Increased distal fractures in women  Edema-renal sodium and total body water retention - can be prevented/minimized (patient selection, NAS diet) - treated with spironolactone, amilioride, triamterene  Weight gain not an obligatory side effect-- portion control/ education freq.  Bone loss in women = risk/benefit evaluation for each patient  Bladder CA- signal, but FDA advises continued use except those with Dx  CHF not a cardiac issue except more susceptible with diastolic dysfunction –function of renal sodium and total body water retention -Can be prevented/reduced- low salt diet/ patient selection; ranolazine

4. Weight Loss With Exenatide added to TZD Also presume Pio- Added to GLP-1 receptor-agonist PREVENTS weight gain

5. Natural History of Type 2 Diabetes- Insulin Secretion IR phenotype Atherosclerosis obesity hypertension  HDL,  TG Endothelial dysfunction PCO Envir.+ Other Disease Obesity Poor Diet Inactivity Insulin Resistance Risk of Dev. Complications ETOH BP Smoking Eye Nerve Kidney  Beta Cell Secretion Genes Blindness Amputation CRF Disability MI CVA Amp Age 0-1515-40+15-50+25-70+ Macrovascular Complications IGT Type II DM Microvascular Complications DEATH d.ec 1st phase Inc 2nd phase

6. Euglycemia Healthy Subjects (n = 14)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Hyperglycemia Type 2 Diabetes (n = 12)   Beta-Cell Workload   Beta-Cell Workload   Beta-Cell Response   Beta-Cell Response   Beta-Cell Workload   Beta-Cell Workload Mean (SE) The Pathogenesis of Type 2 Diabetes Beta-Cell Workload Outpaces Beta-Cell Response Carbohydrate Meal

7. Acute Insulin Response (AIR) (  U/mL) M-Low Insulin Sensitivity (mg/kg EMBS/minute) IGT NGT Diabetic 500 400 300 200 100 0 012345012345 Progressors Nonprogressors NGT=normal glucose tolerance. IGT=impaired glucose tolerance. EMBS=estimated metabolic body size. Changes in AIR relative to changes in rate of insulin-stimulated glucose disposal with low dose (M-low) in 11 Pima Indian subjects in whom glucose tolerance deteriorated from NGT to IGT to diabetic (DIA) (progressors), and in 23 subjects who retained NGT (nonprogressors). The lines represent the prediction line and the lower and upper limits of the 95% confidence interval of the regression between AIR and M-low as derived from a reference population of 277 Pima Indians with NGT. Adapted from: Weyer C, et al. J Clin Invest. 1999;104(6):787-794. Relationship of Insulin Secretion to Insulin Resistance

9. Flatbush diabetes

10. Incretin Effect, Normal and with Diabetes

11. Incretins Gut-derived hormones, secreted in response to nutrient ingestion, that potentiate insulin secretion from islet  -cells Stimulation of insulin secretion is glucose-dependent. Incretins only work when glucose levels are above basal levels- THUS, NO HYPOGLYCEMIA if not on secreatogogue or insulin Two predominant incretins –glucagon-like peptide-1 (GLP-1) –glucose-dependent insulinotropic peptide ([GIP] also known as gastric inhibitory peptide) Holst JJ et al. Diabetes. 2004;53(suppl 3):s197-s204; Meier JJ et al. Diabetes Metab Res Rev. 2005;21:91-117.

12. Insulin secretion - overcomes decreased insulin secretion of steroids and tacrolimus Glucagon secretion Gastric emptying Appetite Cardioprotection Cardiac output Insulin biosynthesis  cell proliferation  cell apoptosis Neuroprotection Glucose production Insulin sensitivity Brain Heart GI tract Liver Muscle Stomach GLP-1 Drucker D. J. Cell Metabolism 2006 Summary of Incretin Actions on Different Target Tissues

13. GLUT2 Glucose ATP Pyruvate K+K+ Potassium channel Insulin [Ca 2+ ] Glucose Independent Triggering cAMP ATP AC Amplifying- Glucose Dependent + Pancreatic Beta Cell GK GLP-1 Glucose-Stimulated Secretion of Insulin- Logic for Benefit of Incretins in Stress and Transplant DM Calcium channel SUR GIP + 3 1 Glucose metabolism TCA Cycle* 2 AC = adenylyl cyclase ATP = adenosine triphosphate cAMP = cyclic adenosine monophosphate GK = glucokinase GLUT2 = glucose transporters SUR = sulfonylurea receptor *TCA = Tricarboxylic acid (Kreb’s cycle) Hinke SA et al. J Physiol. 2004;558:369–380. Henquin JC. Diabetes. 2000;49:1751–1760. Henquin JC. Diabetes. 2004;53:S48–S58. Gillison, Tranplantation 1991;52:890 corticosteroids PKA Calmodulin inhibitors (Transplant meds )

14. Glucose-Dependent Effects of GLP-1 on Insulin and Glucagon Levels in Patients With Type 2 Diabetes Glucose Glucagon When glucose levels approach normal values, glucagon levels rebound. When glucose levels approach normal values, insulin levels decreases. *P <0.05 Patients with type 2 diabetes (N=10) mmol/L 15.0 12.5 10.0 7.5 5.0 250 200 150 100 50 mg/dL * * * * * * * pmol/L 250 200 150 100 50 40 30 20 10 0 mU/L * * * * * * * * Infusion Minutes pmol/L 20 15 10 5 060120180240 * * * * pmol/L 20 15 10 5 Placebo GLP-1 Insulin 2.5 0 0 0 0 0 Adapted with permission from Nauck MA et al. Diabetologia. 1993;36:741–744. Copyright © 1993 Springer-Verlag. –30

15. CV Benefits of GLP-1 Including human Sokos et al.J of Card. Failure. 2006; 9; 694 Improves CHF in humans Nikolaidis LA, Circulation. 2004 Mar 2;109(8):962-5 Sitagliptin inc. EF with Cath 2010