Diabetes: Diagnosis, Classification, Management Controversies and News

1. Diabetes:Diagnosis, Classification, Management Controversies and News Leonid Poretsky, MD Chief, Division of Endocrinology and Metabolism Director, Gerald J. Friedman Diabetes Institute Gerald J. Friedman Chair in Endocrinology Professor of Medicine, Albert Einstein College of Medicine Bianca Alfonso, MD Endocrinology Fellow, Year 1 Marina Krymskaya, ANP, CDE Diabetes Nurse Educator Jill Gregory Medical Illustrator

2. Diabetes Care Enhancement Initiative • Team: Leonid Poretsky, MD; Agustin Busta, MD; Morton Davidson, MD; Marina Krymskaya, RN, NP; Jason Park, MD; Carmen Schmidt, RN; Daniel Steinberg, MD; • Goal: Improvement of diabetes care for both inpatients and outpatients throughout the Beth Israel System. • The first event of the Initiative – Grand Rounds on June 16th, presented by Dr. Silvio E. Inzucchi,of Yale University: Successful Management of Inpatient Hyperglycemia. • The Initiative includes educational and clinical components. Plan • Educational aspects: • To include physicians, nurses, house staff, patients and their significant others; • The series of lectures, grand rounds, in-service events to be planned; • The “discharge kit” with general and individualized instructions to be developed and piloted; • Educational video materials for inpatient TV to be selected/created and used throughout BIMC; • Clinical aspects: • review of all existing diabetes protocols for general wards; • review of current PRIZM orders; • review of current diabetes-related protocols in CCU, MICU, CT ICU, SICU; • Quality Improvement: • jointly with GMA, develop program for house staff • Open for suggestions. Please direct any comments to Marina Krymskaya at Mkrymska@chpnet.org or 212-420-2062

3. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

4. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

5. Definition • Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both.* • The name 'diabetes mellitus' derives from: Greek: 'diabetes' – “siphon” or “to pass through” Latin: 'mellitus' – “honeyed” or “sweet”** * Diagnosis and Classification of Diabetes Mellitus. ADA 2009. ** http://science.jrank.org/pages/2044/Diabetes-Mellitus.html

6. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

7. Epidemiology • 20.8 million Americans (7% of US population) • About 10% have Type 1 DM • 14.6 million diagnosed • 6.2 million remain undiagnosed • 41 million have pre-diabetes • Lifetime risk for developing DM (Type 1 or 2) is 33 % in males and 39% in females for individuals born in 2000 • Up to 45% of newly diagnosed cases of DM in US children and adolescents are type 2 AACE Diabetes Mellitus Guidelines, Endocr Pract. 2007;13(Suppl 1) 2007

8. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

9. Classification • Type 1 diabetes • Type 2 diabetes • Other • Genetic defects of beta cell function • Genetic defects in insulin action • Diseases of the exocrine pancreas • Endocrinopathies • Drug/ chemical - induced • Infections • Uncommon forms of immune-mediated diabetes • Genetic syndromes sometimes associated with diabetes • Gestational diabetes mellitus

10. Type 1 diabetes • A. Immune-mediated • B. Idiopathic • Type 1 diabetes is characterized by β-cell destruction, usually leading to absolute insulin deficiency.* * Diagnosis and Classification of Diabetes Mellitus. ADA 2009.

11. Atkinson MA and Eisenbarth GS. Lancet 2001;358:221-229.

12. Type 1 diabetes mellitus – immune mediated • Absolute insulin deficiency • Usually due to autoimmune destruction of the pancreatic beta cells • Islet-cell antibodies (ICA) or other autoantibodies (antibodies to glutamic acid decarboxylase [anti-GAD] and anti-insulin)

13. Type 2 diabetes • Hyperglycemia • Insulin resistance • Relative impairment in insulin secretion.

14. ­cell dysfunction and insulin resistance produce hyperglycemia in type 2 diabetes Insulin Resistance ­Cell Dysfunction Increased Lipolysis Pancreas Liver Elevated Plasma FFA ↓Glucose Uptake ↑Glucose Production Islet ­Cell Degranulation;Reduced Insulin Content Muscle Adipose Tissue Increased Glucose Output Reduced Plasma Insulin Decreased Glucose Transport & Activity (expression) of GLUT4 Hyperglycemia

17. Maturity–onset diabetes of the young (MODY) 6 subtypes Other specific types of diabetes – Genetic defects of beta cell function

18. Maturity:Onset diabetes of the young (MODY) • MODY 1 - Mutation in HNF-4-alpha (transcription factor), chromosome 20 • MODY 2 - Mutation in glucokinase gene, chromosome 7 • MODY 3 - Mutation in HNF-1-alpha (transcription factor), chromosome 12 (most common form) • MODY 4 - Mutation in insulin promoter factor-1 (IPF-1), chromosome 13 • MODY 5 - Mutation in HNF-1-beta, chromosome 17 • MODY 6 - Mutation in Neurogenic Differentiation Factor-1 (NEUROD1) , chromosome 2

19. Other specific types of diabetes: Genetic defects in insulin action • Type A insulin resistance • Leprechaunism • Rabson- Mendenhall syndrome • Lipoatrophic diabetes • Others

20. Latent Autoimmune Diabetes in Adults (LADA) • Adult-onset diabetes with circulating islet antibodies but not requiring insulin therapy initially • Adults who should be considered for antibody testing*: • age of onset <50 years • acute symptoms • BMI <25 kg/m2 • personal or family history of autoimmune disease *A clinical screening tool identifies autoimmune diabetes in adults. Fourlanos S; Perry C; Stein MS; Stankovich J; Harrison LC; Colman PG. Diabetes Care. 2006 May;29(5):970-5

21. Gestational DM Definition • Any degree of impaired glucose tolerance with onset or first recognition during pregnancy • Gestational diabetes (GDM) occurs when pancreatic function is not sufficient to overcome the insulin resistance created by changes in diabetogenic hormones during pregnancy • Most have impaired glucose tolerance that begins in pregnancy • Some have previous undiagnosed type 2 diabetes mellitus • 10% have circulating islet cell antibodies

22. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

23. Diagnosis • Diabetes mellitus • Impaired fasting glucose (IFG) • Impaired glucose tolerance (IGT) • Gestational diabetes mellitus (GDM)

24. Diagnosis: Diabetes mellitus • Symptoms of diabetes (polydipsia, polyuria, unexplained weight loss) PLUS a random plasma glucose >200 mg/dL (11.1 mmol/L) or • Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) after overnight (at least 8 hours) fast or • Two-hour plasma glucose> 200mg/dL (11.1 mmol/L) during a standard 75g oral glucose tolerance test • Any of these criteria establishes the diagnosis but needs to be confirmed on a later day

25. Diagnosis: Impaired fasting glucose (IFG) • Fasting plasma glucose (FPG) < 100 mg/dl (5.6 mmol/l) = normal • FPG 100-125 mg/dl (5.6-6.9 mmol/l) = impaired fasting glucose (IFG)

26. Diagnosis: Impaired glucose tolerance (IGT) • Oral glucose tolerance test (OGTT) – glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water • 2-h postload glucose < 140 mg/dl (7.8 mmol/l) = normal • 2-h postload glucose 140 - 199 mg/dl (7.8 – 11.1 mmol/l) = impaired glucose tolerance (IGT)

27. Diagnosis: Gestational Diabetes Mellitus (GDM) Fasting plasma glucose > 126 mg/dL (7.0 mmol/L) • Unequivocal hyperglycemia • (confirmed on a subsequent day) Random plasma glucose >200 mg/dL (11.1 mmol/L) OR 100-g glucose load 2. Diagnostic OGTT

28. Diabetes:diagnosis, classification, management • Definition • Epidemiology • Classification • Diagnosis • Treatment • Evidence • Treatment goals

29. Treatment • Lifestyle intervention • Hypoglycemic drugs • oral hypoglycemic drugs • insulin and insulin analogs • others (incretins, pramlintide)

30. Treatment:Lifestyle Interventions • Weight loss • Increased exercise

31. Treatment:Oral Antihyperglycemic Drugs • Biguanides • Sulfonylureas • Meglitinide analogs • Thiazolidinediones • -Glucosidase Inhibitors • DPP-4 Inhibitors

32. Treatment:Oral Antihyperglycemic Drugs

33. Oral antihyperglycemic drugs: Biguanides • Metformin (Glucophage) • Extended-release metformin (Glucophage-XR) • decrease hepatic glucose output • lower fasting glycemia • reduce HbA1c by 1.5% • adverse effects: lactic acidosis, gastro-intestinal disturbances

34. Oral antihyperglycemic drugs: Metformin AMPK - adenosine monophosphate-activated protein kinase, ACC - acteyl-CoA carboxylase, SREPB-1 - sterol-regulatory-element-binding-protein-1. Diagram adapted from Alice Y.Y. Cheng, I. George Fantus, 'Oral antihyperglycemic therapy for type 2 diabetes mellitus' Canadian Medical Association Journal 172(2),2005 pp213-226

35. Treatment:Oral Antihyperglycemic Drugs

36. Oral antihyperglycemic drugs: Sulfonylureas • 1st generation : Tolbutamide (Orinase), Tolazamide (Tolinase), Acetohexamide (Dymelor), Chlorpropamide (Diabinese) • 2nd generation : Glyburide (DiaBeta, Glynase) Glipizide (Glucotrol), Glimepiride (Amaryl) • enhance insulin secretion • lower HbA1c by 1.5 % • side effects: hypoglycemia, weight gain

37. Treatment:Oral Antihyperglycemic Drugs

38. Oral antihyperglycemic drugs: Meglitinide analogs • Repaglinide (Prandin) • Nateglinide (Starlix) • enhance insulin secretion (early-phase insulin release) • lower HbA1c by 0.1- 2.1 % (repaglinide) and by 0.2- 0.6% (nateglinide) • side effects: weight gain, hypoglycemia Black C, Donnelly P, McIntyre L et al. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004654.  

39. Treatment:Oral Antihyperglycemic Drugs

40. Oral antihyperglycemic drugs: Thiazolidinediones (TZDs) • Rosiglitazone (Avandia) • Pioglitazone (Actos) • peroxisome proliferator-activated receptor γ modulators (PPAR γ) • insulin sensitizers (increase the sensitivity of muscle, fat and liver to endogenous and exogenous insulin) • lower HbA1c by 0.5 - 1.4 % • adverse effects: weight gain, fluid retention

41. Treatment:Oral Antihyperglycemic Drugs

42. Oral antihyperglycemic drugs:-Glucosidase Inhibitors • Acarbose (Precose) • Miglitol (Glyset) • reduce the rate of digestion of polysaccharides in the proximal small intestine, primarily lowering post-prandial glucose levels • lower HbA1c by 0.5 – 0.8 % • side effects: increased gas production and gastro-intestinal symptoms

43. Oral antihyperglycemic drugs:DPP-IV inibitors • Sitagliptin (Januvia) : DPP-IV inhibitor • Dipeptidyl peptidase IV (DPP-IV) is a ubiquitous enzyme that deactivates a variety of bioactive peptides, including GIP and GLP-1

44. Oral antihyperglycemic drugs -Sitagliptin (Januvia) • Used alone or in combination with metformin or TZDs • Reduces HbA1c by 0.5 – 0.7 % • Side effects: increased rate of respiratory infections, headaches

45. "Januvia" by Byron Rubin • Sculpture was installed at the West Point Pennsylvania Merck location.

46. Other antihyperglycemic drugs: Incretins • Exenatide (Byetta) • glucagon-like peptide 1 (GLP-1) agonist

47. Antihyperglycemic drugs: Exenatide (Byetta)

48. Glucagon-like Peptide - 1 • The majority of GLP-1 producing cells are in the terminal ileum and proximal colon. • GLP-1 levels in the blood increase rapidly after a meal. • Half-life being very short, approximately one minute. • GLP-1 binding to its G-protein coupled receptor on ß-cells increases glucose stimulated insulin secretion • GLP-1 infused into healthy subjects decreases gastric emptying, causes a sensation of satiety, and decreases appetite. • Effects: • enhances insulin secretion • limits postprandial hyperglycemia.

49. Incretin Effect Figure 1. Insulin levels following oral vs IV glucose administration in healthy individuals. Despite identical glucose concentrations, plasma insulin levels peaked much earlier and were greater in response to an oral vs IV dose of glucose. Figure 2. Insulin levels following oral vs IV glucose administration in patients with type 2 diabetes. The markedly reduced early peak of insulin after oral glucose, along with the smaller differences in insulin levels in response to oral and IV glucose doses, illustrate the diminished incretin effect. Data extrapolated from Perley, et al. @ http://www.byettahcp.com/hcp/hcp_incretin_effect.jsp

50. Antihyperglycemic drugs:Exenatide (Byetta) • active ingredient in Exenatide (Byetta) is a synthetic version of a protein present in the saliva of the Gila monster