Pathogenesis of Type 2 Diabetes

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1 9/23/215 Multiple, Complex Pathophysiological Abnmalities in T2DM incretin effect gut carbohydrate delivery & absption pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA? Pathogenesis of Type 2 Diabetes Genes Nmal Insulin Resistance Decreased Insulin Secretion Environment hepatic glucose production peripheral glucose uptake Type 2 Diabetes CR Kahn Diabetes 43: , 1994 Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 211 HbA 1c (%) UKPDS: Progressive Hyperglycemia Secondary to Beta-Cell Failure Conventional NOT your fault! Intensive Conventional Metfmin Years from Randomization Lancet 1998;352: UKPDS 16. Diabetes 1995;44: Beta- Cell Functio n(%) Incretins and Insulin: Management of T2DM GLP-1R s incretin effect inhibits gut carbohydrate delivery & absption hepatic glucose production Adapted from: Inzucchi SE, Sherwin RS in: Cecil Medicine 211 Insulin pancreatic insulin secretion pancreatic glucagon secretion HYPERGLYCEMIA? peripheral glucose uptake 1

2 9/23/215 Plasma Insulin ( U/mL) The Holy Grail is to mimic Physiologic Serum Insulin Secretion Profile Breakfast Lunch Dinner Doesn t seem that hard. 4: 8: 12: 16: 2: 24: 28: 32: Time Polonsky KS et al, N Engl J Med Insulin Therapy in Type 2 DM Take home points: Insulin controls blood glucose Insulin is not a penalty Using basal insulin is simple and safe Complex regimens are demanding f the patient and the provider Ideal Basal/Bolus Insulin Absption Pattern: Multiple daily injections insulin pump Many insulin regimens are effective Breakfast Lunch Supper Breakfast Lunch Dinner Plasma Insulin ( U/mL) 75 5 Breakfast Lunch Dinner Glucose Bolus Insulin Basal Insulin Plasma Insulin Immediate Insulin 5% 5% Glargine Detemir 8: 12: 4: 16: 2: 24: 4: Time Dinner Breakfast Lunch Plasma Insulin Prandial Insulin 5% NPH 5% 8: 12: 4: 16: 2: 24: 4: Time Dinner Breakfast Lunch 25 Plasma Insulin NPH Prandial Insulin 5% Plasma Insulin NPH 5% 4: 8: 12: 16: 2: 24: 4: 8: Time Skyler J, Kelley s Textbook of Internal Medicine 2. 5% 5% 4: 8: 12: 16: 2: 24: 4: 4: 8: 12: 16: 2: 24: 4: Time Time SMBG is based on regimen 2

3 9/23/215 Is there another way? Glucagon Like Peptide recept s GLP1 RA Pancreatic Islet Mphology: Nmal Glucose Tolerance and T2DM NGT β-cells (insulin) α-cells (glucagon) T2DM Insufficient Insulin and Elevated Glucagon in T2DM ( Insulin/Glucagon Ratio) mg/dl U/mL pg/ml CHO meal Glucose Insulin Glucagon NGT T2DM T2DM = type 2 diabetes mellitus Adapted from Rhodes CJ. Science. 25; 37: Time (min) T2DM = type 2 diabetes mellitus; NGT = nmal glucose tolerance; CHO=carbohydrate Adapted from Muller WA, et al. N Engl J Med. 197;283:

4 9/23/215 GLP-1 and DPP4 The Incretin Effect in Healthy Subjects GLP-1 Modulates Numerous Functions in Humans Plasma Glucose (mg/dl) 2 1 Oral Glucose Intravenous (IV) Glucose Time (min) C-peptide (nmol/l) * * * * Incretin Effect * * * Time (min) GLP-1: Secreted upon the ingestion of food Beta cells: Enhances glucose-dependent insulin secretion Promotes satiety and reduces appetite Alpha cells: Postprandial glucagon secretion Liver: Glucagon reduces hepatic glucose output Stomach: Helps regulate gastric emptying N = 6; Mean (SE); *P.5 Data from Nauck MA, et al. J Clin Endocrinol Metab. 1986;63: Data from Flint A, et al. J Clin Invest. 1998;11:515-52; Data from Larsson H, et al. Acta Physiol Scand. 1997;16: Data from Nauck MA, et al. Diabetologia. 1996;39: ; Data from Drucker DJ. Diabetes. 1998;47: GLP-1 This is overwhelming Mrs Jones is here f a 3 minute visit 4

5 9/23/215 Lifestyle: Always first line Relationship of walking to mtality among US adults with diabetes DESIGN: Prospective coht study BJECTS: 2896 adults 199 and 1991 National Health Interview Survey RELTS: Mtality Inactive 2 hours/wk 3-4 hours/wk All Cause Ref 1. 39% 54% CV Ref 1. 34% 53% CONCLUSIONS: Walking was associated with er mtality across a diverse spectrum of adults with diabetes. One death per year may be preventable f every 61 people who could be persuaded to walk at least 2 h/wk. Arch Intern Med. 23 Jun 23;163(12):144-7 Patient Centered: PATIENT / DISEASE FEATURES Risks potentially associated with and other drug adverse effects me Approach to the management of hyperglycemia Disease duration Life expectancy Imptant combidities newly diagnosed long long-standing sht Usually not Risks potentially associated with, other drug adverse effects me Low High Established vascular complications Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities motivated, non-adherent, po self-care capacities Potentially Resources and suppt system Courtesy of S Inzucchi Readily available limited Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s Diabetes Care 212;35: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s ;55:

6 9/23/215 me Disease duration Newly diagnosed Long-standing Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s me Life expectancy Imptant combidities Absent Few / Mild Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s Long Sht Severe Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s me me Established vascular complications Absent Few / Mild Severe Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s

7 9/23/215 me Patient attitude & expected treatment effts Highly motivated, adherent, excellent self-care capacities Less motivated, non-adherent, po self-care capacities me Resources and suppt systems Readily available Limited P O T E N T I A L LY MODIFIABLE P O T E N T I A L LY MODIFIABLE Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s Diabetes Care 212;35: ;55: of glucose ering in T2DM Diabetes Care 215;38:14-149; Diabetologia Diabetologia 215;1.177/s Figure 1. Modulation of the intensiveness of glucose ering in T2DM Figure 1. Modulation of the intensiveness of glucose ering in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with and other drug adverse effects Disease duration Life expectancy Imptant combidities Established vascular complications Patient attitude and expected treatment effts Resources and suppt system Approach to the management of hyperglycemia me PATIENT / DISEASE FEATURES Risks potentially associated with and other drug adverse effects newly diagnosed Disease duration long-standing Usually not long sht ly motivated, adherent, excellent self-care capacities Readily available motivated, non-adherent, po self-care capacities Life expectancy Imptant combidities Established vascular complications Potentially limited Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s Patient attitude and expected treatment effts Resources and suppt system Approach to the management of hyperglycemia me newly diagnosed long-standing Usually not long sht ly motivated, adherent, excellent self-care capacities Readily available motivated, non-adherent, po self-care capacities Potentially limited Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s

8 9/23/215 Figure 1. Modulation of the intensiveness of glucose ering in T2DM PATIENT / DISEASE FEATURES Risks potentially associated with and other drug adverse effects Disease duration Life expectancy Imptant combidities me newly diagnosed long Approach to the management of hyperglycemia long-standing sht Established vascular complications Usually not Management of Hyperglycemia in Type 2 Diabetes, 215: A Patient-Centered Approach Update to a Position Statement of the American Diabetes Association (ADA) and the European Association f the Study of Diabetes (EASD) Inzucchi SE, Bergenstal RB, Buse JB, Diamant M, Ferrannini E, Nauck M, Peters AL, Tsapas A, Wender R, Matthews DR Patient attitude and expected treatment effts ly motivated, adherent, excellent self-care capacities motivated, non-adherent, po self-care capacities Potentially Resources and suppt system Readily available limited Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s Diabetes Care 215;38: Diabetologia 215;1.177/s Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/ GI / lactic acidosis Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/ GI / lactic acidosis If target not achieved after ~3 months of mono, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): If target not achieved after ~3 months of mono, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Dual Metfmin moderate risk Metfmin edema, HF, fxs Metfmin inhibit neutral rare Metfmin SGLT2 inhibit GU, dehydration Metfmin GLP-1 recept GI Metfmin est risk variable Dual Metfmin moderate risk Metfmin edema, HF, fxs Metfmin inhibit neutral rare Metfmin SGLT2 inhibit GU, dehydration Metfmin GLP-1 recept GI Metfmin est risk variable If target not achieved after ~3 months of dual, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): If target not achieved after ~3 months of dual, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Triple Metfmin Metfmin Inhibit SGLT-2 Inhibit Metfmin Metfmin GLP-1 recept Metfmin Triple Metfmin Metfmin Metfmin Metfmin Inhibit SGLT-2 Inhibit Metfmin Metfmin GLP-1 recept Metfmin If target not achieved after ~3 months of triple and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding SGL T2-i: Metfmin Combination Figure injectable 2. An hyperglycemic Basal Insulin Mealtime Insulin in T2DM: General recommenda ons Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s If target not achieved after ~3 months of triple and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding SGL T2-i: Metfmin Combination Figure injectable 2. An hyperglycemic Basal Insulin Mealtime Insulin in T2DM: General recommenda ons Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s

9 9/23/215 Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/ GI / lactic acidosis Healthy eating, weight control, increased physical activity & diabetes education Metfmin neutral/ GI / lactic acidosis If target not achieved after ~3 months of mono, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): If target not achieved after ~3 months of mono, proceed to 2-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Dual Metfmin moderate risk Metfmin edema, HF, fxs Metfmin inhibit neutral rare Metfmin SGLT2 inhibit GU, dehydration Metfmin GLP-1 recept GI Metfmin est risk variable Dual Metfmin moderate risk Metfmin edema, HF, fxs Metfmin inhibit neutral rare Metfmin SGLT2 inhibit GU, dehydration Metfmin GLP-1 recept GI Metfmin est risk variable If target not achieved after ~3 months of dual, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): If target not achieved after ~3 months of dual, proceed to 3-drug combination (der not meant to denote any specific preference - choice dependent on a variety of patient- & disease-specific facts): Triple Metfmin Metfmin Inhibit SGLT-2 Inhibit Metfmin Metfmin GLP-1 recept Metfmin Triple Metfmin Metfmin Metfmin Metfmin Inhibit SGLT-2 Inhibit Metfmin Metfmin GLP-1 recept Metfmin If target not achieved after ~3 months of triple and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding SGL T2-i: Metfmin Combination Figure injectable 2. An hyperglycemic Basal Insulin Mealtime Insulin in T2DM: General recommenda ons Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s Combination injectable If target not achieved after ~3 months of triple and patient (1) on al combination, move to injectables, (2) on GLP-1 RA, add basal insulin, (3) on optimally titrated basal insulin, add mealtime insulin. In refracty patients consider adding SGL T2-i: Metfmin Basal Insulin Mealtime Insulin Diabetes Care 215;38:14-149; Diabetologia 215;1.177/s Common themes: The 5 P s: Consideration in the Design of a Personalized T2DM Treatment Regimen Diet and physical activity Patient goals and resources Start with metfmin If A1c>9% start insulin 9

10 9/23/215 - Biguanide - - Insulin 1_FUL-v4e.pdf Combo Therapy - Biguanide - Biguanide insulin - insulin The 65 P s: Consideration in the Design Pathophysiology infms of a Personalized T2DM Treatment Regimen treatment $ $ 1

11 9/23/215 Steno-2 Study Patients (%) Percentage of Patients Who Reached the Intensive-Treatment 8 Goals at a Mean of 7.8 Years P<.1 P=.21 7 P=.19 6 Intensive 5 P=.1 Conventional P=.6 Primary Composite End Point (%) Composite End Point of Death from CV Causes, Nonfatal MI, CABG, PCI, Nonfatal Stroke, Amputation, Surgery f Peripheral Atherosclerotic Artery Disease P=.7 Hazard ratio =.47 (95 percent c.i.,.24 to.73; P=.8) Conventional Therapy Intensive 1 Glycosylated Hemoglobin <6.5% Cholesterol <175 mg/dl Triglycerides <15 mg/dl Systolic BP <13 mm Hg Diastolic BP <8 mm Hg Months of Fol-up Gæde P et al. NEJM. 23;348: Gæde P et al. NEJM. 23;348:

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