Diabetes DIABETES MELLITUS. Types of Diabetes. Classification of Diabetes Prediabetes: IFG, IGT, Increased A1C

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1 Diabetes Diabetes mellitus is a chronic disease characterized by high levels of blood glucose resulting from defects in insulin production, insulin action, or both. A state of raised blood glucose (hyperglycaemia) associated with premature mortality. DIABETES MELLITUS Hyperglycaemia seriously damages many of the body s systems, especially the blood vessels and nerves. 5 th class, general medicine, practical seminar Classification of Diabetes Types of Diabetes Type 1 diabetes β-cell destruction Type 2 diabetes Progressive insulin secretory defect Other specific types of diabetes Genetic defects in β-cell function, insulin action Diseases of the exocrine pancreas Drug- or chemical-induced Gestational diabetes mellitus Type 1 (T1DM, DM1) onset in youth, destruction of beta cells and a requirement for insulin Type 2 (T2DM, DM2) onset as adult or young adult, related to insulin resistance. May be treated with lifestyle modification, oral medications, and later may require insulin ADA. I. Classification and Diagnosis. Diabetes Care 2012;35(suppl 1):S11. Criteria for the Diagnosis of Diabetes Prediabetes: IFG, IGT, Increased A1C Categories of increased risk for diabetes (prediabetes) * A1C 6.5% OR Fasting plasma glucose (FPG) 126 mg/dl (7.0 mmol/l) OR 2-h plasma glucose 200 mg/dl (11.1 mmol/l) during an OGTT OR A random plasma glucose 200 mg/dl (11.1 mmol/l) IMPAIRED FASTING GLUCOSE FPG mg/dl ( mmol/l) IMPAIRED GLUCOSE TOLERANCE 2-h plasma glucose in the 75-g OGTT mg/dl ( mmol/l): PREDIABETES A1C % *For all three tests, risk is continuous, extending below the lower limit of a range and becoming disproportionately greater at higher ends of the range. 1

2 Beta-cell mass Who is at risk for developing T2DM Testing for GDM Overweight or obese (BMI >25kg/m2). Abdominal circumference > 35 for women and > 40 for men. First-degree relative with diabetes Sedentary lifestyle (not very physically active) Members of a high-risk ethnic population (Blacks, Hispanics, Native American, Asian American, Pacific Islanders) Females with prior Gestational Diabetes and/or delivered a baby >9lb Have a history of high blood pressure, high cholesterol, high LDL, and low HDL Females with Polycystic Ovarian Syndrome (PCOS) Previously told that they have slight elevated blood sugar (pre-diabetes) Have other clinical conditions associated with insulin resistance Chronic use of steroid-based medications (Prednisone) In the absence of above criteria, testing should begin at age 45 years In pregnant women not previously known to have diabetes, screen for GDM at weeks gestation, using a 75-g OGTT and specific diagnostic cut points Use risk factor analysis and OGTT if appropriate versus low risk Testing high risk at weeks of gestation Screening for and Diagnosis of GDM Criteria for the diagnosis of T1DM Perform a 75-g OGTT, with plasma glucose measurement fasting and at 1 and 2 h, at weeks gestation in women not previously diagnosed with overt diabetes Perform OGTT in the morning after an overnight fast of at least 8 h GDM diagnosis: when any of the following plasma glucose values are exceeded Fasting 92 mg/dl (5.1 mmol/l) 1 h 180 mg/dl (10.0 mmol/l) 2 h 153 mg/dl (8.5 mmol/l) Diagnosing type 1 diabetes: Signs and symptoms of hyperglycemia (polyuria, polydipsia, polyphagia, weight loss) Labs to differentiate diagnosis: Anti-GAD-65 (normal: less than 1u/mL) Islet cells antibody (normal: negative) C-peptide (normal: ng/mL) Age, weight, etc. Laboratory Evaluation Progression of Type 1 Diabetes A1C, if results not available within past 2 3 months If not performed/available within past year Fasting lipid profile, including total, LDL, and HDL cholesterol and triglycerides Liver function tests Test for urine albumin excretion with spot urine albumin-to-creatinine ratio Serum creatinine and calculated GFR Thyroid-stimulating hormone in type 1 diabetes, dyslipidemia, or women over age 50 years Genetic predisposition Precipitating Event Normal insulin release Antibody Age (y) Progressive loss of insulin release Glucose normal Overt diabetes C-peptide present No C-peptide present Adapted from: Atkinson. Lancet. 2002;358:

3 Main Pathophysiological Defects in T2DM incretin effect gut carbohydrate delivery & absorption - pancreatic glucagon secretion HYPERGLYCEMIA pancreatic insulin secretion? Anti-hyperglycemic therapy Therapeutic options: LIFESTYLE Weight optimization Healthy diet hepatic glucose production + - peripheral glucose uptake Inzucchi SE, Sherwin RS in: Cecil Medicine 2011 Increased activity level Diabetes Care 2012;35: Diabetologia 2012;55: Oral agents & non-insulin injectables Properties of anti-hyperglycemic agents Metformin Sulfonylureas Thiazolidinediones DPP-4 inhibitors GLP-1 receptor agonists Meglitinides a-glucosidase inhibitors Bile acid sequestrants Dopamine-2 agonists Amylin mimetics Class Mechanism Advantages Disadvantages Cost Biguanides (Metformin) SUs / Meglitinides TZDs Activates AMP-kinase Hepatic glucose production Closes KATP channels Insulin secretion Activates PPAR-g Insulin sensitivity Extensive experience Weight neutral? CVD events Extensive experience Microvascular risk Durability TGs, HDL-C? CVD events (pio) Gastrointestinal Lactic acidosis B-12 deficiency Contraindications Hypoglycemia Weight gain Low durability? Ischemic preconditioning Weight gain Edema / heart failure Bone fractures? MI (rosi)? Bladder ca (pio) Low Low a-gis Inhibits a-glucosidase Slows carbohydrate absorption Nonsystemic Post-prandial glucose? CVD events Gastrointestinal Dosing frequency Modest A1c Mod. Class Mechanism Advantages Disadvantages Cost DPP-4 inhibitors GLP-1 receptor agonists Inhibits DPP-4 Increases GLP-1, GIP Activates GLP-1 receptor Insulin, glucagon gastric emptying satiety Well tolerated Weight loss? Beta cell mass? CV protection Modest A1c? Pancreatitis Urticaria GI? Pancreatitis Medullary ca Injectable Insulin Class Mechanism Advantages Disadvantages Cost Activates insulin receptor Glucose disposal Hepatic glucose production Universally effective Unlimited efficacy Microvascular risk Hypoglycemia Weight gain? Mitogenicity Injectable Training requirements Stigma Variable Amylin mimetics Activates amylin receptor glucagon gastric emptying satiety Weight loss Post-prandial glucose GI Modest A1c Injectable Hypo w/ insulin Dosing frequency Bile acid sequestrants Binds bile acids Hepatic glucose production Nonsystemic LDL-C GI Modest A1c TGs Dosing frequency Dopamine-2 agonists Activates DA receptor Modulates hypothalamic control of metabolism Insulin sensitivity? CVD events Modest A1c Dizziness/syncope Nausea Fatigue 3

4 Medications for Diabetes TYPE NAME MECHANISM ROUTE, TIME Sulfonylureas Glimepiride Glipizide Glyburide Increases insulin production through K channels of beta cells Biguanides Metformin Reduce hepatic glucose output and increase its muscle uptake Thiazolidinedio nes Glitazones Meglitinides Rosiglitazone Pioglitazone Repaglinide Nateglinide DPP-4 Inhibitors Sitagliptin Vildagliptin Linagliptin Incretin Mimetics Exenatide Liraglutid PPAR gamma ligand improves glucose utilization Close K channel and open Ca channel in Beta cell increasing insulin Blocks, DPP-4 which catalyzes enzyme breaking down insulin Stimulates beta cells and slows digestion Po qd or bid Po bid tid XR po qd Po qd Po 5 30 min AC 100 mg po qd Sc bid or 1xd, 1xweek To target the rise of blood sugar after the meals Sulfonylureas First category of oral agents for diabetes now in third generation Increase secretion of insulin from pancreas by binding to potassium channels and opening calcium channels Requires functioning pancreatic beta-cells Can cause hypoglycemia and weight gain Be alert of renal insufficiency with any medications Biguanides - Antihyperglycemic agent, not hypoglycemic agents 4

5 Metformin CAVE: Lactic acidosis in patients using metformin Metformin should be used in all type 2 diabetics Improves the liver s response to insulin reduces overnight glucose production reduces fasting hyperglycemia Also has effect on increasing sensitivity of peripheral tissues (muscle and adipose) to insulin Maximum reduction in A1c after 6 months Reduced cardiovascular risks Taken with meals to lessen side effects Hold for any studies using dyes/contrast Clinically significant lactic acid accumulation almost always occurs in the presence of comorbid conditions, such as: Renal insufficiency (serum creatinine concentration above 1.4 mg/dl [124 µmol/l] in women and 1.5 mg/dl [132 µmol/l] in men), or low creatinine clearance. Concurrent liver disease or alcohol abuse Heart failure History of lactic acidosis Decreased tissue perfusion or hemodynamic instability Hypoxic states or serious acute illness Meglitinides (Insulin secretagogues) glucose dependent (unlike the sulfonylureas that cause an increase in insulin release, regardless of glucose levels) Work by increasing insulin release after the meal (like second phase of normal insulin release) Best if taken minutes before the meal More expensive Thiazolidinediones (TZDs) Stimulates the PPARγ receptor Makes fat and muscle tissue more sensitive to insulin thus decreasing insulin resistance Modest effect on the decrease of liver glucose production Effects on blood sugar are not immediate (6-8 weeks) Can cause weight gain/fluid retention Close monitoring of liver function for first several months of therapy Caution with cardiac patients - Not to be used in heart failure Can increased fractures 5

6 Alpha-Glucosidase Inhibitors Delay the digestion and absorption of complex carbohydrates (but most of the meal is absorbed) Medication is taken with the first bite of each meal Doses start low and increase slowly to avoid/decrease gastrointestinal side-effects (flatulence, diarrhea, stomach discomfort) Normally not prescribed for patients that have chronic intestinal problems and/or gastroparesis The Incretin System Incretin mimetics and DPP4 inhibitors If you don t take better care of your diabetes, you will end up on insulin Normally, two types of hormones (GLP1 and GIP) secreted in gut in response to food signal the pancreas to release insulin, decreases the release of glucagon (hormone that stimulates the liver to release glucose) improving insulin resistance. GLP1 receptors in the stomach delay gastric emptying when stimulated. Barriers to initiating insulin WHEN TO START INSULIN Start with oral agents (metformin) and proceed to insulin if goal is not achieved May be able to manage for up to 6 years HgbA1C use a target In kidney patients and those who may be operating heavy machinery because of the risk of hypoglycemia may want to have a higher goal Mono-duo-triple therapy disease has advanced 6

7 Change in Serum Insulin Insulins Rapid-acting analogues: Aspart, Lispro, Glulisine Short acting: Regular Intermediate-acting NPH Long acting basal analogues Glargine, Detemir Pre-mixed varieties NPH + regular 70/30, NPL + aspart 70/30, NPL + lispro 50/50, 75/25 Insulin Time-Action Patterns Insulin Time-Action in daily use Normal Insulin Secretion at Meal Time Regular insulin NPH Insulin Premix 70/30 Baseline Level s.c. Injection Time (hours) Types of insulin The Basal/Bolus Insulin Concept RAPID ACTING PREPARATION ONSET PEAK DURATION MAX DURATION Lispro (Humalog) 5 15 min hr 5 hr 4-6 hr Aspart (Novolog) Glulisine (Apidra) SHORT Regular hr 2 3 hr 5 8 hr 6 10 hr INTERMEDIATE NPH (isophane) 2 4 hr 4-10 hr hr hr Lente (zinc) 2 4 hr 4-12 hr hr hr LONG Ultralente 6 10 hr hr hr hr LONG ANALOGUE Glargine (Lantus) 2 4 hr No Peak hr 24 hr Basal insulin Suppresses glucose production between meals and overnight 40% to 50% of daily needs Bolus insulin (mealtime) Limits hyperglycemia after meals Immediate rise and sharp peak at 1 hour 10% to 20% of total daily insulin requirement at each meal Detemir (levemir) 2-4 hr No Peak hr 24 hr COMBINATIONS 70/30 NPH/Reg 0.5 to 1 hr Dual hr hr 50/50 NPH/Reg CONBINATION ANALOGUES 75/25 NPL/lispro 5 15 min Dual hr hr 70/30 NPL/aspart 7

8 Plasma insulin Basal/Bolus Treatment Program with Rapid-acting and Long-acting Analogs Basal-Bolus Insulin Replacement Breakfast Lunch Dinner Aspart Aspart Aspart or or or Lispro Lispro Lispro An effective insulin treatment strategy provides both basal and prandial insulin coverage Initially, prandial insulin may be needed only at the largest meal of the day, with coverage at other meals added based on postprandial glucose concentrations Rapid-acting insulin analogs more closely match post-meal carbohydrate absorption Glargine 4:00 8:00 12:00 16:00 20:00 24:00 4:00 Time 8:00 Site of injection affects absorption Goals of anti-hyperglycemic therapy Second best Glycemic targets HbA1c < 7.0% (mean PG mg/dl [ mmol/l]) Pre-prandial PG <130 mg/dl (7.2 mmol/l) Post-prandial PG <180 mg/dl (10.0 mmol/l) Best absorption Third Best Individualization is key: Tighter targets ( %) - younger, healthier Looser targets ( %+) - older, comorbidities, hypoglycemia prone, etc. Avoidance of hypoglycemia PG = plasma glucose Diabetes Care 2012;35: Diabetologia 2012;55: Correlation of A1C with Average Glucose (AG) Mean plasma glucose A1C (%) mg/dl mmol/l These estimates are based on ADAG data of ~2,700 glucose measurements over 3 months per A1C measurement in 507 adults with type 1, type 2, and no diabetes. The correlation between A1C and average glucose was A calculator for converting A1C results into estimated average glucose (eag), in either mg/dl or mmol/l, is available at 8

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