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Diabetes Mellitus and Metabolic Syndrome By: Susan Yu-Gan, MD, FPCP.

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1 Diabetes Mellitus and Metabolic Syndrome By: Susan Yu-Gan, MD, FPCP

2 Definition refers to a group of common metabolic disorders that share the phenotype of hyperglycemia. Defect in metabolism of carbohydrates, fats and proteins due to relative/absolute deficiency in insulin secretion or action Result in severe complications

3 Diabetes is a serious disease

4 Morales D et al. for the NNHeS Group. PSH-PLS Convention. Feb Sy R et al. PJIM. 2003; 41: *FBS > 125 mg/dL **FBS ≥101 mg/dL Population = 80 M DM Prevalence: *FBS : 3.4 % ** FBS : 6.6 % FBS/history : 4.6 % Population = 80 M DM Prevalence: *FBS : 3.4 % ** FBS : 6.6 % FBS/history : 4.6 % DM Local Prevalence Rate Filipino DM : 3.4 M

5 Numbers Of People With Diabetes: Regional Figures For 2007 And Estimates For 2025 International Diabetes Federation. Diabetes Atlas, 3rd edn. Brussels: IDF, AFR, Africa; EMM, Eastern Mediterranean; EUR, Europe; NA, North America; SAC, South and Central America; SEA, South -East Asia; WP, Western Pacific

6 The Epidemic of Type 2 Rise in the prevalence and incidence of type 2 diabetes. Why? –Increased awareness, more diagnosed –New ADA and WHO criteria –Longer life span –Obesity –Geographic variations Potential huge economic burden - complications

7 Walking the dog

8 Unique Features Of The Diabetes Epidemic In Asia The increase in type 2 diabetes in Asia developed: –in a shorter time –in a younger age group –in people with a much lower BMI –in people with a high predisposition to insulin resistance at a lesser degree of obesity than people of European descent Yoon KH et al. Lancet 2006; 368: 1681–8.

9 ADA. Screening for Type 2 Diabetes. Diabetes Care 2003; 26(Suppl1):s21-s24 Risk Factors for Type 2 Diabetes Patient Characteristics Medical History Clinical Findings Age > 45 years oldFamily historyHypertension Overweight/Obesity (BMI > 25 kg/m 2 ) Coronary artery disease Dyslipidemia Physical inactivity Cerebrovascular accidents Race-Asians Previous history of IFG/IGT/GDM

10 The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26 (Suppl 1) S5-20 Screening Recommendations Mass screening for type 2 diabetes in the general population is not recommended (Grade D, consensus) Testing for diabetes should be performed every 3 years in those over 45 years of age (Grade D, consensus)

11 Who Should Be Screened? All adults  45 y/o; and, if normal, at 3-yr intervals Younger age and more frequently in those at risk –Obese –First degree relative with diabetes –High risk ethnic group –Hx of GDM or delivered baby > 9 lbs. –Hypertension (BP  140/90) –Dyslipidemia (HDL  35 mg/dL and/or triglyceride  250 mg/dL –Previous IFG or IGT ADA. Diabetes Care 2000: 23 (suppl 1);

12 Confirming the Diagnosis of Type 2 Diabetes mellitus Only possible through serum glucose measurement

13 FPG  126 mg/dL (after 8 hr fast) Random Plasma Glucose  200 mg/dL w/ classic diabetes symptoms –Polyuria, polydipsia, unexplained wt loss OGTT value  200 mg/dL in the 2-h sample Confirmed on at least 2 occasions A1c not routine test for diagnosis (2006) Methods for Diagnosing DM ADA. Diabetes Care 2000:23(suppl.1);

14 NormalPre-Diabetes (IFG and IGT) Diabetes Mellitus FPG<100 mg/dL (5.6 mmol/L) mg/dL ( mmol/L) > 126 mg/dL (7.0 mmol/L) 2hPG< 140 mg/dL (7.8 mmol/L) mg/dL ( mmol/L) > 200 mg/dL (11.1 mmol/L) Levels of Glycemia

15 ADA. Standards of medical care in diabetes. Diabetes Care 2004; 27 (Suppl 1):S13-34 Impaired Glucose Tolerance (IGT) and Impaired Fasting Glucose (IFG) IGT and IFG refer to a metabolic stage intermediate between normal glucose homeostasis and diabetes IGT: 2hPG mg/dL to 199 mg/dL IFG: FBG mg/dL to 125 mg/dL Both are risk factors for future diabetes and cardiovascular disease

16 Etiologic Classification of Diabetes Mellitus Type 1 Diabetes Type 2 Diabetes Other specific types Gestational Diabetes Mellitus

17 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20 Type 1 Diabetes Results from autoimmune destruction of pancreatic beta-cells Absolute insulin deficiency Patients typically dependent on insulin for survival Patients may present with ketoacidosis as initial sign of the disorder

18 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20 Type 2 Diabetes Insulin resistance and relative insulin deficiency Patients may or may not need insulin treatment to survive May remain undiagnosed for many years, as hyperglycemia develops slowly Associated with strong genetic predisposition Heterogenous

19 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20 Other Specific Types Genetic defects of B cell function Genetic defects in insulin action Diseases of the exocrine pancreas Endocrinopathies Drug - or chemical - induced Infections Uncommon forms of immune-mediated diabetes Other genetic syndromes sometimes associated with diabetes

20 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20 Gestational Diabetes Mellitus (GDM) Any degree of glucose intolerance with onset or first recognition during pregnancy Associated with increased perinatal morbidity and mortality 6 weeks or more after pregnancy ends, the woman should be reclassified High risk for type 2 DM.

21 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 2003; 26(Suppl 1):s5-s20 Diagnosis of GDM with a 100-g or 75-g Glucose Load mg/dLmmol/L 100-g Glucose Load Fasting h h h g Glucose Load Fasting h h

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23 PANCREAS The pancreas is an elongated organ nestled next to the first part of the small intestine. The endocrine pancreas refers to those cells within the pancreas that synthesize and secrete hormones. The endocrine portion of the pancreas takes the form of many small clusters of cells called islets of Langerhans or, more simply, islets. Humans have roughly one million islets.

24 Pancreatic islets house three major cell types, each of which produces a different endocrine product: Alpha Cells (A cells) –secrete the hormone glucagon. Beta Cells (B cells) –produce insulin and are the most abundant of the islet cells. Delta Cells (D cells) –secrete the hormone somatostatin which is also produced by a number of other endocrine cells in the body. PANCREAS

25 Interestingly, the different cell types within an islet are not randomly distributed - beta cells occupy the central portion of the islet and are surrounded by a "ring" of alpha and delta cells. Aside from the insulin, glucagon and somatostatin, a number of other "minor" hormones have been identified as products of pancreatic islets cells. PANCREAS

26 Structure of Insulin Insulin is a rather small protein, with a molecular weight of about 6000 Daltons. It is composed of two amino acid chains held together by disulfide bonds. When this two amino acid chains are split apart, the functional activity of insulin is lost. The amino acid sequence is highly conserved among vertebrates, and insulin from one mammal almost certainly is biologically active in another. Insulin

27 INSULIN BIOSYNTHESIS

28 INSULIN BIOCHEMISTRY Proinsulin- inactive chain of 86 a.a. C Peptide- connecting peptide of 31 a.a. Insulin – remaining 51 a.a. made up of chains A and B

29 INSULIN SECRETION Pancreas secrets units insulin/day Basal insulin conc. in fasting state 10  U/mL Food ingestion, insulin conc min. initial increase min peak min. returns to baseline values.

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31 Control of Insulin Secretion –Insulin is secreted primarily in response to elevated blood concentrations of glucose –Some neural stimuli (e.g. site and taste of food) and increased blood concentrations of other fuel molecules, including amino acids and fatty acids, also promote insulin secretion. –Glucose is transported into the B cell by facilitated diffusion through a glucose transporter; elevated concentrations of glucose in extracellular fluid lead to elevated concentrations of glucose within the B cell. INSULIN

32 Control of Insulin Secretion INSULIN Parasympathetic Nervous System Glucose Stimulus D i g e s t i v e hormones  -Sympathetic nervous symtem  -Sympathetic Nervous system Somastatin Growth hormone ACTH Glucagon Insulin

33 Control of Insulin Secretion –Elevated concentrations of glucose within the B cell ultimately leads to membrane depolarization and an influx of extra cellular calcium. –The resulting increase in intracellular calcium is thought to be one of the primary triggers for exocytosis of insulin-containing secretory granules. –An increased level of glucose within B cells also appears to activate calcium-independent pathways that participate in insulin secretion. INSULIN

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35 Physiologic Effects of Insulin –Insulin is a key player in the control of intermediary metabolism. –Insulin has profound effects on: –Carbohydrate metabolism Lipid metabolism Significant influences on protein and mineral metabolism Consequently, derangements in insulin signaling have widespread and devastating effects on many organs and tissues. INSULIN

36 The Insulin Receptor and Mechanism of Action –Like the receptors for other protein hormones, the receptor for insulin is embedded in the plasma membrane. –The insulin receptor is composed of two alpha subunits and two beta subunits linked by disulfide bonds. –The alpha chains are entirely extra cellular and house insulin binding domains, while the linked beta chains penetrate through the plasma membrane. INSULIN

37 Insulin and Carbohydrate Metabolism –Insulin facilitates entry of glucose into muscle, adipose and several other tissues. –The only mechanism by which cells can take up glucose is by facilitated diffusion through a family of hexose transporters of many tissues - muscle being a prime example –The major transporter used for uptake of glucose called GLUT4 is made available in the plasma membrane through the action of insulin. –Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. INSULIN

38 Insulin and Carbohydrate Metabolism –It should be noted here that there are some tissues that do not require insulin for efficient uptake of glucose: important examples are brain and the liver. –This is because these cells don't use GLUT4 for importing glucose, but rather, another transporter that is not insulin-dependent. –Insulin stimulates the liver to store glucose in the form of glycogen. A large fraction of glucose absorbed from the small intestine is immediately taken up by hepatocytes, which convert it into the storage polymer glycogen. When the supply of glucose is abundant, insulin “tells" the liver to bank as much of it as possible for use later. INSULIN

39 INSULIN EFFECTS ON LIVER

40 INSULIN EFFECTS ON MUSCLE

41 INSULIN EFFECTS ON ADIPOSE TISSUE

42 Insulin and Lipid Metabolism –When the liver is saturated with glycogen, any additional glucose taken up by hepatocytes is shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. –The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride. –Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intracellular lipase that hydrolyzes triglycerides to release fatty acids. INSULIN

43 Other Notable Effects of Insulin –Insulin also stimulates the uptake of amino acids, again contributing to its overall anabolic effect. –Insulin also increases the permeability of many cells to potassium, magnesium and phosphate ions. –The effect on potassium is clinically important. Insulin activates Na/K ATPase in many cells, causing a flux of potassium into cells. INSULIN

44 What happens to glucose in the body? EXTERNAL DIET DIGESTION GLUCOSE GlycolysisENERGY GlycogenSTORAGE LipogenesisFATSSTORAGE Glycogenesis Glycogenolysis Pyruvates + Lactates Amino acids Glycerol INTERNAL Gluconeogenesis (Liver)

45 What happens between meals? Blood Glucose Liver mobilizes glycogen stores Break down of Glycogen = GLYCOGENOLYSIS Glucose Blood stream N.B. The liver is the only organ able to liberate glucose from its glycogen stores

46 What happens after a meal?

47 Blood glucose  Insulin and Glucagon Regulate Normal Glucose Homeostasis Glucose output Glucose uptake Glucagon ( α cell) Insulin (β cell) Pancreas Liver Muscle Adipose tissue Fasting stateFed state   Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168.

48 Major Pathophysiologic Defects in Type 2 Diabetes Adapted with permission from Kahn CR, Saltiel AR. In: Kahn CR et al, eds. Joslin’s Diabetes Mellitus. 14th ed. Lippincott Williams & Wilkins; 2005:145–168; Del Prato S, Marchetti P. Horm Metab Res. 2004;36:775–781; Porte D Jr, Kahn SE. Clin Invest Med. 1995;18:247–254. Hepatic glucose output Insulin resistance Glucose uptake Glucagon ( α cell) Insulin (β cell) Liver Hyperglycemia Islet-cell DysfunctionMuscle Adipose tissue Pancreas

49 Incretin Hormones Regulate Insulin and Glucagon Levels GLP-1 = glucagon-like peptide-1; GIP = glucose insulinotropic polypeptide Adapted from Kieffer T. Endocrine Reviews. 1999;20:876–913. Drucker DJ. Diabetes Care. 2003;26:2929–2940. Nauck MA et al. Diabetologia. 1993;36:741–744. Adapted with permission from Creutzfeldt W. Diabetologia. 1979;16:75–85. Copyright © 1979 Springer-Verlag. Pancreas Gut Nutrient signals ● Glucose Hormonal signals GLP-1 GIP Glucagon (GLP-1) Insulin (GLP-1,GIP) Neural signals  cells  cells

50 The Incretin Axis Peptides released by the gut throughout the day and increased in response to meals — participate in normal glucoregulation GLP-1 and GIP are the dominant incretins Both stimulate insulin release from β-cells and GLP-1 inhibits glucagon release from  -cells The incretin axis is abnormal in patients with T2DM  Reduced release of GLP-1  Reduced response to GIP Drucker DJ. Diabetes Care. 2003: ; Ahren B. Curr Diab Rep. 2003;3: ; Drucker DJ Gastroenterology. 2002;122: ; Dunning BE, et al. Diabetologia. 2005;48: ADA 2006 Late Breaking Clinical Presentation (Stein).

51 Demonstrated Effects of the Incretin Hormones GLP-1 and GIP  Is released from L cells in ileum and colon  Stimulates insulin response from β cells in a glucose-dependent manner  Inhibits gastric emptying  Reduces food intake and body weight  Inhibits glucagon secretion from α cells in a glucose-dependent manner  Effect on β-cell turnover in preclinical models  Is released from K cells in duodenum  Stimulates insulin response from β cells in a glucose-dependent manner  Has minimal effects on gastric emptying  Has no significant effects on satiety or body weight  Does not appear to inhibit glucagon secretion from α cells  Effect on β-cell turnover in preclinical models GLP-1 GIP Meier JJ et al. Best Pract Res Clin Endocrinol Metab. 2004;18:587–606; Drucker DJ. Diabetes Care. 2003;26:2929–2940. Farilla L et al. Endocrinology. 2003;144:5149–5158.

52 Role of Incretins in Glucose Homeostasis Adapted from Kieffer TJ, Habener JF. Endocr Rev. 1999;20:876–913; Ahrén B. Curr Diab Rep. 2003;2:365–372; Drucker DJ. Diabetes Care. 2003;26:2929–2940; Holst JJ. Diabetes Metab Res Rev. 2002;18:430–441. Ingestion of food β cells α cells Release of gut hormones — incretins * Pancreas Glucose-dependent  Insulin from β cells (GLP-1 and GIP) Glucose uptake by muscles Glucose dependent  Glucagon from α cells (GLP-1) GI tract Active GLP-1 & GIP DPP-4 enzyme Inactive GIP Inactive GLP-1 *Incretins are also released throughout the day at basal levels. Glucose production by liver Blood glucose in fasting and postprandial states

53 Fate of Glucose If energy is needed immediately, glucose is metabolized to produce energy via glycolysis. If more glucose is available than what the cells need immediately for energy, the extra glucose is converted to glycogen via a process called glycogenesis. Glycogenesis occurs primarily in liver cells and, to a limited extent, in muscle cells. When glucose is not immediately required for energy and the storage capacity for glycogen is reached in the liver and muscle, additional glucose can be oxidized or converted to fat.

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55 GLUT 4 Transporters BeforeAfter

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57 DeFronzo RA. Med Clin N Am 2004; 88:787–835. Prevention Treatment –1010 Years Diagnosis Macrovascular complications 0 IGT/IFG Type 2 diabetes Natural History Of Disease Progression Microvascular complications Blood glucose  -cell function Insulin resistance

58 Glucose Homeostasis Pancreas

59 Insulin receptors (GLUT 4) Glucose transport proteins Cell Insulin Action in Normal Tissues (Cellular Level)

60 Insulin receptors (GLUT 4) Glucose transport proteins Insulin Action in Normal Tissues (Cellular Level) Cell

61 Insulin receptors (GLUT 4) Glucose transport proteins Insulin Action in Normal Tissues (Cellular Level) Cell

62 Insulin receptors (GLUT 4) Glucose transport proteins Insulin Action in Normal Tissues (Cellular Level) Cell

63 Insulin receptors (GLUT 4) Glucose transport proteins Cell Insulin Resistance

64 Insulin receptors (GLUT 4) Glucose transport proteins Cell Insulin Resistance

65 Insulin receptors Cell Insulin Resistance Insulin receptors (GLUT 4) Glucose transport proteins Cell

66 Insulin receptors Cell Insulin Resistance

67 INSULIN RESISTANCE Phase: Disease Progression Stage : POST-Receptor Level Early stage - normal to IGT Receptor Level Hyperinsulinemia- IGT to T2D

68 INSULIN RESISTANCE Phase: Disease Progression Stage : Pre- Receptor Level Latter Part Stage - Beta-cell Dysfuntion (Pancreatic exhaustion)

69 Pathogenesis of Type 2 Diabetes

70 ADA and IDF Guidelines: Treatment Goals for HbA 1c, FPG, and PPG Parameter Normal Level ADA Goal IDF Goal FPG, mg/dL (mmol/L) <110 (<6.1) 90–130 (5.0–7.2) <110 (<6.1) PPG, mg/dL (mmol/L) <140 (<7.8) <180 (<10.0) <145 (<8.1) HbA 1c 4%–6% <7%*<6.5% *The HbA 1c goal of an individual patient is to achieve an HbA 1c as close to normal (<6%) as possible without significant hypoglycemia. ADA=American Diabetes Association; IDF=International Diabetes Federation. ADA. Diabetes Care. 2007;30(suppl 1):S4–S41; International Diabetes Federation. 2005:1–79.

71 Therapy for Type 2 DM Lifestyle changes –Diet –Exercise –Stop smoking –Glycemic control –Prevent complications –Prevent disease progression Pharmacologic –Glycemic control –Prevent complications –Prevent disease progression –Treat co-morbid conditions –Minimal side effects

72 Nutrient Composition of the Therapeutic Lifestyle Change (TLC) Diet NutrientRecommended Intake Carbohydrate50% to 60% of total calories; mostly from food rich in complex carbohydrates Fiber20-30 g/day ProteinApproximately 15% of total calories Cholesterol<200 mg/day Total CaloriesBalance energy intake and expenditure; should include at least moderate physical activity Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:

73 Glucose Adipose tissue Gut Stomach Liver Biguanides Muscle Pancreas Sulphonylureas and meglitinides Insulin  -glucosidase inhibitors Thiazolidinediones GLP-1 GLP-1 analogues Adapted from Kobayashi M. Diabetes Obes Metab 1999; 1(Suppl. 1):S32–S40. Nattrass M & Bailey CJ. Baillieres Best Pract Res Clin Endocrinol Metab 1999; 13:309–329. Pratley RE & Salsali A. Curr Med Res Opin 2007; 23:919–931. Todd JF & Bloom SR. Diabet Med 2007; 24:223–232. Primary Sites Of Action Of Oral Anti-diabetic Agents DPP-4 inhibitors DPP-4

74 Insulin Secretagogues: Basic Characteristics Mechanism of action: –Increase basal and postprandial insulin secretion Therapeutic efficacy: –Decreases HbA 1c 1%-2%* Recommended dosing: –Sulfonylureas: 1-2x daily –Repaglinide, nateglinide: 3x daily Adverse effects: –Weight gain, hypoglycemia *Results vary according to clinical trial design, individual patient characteristics, and data analyses. Amaryl PI. Hoechst Marion Roussel, August 1997; DiaBeta PI. Hoechst Marion Roussel, September 1997; Glucotrol PI. Pfizer, September 1993; Glynase PI. Pharmacia & Upjohn, February 1999; Micronase PI. Pharmacia & Upjohn, January 1999; Prandin PI. Novo Nordisk, October 1998.

75 Sulfonylureas Tolbutamide Chlorpropamide Glibenclamide/Glyburide Gliclazide Glipizide Glimepiride

76 Guideline for Use of SULFONYLUREAS Action GenericTrade Name Preparation Daily Dose Short Tolbutamide Rastinon500 mg tablet1/2 - 6 tabs Inter- mediate Glibenclamide Gliclazide Glipizide Glimepiride Euglucon Daonil Orabetic Diamicron MR Diamicron Dianorm Glubitor Minidiab OD Solosa Norizec 2.5/5.0 mg tab 5.0 mg tablet 5.0 mg tablet 30 mg tablet 80 mg tablet 80 mg tablet 5/10 mg tab 1,2,3 mg tab 1/2 - 3 tabs pre- breakfast 1/2 - 4 tabs ½ -6 tabs 1-4 mg Long Acting ChlorpropamideDiabenese250 mg tablet 1/2 - 2 tabs

77 Meglitinides Also stimulates insulin secretion by the pancreas Shorter acting than sulfonylureas Targets the postprandial elevation of blood sugar

78 Meglitinides Repaglinide Nateglinide

79 Biguanides (Metformin) Suppresses hepatic glucose output An insulin sensitizer May cause Lactic acidosis Contraindicated in patients with hepatic and renal insufficiency and in patients with hypoxemia

80 Metformin Action Reduce liver glucose production Insulin sensitivity Yes (liver predominantly) Hepatic glucose output Reduced Serum insulin No effect Hypoglycaemia No Lipids Reduced Onset of action Moderate Weight Neutral or reduced Effectiveness over time Reduced Safety GI effects Drug interactions Renal insufficiency (Lactic acidosis)

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82 Acarbose Action Reduced glucose absorption Insulin sensitivity No effect Hepatic glucose output No effect Serum insulin No effect Hypoglycaemia No effect Lipids No effect Onset of action Moderate Weight Neutral or reduced Effectiveness over time Uncertain (at 3 years) Safety GI effects Hepatic (LFT elevation) Drug interactions (few

83 Thiazolidinediones Insulin sensitizers Acts by activation of PPAR Must monitor liver enzymes Side effects include fluid retention, edema, anemia

84 Thiazolidinediones Troglitazone Rosiglitazone Pioglitazone

85 Hepatic (Inc LFT in Troglitazone) Drug interactions (few) Weight gain ? Edema ? Safety Durable Effectiveness over time Increased Weight Moderate to late Onset of action Generally positive Lipids No effect Hypoglycaemia Decreased Serum insulin Slight decrease Hepatic glucose output Increased Insulin sensitivity Insulin sensitizer Action Thiazolidinediones

86 Indications for Insulin in Type 2 Diabetes Hyperglycemia despite maximum doses of oral agents Decompensation due to intercurrent events e.g., infection, acute injury, or other stress Development of severe hyperglycemia with ketonemia and/or ketonuria Uncontrolled weight loss

87 Indications for Insulin in Type 2 Diabetes Perioperative in patients undergoing surgery Pregnancy Renal or hepatic disease Allergy or other serious reaction to oral agents

88 Tier 1: Well-validated core therapies At diagnosis: Lifestyle + Metformin STEP 1 Tier 2: Less well-validated therapies Lifestyle + Metformin + Intensive insulin STEP 3 Lifestyle + Metformin + GLP-I agonists No hypoglycemia Weight loss Nausea/vomiting Lifestyle + Metformin + Pioglitazone No hypoglycemia Oedema/CHF Bone loss Lifestyle + Metformin + Basal insulin Lifestyle + Metformin + Sulfonylurea STEP 2 Lifestyle + Metformin + Pioglitazone + Sulfonylurea Lifestyle + Metformin + Basal Insulin Algorithm for the Metabolic Management of Type 2 Diabetes

89 Diabetic Retinopathy Leading cause of blindness in adults 1,2 Diabetic Nephropathy Leading cause of end-stage renal disease 3,4 Cardiovascular Disease Stroke 2- to 4-fold increase in cardiovascular mortality and stroke 5 Diabetic Neuropathy Leading cause of non-traumatic lower extremity amputations 7,8 8/10 individuals with diabetes die from CV events 6 Type 2 diabetes is associated with serious complications 1 UK Prospective Diabetes Study Group. Diabetes Res 1990; 13:1–11. 2 Fong DS, et al. Diabetes Care 2003; 26 (Suppl. 1):S99–S The Hypertension in Diabetes Study Group. J Hypertens 1993; 11:309– Molitch ME, et al. Diabetes Care 2003; 26 (Suppl. 1):S94–S98. 5 Kannel WB, et al. Am Heart J 1990; 120:672– Gray RP & Yudkin JS. Cardiovascular disease in diabetes mellitus. In Textbook of Diabetes 2nd Edition, Blackwell Sciences. 7 King’s Fund. Counting the cost. The real impact of non-insulin dependent diabetes. London: British Diabetic Association, Mayfield JA, et al. Diabetes Care 2003; 26 (Suppl. 1):S78–S79.

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91 Hyperglycemia Neuropathy – Peripheral – Autonomic Biology of Microvascular Complications Kidney Nerves Retinopathy Cataract Glaucoma Nephropathy – Microalbuminuria – Gross albuminuria BlindnessKidney failure Amputation Death and/or disability Eye

92 Metabolic injury to large vessels HeartBrain Extremities Cardiovascular disease Acute coronary syndrome Myocardial infarction (MI) Congestive heart failure Cerebrovascular disease Transient ischemic attack Stroke Cognitive impairment Peripheral vascular syndrome Ulcers Gangrene Amputations Biology of Macrovascular Complications

93 Impact of Type 2 Diabetes on Macrovascular Disease Largest cause of morbidity and mortality Risk of CVD increased 2- to 4- fold Higher case fatality vs non diabetic individuals Reduced survival post–MI, post–CABG, and particularly post–PTCA Risk of stroke and peripheral vascular disease substantially increased Betteridge DJ. Acta Diabetol. 1999;36:S25-S29. Nesto R. Acta Diabetol. 2001;38:S3-S8.

94 Diabetic Macroangiopathy Atherosclerosis –Atherosclerosis begins to appear in most diabetics whatever their age, within a few year of onset of diabetes. –The susceptibility of diabetics to atherosclerosis is due to several factors: Hyperlipidemia HDL Levels are reduced in type 2 diabetics Diabetics have increased platelet adhesiveness and response to aggregative agents. Most type 2 diabetic patients are obese and hypertensive which further contributes to Atherosclerosis

95 CLINICAL PRESENTATION OF MACROANGIOPATHY Stroke –Estimated relative risk of stroke in diabetes mellitus: –2 – 8% –Mainly due to the atherosclerosis of the cerebral vessels leading to the rupture and ischemia of the cerebral tissue. Coronary Heart Diseases √ Ischaemic heart disease –Type 2 diabetics develop CHD at a young age –The 5-Years risk of ischaemic events is doubled –Worse outcome post –MI

96 PATHOPHYSIOLOGY OF THE DIABETIC FOOT

97 atherosclerosis Of the leg vessels Infection (contributes to tissue necrosis) Peripheral neuropathy claudicationulcerationgangrenerest pain Ischemia (Often bilateral) Sensory deficit Autonomic dysfunction

98 Diabetic Neuropathy Numbness, tingling or pain in the toes, feet, legs, hands, arms and fingers Wasting of muscles of feet or hands Indigestion, nausea or vomiting Diarrhea or constipation Dizziness or faintness due to a drop in postural blood pressue Problems with urination Erectile dysfunction (impotence) or vaginal dryness Weakness

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100 INFECTIONS Hyperglycemia favors Development of infection Urinary tract Infection Skin infection Respiratory tract infection Treatment of infection And improved blood glucose Control

101 DIABETIC RETINOPATHY One of the most threatening aspects of DM’s the development of visual impairment Epidemiology –Leading cause of blindness in Western countries –Retinopathy is the most common complication of diabetes. –Risk factors are: duration of diabetes, poor BG control, high –Blood pressure, hypercholesterolemia, proteinuria.

102 Symptoms –Reduction in visual acuity –Reduction in visual fields –Reduction in vision of colors DIABETIC RETINOPATHY

103 DIABETIC NEPHROPATHY A major cause of end-stage renal disease and dialysis. The kidneys are usually the most severely damaged organs in diabetics Diabetic nephropathy with proteinuria is a common serious complication affecting Type 1 and Type 2 diabetes. Affect 25% of the diabetics

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105 Natural History of Diabetic Nephropathy

106 Definition of Abnormal Albumin Excretion UAERUAERUrinary (mg/24H)(mcg/min) albumin/ creatinine (mg/gm) Normal< 30< 20< 30 Microalbuminuria30 – – – 300 Macroalbuminuria> 300> 200> 300

107 Measurements Albumin to creatinine ratio 24 hour urine collection Timed collection (4 H or overnight) Screen for with reagent strips

108 False Positives Short time hyperglycemia Exercise Acute febrile illness UTI Marked hypertension CHF

109 Microvascular Complications of Diabetes StageUAE Rate (μg/min) Blood Pressure Glomerular Filtration rate (GFR) Histological Changes 1 Hyperfiltration 0 – 20NormalIncreased by 20 – 50 % Increased Glomerular size 1 Normoalbuminuria 0 – 20NormalIncreased by 20 – 50 % Basement Membrane (BM) thickening 2 Microalbuminuria 21 – 200Normal or elevated Still high, but declines with proteinuria BM thickening Mesangial expansion 3 Proteinuria >200ElevatedDecline ~10ml/min/yr Pronounced abnormalities 4 End-stage renal Failure >200Hypertension<10ml/minAdvanced glomerulopathy Stages of diabetic nephropathy (Adapted from Mogensen 1999)

110 Risk Factors DM Nephropathy  Poor glycemic control and insulin resistance  Hypertension  Albuminuria  Smoking  High dietary intake of protein  Hyperlipidemia

111 Microvascular Complications of Diabetes Microalbuminuria predicts cardiovascular morbidity and mortality as well as renal disease Treatment should delay or prevent the progression of microalbuminuria to proteinuria Trials have shown that therapeutic strategies should include: - intensive glycaemic control - aggressive control of blood pressure (ACE inhibitors) Diabetic Nephropathy: Therapeutic Strategies

112 Treatment Recommendations for Diabetic Patients with Albuminuria/Nephropathy In the treatment of albuminuria/nephropathy, both ACE inhibitors and ARBs can b used: –In hypertensive and non-hypertensive T1 DM: ACE-inhibitors are the initial agents of choice –In hypertensive and non-hypertensive T2 DM: ARBs are the initial agents of choice Diabetes Care. 2002;25(1):S33

113 Strategies for Preventing Complications of Diabetes Control blood glucose –HbA1c below 7% –FBS below 110 mg% –RBS below 160 mg% Control blood pressure –Below 130/80 Control lipids –LDL below 100 mg% –HDL above 45 for males and 55 for females –Triglycerides below 150 mg% Weight loss Stop smoking

114 Summary of Recommendations for Adults With Diabetes Glycemic Control A1C<7.0%* Preprandial plasma glucose mg/dL ( mmol/L) Postprandial plasma glucose†<180 mg/dL (<10.0 mmol/L) Blood pressure<130/80 mmHg Lipids‡ LDL<100 mg/dL (<2.6 mmol/L) Triglycerides<150 mg/dL (<1.7 mmol/L) HDL>40 mg/dL (1.1 mmol/L)§ *Nondiabetic range of % using DCCT-based assay †PPG made 1-4 h after beginning of meal ‡NCEP/ATP III guidelines: for TG>200 mg/dL, use non-HDL cholesterol = TC-HDL §For women, HDL goal >50 mg/dL Diabetes Care 2004; 27(Suppl1):S15-S35

115 What is the Metabolic Syndrome A group of metabolic risk factors in one person. Central obesity Atherogenic dyslipidemia - mainly high triglycerides and low HDL cholesterol Insulin resistance or glucose intolerance Prothrombotic state (e.g., high fibrinogen or plasminogen activator inhibitor [–1] in the blood) Raised blood pressure (130/85 mmHg or higher) Proinflammatory state (e.g., elevated high-sensitivity C- reactive protein in the blood)

116 Clinical Identification - Any 3 of the following Metabolic Syndrome LOW HDL-C Men < 40 mg/dL (1.0 mmol/L) Women < 50 mg/dL (1.2 mmol/L) HIGH Triglycerides ≥ 150 mg/dL ( ≥ 1.7 mmol/L) Abdominal Obesity Men > 40 inches (>102 cm) Women > 35 inches (>88 cm) (Waist circumference) Hypertension ≥ 130 / ≥ 85 mmHg Fasting Glucose ≥100 mg/dL ≥ 5.5 mmol/L NCEP-ATP III – JAMA 2001

117 New IDF Definition of Metabolic Syndrome Waist circumference Plus 2 of the ff: (cm) Europids FBS >5.6 (100mg/dL) >94 male >80 female TRIG >1.7 (150mg/dL) South Asians >90 male HDL < 0.9 (<40mg/dL) M >80 female <1.1 (<50mg/dL) F Chinese >90 male BP >130 systolic >80 female >85 diastolic Japanese >85 male >90 female

118 Prevalence (%) Low HDL 6554 Obesity (BMI>30) Obesity (WHR  1/0.85)34.9 Smoking 34.8 Hypertriglyceridemia 9 21 Hypertension DM 3.9* 3.4* 4** 4.6** 6.6 *** Metabolic Syndrome (NCEP) Morales D et al. for the NNHeS Group. PSH-PLS Convention. Feb Sy R et al. PJIM. 2003; 41: *FBS > 125 mg/dL** FBS or history *** FBS ≥101 mg/dL Risk Factors Among Filipinos

119  genetic predisposition  excess body fat (abdominal obesity)  sedentary lifestyle  physical inactivity Ford ES et al. JAMA. 2002; 287: Risk Factors for Metabolic Syndrome

120 While the pathogenesis of the metabolic syndrome and each of its components is complex and not well understood, central obesity and insulin resistance are acknowledged as important causative factors.

121 IDF Consensus 2004 Recommendations for Treatment Primary Intervention IDF recommends that primary management for the MS is healthy lifestyle promotion. This includes : * moderate calorie restriction ( to achieve a 5-10% loss of BW in the 1 st year ) * moderate increase in physical activity * change in dietary composition

122 IDF Consensus 2004 Recommendations for Treatment Secondary intervention * In people for whom lifestyle change is not enough and who are considered to be at high risk for CVD, drug therapy may be required to treat the metabolic syndrome. * However, specific pharmacological agents are not yet available. * It is currently necessary instead to treat the individual components of the metabolic syndrome.

123 IDF recommended treatment of the individual components of the metabolic syndrome. Atherogenic dyslipidemia Primary aims for therapy : * Lower Tg * Raise HDL * Reduce LDL Options : * Fibrates * Statins

124 IDF recommended treatment of the individual components of the metabolic syndrome. Elevated blood pressure In patients with established diabetes, anti- HPN therapy should be introduced at BP ≥130/≥80 mmHg. Options : * ACEI and ARB. Effect of lowering of BP per se more important than the drug itself? * No particular agents have been identified as being preferable for HPN patients with MS.

125 IDF recommended treatment of the individual components of the metabolic syndrome. Insulin resistance and hyperglycemia There is growing interest in the possibility that drugs that reduce IR will delay the onset of type 2 DM and will reduce the CVD risk when the MS is present.

126 Cardiovascular Risk Factors and Therapies  ↑ LDL cholesterol  ↓ HDL cholesterol  ↑ Triglycerides  ↑ Blood Pressure  ↑ Blood Glucose  ↑ Waist Circumference  ↓ Insulin Sensitivity  ↑ Thrombotic risk Lipid Modifiers Anti-hypertensives Anti-diabetic agents Weight Loss Agents + Diet and exercise Insulin sensitizers Anti-platelet agents NCEP-ATP III / IDF criteria for the metabolic syndrome

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