Pathogenesis, Diagnosis and Classification of Glycemic Disorders

Featuring………  Definition  Diagnosis  Metabolic syndrome concept  Classification  Case scenarios

Definition Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action or both. Diagnosis and Classification of Diabetes Mellitus American Diabetes Association Diabetes Care 28: 2005

Criteria for diagnosis of impaired fasting glucose and impaired glucose tolerance Impaired fasting glucose Fasting glucose: mg/dl on one occasion Impaired Glucose Tolerance 2-hour post-load glucose: mg/dl

Impaired fasting Glycaemia (IFG): mg% Impaired Glucose Tolerance (IGT): 140 – 199 mg% (ADA criteria) Fasting Plasma Glucose Oral Glucose Tolerance Test Criteria for diagnosis of impaired fasting glucose and impaired glucose tolerance

Criteria for the diagnosis of Diabetes Mellitus One of three criteria: Symptoms of hyperglycemia and a casual plasma glucose = 200 mg/dl. Casual is defined as any time of any day without regard to time since last meal. Fasting blood glucose: 126 mg/dl. Fasting is defined as no caloric intake for at least 8 hours. 2h plasma glucose during an oral glucose tolerance test: 200 mg/dl. Glucose load = 75 g anhydrous glucose dissolved in water.

Prevalence of retinopathy by deciles of the distribution of fasting plasma glucose, 2hr post- prandial glucose and HbA 1C National Health And Nutritional Epidemiologic Survey (NHANES III) The prevalence of microvascular change in the eye increases markedly when the plasma glucose levels cross 110 mg/dl and more so above 126 mg/dl. This is the basis for placing a cut-off for fasting plasma glucose >126 mg/dl.

What do the terms Impaired fasting Glycaemia AND Impaired glucose tolerance imply ?

The significance of impaired fasting glycemia and impaired glucose tolerance Increased risk for Cardiovascular /Cerebrovascular disease A predictor for subsequent diabetes mellitus Diabetic range glucose values unmasked with stress

FPG …………Relative risk of developing DM >90mg/dl 1.7 >100mg/dl 3.2 >110mg/dl 6.0 Data from rural Vellore, India Fasting Plasma Glucose checked in 1995 Oral Glucose Tolerance Test done in 2006

Concept of “The Metabolic Syndrome” The Metabolic Syndrome, also referred to as Syndrome X or Insulin Resistance Syndrome describes a cluster of cardiovascular disease risk factors and metabolic alterations associated with excess body fat.

Concept of the metabolic syndrome Cardiovascular risk factors and metabolic alterations associated with excess body fat Abdominal obesity Glucose Intolerance / Diabetes HypertensionDyslipidaemia

Concept of “The Metabolic syndrome” Diabetes mellitus Obesity Hypertension Fatty Liver Insulin Resistance Mixed dyslipoproteinemia (FCHL) Coronary Heart Disease

Adult Treatment Panel III (ATPIII) Operational Definition of Metabolic Syndrome Occurrence of any 3 of the following abnormalities: ↑ Fasting Serum TGL: >150 mg/dL ↑ Blood pressure (> 130/85 mm Hg) Serum Serum HDL Cholesterol  < 40 mg/dL  < 50mg/dL ↑ waist circumference  > 102 cm  > 88 cm Impaired fasting glucose (>100 mg/dL)

WHO Definition of Metabolic Syndrome Impaired glucose tolerance / impaired fasting glucose / T2DM + any of the two below ↑ waist: hip ratio  > 0.9  > 0.85 Elevated Blood Pressure > 140/90 mm Hg Elevated Triglycerides > 150mg/dl Low HDL cholesterol Microalbuminuria

Prevalence of the Metabolic Syndrome EGIR %ATPIII %IDF % Women (n=289) 678 Men (n=279) Women Men

Body mass Index vs Waist-to-hip ratio in relation to Coronary Heart Disease risk Yusuf S et al. Lancet 2005;366:1640-9

Klein S et al. NEJM 2004;350:

Etiological classification of Diabetes 1. Type-1 diabetes mellitus o Immune mediated o Idiopathic 2. Type-2 diabetes mellitus 3. Other specific types of diabetes mellitus o Genetic defects in beta cell function – MODY1-MODY6 o Genetic defects in insulin action: type A insulin resistance, Lipoatrophic diabetes

o Pancreatic diseases: Fibrocalcific pancreatitis, Pancreatectomy, Cystic fibrosis o Endocrinopathies: Acromegaly, Cushing’s syndrome, Pheochromocytoma, Hyperthyroidism o Drug Induced: Glucocorticoids, Thyroid hormone, Diazoxide, Thiazides, Dilantin o Infections: Congenital rubella, Cytomegalovirus, Mumps o Uncommon forms of immune-mediated diabetes: Stiff- man syndrome, Anti-insulin receptor antibodies Etiological classification of Diabetes

o Genetic syndrome association: Down’s syndrome, Turner’s syndrome, Klinefelter’s syndrome, Myotonic dystrophy, Prader Willi syndrome o Gestational Diabetes Etiological classification of Diabetes

Type-1 Diabetes Mellitus ß-cell destruction, leading to absolute insulin deficiency Immune-mediated diabetes (common) Idiopathic diabetes.

Pathogenesis of type-1 diabetes mellitus Genetic (HLA- DR3/DR4; others) Environment Viral Infection Type-1 diabetes mellitus Autoimmune insulitis autoantibodies against GAD-65, ICA, IAA,…. Memory T cells specific for insulin, GAD65, …. Beta cell destruction Severe insulin deficiency

Type-1 Diabetes Mellitus Insulitis

Type-2 Diabetes Mellitus May range from predominantly insulin resistance to predominantly an insulin secretory defect

Pathogenesis of Type 2 DMEnvironment Low Birth Weight ObesityGenetic ß cell defect Genetic ß cell exhaustion Type 2 DM Insulin resistance Relative Insulin Def. May require Insulin Secretory Defect

Type 2 Diabetes  Loss of ß cells  Amyloid deposits  Hyalinization

Physical Activity on the decline…………..

The economic driving factors in India…… Adam Drewnowski and SE Specter. Poverty, obesity, and diet costs. Am J Clin Nutr 2004;79:6 –16 > Rs. 70/- per kg Rs. 90/- per kg … Consumer Price Index shifts favour unhealthy products

Risk factors for type-2 diabetes mellitus Age > 45 years BMI > 25 kg/m 2 Family history of diabetes Habitual physical inactivity Previously identified impaired fasting glucose or impaired glucose tolerance History of gestational diabetes mellitus or delivery of baby weighing > 3.5 kg Hypertension > 140/90 mm Hg Triglyceride level > 250 mg/dL Clinical conditions associated with insulin resistance (Polycystic ovary syndrome) History of vascular disease

LADA (Latent Autoimmune Diabetes of the Adult)

Other Specific Types A. Genetic defects in Beta Cell function / Insulin secretion B. Genetic defects in Insulin Action C. Diseases of the Exocrine Pancreas D. Endocrinopathies E. Drug or Chemical Induced F. Infections G. Uncommon Immune forms H. Genetic Syndromes with Diabetes

Maturity Onset Diabetes of the Young (MODY) Six genetic loci on different chromosomes have been identified to date

MODY-2 and MODY-3 are most common, but in India MODY-1 is common. Usually Nonketotic /Nonobese Often in successive generations Clinical course: resembles a a mild version of type-1 diabetes mellitus. Diagnostic criteria: (a) Mild to moderate hyperglycemia ( mg/dl) discovered before 30 years of age. (b) First degree relative with a similar type of diabetes. (c) Absence of positive autoantibodies (against ICA, IAA, GAD-65, IA2A/ICA512, Znt8) or other autoimmunity (e.g., thyroiditis) in the patient and the family. (d) Persistence of a low insulin requirement. (e) Identification of genetic mutation. Maturity Onset Diabetes of the Young (MODY)

Wolfram Syndrome (DIDMOAD) Mutation of WFSI or Wolframin gene Wolframin protein expressed in the endoplasmic reticulum and may be involved in protein folding DIDMOAD characterized by Diabetes Insipidus, Diabetes Mellitus, a gradual loss of vision caused by Optic Atrophy and Deafness

Genetic defects in insulin action 1. Type A insulin resistance 2. Leprechaunism 3. Rabson-Mendenhall syndrome 4.Lipoatrophic diabetes 5. Others

Lipoatrophic diabetes Characterized by progressive loss of fat tissue (mainly subcutaneous) associated with insulin resistance and diabetes mellitus. Congenital generalized lipodystrophy (CGL) associated with mutations of 1-acylglycerol-3-phosphate-O-acyltransferase 2 (AGPAT2), Berardinelli-Seip Congenital Lipodystrophy 2 (BSCL2) and caveolin 1 (CAV1). Familial partial lipodystrophy (FPL) associated with mutations of lamin A/C (LMNA), peroxisome proliferator-activated receptor gamma (PPARG), v-AKT murine thymoma oncogene homolog 2 (AKT2) and zinc metalloprotease (ZMPSTE24).

Rabson-Mendenhall syndrome Insulin receptor disorder Severe insulin resistance Developmental abnormalities Acanthosis nigricans Hypertrophic pineal gland in some Rabson S, Mendenhall E. Familial hypertrophy of pineal body, hyperplasia of adrenal cortex and diabetes mellitus; report of 3 cases. Am J Clin Pathol 1956; 26 : 283–90. Kadowaki T, Kadowaki H, Rechler MM, Serrano-Rios M, Roth J, Gorden P, Taylor SI. Five mutant alleles of the insulin receptor gene in patients with genetic forms of insulin resistance. J Clin Invest :254-64; Kasuga M, Kadowaki T (1994). "Insulin receptor disorders in Japan". Diabetes Res Clin Pract. 24 (Suppl.): 145–151.

Adapted from F Karpe

Diseases of the pancreas Acquired causes include Pancreatitis, Trauma, infection, pancreatectomy, and pancreatic carcinoma. Fibrocalculous pancreatopathy Cystic fibrosis and Hemochromatosis

Fibrocalculous pancreatic diabetes The classical triad of clinical presentation in tropical chronic pancreatitis: Abdominal pain. Maldigestion leading to steatorrhoea. Diabetes (fibrocalculous pancreatic diabetes).

Drug induced diabetes Drugs and hormones can impair insulin sensitivity and reduce insulin action. glucocorticoids, phenytoin, thiazides & interferons Intravenous pentamidine can permanently destroy pancreatic ß-cells.

Summary of recommendations for Adults with Diabetes Mellitus Screen for impaired fasting glucose and / or impaired glucose tolerance in those with BMI > 25 kg/m2 and / or are > 45 years of age. Glycemic control targets o HbA1C: <6.5% o Fasting glucose: mg/dL o Postprandial glucose: <180 mg/dL Blood Pressure: <130 / 80 mm Hg Lipids o LDL cholesterol: <100 mg / dL o Triglycerides: <150 mg / dL o HDL cholesterol: >40 mg / dL (men); > 50 mg/dl (women)

Glycosylated Hemoglobin (HbA1c) Glycation refers to non-enzymatic addition of a sugar residue to an amino group of a protein. Hemoglobin, plasma proteins, membrane proteins, lens proteins may undergo glycation. Glycated hemoglobins (HbA1a, HbA1b, HbA1c) are collectively called fast H. HbA1c forms the major fraction (~80%). In HbA1c, the N-terminal valine residue of each beta chain gets glycated. Normal HbA1c values and interpretation o Normal: 4.5 – 5.5% o Serious risk of hyoglycemia: <4.5% o Diabetic range: >6%

Approximate correlation between HbA1c and mean plasma glucose levels Hb A1C% Mean plasma glucose (mg/dl) Hemoglobinopathies (e.g. thalassemia), a low hemoglobin level (<7 g/dL) and uremia can all cause falsely low levels of HbA1c.

Follow up of patients and frequency of testing TestsTime to visit Blood GlucoseControlled (HbA1c < 6.5%) every 3 months Uncontrolled: every 2 weeks until target sugars achieved HbA1cControlled (HbA1c < 6.5%): months Uncontrolled: every 3 months Tests for neuropathy Monofilament Biothesiometer Foot Examination Annual Once in 3 months

Follow up of patients and frequency of testing TestsTime to visit Tests for retinopathy Fundus examination If retinopathy detected at first visit, follow-up every 3-6 months. Otherwise annually. Tests for nephropathy Urinary microalbumin (or 24 h urinary protein excretion) Serum creatinine Annual Miscellaneous tests Electrocardiogram Lipid Profile Plain X-ray abdomen Annual If BMI < 20 kg / m 2

Algorithm for Management of Diabetes Mellitus Newly diagnosed diabetes HbA1c: 6-7.5% HbA1c: >8.5% Diet and exercise Initiate oral hypoglycemic therapy (monotherapy) Maximize dose of OHA, add 2 nd OHA Maximize the dose of 2 nd OHA; add on 3 rd OHA Maximize the dose of 3 rd OHA; reinforce diet and exercise Add Insulin to existing OHA therapy HbA1c: >7.5% HbA1c > 7.5% HbA1c: >8.5%

General Indications for use of Oral hypoglycemic agent DrugIndicationContraindication MetforminBMI > 23 kg/m 2, Insulin resistance, Dyslipidemia, high fasting blood glucose >80 years old, any major organ failure, factors predisposing to lactic acidosis SulfonylureasRelative insulin deficiency, thin patients, postprandial hyperglycemia Frequent hypoglycemia, marked weight gain Thiazolidine diones Insulin resistance, dyslipidemiaPeripheral edema, CHF (III/IV), marked wt gain Repaglinide/Nat eglinide Relative insulin deficiency. Flexible meal schedule, hepatic or renal insufficiency Hyperglycemia > 350 mg/dl, weight gain Alpha glucosidase inhibitor Postprandial hyperglycemiaLower gastrointestinal disturbances

Clinical Scenarios

CASE 1 36 year old Mr. R who had his blood glucose levels checked since he had a family history of diabetes BMI : 31 kg/m 2 His fasting plasma glucose (FPG) was 118 mg%, 2hr postprandial blood glucose was 155 mg%. DIAGNOSIS ?

Case 2 20 year old gentleman was diagnosed to have diabetes on a pre-employment check up. He was born of non-consanguineous marriage and his mother and his maternal grand father were diabetic. His BMI was 21 kg/m 2. BP =120/80mm Hg. What is his diagnosis?

Case 3 39 yr old Mr. Al was diagnosed to have diabetes. Polyuria and weight loss in previous 4 months. No recurrent abdominal pain/steatorrhea. BMI: 20 kg/m 2. Urine ketones: negative. Glycemic control for first one year achieved with Oral hypoglycemia agents. Required insulin thereafter. GAD antibodies were positive What type of diabetes does he have?

Answers to self assessment test Case 1: Diagnosis is impaired glucose tolerance or possible metabolic syndrome. Case 2: Diagnosis is Maturity Onset Diabetes of the Young (MODY) Case 3: Diagnosis is Latent Autoimmune diabetes of the Adult.

Summarizing………. Diabetes Mellitus should be considered together with the metabolic syndrome. Impaired fasting glucose and impaired glucose tolerance should be given due importance In the young, the clinical features should be taken into account to determine the cause of diabetes.

Thank you The fort in Vellore, India