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: 100-125 mg/dl on one

occasion

Impaired Glucose Tolerance

2-hour post-load glucose: 140-199 mg/dl

Impaired fasting Glycaemia (IFG): 100 - 125 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 MellitusOne 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 HbA1C

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.

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 /

DiabetesHypertensionDyslipidaemia

Concept of “The Metabolic syndrome”

Diabetes mellitus

Obesity

Hypertension

Fatty Liver

Insulin Resistance

Mixed dyslipoproteine

mia

(FCHL)

Coronary Heart Disease

Adult Treatment Panel III (ATPIII) Operational Definition of Metabolic SyndromeOccurrence 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 HgElevated Triglycerides > 150mg/dlLow HDL cholesterolMicroalbuminuria

Prevalence of the Metabolic Syndrome

EGIR % ATPIII % IDF %

Women(n=289)

6 7 8

Men(n=279)

13 18 19

IDF

EGIRATPIII

14.7

2.7

22.1

11

11.9

20.2

17.4

IDF

EGIRATPIII

20.9

0

41.8

16.3

14

0

7

WomenMen

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;350:2549-2557

Etiological classification of Diabetes1. 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

InsulitisInsulitis

Type-2 Diabetes Mellitus

May range from predominantly insulin resistance to predominantly an insulin secretory defect

EnvironmentEnvironment

Low Birth WeightLow Birth Weight

ObesityObesity

GeneticGenetic

ß cell defectß cell defect

GeneticGenetic

ß cell ß cell

exhaustionexhaustion Type 2 DMType 2 DM

Insulin resistanceInsulin resistance

Relative Insulin Def.Relative Insulin Def.

May requireMay require

InsulinInsulin

Secretory DefectSecretory Defect

Type 2 Diabetes

Loss of ß cellsLoss of ß cellsAmyloid Amyloid depositsdepositsHyalinizationHyalinization

Physical Activity on the decline…………..

Physical Activity on the decline…………..

Risk factors for type-2 diabetes mellitusAge > 45 yearsBMI > 25 kg/m2

Family history of diabetesHabitual physical inactivityPreviously identified impaired fasting glucose or impaired

glucose toleranceHistory of gestational diabetes mellitus or delivery of baby

weighing > 3.5 kgHypertension > 140/90 mm HgTriglyceride level > 250 mg/dLClinical conditions associated with insulin resistance

(Polycystic ovary syndrome)History of vascular disease

LADA(Latent Autoimmune Diabetes of the Adult)

Other Specific TypesA. 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 Mutant Gene

MODY-1 hepatocyte nuclear factor 4α, chromosome 20

MODY-2 Glucokinase, chromosome 7

MODY-3 hepatocyte nuclear factor 1α, chromosome 12

MODY-4 insulin promoter factor-1, chromosome 13

MODY-5 hepatocyte nuclear factor 1β, chromosome 17

MODY-6 neurogenic differentiation 1, chromosome 2

MODY-2 and MODY-3 are most common, but in India MODY-1 is common.

Usually Nonketotic /NonobeseOften in successive generationsClinical course: resembles a a mild version of type-1

diabetes mellitus. Diagnostic criteria: (a) Mild to moderate hyperglycemia

(130-250 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 geneWolframin 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 diabetesCharacterized 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 syndromeInsulin receptor disorderSevere insulin resistanceDevelopmental abnormalitiesAcanthosis nigricansHypertrophic 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. 1990 86:254-64;

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 targetso HbA1C: <6.5%o Fasting glucose: 90-130 mg/dLo Postprandial glucose: <180 mg/dLBlood Pressure: <130 / 80 mm HgLipidso LDL cholesterol: <100 mg / dLo Triglycerides: <150 mg / dLo 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 interpretationo Normal: 4.5 – 5.5%o Serious risk of hyoglycemia: <4.5%o Diabetic range: >6%

Approximate correlation between HbA1c and mean plasma glucose levelsHb A1C%

Mean plasma glucose (mg/dl)

6 135

7 170

8 205

9 240

10 275

11 310

12

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

Tests Time to visitBlood Glucose Controlled (HbA1c < 6.5%) every 3

monthsUncontrolled: every 2 weeks until target sugars achieved

HbA1c Controlled (HbA1c < 6.5%): 6 -12 monthsUncontrolled: every 3 months

Tests for neuropathyMonofilamentBiothesiometerFoot Examination

AnnualAnnualOnce in 3 months

Follow up of patients and frequency of testingTests Time to visitTests for retinopathyFundus examination

If retinopathy detected at first visit, follow-up every 3-6 months. Otherwise annually.

Tests for nephropathyUrinary microalbumin(or 24 h urinary protein excretion)Serum creatinine

Annual

Annual

Miscellaneous testsElectrocardiogramLipid ProfilePlain X-ray abdomen

AnnualAnnualIf BMI < 20 kg / m2

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 2nd OHA

Maximize the dose of 2nd OHA; add on 3rd OHA

Maximize the dose of 3rd OHA; reinforce diet and exercise

Add Insulin to existing OHA therapy

HbA1c: >7.5%

HbA1c > 7.5%

HbA1c: >8.5%

HbA1c: >8.5%

General Indications for use of Oral hypoglycemic agent

Drug Indication Contraindication

Metformin BMI > 23 kg/m2, Insulin resistance, Dyslipidemia, high fasting blood glucose

>80 years old, any major organ failure, factors predisposing to lactic acidosis

Sulfonylureas Relative insulin deficiency, thin patients, postprandial hyperglycemia

Frequent hypoglycemia, marked weight gain

Thiazolidinediones

Insulin resistance, dyslipidemia

Peripheral edema, CHF (III/IV), marked wt gain

Repaglinide/Nateglinide

Relative insulin deficiency. Flexible meal schedule, hepatic or renal insufficiency

Hyperglycemia > 350 mg/dl, weight gain

Alpha glucosidase inhibitor

Postprandial hyperglycemia

Lower gastrointestinal disturbances

Clinical Scenarios

CASE 136 year old Mr. R who had his blood glucose

levels checked since he had a family history of diabetes

BMI : 31 kg/m2 His fasting plasma glucose (FPG) was 118 mg%,

2hr postprandial blood glucose was 155 mg%.

DIAGNOSIS ?

Case 220 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/m2 . 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/m2. Urine ketones: negative.Glycemic control for first one year achieved

with Oral hypoglycemia agents. Required insulin thereafter.

GAD antibodies were positiveWhat 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