DIABETES MELLITUS

DEFINITION,

CLASSIFICATION & AETIOPATHOGENESIS

CHAIR: Prof.Dr.B.Jayakumar.

Introduction

The prevalence of Diabetes is increasing rapidly,particularly in children and young adults.

One third of cases of Diabetes remain undiagnosed.

The burden of death and disability from Diabetes remains great despite broad advances in understanding and therapeutic techniques.

Only few patients with Diabetes broadly achieve targets for blood pressure,lipid, or glucose management.

Only few patients with Diabetes receive all the recommended annual screening evaluations for complications or preventive services.

Organised system of health care delivery can achieve better control of diabetes and its comorbidities.

Definition:

Second century understanding:

Diabetes is a dreadful affliction, not very frequent among men, being a melting down of the flesh and limbs in to urine. The patients never stop making water and the flow is incessant…….Life is short and unpleasant.

Greek Physician Aretaeus of Cappadocia

Present WHO definition:

The term diabetes mellitus describes a metabolic disorder of multiple aetiology characterized by chronic hyperglycaemia with disturbances of carbohydrate, fat and protein metabolism resulting from defects in insulin secretion, insulin action, or both.

The effects of diabetes mellitus include long-term damage, dysfunction and failure of various organs.

Diabetes mellitus may present with characteristic symptoms such as thirst, polyuria, blurring of vision, and weight loss.

In its most severe forms, ketoacidosis or a non-ketotic hyperosmolar state may develop and lead to stupor, coma and, in absence of effective treatment, death.

Often symptoms are not severe, or may be absent, and consequently hyperglycaemia sufficient to cause pathological and functional changes may be present for a long time before the diagnosis is made.

The long-term effects of diabetes mellitus include progressive development of the specific complications of retinopathy with potential blindness, nephropathy that may lead to renal failure, and/or neuropathy with risk of foot ulcers, amputation, Charcot joints, and features of autonomic dysfunction, including sexual dysfunction.

People with diabetes are at increased risk of cardiovascular, peripheral vascular and cerebrovascular disease

Several pathogenetic processes are involved in the development of diabetes. These include processes which destroy the beta cells of the pancreas with consequent insulin deficiency, and others that result in resistance to insulin action.

The abnormalities of carbohydrate, fat and protein metabolism are due to deficient action of insulin on target tissues resulting from insensitivity or lack of insulin.

Classification: Now Diabetes Mellitus is classified

on the basis of the pathogenic process that leads to hyperglycemia.

I. Type 1 diabetes A. Immune-mediated   B. Idiopathic

II. Type 2 diabetes

III. Other specific types of diabetes   A. Genetic defects of Beta cell function

characterized by mutations in:     1. Hepatocyte nuclear transcription factor

(HNF) 4alfa (MODY 1)     2. Glucokinase (MODY 2)     3. HNF-1alfa (MODY 3)     4. Insulin promoter factor-1 (IPF-1; MODY 4)     5. HNF-1beta (MODY 5)     6. NeuroD1 (MODY 6)     7. Mitochondrial DNA     8. Subunits of ATP-sensitive potassium

channel     9. Proinsulin or insulin conversion

  B. Genetic defects in insulin action

    1. Type A insulin resistance     2. Leprechaunism     3. Rabson-Mendenhall syndrome     4. Lipodystrophy syndromes C. Diseases of the exocrine

pancreas—pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy, mutations in carboxyl ester lipase

  D. Endocrinopathies— acromegaly, Cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma.

E. Drug- or chemical-induced— Vacor, pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapine

F. Infections— congenital rubella, cytomegalovirus, coxsackie.

G. Uncommon forms of immune-mediated diabetes — "stiff-person syndrome , anti-insulin receptor antibodies.

H. Other genetic syndromes sometimes associated with diabetes— Down's syndrome, Klinefelter's syndrome, Turner's syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome.

IV. Gestational diabetes mellitus (GDM)

Aetiopathogenesis:

I.Type 1 Diabetes A. Immune-mediated:

Type 1 DM is the result of interactions of Genetic Environmental & Immunological factors leading to destruction of beta cells and insulin deficiency.

Genetic factors:

Susceptibility to type 1 DM involves multiple genes

The major susceptibility gene for type 1 DM is located in the HLA region on chromosome 6.

Commonly associated haplotypes are HLA DR3 and/or DR4, DQA1*0301, DQB1*0302, and DQB1*0201.

Genetic loci contributing susceptibility to Type 1 DM are polymorphisms in the promoter region of the insulin gene, the CTLA-4 gene, interleukin-2 receptor, and PTPN22.

Although the risk of developing type 1 DM is increased tenfold in relatives of individuals with the disease, most individuals with type 1 DM do not have a first-degree relative with this disorder.

Environmental factors:

Environmental triggers include viruses (coxsackie and rubella most prominently), bovine milk proteins, and nitrosourea compounds.

Identification of an environmental trigger has been difficult because the event may precede the onset of DM by several years.

Immunologic Factors:

Following abnormalities in humoral and cellular arms of immune system have been identified.

1)Islet cell autoantibodies 2)Activated lymphocytes in islets,peripancreatic lymph nodes and systemic circulation 3) T lymphocytes that proliferate when stimulated with islet proteins; and 4) release of cytokines within the insulitis

Pancreatic islet molecules targeted by the autoimmune process include

Insulin, glutamic acid decarboxylase (GAD), ICA-512/IA-2 , and phogrin (insulin secretory granule protein).

These Genetic Environmental & Immunological factors interact leading to destruction of beta cells and insulin deficiency.

Features of diabetes do not become evident until a majority of beta cells are destroyed.

These patients may also have other autoimmune disorders such as Graves’ disease,Hashimoto’s thyroiditis, and Addison’s disease.

B. Idiopathic Some individuals who have the

clinical phenotype of type 1 DM lack immunologic markers indicative of an autoimmune process involving the beta cells.

These individuals are thought to develop insulin deficiency by unknown, nonimmune mechanisms.

II. Type 2 diabetes Environmental factors (such as

obesity, nutrition, and physical activity) in Genetic susceptible patients leads to . a)Impaired insulin secretion b)Insulin resistance c)Excessive hepatic glucose & lipid production d)Abnormal fat metabolism.

a)Impaired insulin secretion

In type 2 DM, insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance.

Eventually, the insulin secretory defect progresses to a state of grossly inadequate insulin secretion.

The reason(s) for the decline in insulin secretory capacity in type 2 DM is

1)A second genetic defect—superimposed upon insulin resistance—leads to beta cell failure. 2)Glucose toxicity - Chronic hyperglycemia paradoxically impairs islet function. 3) Lipotoxicity - Elevation of free fatty acid levels and dietary fat also worsen islet function

b)Insulin resistance

Insulin resistance, the decreased ability of insulin to act effectively on target tissues is a prominent feature of Type2 DM.

Insulin binds to receptors on target site

Receptor autophosphorylation

Recruitment of intracellular signalling molecules

Insulin Receptor Substrate(IRS) and other protein complex initiate a cascade of phosphorylation and autophosphorylation reactions resulting in metabolic and mitogenic effects of insulin.

Postreceptor defects in insulin-regulated phosphorylation/dephosphorylation plays the predominant role in insulin resistance.

The accumulation of lipid within skeletal myocytes, which may impair mitochondrial oxidative phosphorylation and reduce insulin-stimulated mitochondrial ATP production leading to insulin resistance.

Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, but these alterations are most likely secondary to hyperinsulinemia and are not a primary defect.

Insulin resistance in Liver

Failure to supress gluconeogenesis

Fasting hyperglycemia.

.

Insulin Resistance in liver

Decreased glycogen storage in

postprandial state

Postprandial hyperglycemia

Peripheral insulin resistance.

Decreased peripheral gluose usage.

Postprandial hyperglycemia.

c)Excessive hepatic glucose & lipid production:

Insulin resistance in liver Excess production of glucose.

Insulin resistance in Adipose tissue Free Fatty Acid flux from

adipocytes Increased lipid synthesis in hepatocytes.

d)Abnormal fat metabolism:

The obesity accompanying type 2 DM, is thought to be part of the pathogenic process

The adipocytes secrete a number of biologic products.

The increased production of Resistin,TNFalfa, IL-6 by adipocytes are associated with insulin resistance.

Adiponectin and Leptin secreted by adipocytes increase insulin sensitivity and are decreased in obesity.

III. Other specific types of diabetes A. Genetic defects of Beta cell function

characterized by mutations :

I. (MODY 1) : Mutation in Hepatocyte nuclear transcription (HNF) 4 alfa.

This transcription network plays a role in the early development of the pancreas.

In the pancreas these genes influence expression of, among others, the genes for insulin, the principal glucose transporter (GLUT2), and several proteins involved in glucose and mitochondrial metabolism.

MODY2: MODY 2 is due to any of several

mutations in the GCK gene on chromosome 7 for glucokinase.

Glukokinase serves as the glucose sensor for the beta cell.

These loss-of-function mutations result in a glucokinase molecule that is less sensitive or less responsive to rising levels of glucose.

3. HNF-1alfa (MODY 3) MODY 3 is caused by mutations of

the HNF1α gene, a homeobox gene on chromosome 12.

HNF1α is a transcription factor important for differentiation of beta cells.

Mutations of this gene lead to reduced beta cell mass or impaired function

4. Insulin promoter factor-1 (IPF-1; MODY 4) MODY 4 arises from mutations of the IPF1 homeobox gene on chromosome 13.

IPF1 is a transcription factor vital to the development of the embryonic pancreas.

Even in adults it continues to play a role in the regulation and expression of genes for insulin, GLUT2, glucokinase, and somatostatin

5. HNF-1 . (MODY5):

HNF1β is involved in early stages of embryonic development of several organs, including the pancreas.

Most of those who develop diabetes show atrophy of the entire pancreas, with mild or subclincal deficiency of exocrine as well as endocrine function (MODY 5).

 

6. NeuroD1 (MODY 6) MODY 6 arises from mutations of

the gene for the transcription factor referred to as neurogenic differentiation .

NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of beta cells and parts of the nervous system  

7.MitochondrialDNA:

Point mutations in mitochondrial DNA have been found to be associated with diabetes mellitus and deafness.

8. Subunits of ATP-sensitive potassium channel : Mutations in subunits of the ATP-sensitive potassium channel subunits are the major causes of permanent neonatal diabetes.

9. Proinsulin or insulin conversion:

Genetic abnormalities that result in the inability to convert proinsulin to insulin and the resultant carbohydrate intolerance have been identified

    B. Genetic defects in insulin action

    1. Type A insulin resistance:

Individuals with the type A insulin resistance syndrome have an undefined defect in the insulin-signaling pathway

   

 2. Leprechaunism

and 3. Rabson-Mendenhall syndrome

are two paediatric syndromes that

have mutations in the insulin receptor gene with subsequent alterations in insulin receptor function and extreme insulin resistance.

C. Diseases of the pancreas :

Any process that diffusely injures the pancreas can cause diabetes pancreas:

pancreatitis, pancreatectomy, neoplasia, cystic fibrosis, hemochromatosis, fibrocalculous pancreatopathy.

D. Endocrinopathies—

Several hormones (e.g. growth hormone, cortisol, glucagon,

epinephrine) antagonize insulin action.

Diseases associated with excess secretion of these hormones can cause diabetes.

(e.g. Acromegaly, Cushing’s Syndrome, Glucagonoma and Phaeochromocytoma).

These forms of hyperglycaemia typically resolve when the hormone excess

is removed.

E. Drug- or chemical-induced DM: Many drugs can impair insulin

secretion. These drugs may not, by themselves,

cause diabetes but they may precipitate

diabetes in persons with insulin resistance.

Vacor, pentamidine, can permanently destroy pancreatic beta cells.

Nicotinic acid, glucocorticoids, can impair insulin action.

F. Infections—

Certain viruses have been associated with beta–cell destruction.

Congenital rubella, cytomegalovirus, coxsackie, adenovirus and mumps have been implicated in inducing the disease.

G. Uncommon forms of immune-mediated diabetes —

"stiff-person syndrome and anti-insulin receptor antibodies.

The “stiff person syndrome” is an autoimmune disorder of the central nervous system, characterized by stiffness of the axial muscles with painful spasms (87). Affected people usually have high titresof the GAD autoantibodies and approximately one-half will

develop diabetes.

Anti–insulin receptor antibodies occasionally found in patients with systemic lupus erythematosus and other autoimmune diseases can cause diabetes by

binding to the insulin receptor.  

Other genetic syndromes sometimes associated with diabetes—

Many genetic syndromes are accompanied by an increased incidence of diabetes mellitus.

These include the chromosomal abnormalities of Down’s syndrome,Klinefelter’s syndrome and Turner’s syndrome, Wolfram's syndrome, Friedreich's ataxia, Huntington's chorea, Laurence-Moon-Biedl syndrome, myotonic dystrophy, porphyria, Prader-Willi syndrome.

IV. Gestational diabetes mellitus (GDM)

Gestational diabetes is carbohydrate intolerance resulting in hyperglycaemia of variable severity with onset or first

recognition during pregnancy. It does not exclude the possibility

that the glucose intolerance may antedate pregnancy but has been previously unrecognized.

Insulin resistance related to the metabolic changes of late pregnancy, and

The increased insulin requirements may lead to IGT .  

Screening & Diagnosis SCREENING FOR DIABETES: Recommendations: The ADA recommends screening of all

individuals >45 years every 3 years. screening individuals at an earlier

age if they are overweight [body mass index (BMI) > 25 km/m2] and have one additional risk factor for diabetes

Risk Factors for Type 2 Diabetes Mellitus

Family history of diabetes (i.e., parent or sibling with type 2 diabetes)

Obesity (BMI 25 kg/m2) Habitual physical inactivity Race/ethnicity (e.g., African American, Latino,

Native American, Asian American, Pacific Islander) Previously identified IFG or IGT History of GDM or delivery of baby >4 kg (>9 lb) Hypertension (blood pressure 140/90 mmHg) HDL cholesterol level <35 mg/dL (0.90 mmol/L)

and/or a triglyceride level >250 mg/dL (2.82 mmol/L)

Polycystic ovary syndrome or acanthosis nigricans History of vascular disease

● To screen for diabetes/pre-diabetes, either

An FPG test or 2-h OGTT (75-g glucose load) or both are

appropriate.

(B) An OGTT may be considered in patients with IFG to better define the risk

of diabetes.

Immunolical markers: In contrast to type 2 DM, a long asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM. A number of immunologic markers for type 1 DM are becoming available (discussed below), but their routine use is not recommended now.

Diagnosis of Diabetes: ADA Criteria for the diagnosis of

diabetes 1. Symptoms of diabetes and a casual

plasma glucose 200 mg/dl (11.1 mmol/l).

OR 2. FPG 126 mg/dl (7.0 mmol/l). OR 3. 2-h plasma glucose 200 mg/dl

(11.1 mmol/l) during an OGTT. (75gm)

WHO Criteria for diagnosis of diabetes mellitus

Diabetes:

Fasting > 7.0 (> 126)Or 2-h post glucose load > 11.1 (> 200)or both Impaired Glucose Tolerance (IGT): Fasting (if measured) < 7.0 (< 126) & 2-h post glucose load > 7.8 (> 140) & <

11.1(<200)

Impaired Fasting Glycaemia (IFG): Fasting > 6.1 (> 110) & < 7.0 (<

126) and (if measured) 2-h post glucose load < 7.8 (< 140

Some investigators have advocated the hemoglobin A1C (A1C) as a diagnostic test for DM.

Though there is a strong correlation between elevations in the plasma glucose and the A1C , the relationship between the FPG and the A1C in individuals with normal glucose tolerance or mild glucose intolerance is less clear, and thus the use of the A1C is not currently recommended to diagnose diabetes.

III. DETECTION AND DIAGNOSIS OF GDM

Recommendations:

● Screen for diabetes in pregnancy using

risk factor analysis and, if appropriate,use of an OGTT.

The OGTT should be done in the morning after an overnight fast of 8–14 h.

● Risk assessment for GDM should be undertaken at the first prenatal visit.

Women with clinical characteristics consistent with a high risk for GDM (those with marked obesity, personal history of GDM, glycosuria, or a strong family history of diabetes) should undergo glucose testing as soon as possible.

An FPG _126 mg/dl or a casual plasma glucose _200 mg/dl meets the threshold for the diagnosis of diabetes

High-risk women not found to haveGDM at the initial screening and average-risk women should be tested between 24 and 28 weeks of gestation.

Testing should follow one of two approaches:

● One-step approach: perform a

diagnostic 100-g OGTT ● Two-step approach: perform an initial screening by measuring the plasma or

serum glucose concentration 1 h after a 50-g oral glucose load (glucose challenge test) and perform a diagnostic 100-g OGTT on that subset of women exceeding the glucose threshold value on the glucose challenge test.

When the two-step approach is used, a glucose threshold value _140 mg/dl identifies 80% of women with GDM, and the yield is further increased to 90% by using a cutoff of _130 mg/dl.

criteria for the 100-g OGTT are as follows: _95 mg/dl fasting, _180 mg/dl at 1 h, _155 mg/dl at 2 h, and _140 mg/dl at 3 h. Two or more of the plasma glucose values must be met or exceeded for a positive diagnosis.

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