Diabetes Mellitus

Talya Wolak

Overview

• Diabetes mellitus is a chronic disorder characterized by the impaired metabolism of glucose

• Late development of vascular and neuropathic complications

Classification

• Type 1 -A. Immune-mediated

 B. Idiopathic

• Type 2

• Other specific types

• Gestasional diabetes mellitus

Other Specific Types Of Diabetes

• Endocrinopathies—acromegaly, cushing's syndrome, glucagonoma, pheochromocytoma, hyperthyroidism, somatostatinoma, aldosteronoma

• Genetic defects of cell function –MODY• Drug- or chemical-induced—Vacor,

pentamidine, nicotinic acid, glucocorticoids, thyroid hormone, diazoxide, -adrenergic agonists, thiazides, phenytoin, -interferon, protease inhibitors, clozapine, beta blockers

How To Define Diabetes?

• The spectrum of fasting plasma glucose and the response to an oral glucose load varies among normal individuals

• DM is defined as the level of glycemia at which diabetes-specific complications occur

Terminology

• Diabetes Mellitus -DM

• Fasting plasma glucose -FPG

• Impaired fasting glucose –IFG

• Impaired glucose tolerance –IGT

Diagnostic Criteria For DM

• FPG at or above 126 mg/dL• A two-hour value in an OGTT (2-h PG) at

or above 200 mg/dL • A random plasma glucose concentration

200 mg/dL in the presence of symptoms.

Normal IGF&IGT Diabetes Mellitus

FPG<100 mg/dL

IGF- FPG :100-126 mg/dL

FPG>=126 mg/dL

2H-PG<140 mg/dL

IGT - 2H-PG: 140-200 mg/dL

2H-PG>=200 mg/dL

PG>200 + SYMPTOMS

Impaired Glucose Tolerance -IGT

• Category between normality and diabetes

• Subjects with IGT are at increased risk of developing overt diabetes and atherosclerotic vascular disease

Con…

• Abnormalities on screening tests for diabetes should be repeated before making a definitive diagnosis of DM

• Unless acute metabolic derangements or a markedly elevated plasma glucose are present

Type 2 DM Screening

• The FPG as a screening test for type 2 DM is recommended

Why ?

• Type 2 DM may be present for up to a decade before diagnosis

• A large number of individuals who meet the current criteria for DM are asymptomatic.

• 50% of individuals with type 2 DM have one or more diabetes-specific complications at the time of their diagnosis

• Treatment of type 2 DM may favorably alter the natural history of DM

Type I DM Screening

• Screening for type 1 DM is no recommended

• In contrast to type 2 DM, a long asymptomatic period of hyperglycemia is rare prior to the diagnosis of type 1 DM

Prevalence of DM

• Has risen dramatically over the past two decades

• The prevalence of both type 1 and type 2 DM is increasing worldwide

• The prevalence of type 2 DM is expected to rise more - increasing obesity and reduced activity levels

Type IA Pthogenesis

Decline

• Beta cell mass then begins to decline, and insulin secretion becomes progressively impaired, although normal glucose tolerance is maintained .

• Residual functional beta cells still exist but are insufficient in number to maintain glucose tolerance.

• The events that trigger the transition from glucose intolerance to frank diabetes: associated with increased insulin requirements, as infections or puberty.

• Features of diabetes do not become evident until a majority of beta cells are destroyed ( 80%).

"Honeymoon" Phase

• Time glycemic control is achieved with modest doses of insulin or, rarely, insulin is not needed.

• fleeting phase of endogenous insulin production from residual beta cells disappears as the autoimmune process destroys the remaining beta cells

• The individual becomes completely insulin deficient

Genetic Factor

• Genetic susceptibility to type 1A DM involves multiple genes.

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

• The risk of developing type 1A DM is increased tenfold in relatives of individuals with the disease

Autoimmune Factors

• The pancreatic islets are infiltrated with lymphocytes - Insulitis

• Pancreatic islet molecules targeted by the autoimmune process include insulin, glutamic acid decarboxylase

Immunologic Markers -ICAs

• Islet cell autoantibodies (ICAs) - different antibodies directed at pancreatic islet molecules: GAD, insulin, IA-2/ICA-512, and an islet ganglioside

• Serve as a marker of the autoimmune process of type 1A DM.

• Assays for autoantibodies to GAD-65 are available.

Testing for ICAs

• Classifying the type of DM as type IA

• Identifying nondiabetic individuals at risk for developing type 1A DM

ICAs Are Present :

• In individuals diagnosed with new-onset type 1A DM (>75%)

• In individuals with newly diagnosed type 2 DM (5 to 10%)

• Individuals with GDM (<5%)

• 3 to 4% of first-degree relatives of individuals with type 1A DM

Markers

• Genetic markers -present from birth

• Immune markers - after the onset of the autoimmune process

• Metabolic markers can be detected with sensitive tests once enough beta-cell damage, but before the onset of symptomatic hyperglycemia

Prediction Of Type 1A DM

• ICAs In combination with impaired insulin secretion after intravenous glucose tolerance testing, they predict a >50% risk of developing type 1A DM within 5 years

Environmental Factors

• Trigger the autoimmune process in genetically susceptible individuals

• Viruses (coxsackie and rubella most prominently), bovine milk proteins

• None have been conclusively linked to diabetes

Prevention of Type 1A DM

• Though results in animal models are promising

• have not been successful in preventing type 1A DM in humans.

• The Diabetes Prevention Trial—type 1 recently concluded that administering insulin to individuals at high risk did not prevent type 1A DM

Type II Pthogenesis

Type 2 DM

1. Insulin resistance

2. Abnormal insulin secretion

• Insulin resistance precedes insulin secretory defects

• Diabetes develops only if insulin secretion becomes inadequate

Genetic Considerations

• Type 2 DM has a strong genetic component.

• Major genes that predispose to this disorder have yet to be identified

• The disease is polygenic and multifactorial

• Insulin resistance is present in many nondiabetic, first-degree relatives of individuals with type 2 DM

Some Numbers

• The concordance of type 2 DM in identical twins is between 70 and 90%

• If both parents have type 2 DM, the risk approaches 40%

Pathophysiology -Type 2 DM

• Peripheral insulin resistance

• Impaired insulin secretion

• Excessive hepatic glucose production

Insulin Resistance

• Insulin resistance is a state in which a given concentration of insulin is associated with a subnormal glucose response

Early Stages

• Insulin resistance

• Pancreatic beta cells compensate by increasing insulin output - hyperinsulinisim

• Glucose tolerance remains normal

Impaired Glucose Tolerance

• As insulin resistance and compensatory hyperinsulinemia progress

• Pancreatic islets are unable to sustain the hyperinsulinemic state - Impaired insulin secretion

• IGT- elevations in postprandial glucose develops

Diabetes Mellitus

• A further decline in insulin secretion

• An increase in hepatic glucose production

• Fasting hyperglycemia

• Overt diabetes mellitus

In The End…

• Ultimately, beta cell failure may ensue. Markers of inflammation such as IL-6 and C-reactive protein are often elevated in type 2 diabetes

• May become insulin deficient

Insulin Resistance

• The decreased ability of insulin to act effectively on peripheral target tissues - muscle and liver

• Prominent feature of type 2 DM

• Results from a combination of genetic susceptibility and obesity

• Supernormal levels of circulating insulin will normalize the plasma glucose

• Reduced sensitivity, and a reduced maximal response, indicating an overall decrease in maximum glucose utilization (30 to 60% lower than normal individuals).

Insulin Resistance-hyperglycemia

1. Impairs glucose utilization by insulin-sensitive tissues

2. Increases hepatic glucose output

• Both effects contribute to the hyperglycemia.

FPG Versus IGT

• Increased hepatic glucose output predominantly accounts for increased FPG levels

• Decreased peripheral glucose usage results in postprandial hyperglycemia - IGT

Molecular Mechanism Of Insulin Resistance

• Insulin receptor levels and tyrosine kinase activity in skeletal muscle are reduced, - not primary defect

• Postreceptor defects are believed to play the predominant role in insulin resistance

Free Fatty Acids

• Free fatty acids a common feature of obesity :

1. Can impair glucose utilization in skeletal muscle

2. Promote glucose production by the liver

3. Impair beta cell function

Obesity

Obesity

• Visceral or central obesity (as evidenced by the hip-waist ratio), is very common in type 2 DM.

• Adipocytes secrete a number of biologic products (leptin, TNF- , free fatty acids, resistin, and adiponectin)

• Modulate insulin secretion, insulin action, and body weight contribute to the insulin resistance.

Impaired Insulin Secretion

• Insulin secretion initially increases in response to insulin resistance to maintain normal glucose tolerance

• The insulin secretory defect progresses to a state of grossly inadequate insulin secretion

Why?

• Excluded mutations in islet candidate genes

• Islet amyloid polypeptide found in the islets of individuals with long-standing type 2 DM

• Glucose toxicity

• Lipotoxicity

Glucose Toxicity& Lipotoxicity

• Chronic hyperglycemia paradoxically impairs islet function

• Leads to a worsening of hyperglycemia.

• Improvement in glycemic control associated with improved islet function

• Elevation of free fatty acid levels and dietary fat also worsen islet function.

Increased Hepatic Glucose Production

• Insulin resistance in the liver - failure of hyperinsulinemia to suppress gluconeogenesis

• Fasting hyperglycemia

• Decreased glycogen storage by the liver in the postprandial state

• Insulin secretory abnormalities

• Insulin resistance in skeletal muscle.

• Increased hepatic glucose production .

Insulin Resistance Syndromes

• The metabolic syndrome

• The insulin resistance syndrome

• Syndrome X

Definition

• The presence of any three of the following traits:

1. Abdominal obesity- a waist circumference in men >102 cm and in women >88 cm

2. Serum triglycerides 150 mg/dL

3. Serum HDL cholesterol <40 mg/dL in men and <50 mg/dL in women.

Definition con.

4. Blood pressure >130/85 mmHg.

5. Fasting plasma glucose > 110 mg/dL

Rare Forms Of Severe Insulin Resistance

• Include features of type 2 DM or IGT

• Type A- young women

• Type B- middle-aged women

• Severe hyperinsulinemia, obesity, and features of hyperandrogenism

Polycystic Ovary Syndrome PCOS

• Premenopausal women - chronic anovulation and hyperandrogenism

• Insulin resistance

• Increases the risk for type 2 DM.

• Both metformin and the thiazolidinediones attenuate hyperinsulinemia, ameliorate hyperandrogenism, induce ovulation, and improve plasma lipids

Prevention in IGT

• Intensive changes in life-style in individuals with :

1. Diet

2. Exercise for 30 min/day five times/week

• Prevented or delayed the development of type 2 diabetes by 58% compared to placebo

Prevention in IGT con.

• Metformin prevented or delayed diabetes by 31% compared to placebo

For Who?

• Strong family history

• IFG or IGT

• Strongly encouraged to maintain a normal body mass index (BMI) and engage in regular physical activity.