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DIABETES MELLITUS

Definition, classification and pathogenesis

Modern Life Has Both Conveniences and Costs

Illustration taken from: Lambert C, Bing C. The Way We Eat Now. Harvard Magazine. May-June, 2004;50.

The Problem

Diabetes Today: An Epidemic


20.8 million Americans have diabetes 1.5 million new cases in 2005 more than 3500 each day

Complications of diabetes are a major cause of mortality and morbidity (2002 statistics)

90% of patients with diabetes are treated by primary care physicians

ADA National Diabetes Fact Sheet. Available at: http://www.cdc.gov/diabetes/pubs/pdf/ndfs_2005.pdf. Accessed April 11, 2005; ADA Diabetes Statistics. Available at http://www.diabetes.org/utils/printthispage.jsp?PageID=STATISTICS_233181. December 29, 2005.

Countries with the highest numbers of estimated cases of diabetes for 2030
Egypt Philippines Japa n Bangladesh

Brazil
Pakistan Indonesia USA China India 0 20 40 60 80 100

People with diabetes (millions)


Adapted from Wild SH et al. Diabetes Care 2004; 27: 256970.

Definition of diabetes

Characterized by hyperglycaemia
Defects in insulin production Autoimmune or other destruction of beta cells Insulin insensitivity

Impaired action of insulin on target tissues

Definition of diabetes
Chronic hyperglycaemia associated with long-term damage to:

Eyes Kidneys Nerves Heart and blood vessels

Classification

Type 1 diabetes
autoimmune LADA idiopathic Type 2 diabetes

Classification
Other specific types

MODY Defects in insulin action Diseases of the pancreas Endocrine disorders Drug- or chemical-induced Infections

Classification
Uncommon forms of immunemediated diabetes Other genetic syndromes Gestational diabetes

Insulin and glucose disposal


Gluconeogenesis Glycogenolysis Glycogen synthesis Insulin

Blood glucose

Glycogen synthesis

Glucose uptake Free fatty acid release

Insulin deficiency in type 1 diabetes

Glucose uptake Glycogenolysis Gluconeogenesis (amino acids) Ketone production (fatty acids)

Blood glucose

Glucose uptake Protein degradation amino acids


Triglyceride degradation fatty acids

Insulin insensitivity in type 2 diabetes


Glucose uptake

Glycolysis
Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake Protein degradation amino acids

Insensitivity to insulin in type 2 diabetes


Glucose uptake Glycolysis Gluconeogenesis (amino acids)

Blood glucose

Glucose uptake Protein degradation amino acids Glucose uptake

Effect of insulin resistance in type 2 diabetes


Glucose uptake Glycolysis Gluconeogenesis (amino acids)

Blood glucose

Converted to triglycerides

Glucose uptake Protein degradation amino acids Glucose uptake

Pathogenesis of type 1 diabetes Immunological activation


Progressive beta-cell destruction Insufficient beta-cell function Dependent on exogenous insulin Risk of ketoacidosis

Pathogenesis of type 1 diabetes


Genetic susceptibility Immune factors other autoimmune disease antigen-specific antibodies Environmental trigger viruses bovine serum albumin nitrosamines: cured meats chemicals: vacor (rat poison), streptozotin

Pathogenesis of type 1 diabetes


Trigger Immunological abnormalities Genetic Beta-cell mass

Clinical diabetes
Pre-diabetes Honeymoon Chronic phase Time (months - years)

Idiopathic type 1 diabetes


Non-autoimmune type 1 diabetes

No autoimmune markers Permanent insulinopenia Ketoacidosis People of African and Asian origin

Epidemiology of type 1 diabetes

Increasing in recent years Geographic variation Relative affluence

Lack of treatment

IDF Diabetes Atlas

Epidemiology of type 1 diabetes


Age of onset peaks
preschool puberty

Autumn/winter peaks

Type 2 diabetes
90%-95% of people with diabetes Insulin insensitivity and relative insulin deficiency Obesity or overweight Complications often present at diagnosis

Pathogenesis of type 2 diabetes

Multiple genes involved Hyperinsulinaemia

Poor fetal nutrition beta-cell formation


Low birth weight/weight change Thrifty gene 7% beta-cell loss

Insulin resistance and -cell dysfunction are core defects of type 2 diabetes
Genetic susceptibility, obesity, Western lifestyle

Insulin resistance

IR

-cell dysfunction

Type 2 diabetes

Rhodes CJ & White MF. Eur J Clin Invest 2002; 32 (Suppl.

Possible Mechanisms for Decline of -Cell Function


Glucose Toxicity (Hyperglycemia) Genetic factors Amyloid deposits Proinsulin cleavage Hexosamines TNF-a AGEs

Insulin resistance

-cell

Lipotoxicity (Elevated FFA, TG)

Adapted from Reaven GM. Physiol Rev 1995;75:473486.

The natural history of type 2 diabetes


Beta-cell loss Insulin requirements Primary failure Insulin requirements with age Endogenous insulin

Age (years)

The natural history of type 2 diabetes


Beta-cell loss
Hyperinsulinaemia Insulin requirements with age Endogenous insulin

Insulin requirements

Insulin insensitivity

Age (years)

The natural history of type 2 diabetes


Beta-cell loss Hyperinsulinaemia Secondary failure Effect of oral drugs Insulin requirements with age Endogenous insulin

Insulin requirements

Insulin insensitivity

Age (years)

Epidemiology of type 2 diabetes


Dramatic increase Aging population

Disturbing trends parallel obesity epidemic


Especially in adolescents and minority groups Increasing in young people

Risk factors for type 2 diabetes


Age > 40 years First-degree relative with diabetes Member of high risk population History of impaired glucose tolerance, impaired fasting glucose Vascular disease History of gestational diabetes History of delivery of macrosomic baby
CDA 2003

Risk factors for type 2 diabetes


Hypertension Dyslipidaemia Abdominal obesity Overweight Polycystic ovary disease Acanthosis nigricans Schizophrenia

Common Symptoms
Classic symptoms increased hunger increased thirst frequent urination weight loss
Others sympmtoms fatigue tingling or numbness in hands and feet recurring infections gums, skin, lung, urinary bladder slow healing blurred vision pruritus vulvae erectile dysfunction

ADA definition of hyperglycaemic states


Criteria for the diagnosis of diabetes
Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l) or
FPG < 100 mg/dl (5.6 mmol/l) 100125 mg/dl (5.66.9 mmol/l) 126 mg/dl (7.0 mmol/l) or OGTT 2-h post-load glucose < 140 mg/dl (7.8 mmol/l) 140199 mg/dl (7.811.1 mmol/l) 200 mg/dl (11.1 mmol/l)
ADA = American Diabetes Association
Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10.

normal fasting glucose impaired fasting glucose diabetes

normal glucose tolerance impaired glucose tolerance diabetes

Impaired glucose tolerance Impaired fasting glucose


Intermediate states Increased risk of developing diabetes Prevention strategies to prevent or delay progression Increased risk of cardiovascular disease

Uncertain diagnosis: Oral glucose tolerance test

75 g glucose load after 8 hours fasting Readings taken in fasting state and at 1 and 2 hours Possible problems

Tests for differential diagnosis


Urinary ketones

Antibodies
C-peptide

Gestational diabetes mellitus (GDM)

Any degree of glucose intolerance with onset during pregnancy Return to normal glucose regulation after delivery is common Increased perinatal morbidity and mortality if untreated
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

Gestational diabetes mellitus (GDM)

Diagnostic criteria for the 100-g OGTT are as follows:


95 mg/dl fasting, 180mg/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.

The test should be done in the morning after an overnight fast of 814 h.