DIABETES DIABETES

MELLITUSMELLITUSMELLITUSMELLITUS

Definition, classification and Definition, classification and

pathogenesispathogenesis

�� 20.8 million Americans have diabetes20.8 million Americans have diabetes

�� 1.5 million new cases in 2005 more than 1.5 million new cases in 2005 more than

3500 each day3500 each day

�� Complications of diabetes are a major Complications of diabetes are a major

Diabetes Today: An EpidemicDiabetes Today: An Epidemic

�� Complications of diabetes are a major Complications of diabetes are a major

cause of mortality and morbidity (2002 cause of mortality and morbidity (2002

statistics)statistics)

90% of patients with diabetes are treated by 90% of patients with diabetes are treated by

primary care physiciansprimary 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

Japan

Bangladesh

Brazil

Adapted from Wild SH et al. Diabetes Care 2004; 27: 2569–70.

People with diabetes (millions)

0 20 40 60 80 100

Brazil

Pakistan

Indonesia

USA

China

India

Definition of diabetes

Diabetes mellitus is characterized by

chronic hyperglycemia with

disturbances of carbohydrate, fat, and

protein metabolism resulting from protein metabolism resulting from

defects in insulin secretion, insulin

action, or both.

Definition of diabetesDefinition of diabetes

Chronic hyperglycaemia associated Chronic hyperglycaemia associated

with longwith long--term damage to:term damage to:

•• EyesEyes•• EyesEyes

•• KidneysKidneys

•• NervesNerves

•• Heart and blood vesselsHeart and blood vessels

CLASSIFICATION OF DIABETES

MELLITUS

1. Type 1 diabetes (cell destruction, usually leading to absolute insulin deficiency)

2. Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance)

3. Other specific types of diabetes

4. Gestational diabetes mellitus (GDM)

Insulin

Gluconeogenesis

Glycogenolysis

Glycogen synthesis

Insulin and glucose disposalInsulin and glucose disposal

Glucose uptakeGlycogen synthesis

Blood glucose

Free fatty acid release

Type 1 diabetes

�� Insulin deficiency secondary to Insulin deficiency secondary to ββ--cell cell destruction usually by autoimmune processdestruction usually by autoimmune process

�� Insulin and CInsulin and C--peptide levels lowpeptide levels low

�� May have islet cell autoantibodies, May have islet cell autoantibodies, �� May have islet cell autoantibodies, May have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine glutamic acid decarboxylase or tyrosine phosphatases. phosphatases.

�� 20% risk of other autoimmune diseases20% risk of other autoimmune diseases

�� Typically will present with DKA due to absolute Typically will present with DKA due to absolute lack of insulinlack of insulin

Glucose uptake

Glycogenolysis

Gluconeogenesis (amino acids)

Ketone production (fatty acids)

Blood glucose

Insulin deficiency in Insulin deficiency in

type 1 diabetestype 1 diabetes

Glucose uptakeProtein degradation → amino acids

Blood glucose

Triglyceride degradation → fatty acids

Pathogenesis of type 1 diabetes

• Genetic susceptibility

• Immune factors– other autoimmune disease– antigen-specific antibodies– antigen-specific antibodies

• Environmental trigger– viruses– bovine serum albumin– nitrosamines: cured meats– chemicals: vacor (rat poison),

streptozotin

Beta-cell

Pathogenesis of type 1 Pathogenesis of type 1

diabetesdiabetesTrigger

GeneticImmunological abnormalities

Beta-cell mass

Time (months - years)

Pre-diabetes ‘Honeymoon’

Chronic phase

Clinical diabetes

Idiopathic type 1 diabetesIdiopathic type 1 diabetes

NonNon--autoimmune type 1 diabetesautoimmune type 1 diabetes

�� No autoimmune markersNo autoimmune markers

�� Permanent insulinopeniaPermanent insulinopenia

�� KetoacidosisKetoacidosis

�� People of African and Asian originPeople of African and Asian origin

Type 2 diabetes

• 90%-95% of people with diabetes

• Insulin insensitivity and • 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 • Poor fetal nutrition → ↓ beta-cell formation

• Low birth weight/weight change

• “Thrifty gene”

• 7% beta-cell loss

Epidemiology of type 2 Epidemiology of type 2

diabetesdiabetes

• Dramatic increase

• Aging population

• Disturbing trends parallel obesity • 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

Type 2 Diabetes: Two Principal DefectsType 2 Diabetes: Two Principal Defects

Insulin resistanceββββ-cell dysfunction/

failure

GenesGenes

Reaven GM. Physiol Rev. 1995;75:473-486

Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;

Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.

±Environment ± Environment

IGT IGT

Type 2 diabetesGlucose

Toxicity

Glucose

Toxicity

Insulin insensitivity in ttype 2 diabetes

Glycogenogenosis

Glycolysis

Gluconeogenesis LipogenesisGlycolysis

Liver Fat tissues Muscles

Gluconeogenesis Lipogenesis

LipolysisGlycogenogenesis

Glycolysis

FFA

Hyperglycaemia

Glucose Storage ↓↓↓↓Glucose production ↑↑↑↑

Possible Mechanisms for Possible Mechanisms for

Decline of Decline of ββββββββ--Cell FunctionCell Function

“Glucose Toxicity”(Hyperglycemia)

•Genetic factors Insulin resistance•Genetic factors•Amyloid deposits•Proinsulin cleavage•Hexosamines•TNF-α•AGEs

β-cell

Insulin resistance

“Lipotoxicity”(Elevated FFA, TG)

Adapted from Reaven GM. Physiol Rev 1995;75:473–486.

Pancreatic ββββ-cell Insulin resistance

Liver

Islet β-cell degranulation

Increased

lipolysis

Elevated plasma FFA

+ - Elevated

Insulin resistance and β-cell dysfunction

produce hyperglycaemia in type 2 diabetes

HYPERGLYCAEMIA

Islet β-cell degranulation

Reduced insulin content

Adipose tissue

Decreased glucose transport

& activity (expression) of GLUT-4

-

Low plasma

insulin

Increased glucose output

ElevatedTNFαααα

Modified from: Turner N, Clapham JC. Prog Drug Res 1998;51:34–94

Development of type 2 diabetesDevelopment of type 2 diabetes

Fasting glucose

Glucose tolerance

Hyperglycemia

Abnormalglucose tolerance

I II III IV V

Normal IGT Type 2 diabetes

Insulin sensitivity

Insulinsecretion

Decreased insulinsensitivity

Hyperinsulinemia,then β-cell failure

Genetics

Environment

• nutrition

• obesity

• exercise

Natural History of Type 2 Natural History of Type 2

DiabetesDiabetes

Onset of

diabetes

Disability

Impaired

Complications

RetinopathyRetinopathyNephropathyNephropathyNeuropathyNeuropathy

BlindnessBlindnessRenal failureRenal failure

Insulin resistanceHyperinsulinemiaHypertensionDecreased HDL-CIncreased TG Atherosclerosis

Coronary diseaseLE amputation

Death

Impaired

glucose

tolerance

Ongoing

hyperglycemia

Impaired entry of glucose into the cellsAccumulation of glucose in the blood

Plasma osmolarity ⇑Inability of the cellsutilize glucose

Pathophysiology Pathophysiology

Cellular starvation

Stimulating hunger

Urinary loss of glucose⇑⇑⇑⇑

Loss of water and Na

Dehydration of cells

Compensatory mechanismSuch as thirst

Lipolysis andproteolysis

Body weight

Common SymptomsCommon Symptoms

Classic symptomsClassic symptoms

�� increased hungerincreased hunger

�� increased thirstincreased thirst

�� frequent urinationfrequent urination

Others symptomsOthers symptoms

�� fatigue fatigue

�� tingling or numbness in tingling or numbness in hands and feethands and feet

�� recurring infectionsrecurring infections�� frequent urinationfrequent urination

�� weight lossweight loss

�� recurring infectionsrecurring infections

•• gums, skin, lung, urinary gums, skin, lung, urinary bladderbladder

�� slow healingslow healing

�� blurred visionblurred vision

�� pruritus vulvaepruritus vulvae

�� erectile dysfunctionerectile dysfunction

ADA definition of hyperglycaemic statesADA definition of hyperglycaemic states

Criteria for the diagnosis of diabetes

Symptoms of diabetes plus casual plasma glucose ≥≥≥≥ 200 mg/dl (11.1 mmol/l)

FPG

< 100 mg/dl (5.6 mmol/l) normal fasting glucose

100–125 mg/dl (5.6–6.9 mmol/l) impaired fasting glucose

or

ADA = American Diabetes Association

OGTT 2-h post-load glucose

< 140 mg/dl (7.8 mmol/l) normal glucose tolerance

140–199 mg/dl (7.8–11.1 mmol/l) impaired glucose tolerance

≥≥≥≥ 200 mg/dl (11.1 mmol/l) diabetes

Adapted from American Diabetes Association. Diabetes Care 2004; 27:S5–S10.

≥≥≥≥ 126 mg/dl (7.0 mmol/l) diabetes

or

Classic symptoms (+)

Fasting BG > 126 mg/dl Fasting BG < 126 mg/dl

(casual BG > 200) (casual BG <200)

Repeat BG

.

Fasting BG < 126 or Fasting BG >126 or

DIABETES MELLITUS OGTT

Diagnosis of type 2 Diabetes

Mellitus

Fasting BG < 126 or

Casual BG < 200Fasting BG >126 or

Casual BG > 200

Impaired glucose toleranceImpaired glucose tolerance

Impaired fasting glucoseImpaired fasting glucose

�� Intermediate statesIntermediate states

�� Increased risk of developing Increased risk of developing �� Increased risk of developing Increased risk of developing

diabetes diabetes

�� Prevention strategies to prevent or Prevention strategies to prevent or

delay progressiondelay progression

�� Increased risk of cardiovascular Increased risk of cardiovascular

diseasedisease

Uncertain diagnosis:Uncertain diagnosis:

Oral glucose tolerance testOral glucose tolerance test

�� 75 g glucose load after 8 hours 75 g glucose load after 8 hours

fastingfastingfastingfasting

�� Readings taken in fasting state Readings taken in fasting state

and at 1 and 2 hoursand at 1 and 2 hours

�� Urinary ketonesUrinary ketones

AntibodiesAntibodies

Tests for differential Tests for differential

diagnosisdiagnosis

�� AntibodiesAntibodies

�� CC--peptidepeptide

Other specific types of diabetes

A. Genetic defects of B-cell function� Chromosome 12, HNF-1 (MODY3); Chromosome 7,

glucokinase (MODY2); Chromosome 20, HNF-4 (MODY1); Chromosome 13, insulin promoter factor-1 (IPF-1; MODY4); Chromosome 17, HNF-1 (MODY5); Chromosome 2, NeuroD1 (MODY6); Mitochondrial DNA

B. Genetic defects in insulin actionB. Genetic defects in insulin action� Type A insulin resistance; Leprechaunism; Rabson-

Mendenhall syndrome; Lipoatrophic diabetes.

C. Diseases of the exocrine pancreas� Pancreatitis; Trauma/pancreatectomy; Neoplasia; Cystic

fibrosis; Hemochromatosis; Fibrocalculous pancreatopathy.

D. Endocrinopathies� Acromegaly; Cushing’s syndrome; Glucagonoma;

Pheochromocytoma; Hyperthyroidism; Somatostatinoma; Aldosteronoma.

Other specific types of diabetes

E. Drug- or chemical-induced� Vacor; Pentamidine; Nicotinic acid; Glucocorticoids; Thyroid

hormone; Diazoxide; adrenergic agonists; Thiazides; Dilantin; Interferon.

F. InfectionsCongenital rubella; Cytomegalovirus.� Congenital rubella; Cytomegalovirus.

G. Uncommon forms of immune-mediated diabetes� “Stiff-man” 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

Gestational diabetes mellitus (GDM)Gestational diabetes mellitus (GDM)

� Gestational diabetes mellitus (GDM) is carbohydrate

intolerance associated with hyperglycemia of variable

severity with the onset or first recognition during pregnancy

� Return to normal glucose regulation after delivery is

commoncommon

� 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

PathophysiologyPathophysiology

�� The pregnant woman undergoes a complex series of The pregnant woman undergoes a complex series of maternal hormonal actions (ie, a rise in blood glucose; maternal hormonal actions (ie, a rise in blood glucose; the secondary secretion of pancreatic insulin, glucagon, the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines). somatomedins, and adrenal catecholamines).

�� These hormones confer increasing tissue insulin These hormones confer increasing tissue insulin resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased resistance as their levels rise, the demand for increased insulin secretion with feeding escalates progressively insulin secretion with feeding escalates progressively during pregnancy. during pregnancy.

�� If the maternal pancreatic insulin response is If the maternal pancreatic insulin response is inadequate, maternal and, then, fetal hyperglycemia inadequate, maternal and, then, fetal hyperglycemia results. results.

�� This typically manifests as recurrent postprandial This typically manifests as recurrent postprandial hyperglycemic episodes. hyperglycemic episodes.

Gestational diabetes mellitus (GDM)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. 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 8–14 h.