DIABETES MELLITUS

Definition, classification and pathogenesis

20.8 million Americans have diabetes1.5 million new cases in 2005 more than 3500 each dayComplications of diabetes are a major cause of mortality and morbidity (2002 statistics)90% of patients with diabetes are treated by primary care physiciansDiabetes Today: An EpidemicADA 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 2030Adapted from Wild SH et al. Diabetes Care 2004; 27: 256970.

Definition of diabetesDiabetes mellitus is characterized by chronic hyperglycemia with disturbances of carbohydrate, fat, and protein metabolism resulting from defects in insulin secretion, insulin action, or both.

Definition of diabetesChronic hyperglycaemia associated with long-term damage to:EyesKidneysNervesHeart and blood vessels

CLASSIFICATION OF DIABETES MELLITUS

Type 1 diabetes (cell destruction, usually leading to absolute insulin deficiency)Type 2 diabetes (ranging from predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance)Other specific types of diabetesGestational diabetes mellitus (GDM)

InsulinGluconeogenesisGlycogenolysisGlycogen synthesis Glucose uptakeGlycogen synthesisBlood glucoseInsulin and glucose disposal Free fatty acid release

Type 1 diabetesInsulin deficiency secondary to -cell destruction usually by autoimmune processInsulin and C-peptide levels lowMay have islet cell autoantibodies, Autoantibodies to insulin, or antibodies to glutamic acid decarboxylase or tyrosine phosphatases. 20% risk of other autoimmune diseasesTypically will present with DKA due to absolute lack of insulin

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

Blood glucoseInsulin deficiency in type 1 diabetes Triglyceride degradation fatty acids

Pathogenesis of type 1 diabetesGenetic susceptibility

Immune factorsother autoimmune diseaseantigen-specific antibodies

Environmental triggervirusesbovine serum albuminnitrosamines: cured meatschemicals: vacor (rat poison), streptozotin

Beta-cell massPathogenesis of type 1 diabetesTime (months - years)TriggerGeneticPre-diabetesHoneymoonChronic phaseClinical diabetesImmunological abnormalities

Idiopathic type 1 diabetesNon-autoimmune type 1 diabetes

No autoimmune markersPermanent insulinopenia

Ketoacidosis

People of African and Asian origin

Type 2 diabetes90%-95% of people with diabetes

Insulin insensitivity and relative insulin deficiency

Obesity or overweight

Complications often present at diagnosis

Pathogenesis of type 2 diabetesMultiple genes involved

Hyperinsulinaemia

Poor fetal nutrition beta-cell formation

Low birth weight/weight change

Thrifty gene

7% beta-cell loss

Epidemiology of type 2 diabetesDramatic increase

Aging population

Disturbing trends parallel obesity epidemic

Especially in adolescents and minority groups

Increasing in young people

Risk factors for type 2 diabetesAge > 40 years First-degree relative with diabetesMember of high risk populationHistory of impaired glucose tolerance, impaired fasting glucoseVascular diseaseHistory of gestational diabetes History of delivery of macrosomic baby

CDA 2003

Type 2 Diabetes: Two Principal DefectsReaven GM. Physiol Rev. 1995;75:473-486Reaven GM. Diabetes/Metabol Rev. 1993;9(Suppl 1):5S-12S;Polonsky KS. Exp Clin Endocrinol Diabetes. 1999;107 Suppl 4:S124-S127.

Insulin insensitivity in type 2 diabetesGlycogenogenosisGlycolysis GluconeogenesisLipogenesis

Lipolysis Glycogenogenesis GlycolysisLiverFat tissuesMusclesFFAHyperglycaemiaGlucose Storage Glucose production

Possible Mechanisms for Decline of -Cell FunctionGlucose Toxicity(Hyperglycemia)Genetic factorsAmyloid depositsProinsulin cleavageHexosaminesTNF-aAGEs

b-cellInsulin resistanceLipotoxicity(Elevated FFA, TG)Adapted from Reaven GM. Physiol Rev 1995;75:473486.

Pancreatic -cell Insulin resistanceLiverHYPERGLYCAEMIAIslet -cell degranulation Reduced insulin contentAdipose tissue Decreased glucose transport & activity (expression) of GLUT-4Increased lipolysisElevated plasma FFA+-Low plasmainsulinIncreased glucose outputElevatedTNFInsulin resistance and -cell dysfunctionproduce hyperglycaemia in type 2 diabetesModified from: Turner N, Clapham JC. Prog Drug Res 1998;51:3494

Development of type 2 diabetes

GeneticsEnvironment nutrition obesity exerciseRetinopathyNephropathyNeuropathyBlindnessRenal failureInsulin resistanceHyperinsulinemiaHypertensionDecreased HDL-CIncreased TGAtherosclerosisCoronary diseaseLE amputationNatural History of Type 2 Diabetes

Impaired entry of glucose into the cellsAccumulation of glucose in the bloodPlasma osmolarity Inability of the cells utilize glucoseCellular starvationStimulating hungerUrinary loss of glucoseLoss of water and NaDehydration of cellsCompensatory mechanismSuch as thirstLipolysis andproteolysis Body weight Pathophysiology

Common SymptomsClassic symptomsincreased hungerincreased thirstfrequent urinationweight loss

Others symptomsfatigue tingling or numbness in hands and feetrecurring infectionsgums, skin, lung, urinary bladderslow healingblurred visionpruritus vulvaeerectile dysfunction

ADA definition of hyperglycaemic statesADA = American Diabetes AssociationOGTT 2-h post-load glucose < 140 mg/dl (7.8 mmol/l) normal glucose tolerance140199 mg/dl (7.811.1 mmol/l) impaired glucose tolerance 200 mg/dl (11.1 mmol/l) diabetesAdapted from American Diabetes Association. Diabetes Care 2004; 27:S5S10. Criteria for the diagnosis of diabetes Symptoms of diabetes plus casual plasma glucose 200 mg/dl (11.1 mmol/l) 126 mg/dl (7.0 mmol/l) diabetes FPG< 100 mg/dl (5.6 mmol/l) normal fasting glucose100125 mg/dl (5.66.9 mmol/l) impaired fasting glucoseoror

Classic symptoms (+)

Fasting BG > 126 mg/dl Fasting BG < 126 mg/dl (casual BG > 200) (casual BG 126 or Casual BG > 200

Impaired glucose toleranceImpaired fasting glucoseIntermediate statesIncreased risk of developing diabetes Prevention strategies to prevent or delay progressionIncreased risk of cardiovascular disease

Uncertain diagnosis:Oral glucose tolerance test75 g glucose load after 8 hours fastingReadings taken in fasting state and at 1 and 2 hours

Urinary ketones

Antibodies

C-peptide

Tests for differential diagnosis

Other specific types of diabetesA. Genetic defects of B-cell functionChromosome 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 DNAB. Genetic defects in insulin actionType A insulin resistance; Leprechaunism; Rabson-Mendenhall syndrome; Lipoatrophic diabetes.C. Diseases of the exocrine pancreasPancreatitis; Trauma/pancreatectomy; Neoplasia; Cystic fibrosis; Hemochromatosis; Fibrocalculous pancreatopathy.D. EndocrinopathiesAcromegaly; Cushings syndrome; Glucagonoma; Pheochromocytoma; Hyperthyroidism; Somatostatinoma; Aldosteronoma.

Other specific types of diabetesE. Drug- or chemical-inducedVacor; Pentamidine; Nicotinic acid; Glucocorticoids; Thyroid hormone; Diazoxide; adrenergic agonists; Thiazides; Dilantin; Interferon.F. InfectionsCongenital rubella; Cytomegalovirus.G. Uncommon forms of immune-mediated diabetesStiff-man syndrome; Antiinsulin receptor antibodies.H. Other genetic syndromes sometimes associated with diabetesDowns syndrome; Klinefelters syndrome; Turners syndrome; Wolframs syndrome; Friedreichs ataxia; Huntingtons chorea; Laurence-Moon-Biedl syndrome; Myotonic dystrophy; Porphyria; Prader-Willi syndrome

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 commonIncreased 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

PathophysiologyThe pregnant woman undergoes a complex series of maternal hormonal actions (ie, a rise in blood glucose; the secondary secretion of pancreatic insulin, glucagon, somatomedins, and adrenal catecholamines). These hormones confer increasing tissue insulin resistance as their levels rise, the demand for increased insulin secretion with feeding escalates progressively during pregnancy. If the maternal pancreatic insulin response is inadequate, maternal and, then, fetal hyperglycemia results. This typically manifests as recurrent postprandial hyperglycemic episodes.

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.

*The prevalence of diabetes is escalating. Despite many new treatment options, patients with diabetes are still not achieving optimal treatment goals. Diabetes and its associated complications represent an increasing health care burden, particularly in primary care. Diabetes cost $132 billion (US) ($92 billion in direct medical costs) in 2002, representing approximately 10% of healthcare spending. Individual healthcare costs for diabetes amount to $13,243/yr 2.4 times higher than individuals without diabetes.

References:ADA National Diabetes Fact Sheet. Available at http://www.diabetes.org/diabetes-statistics/national-diabetes-fact-sheet.jsp. Accessed April 11, 2005.ADA Diabetes Statistics. Available at http:diabetes.org/utils/printthispage.jsp?PageID= STATISTICS_233181. Accessed December 29, 2005.R1/p1/P3R4/p8/P7R3/L1R4/p5/P4/L1R3/p5/L2R4/p7/P2/L2R4/p7/P1/L3R3/P6/L1IMS, Xponent TRx*By 2030, seven of the worlds top ten countries with the highest numbers of people with diabetes will be located in Asia.

Adapted from Wild SH et al. Diabetes Care 2004; 27: 256970. *************Type 2 Diabetes:Two Principal DefectsThe pathophysiology of type 2 diabetes mellitus is related to two defects. The clinical expression of this disease usually requires the presence of both impaired insulin secretion and insulin resistance. These traits are thought to be genetically determined although the genes have not yet been identified. Environmental factors, such as obesity, a high-fat diet, physical inactivity, or some medications, usually participate in the expression of these traits. Individuals with one genetic defect, with or without an environmental trigger, may demonstrate impaired glucose tolerance or impaired fasting glucose but may not typically develop frank diabetes. In most instances, both -cell dysfunction and insulin resistance are required for the development of the hyperglycemia of type 2 diabetes.

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.**Type 2 diabetes arises as a combination of two metabolic defects: firstly disregulation of insulin release from the -cells as a result of reduced granulation and reduced insulin content of the -cells and secondly, insulin resistance. These defects give rise to both low plasma insulin, and global insulin resistance in the three key target tissues for insulin action (liver, skeletal muscle, adipose tissue).

In insulin-resistant adipose tissue, the rate of release of free fatty acids is increased and abnormal fatty acid metabolism occurs. This may well be associated with the increased expression and activity of the inflammatory cytokine, tumour necrosis factor-alpha (TNF). It is thought that the PPAR agonists (thiazolidinediones) have an impact on the metabolism of TNF in adipose tissue which may, in part, account for the mechanism by which they improve glycaemic control.

Type 2 diabetes is also associated with decreased activity of the glucose transporter that is responsive to insulin the GLUT-4 isoform. In the type 2 diabetic patient the function of this glucose transporter is also defective in muscle and adipose tissue.Turner NC, Clapham JC. Prog Drug Res 1998;51:3494

*The temporal relationship between insulin resistance, insulin secretion and the development of diabetes is shown in this slideIn the early stages, as insulin sensitivity falls, there is a compensatory increase in insulin secretion and the individual remains normoglycemicIn the long term, as the b-cells begin to fail, insulin secretion falls and abnormal glucose tolerance and hyperglycemia become apparent until frank type 2 diabetes develops Slide 12*1*Casual is defined as any time of day without regard to time since last meal.The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss.Fasting is defined as no caloric intake for at least 8 h.OGTT should be performed as described by WHO, using a glucose load containing the equivalent of 75 g anhydrous glucose dissolved in water.

American Diabetes Association. Diabetes Care 2004; 27: S5S10.

FPG = fasting plasma glucose IFG = impaired fasting glucose IGT = impaired glucose toleranceOGTT = oral glucose tolerance test

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