DIABETES DIABETES MELLITUSMELLITUS

Diabetes mellitus is not a single disease Diabetes mellitus is not a single disease entity but rather a entity but rather a group of metabolic group of metabolic disorders sharing the common underlying disorders sharing the common underlying feature of hyperglycemia.feature of hyperglycemia.

Hyperglycemia in diabetes results from

defects in insulin secretion,defects in insulin secretion, defects in insulin action, defects in insulin action, most commonly, both. most commonly, both.

chronic hyperglycemia and attendant metabolic dysregulation of diabetes mellitus

associated with secondary damage in multiple associated with secondary damage in multiple organ systems, especially the kidneys, eyes, organ systems, especially the kidneys, eyes, nerves, and blood vessels. nerves, and blood vessels.

Diabetes is a leading cause of end-stage renal Diabetes is a leading cause of end-stage renal disease, adult-onset blindness, and nontraumatic disease, adult-onset blindness, and nontraumatic lower extremity amputations lower extremity amputations

greatly increases the risk of developing coronary greatly increases the risk of developing coronary artery disease and cerebrovascular disease. artery disease and cerebrovascular disease.

Diagnosis Blood glucose levels - 70 to 120 mg/dL. Blood glucose levels - 70 to 120 mg/dL. Diagnosis - By Elevation Of Blood Glucose By Diagnosis - By Elevation Of Blood Glucose By

Any One Of Three Criteria: Any One Of Three Criteria: A random blood glucose concentration of 200 mg/dL A random blood glucose concentration of 200 mg/dL

or higher, with classical signs and symptoms or higher, with classical signs and symptoms A fasting glucose concentration of 126 mg/dL or A fasting glucose concentration of 126 mg/dL or

higher on more than one occasion, higher on more than one occasion, An abnormal oral glucose tolerance test (OGTT), in An abnormal oral glucose tolerance test (OGTT), in

which the glucose concentration is 200 mg/dL or which the glucose concentration is 200 mg/dL or higher 2 hours after a standard carbohydrate load (75 higher 2 hours after a standard carbohydrate load (75 gm of glucose). gm of glucose).

Normal glucose homeostasis is tightly regulated by three interrelated processes:

(1) glucose production in the liver, (1) glucose production in the liver, (2) glucose uptake and utilization by (2) glucose uptake and utilization by

peripheral tissues, chiefly skeletal muscle, peripheral tissues, chiefly skeletal muscle, (3) actions of insulin and counter-(3) actions of insulin and counter-

regulatory hormones (e.g., glucagon). regulatory hormones (e.g., glucagon).

The principal metabolic function of insulin The principal metabolic function of insulin is to increase the rate of glucose transport is to increase the rate of glucose transport into certain cells in the bodyinto certain cells in the body

These are the These are the striated muscle cellsstriated muscle cells (including myocardial cells) and, to a lesser (including myocardial cells) and, to a lesser extent, extent, adipocytes,adipocytes, representing collectively representing collectively about two-thirds of the entire body weight.about two-thirds of the entire body weight.

Glucose uptake in other peripheral tissues, Glucose uptake in other peripheral tissues, most notably the brain, is insulin most notably the brain, is insulin independent. independent.

Besides promoting lipid synthesis (lipogenesis), Besides promoting lipid synthesis (lipogenesis), insulin also inhibits lipid degradation (lipolysis) insulin also inhibits lipid degradation (lipolysis) in adipocytes. Similarly, insulin promotes in adipocytes. Similarly, insulin promotes amino acid uptake and protein synthesis while amino acid uptake and protein synthesis while inhibiting protein degradation. inhibiting protein degradation.

metabolic effects of insulin - anabolic, with metabolic effects of insulin - anabolic, with increased synthesis and reduced degradation of increased synthesis and reduced degradation of glycogen, lipid, and protein.glycogen, lipid, and protein.

In addition - several In addition - several mitogenicmitogenic functions, functions, including initiation of DNA synthesis in certain including initiation of DNA synthesis in certain cells and stimulation of their growth and cells and stimulation of their growth and differentiation.differentiation.

Etiologic Classification of Diabetes Mellitus Type 1 DiabetesType 1 Diabetes - - β-β-cell destruction, leads to absolute insulin cell destruction, leads to absolute insulin

deficiencydeficiency Type 2 DiabetesType 2 Diabetes -Insulin resistance with relative insulin -Insulin resistance with relative insulin

deficiencydeficiency Genetic Defects ofGenetic Defects of ββ--Cell FunctionCell Function Genetic Defects in Insulin Processing or Insulin ActionGenetic Defects in Insulin Processing or Insulin Action Exocrine Pancreatic DefectsExocrine Pancreatic Defects EndocrinopathiesEndocrinopathies InfectionsInfections DrugsDrugs Genetic Syndromes Associated with DiabetesGenetic Syndromes Associated with Diabetes Gestational Diabetes MellitusGestational Diabetes Mellitus

Pathogenesis of Type 1 Diabetes Mellitus

autoimmune diseaseautoimmune disease in which islet destruction is caused in which islet destruction is caused primarily by T lymphocytes reacting against as yet poorly primarily by T lymphocytes reacting against as yet poorly defined defined β-β-cell antigens, resulting in a reduction in cell antigens, resulting in a reduction in β-β-cell masscell mass

genetic susceptibility and environmental influences play genetic susceptibility and environmental influences play important roles in the pathogenesis.important roles in the pathogenesis.

most commonly develops in childhood, becomes manifest at most commonly develops in childhood, becomes manifest at puberty, and is progressive with age. puberty, and is progressive with age.

Most individuals with type 1 diabetes depend on exogenous Most individuals with type 1 diabetes depend on exogenous insulin supplementation for survival, and without insulin, they insulin supplementation for survival, and without insulin, they develop serious metabolic complications such as acute develop serious metabolic complications such as acute ketoacidosis and coma.ketoacidosis and coma.

The classic manifestations of the disease The classic manifestations of the disease (hyperglycemia and ketosis) occur late in its (hyperglycemia and ketosis) occur late in its course, after more than 90% of the course, after more than 90% of the β β cells have cells have been destroyed. been destroyed.

Several mechanisms contribute toSeveral mechanisms contribute to ββ--cell cell destruction, and it is likely that many of these destruction, and it is likely that many of these immune mechanisms work together to produce immune mechanisms work together to produce progressive loss ofprogressive loss of β β cells,cells, resulting in clinical resulting in clinical diabetes:diabetes:

Type 1 diabetes

complex pattern of genetic associationcomplex pattern of genetic association the principal susceptibility locus for type 1 diabetes the principal susceptibility locus for type 1 diabetes

resides in the region that encodes the class II MHC resides in the region that encodes the class II MHC molecules on chromosome 6p21 (HLA-D)molecules on chromosome 6p21 (HLA-D). .

Between 90% and 95% - Between 90% and 95% - HLA-DR3HLA-DR3, or , or DR4DR4, or both, , or both, we do not know the actual genes in the many other we do not know the actual genes in the many other

susceptibility loci. susceptibility loci. also evidence to suggest that also evidence to suggest that environmental factorsenvironmental factors, ,

especially infections, - viruses may be an initiating trigger, especially infections, - viruses may be an initiating trigger, -molecular minicry-molecular minicry

Pathogenesis of Type 2 Diabetes Mellitus

pathogenesis of type 2 diabetes remains enigmatic. pathogenesis of type 2 diabetes remains enigmatic. Environmental influences, such as a sedentary life style Environmental influences, such as a sedentary life style and dietary habits, clearly have a role,and dietary habits, clearly have a role,

Nevertheless, Nevertheless, genetic factors are even more important genetic factors are even more important than in type 1 diabetes,than in type 1 diabetes, with linkage demonstrable to with linkage demonstrable to multiple "diabetogenic" genes. Among identical twins, multiple "diabetogenic" genes. Among identical twins, the concordance rate is 50% to 90%, while among first-the concordance rate is 50% to 90%, while among first-degree relatives with type 2 diabetes (including fraternal degree relatives with type 2 diabetes (including fraternal twins) the risk of developing the disease is 20% to 40%, twins) the risk of developing the disease is 20% to 40%, as compared with 5% to 7% in the population at large.. as compared with 5% to 7% in the population at large..

The two metabolic defects that characterize type The two metabolic defects that characterize type 2 diabetes are (1) a decreased ability of 2 diabetes are (1) a decreased ability of peripheral tissues to respond to insulin (insulin peripheral tissues to respond to insulin (insulin resistance) and (2)resistance) and (2) ββ--cell dysfunction that is cell dysfunction that is manifested as inadequate insulin secretion in the manifested as inadequate insulin secretion in the face of insulin resistance and hyperglycemiaface of insulin resistance and hyperglycemia. In . In most cases, insulin resistance is the primary most cases, insulin resistance is the primary event and is followed by increasing degrees of event and is followed by increasing degrees of β-β-cell dysfunction.cell dysfunction.

Maturity onset Diabetes of Young {MODY }

Insulin secretory defect without beta cell Insulin secretory defect without beta cell lossloss

Autosomal dominant inheritance with high Autosomal dominant inheritance with high penetrancepenetrance

Early onset before 25Early onset before 25 Impaired Impaired ββ - cell function , normal weight , - cell function , normal weight ,

lack of GAD antibodies ,lack of GAD antibodies , lack of INSULIN resistance syndrome lack of INSULIN resistance syndrome

Genetic defects in MODY

Mutations in HNF - 4 alpha on chromosome 20 - Mutations in HNF - 4 alpha on chromosome 20 - MODY 1 MODY 1

Mutations in glucokinase gene on chromosome 7 Mutations in glucokinase gene on chromosome 7 - MODY 2- MODY 2

Mutations in HNF - 1Mutations in HNF - 1αα on chromosome on chromosome

12 q - MODY 312 q - MODY 3

Pathogenesis of Complications

NON - ENZYMATIC GLYCOSYLATIONNON - ENZYMATIC GLYCOSYLATIONThe degree of non-enzymatic glycosylation is The degree of non-enzymatic glycosylation is

related to the level of blood glucoserelated to the level of blood glucoseThe Early glycosylation products on collagen & The Early glycosylation products on collagen &

other proteins in interstitial tissues & Blood other proteins in interstitial tissues & Blood vessels chemical rearrangement vessels chemical rearrangement Irreversible advanced glycosylation end Irreversible advanced glycosylation end products (AGE ) products (AGE )

A G E

( 1 ) On proteins such as collagen AGE( 1 ) On proteins such as collagen AGE

CROSS LINKING between polypeptides CROSS LINKING between polypeptides

of collagen molecule trap of collagen molecule trap

plasma / interstitial proteinsplasma / interstitial proteins

Trapping of LDL Retards its efflux from Trapping of LDL Retards its efflux from vessel wall deposition of cholesterol vessel wall deposition of cholesterol in intima accelerates atherogenesis in intima accelerates atherogenesis

In the Renal glomeruli , albumin binds to In the Renal glomeruli , albumin binds to glycosylated BM thickening of BM glycosylated BM thickening of BM - - characterestic ofcharacterestic of DIABETIC MICROANGIOPATHYDIABETIC MICROANGIOPATHY

AGE [ contd. ….]

A G E

AGE BINDS TO RECEPTORS ON AGE BINDS TO RECEPTORS ON ENDOTHELIUM , MONOCYTES , ENDOTHELIUM , MONOCYTES , LYMPHOCYTES , MESANGIAL CELLSLYMPHOCYTES , MESANGIAL CELLS

Binding increases endothelial permeability , Binding increases endothelial permeability , increased monocyte migration , release of increased monocyte migration , release of cytokines , increased procoagulant activity , of cytokines , increased procoagulant activity , of endothelial cells , enhanced proliferation & endothelial cells , enhanced proliferation & synthesis of ECM by fibroblasts & SMCsynthesis of ECM by fibroblasts & SMC

POLYOL Pathways

Nerves , lens , kidneys , blood vessels DO NOT Nerves , lens , kidneys , blood vessels DO NOT require insulin for glucose transportrequire insulin for glucose transport

Hyperglycaemia intracellular Hyperglycaemia intracellular glucose sorbitol fructoseglucose sorbitol fructose

sorbitol & fructose increased sorbitol & fructose increased intracellular osmolarity influx of intracellular osmolarity influx of water osmotic cell injurywater osmotic cell injury

MORPHOLOGY - PANCREAS

TYPE - 1TYPE - 1 - reduction in number & size of islets- reduction in number & size of islets - leukocytic infilteration of islets- leukocytic infilteration of islets TYPE - 2TYPE - 2 - subtle reduction in islet cell mass- subtle reduction in islet cell mass - amyloid replacement of islets - amyloid replacement of islets

MORPHOLOGY – VASCULAR SYSTEM

Vessels of all sizes are affectedVessels of all sizes are affected

Aorta , large , medium sized arteries - accelerated Aorta , large , medium sized arteries - accelerated

severe atherosclerosissevere atherosclerosis

M I - most common cause of deathM I - most common cause of death

Gangrene - 100 times more commonGangrene - 100 times more common

MicroangiopathyMicroangiopathy

MORPHOLOGY - KIDNEY [ Diabetic Nephropathy ]

Glomerular lesionsGlomerular lesions - capillary BM thickening- capillary BM thickening - diffuse glomerulosclerosis- diffuse glomerulosclerosis - nodular glomerulosclerosis - nodular glomerulosclerosis [[ K - WK - W bodies ]bodies ] Renal vascular lesionsRenal vascular lesions PyelonephritisPyelonephritis

OCULAR COMPLICATIONS

RetinopathyRetinopathy

CataractCataract

GlaucomaGlaucoma

Total blindness is one of the most feared Total blindness is one of the most feared

complications of DIABETEScomplications of DIABETES

Diabetic Neuropathy

Peripheral symmetric neuropathy of lower Peripheral symmetric neuropathy of lower

extremitiesextremities

Both sensory & motor functions Both sensory & motor functions