PATHOPHYSIOLOGY OF DIABETES MELLITUS 

Introduction:

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

Diabetes Mellitus is a metabolic disorder characterized by persistent hyperglycaemia (high blood sugar level), resulting either from inadequate secretion of hormone insulin, an adequate response of target cell to insulin or combination of these factors.

Glucose level in the blood is controlled by several hormones. Insulin is the major hormone which controls the level of glucose in blood. Insulin is secreted by beta-cells of Islet of langerhans of pancreas.

Diabetes Mellitus is mainly of two types:

TYPE-1 –IDDM, (Insulin Dependent Diabetes Mellitus)

TYPE-2 –NIDDM, (Non-Insulin Dependent Diabetes Mellitus)

TYPE-3 –Gestational Diabetes, (GDM)

Etiologic Classification of Diabetes Mellitus

Type 1 Diabetes - β-cell destruction, leads to absolute insulin deficiency

Type 2 Diabetes -Insulin resistance with relative insulin deficiency

Genetic Defects of β-Cell Function

Genetic Defects in Insulin Processing or Insulin Action

Exocrine Pancreatic Defects

Endocrinopathies

Infections

Drugs

Genetic Syndromes Associated with Diabetes

Gestational Diabetes Mellitus, (GDM)

Maturity onset Diabetes of Young {MODY}

Insulin secretory defect without beta cell loss, Autosomal  dominant inheritance  with high penetrance, Early onset before 25, Impaired  β - cell function , normal weight , lack of GAD antibodies, lack of INSULIN resistance  syndrome.

Genetic defects in MODY

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

Mutations in glucokinase gene on chromosome 7 - MODY 2

Mutations in HNF - 1α on chromosome 12 q  -  MODY 3.

TYPE-1 –IDDM

It is characterized by loss of the insulin producing beta-cells of islet of langerhans of the pancreas.

Sensitivity and responsiveness to insulin are usually normal. This type of Diabetes Mellitus comprises up to 10%. Type-1 IDDM can affect children or adults. Common causes: Loss of beta-cells leading to Type-1 IDDM is autoimmune destruction or by antibodies directed against insulin and Islet proteins.

PATHOGENESIS OF TYPE-1-IDDM

Three main factors are involved: a) Genetic, b) Environmental, & c) Auto-Immunity.

Genetic Factors: It accounts for about 1/3rd of the susceptibility. In a genetically susceptible person; there is a development of Auto-antigen receptors lead to destruction of beta-cells.

Environmental Factors: Such as viruses; are mainly involved. The environmental factors changes structure features with beta-cell and leads to destruction of beta-cell.

Auto-Immunity Factors: Type-1 IDDM is a slow T-cell mediated Auto-immune disease.

Destruction of the insulin secretion cell in the pancreatic islets takes place over many years.

The pathological changes in the pre-diabetic pancreas in Type-1 IDDM are characterized by Insulinitis. It is the infiltration of Islet with mono-nuclear cells containing activated macrophages, helper cytotoxic T-lymphocytes, Natural Killer cells, B-lymphocytes.

TYPE-2 – NIDDM

Type-2-NIDDM is due to combination of defective insulin secretion and defective responsiveness to insulin or reduced insulin sensitivity. It is quite common; comprising 90% or more of cases in many populations.

PATHOGENESIS OF TYPE -2 NIDDM

It is more common than Type-1 IDDM. There is no evidence of immune activation. It results mainly due to two defects: a) Insulin resistance, b) Pancreatic beta-cell failure. 

Insulin resistance: Increased hepatic production of glucose and resistance to action of insulin. Insulin resistance may be any one of three general causes. Out of these three; target tissue defect is the most common cause of Insulin resistance is Type-2 –NIDDM.

Pancreatic beta-cell failure:  There is only moderate reduction in the total mass of pancreatic Islet tissues, which is inconsistent with a measurable fall in plasma insulin concentration. When related to blood glucose level; beta-cell number is reduced and glucagon secretion is increased which may contribute to hyperglycaemia and caused Type-2-NIDDM. Possible mechanism for beta-cell decomposition include genotoxicity , Intrinsic failure of Insulin production and degranulation of beta-cells.

TYPE-3 GESTATIONAL DIABETES

It involves combination of inadequate insulin secretion and responsiveness. It develops during pregnancy and improve or disappear after delivery. Individuals at higher risk for Gestational Diabetes include: 1. Obese woman, 2. Those with previous history of glucose intolerance, 3. Any pregnant woman who has elevated fasting, or casual, blood glucose level, 4. Those with a history of gestational diabetes mellitus, 5. Those with a history of large for gestational –age-babies, 6. Strong family history of diabetes mellitus.

LATE COMPLICATION OF DIABETES MELLITUS / SECONDARY COMPLICATION

RETINOPATHY

NEPHROPATHY

NEUROPATHY

ATHEROSCLEROSIS

RETINOPATHY: It is characterized by retinal damage such as bleeding in retina due to this retinal damage or retinal detachment occurs from normal position which ultimately leads to cataract or glaucoma.

DIABETIC NEPHROPATHY:  In this renal capillaries become leaky ; due to this proteins appear in the filterate or urine which is known as proteinurea leads to nephron syndrome. It may cause other kidney disorders such as renal atherosclerosis leads to renal failure. Nephropathy occurs due to Advance Glycation End Product (AGE) accumulation. Glycation mainly occur of collagen and other proteins. Initially ; it is reversible , but later on become irreversible ,but this deposit on renal capillaries. 

NEUROPATHY: Defect in peripheral Nervous System mainly involves nerves and these become non-functional symptoms include: Disturbance in urinary bladder functioning, Disturbance in bowel functioning.

ATHEROSCLEROSIS:  Occurs also due to AGE accumulation in blood vessels.

Pathogenesis of Complications

NON - ENZYMATIC  GLYCOSYLATION: The  degree of non-enzymatic  glycosylation is related to the level of blood glucose. The Early glycosylation products on collagen & other proteins in interstitial tissues & Blood vessels - chemical  rearrangement - Irreversible  advanced   glycosylation  end  products (AGE ). On proteins such as collagen, AGE - CROSS LINKING  between polypeptides  of collagen molecule - trap plasma / interstitial proteins.

Trapping of LDL - Retards  its efflux from vessel wall - deposition  of  cholesterol  in  intima -                accelerates  atherogenesis. In the Renal glomeruli , albumin  binds to glycosylated  BM                       thickening of BM - characterestic of  DIABETIC  MICROANGIOPATHY.

AGE BINDS TO RECEPTORS ON ENDOTHELIUM , MONOCYTES , LYMPHOCYTES , MESANGIAL CELLS. Binding increases  endothelial  permeability , increased monocyte migration , release of  cytokines , increased procoagulant activity , of endothelial cells , enhanced proliferation & synthesis of ECM  by fibroblasts & SMC.

POLYOL Pathways:  Nerves , lens , kidneys , blood vessels  DO NOT require insulin for glucose  transport. Hyperglycaemia - intracellular  glucose – sorbitol – fructose. Sorbitol & fructose -                       increased intracellular  osmolarity - influx of water - osmotic cell injury.

MORPHOLOGY – PANCREAS

TYPE - 1

         -   reduction   in  number  & size of  islets

         -   leukocytic infilteration of islets

TYPE - 2

         -   subtle  reduction  in  islet cell mass

         -   amyloid  replacement of islets

Vessels of all sizes are affected. Aorta , large , medium sized arteries - accelerated  severe  atherosclerosis, M I  -  most common cause of death, Gangrene  - 100 times more  common. Microangiopathy.

MORPHOLOGY - KIDNEY [Diabetic  Nephropathy]

Glomerular lesions: capillary  BM thickening, diffuse   glomerulosclerosis,  nodular  glomerulosclerosis [ K - W bodies ], Renal  vascular  lesions, Pyelonephritis.

 OCULAR COMPLICATIONS

Retinopathy, Cataract, Glaucoma, Total  blindness is one of the most feared complications  of  DIABETES.

Diabetic Neuropathy

Peripheral, symmetric neuropathy of lower extremities. Both sensory & motor functions are involved.