Pathogenesis and complications of Type 2 Diabetes

PATHOGENESIS AND COMPLICATIONS OF TYPE 2 DIABETES´
  • Diabetes mellitus is a group of metabolic disorders sharing the common feature of hyperglycemia
  • Hyperglycemia can result due to 
    • Defects in insulin secretion
    • Defects in insulin action
    • Both
  • Diabetes is classified into two main groups depending upon the pathogenesis
    • Type 1 diabetes
    • Type 2 diabetes
Type 2 diabetes
  • Caused by a combination of peripheral resistance to insulin action and an inadequate secretory response by the pancreatic β cells
  • Approximately 90 to 95 % of cases of diabetes are type 2 diabetes
  • Though its called as adult onset but can occur in children and adolescents due to increase rates of obesity
 
Pathogenesis 

  • Type 2 diabetes is complex disease involving an interplay of genetic, environmental factors and proinflammatory state
  • Genetic factors
    • Genetic susceptibility in monozygotic twins and 1st degree relatives are at 5 to 10 folds increased risk of developing Diabetes
    • Polymorphisms in many genes associated with insulin gene are identified
  • Environmental factors
    • Most important – obesity particularly central and visceral obesity
    • Obesity contributes to metabolic abnormalities of diabetes and to insulin resistance
    • Sedentary life style is another risk factor independent of obesit
  • Metabolic defects in Type 2 Diabetes
    • Two important metabolic defects that characterise type 2 diabetes are
      • Decreased response of peripheral tissues, especially skeletal muscles, adipose tissue and liver to insulin
      • Inadequate insulin secretion in the face of insulin resistance and hyperglycemia (β cell dysfunction)
  • In the early stages, there is compensatory β cell hyperfunction and hyperinsulinemia but later β cells cannot adapt and lead to chronic hyperglycemia leading to complications
Insulin resistance
  • Insulin resistance results in
    • Failure to inhibit endogenous glucose production in the liver which contributes to high fasting blood glucose levels
    • Failure of glucose uptake and glycogen synthesis that occurs in skeletal muscle following a meal contributes to high post prandial blood glucose
    • Failure to inhibit lipoprotein lipase in adipose tissue, leading to excess of circulating FFA which inturn amplify insulin resistance
    • In insulin resistance
      • ´Defects in signaling pathways leading to decreased tyrosine phosphorylation of insulin receptor and IRS proteins
      • ´This  leads to decreased levels of GLUT 4 levels on the surface of the cell
      • Exercise causes increased translocation of GLUT 4 to the surface
  • Obesity and insulin resistance

  •  
    • Risk of diabetes increases as the body mass index increases. Central obesity has more risk than peripheral fat depots
    • Free fatty acids
      • Levels of FFA are inversely related to insulin sensitivity
      • Central adipose tissue is more lipolytic than peripheral sites
      • Excess of free fatty acids overwhelm intracellular fatty acid oxidation pathways, leading to accumulation of diacylglycerol (DAG) which attenuates the insulin signaling pathway by serine phosphorylation of insulin receptors
      • Insulin normally inhibits hepatic gluconeogenesis by blocking the activity of phosphoenol pyruvate carboxykinase, which is the first enzymatic step in this process
      • Attenuated insulin signaling leads to increased phophoenolpyruvate carboxykinase activity that causes increased gluconeogenesis

  • Adipokines
    • Adipose tissue acts as endocrine organ releasing hormones called adipokines which include pro hyperglycemic adipokines and anti hyperglycemic adipokines (Leptin and Adiponectin)
    • Leptin and adiponectin improves the insulin secretion
    • Adiponectin levels are decreased in obesity this contributes to insulin resistance
  • Inflammation
    • Proinflammatory cytokines are secreted in response to excess nutrients such as Free fatty acids and glucose
    • Excess FFA with in macrophages and B cells activate the inflammasome, a multipotent complex which leads to secretion of the cytokine interleukin IL-1β
    • Interleukin IL-1β mediates secretion of proinflammatory cytokines from macrophages, islet cells and other cells
    • interleukin IL-1β and other cyokines released into circulation acts on the sites of insulin action and cause resistance

  • B cell dysfunction
    • along with insulin resistance B cell dysfunction is also required for the development of Type 2 diabetes
    • In the initial stages there is β cell function increase inorder to compensate the insulin resistance but later the β cells are exhausted  
    • Mechanisms that promote β cell dysfunction are
      • Excess FFA attenuate insulin release and compromise the β cell function (Lipotoxicity)
      • Chronic hyperglycemia (Glucotoxixity)
      • an abnormal incretin effect
      • Amyloid deposition in the islets
      • Polymorphisms in genes that control insulin secretion
Complications

  • Acute metabolic complications
    • Severe and acute metabolic complications of Type 1 diabetes is Diabetic ketoacidosis
    • In type 2 diabetes, higher portal vein insulin levels prevents unrestricted hepatic fatty acid oxidation
    • Patient develops hyperosmolar hyperosmotic syndrome due to severe dehydration
    • Second common acute complication is hypoglycemia usually as a result of missed meal, excessive physical exercise, an excess of insulin administration.
      • Signs and symptoms are
        • Dizziness, confusion, sweating, palpitations and tachychardia
        • If hypoglycemia continues there is loss of consciousness
  • Chronic metabolic complications
    • Four distinct mechanisms have been implicated in the deleterious effects of persistent hyperglycemia on peripheral tissue
      • Formation of Advanced Glycation end products
      • Activation of protein Kinase C
      • Oxidative stress and disturbances in polyol pathways
      • Hexosamine pathways and generation of Fructose -6-phosphate
    • Formation of Advanced glycation end products
      • AGEs are formed as a result of non-enzymatic reactions between intracellular glucose derived dicarbonyl precursors (Glyoxal, methyl glyoxal and 3-deoxy glucosone) with the amino groups of both intracellular and extracellular proteins
      • Hyperglycemia accelerates AGE formation
      • AGE binds to specific receptors (RAGE) expressed on inflammatory cells (macrophages and T cells), endothelium, and vascular smooth muscle
      • Effect of AGE-RAGE signaling axis within the vascular compartment leads to
        • Release of cytokines and growth factors like
        • TGFβ – leads to excess deposition of basement membrane material
        • VEGF – causes diabetic retinopathy
        • Generation of ROS in endothelial cells
        • Increased procoagulant activity on endothelial cells and macrophages
        • Enhanced proliferation of vascular smooth muscle cells and synthesis of extracellular matrix
      • AGE can directly cross link extracellular matrix proteins
        • Cross linking of collagen type I molecules in large vessels decrease their elasticity which may predispose these vessels to shear stress and endothelial injury
        • AGE induced cross linking of type IV collagen in basement membrane decreases endothelial cell adhesion and increases extravasation of fluid
        • Proteins cross linked by AGEs are resistant to proteolytic digestion and hence cannot be removed
      • AGE modified matrix components also trap non-glycated plasma or interstitial proteins
        • In large vessels trapping of LDL retards its efflux from the vessel wall and enhances the deposition of cholesterol in the intima thus accelerating atherogenesis
        • In capillaries albumin bind to glycated basement membrane, accounting in part for the basement membrane thickening responsible for microangiopathy.
    • Activation of Protein Kinase C
      • Intracellular hyperglycemia stimulates denovo synthesis of DAG from glycolytic intermediates which causes excessive PKC activation
      • The effects of PKC activation are
      • Production of VEGF, TGF-β and procoagulant proteins plasminogen activator inhibitor – 1 by the vascular endothelium
    • Oxidative stress and disturbances in polyol pathways
      • Some tissues like nerves, lenses, kidneys and blood vessels do not require insulin for glucose transport
      • Persistent hyperglycemia in extracellular milieu leads to increase in intracellular glucose
      • This excess glucose is metabolized by enzyme aldose reductase to sorbitol and eventually to fructose which utilizes NADPH in his reaction
      • NADPH is required by the enzyme Glutathione reductase in a reaction that generates reduced glutathione
    • Hexosamine pathways and generation of Fructose–6-Phosphate
      • Hyperglycemia induced flux through the hexosamine pathway increases intracellular levels of fructose-6-phosphate which is substrate for glycosylation of proteins which leads to formation of excess proteoglycans
      • This leads to abnormal expression of TGF β or PAI -1 which further exacerbate the end organ damage.
    • Macrovascular disease
      • The hall mark is accelerated atherosclerosis involving the aorta and large and medium sized arteries
      • Myocardial infarction caused due to atherosclerosis of coronary arteries is the most common cause of death in DM
      • Gangrene of the lower limb occurs in advanced vascular disease
      • Hyaline arteriosclerosis leading to hypertension
    • Microangiopathy
      • Diffuse thickening of the basement membranes of the small capillaries in the skin, skeletal muscle, retina, renal glomeruli and renal medulla
      • Thickening of basement membrane is by concentric layers of hyaline material composed predominantly of type IV collagen
      • These capillaries are more leaky and underlie the development of diabetic nephropathy, retinopathy and neuropathy
      • Diabetic nephropathy
        • Three lesions encountered in kidney  are
          • Glomerular lesions
          • Renal vascular lesions principally arteriosclerosis
          • Pyelonephritis including necrotizing papillitis
          The most important glomerular lesions are –
          • Capillary basement membrane thickening
            • Thickening of basement membrane of glomerular capillaries leads to diabetic microangiopathy
            • Thickening leads to mesangial widening
            • Thickening of BM of capillaries starts at as early as 2 years
            • Later thickening of tubular basement membrane occurs
          • Diffuse mesangial sclerosis
            • Lesion consists of diffuse increase in mesangial matrix
            • Initially there is mesangial proliferation but later mesangial increase is associated with overall thickening of GBM and matrix deposition of PAS positive material
            • As the disease progresses mesangial deposition takes nodular configuration
          • Nodular glomerulosclerosis ( kimmelstiel-wilson lesion )
            • Also known as “intercapillary glomerulosclerosis” or “Kimmelstiel-Wilson disease”
            • Glomerular lesions take the form of ovoid or spherical laminated nodules of matrix situated in the periphery of the glomerulus
            • Nodules are PAS positive and are surrounded by capillary loops
            • Nodular lesions are accompanied by accumulations of hyaline material in capillary loops or adherent to bowman’s capsules
            • As the disease advances individual nodules enlarge and compress capillaries, obliterating the glomerular tuft
            • Both afferent and efferent arterioles show hyalinosis
            • Later due to arteriole and glomerular lesions, kidney develops ischemia which leads to tubular atrophy, interstitial fibrosis and contraction in size of the kidney
      • Diabetic ocular complications
        • The ocular involvement may be in the form of –
          • Retinopathy due to neovascularization
          • Microaneurysms of the retinal vessels and hemorrhages 
          • Macular edema
          • Cataract formation
          • Glaucoma
      • Diabetic neuropathy
        • The most common neural complications are –
          • Peripheral neuropathy –
            • Distal symmetric polyneuropathy of lower extremities that affects both motor and sensory function. Upper extremities are also involved (Glove and Stocking pattern)
            • Mononeuropathy – sudden foot drop, wrist drop or isolated cranial nerve palsy
          • Autonomic neuropathy– involving bladder and bowel
Reference 
  1. Anirban Maitra. The Endocrine system.In: Robbins and Cotran Pathologic basis of disease.9th edition.volume II.chapter 24. pp 1073-1141.