Diabetes Mellitus (DM)

  • A group of disorders sharing the common feature of hyperglycaemia
  • Hyperglycaemia is due to defects in insulin secretion, action or both
  • Chronic hyperglycaemia and metablic dysfunction is associated with secondary damage in multiple organs including, kidney, eye, nerve and blood vessels
  • It is the leading cause of end-stage renal disease, adult onset blindness and nontraumatic lower limb extremity amputations

Diagnosis (WHO criteria)

  • Diagnosis of diabetes is established by noting elevation of blood glucose by one of three criteria;
    • Fasting plasma glucose >7mmol/L
    • Random plasma glucose >11.1mmol/L
    • An abnormal oral glucose tolerance test in which glucose in >11.1mmol/L after 2 hours following a 75g glucose bolus
  • One abnormal lab test is sufficient diagnosis in a symptomatic individual, two values are needed for asymptomatic people

Pathogenesis of Type I Diabetes Mellitus

  • Causes by immune mediated destruction (T cell) of the pancreatic bcells
  • Most commonly develops in childhood and presents at puberty
  • Classic manifestations of disease, hyperglycaemia and ketosis occur when 90% of the b cells have been destroyed
  • Several mechanisms contribute to b cell destruction;
  • CD4 and CD8 T cells mediated b cell destruction. CD4 cells activated macrophages and CD8 cells directly kill b cells. The resulting lymphocytic infiltration and necrosis is termed insulitis. Surviving bcells express MHC II probably as a result of IFNg exposure. Autoantigens may be glutamic acid decarboxylase (GAD) and insulin itself
  • Locally produced inflammatory cytokines such as IFNg, TNF and IL-1 produced by macrophages induce b cell destruction
  • Autoantibodies against islet cells and insulin are present in 70-80% of patients. These may participate in disease of be by-products of T cell mediated cell injury and release of normally sequestered antigen

Genetic susceptibility

MHC

  • MHC contributes half the genetic susceptibility
  • Principally MHC Class II
  • 95% of Caucasians with Type I diabetes have HLA-DR3, DR4 or both
  • Susceptibility to Type I diabetes is associated with a linked HLA-DQ (DQB1*0302) allele which is often linked in disequilibrium with DR4
  • In contrast the HLA-DQB1*0602 is considered protective against diabetes
  • It is suggested that the asparagine at position 57 in the DQb chain is protective and its absence increases susceptibility
  • Most individuals who inherit these MHC molecules do not get disease

Non-MHC genes

  • Tandem repeats in the promoter region of insulin has been associated with disease susceptibility. Possibly this makes the protein less functional or less stable. Alternatively it may be involved in expression of the protein in the thymus, involved in negative selection
  • Patients may also express a splice variant of CTLA-4, involved in T cell regulation

Environmental factors

  • Suggestion infections trigger autoimmune disease
  • Epidemiological data suggests viruses, with diagnosis correlating with seasonal trends of common viral infections
  • Possible mechanisms;
  • Cell damage and inflammation resulting in the release of normally sequestered antigen
  • Cross reactivity between viral antigen and b cell antigen
  • More recent data suggest that infection might be protective in disease – infection inhibit disease in the NOD mouse model

Pathogenesis of Type 2 Diabetes Mellitus

  • As well as the role of environmental factors, there are still important genetic factors at play, possibly even more so than in Type 1 diabetes
  • Among identical twin, the concordance is 50-90% whilst among first degree siblings the risk of developing the disease is 20-40%, compared with a general population risk of 5-7%
  • Disease is not linked to genes involved in immunity and immune regulation
  • Two metabolic defects underlying type II disease are;
  • Decreased ability of the peripheral tissues to respond to insulin (insulin resistance)
  • Reduced insulin production
  • In most cases insulin resistance occurs first and is followed by increasing degrees of b cell dysfunction

Insulin resistance

  • Insulin resistance is often detected 10 to 20 years before the onset of diabetes
  • In prospective studies insulin resistance is the best predictor of subsequent progression to diabetes
  • Insulin resistance leads to a decreased uptake of glucose by muscle and adipose tissue and an inability to suppress hepatic gluconeogenesis
  • Areas of the signalling pathway that may be involved;
    • Down regulation of the insulin receptor
    • Decreased receptor phosphorylation and tyrosine kinase activity
    • Reduced levels of active intermediates in the pathway
    • Impaired translocation, docking and fusing of GLUT-4 containing vesicles with the membrane
  • Obesity is a common phenomenon in the majority of type 2 diabetics
    • The link between obesity and diabetes is mediated via effects of insulin resistance
    • There appears to be a fundamental abnormality of insulin signalling in states of fatty excess
    • Central obesity is more likely to be associated with insulin resistance the peripheral fat
  • There are a number of pathways which may lead to insulin resistance;
    • Increased levels of free fatty acids, the resulting intracellular triglycerides and products of fatty acid metabolism are potent inhibitors of insulin signalling and result in an acquired insulin resistance state
    • Role of adipokines in insulin resistance. Adipose tissue is an endocrine organ and releases adipokines into the circulation. These include leptin, adiponectin and resistin.
    • Role of peroxisome proliferators-activated receptor gamma (PPARg) and thiazolidinediones (TZDs). The target receptor for TZDs is PPARg, a nuclear receptor and transcription factor. PPARg is most highly expressed in adipose tissue and activation changes gene transcription resulting in reduction of insulin resistance. PPARg activation also decreases levels of free fatty acids

b cell dysfunction

  • In states of insulin resistance, insulin secretion is initially higher for each level of glucose than in controls
  • Eventually this compensatory mechanism becomes inadequate and these is progression to overt diabetes
  • b cell dysfunction manifests itself with both qualitative and quantitative defects.
    • Qualitative defects are seen as a loss of pulsatile fashion of insulin secretion and overall there is reduction is insulin secretion
    • Quantitative b cell dysfunction is reflected by a decrease in b cell mass, islet degeneration and amyloid deposition in the islets

Monogenic forms of Diabetes

  • Result from either a primary defect in b cell function or a defect in insulin/insulin receptor signalling

Maturity-onset diabetes of the young (MODY)

  • Around 5% of diabetic patients don’t fall clearly into the type 1 or type2 phenotype and are said to have MODY
  • In these patients there is a primary defect in b cell function without loss of b cells or any defect in b cell mass or insulin production
  • MODY is characterised by;
    • An autosomal dominant inheritance as a monogenic defect with high penetrance
    • Onset usually before the age of 25
    • Absence of obesity
    • Lack of islet autoantibodies or insulin resistance syndrome
  • Mutations associated with MODY are;
    • Hepatocyte nuclear factor-4a (HNF-4a) (MODY1)
    • Glucokinase (MODY2)
    • Hepatocyte nuclear factor-1a (HNF-1a) (MODY3)
    • Insulin promoter factor-1 (MODY4)
    • Hepatocyte nuclear factor-1b (MODY5)
    • Neurogenic differentiation factor 1 (MODY6)
  • MODY1, 3 and 5 are associated with severe b cell insulin secretory defects
  • MODY2 is associated with mild hyperglycaemia that doesn’t seem to worsen over time
  • Mutations associated with MODY don’t contribute to type 2 diabetes
  • 50% of carriers with glucokinase mutations develop gestational diabetes

Mitochondrial diabetes

  • In less than 1% of cases, diabetes is associated with point mutations in tRNA gene, encoded by mitochondrial DNA
  • Inherited maternally
  • Diabetes is caused by a primary defect in b cell function

Diabetes associated with insulin gene or receptor mutations

  • Rare causes of diabetes
  • Receptor mutations effect synthesis, insulin binding, tyrosine kinase activity
  • Metabolic impairment generally rare as patients are heterozygotes for mutation

Pathogenesis of the complications of Diabetes

  • Microvascular disease involving large and medium sized arteries causes accelerated atherosclerosis resulting in increased risk of MI, stroke and lower extremity gangrene
  • Microvascular disease is caused by capillary dysfunction and leads to diabetic retinopathy, nephropathy and neuropathy
  • These complications are due to hyperglycaemia
  • Three metabolic pathways involved in long-term diabetic complications;

Formation of advanced glycation end products (AGEs)

  • Formed as a result of non-enzymatic reactions between intracellular glucose derived dicarbonyl precursors with the amino group of intracellular and extracellular proteins
  • AGEs have a number of biological properties;
    • Formation of AGEs on extracellular matric components such as collagen and laminin results in cross-linking and abnormal matrix-matrix and matrix-cell interactions
    • Cross-linking of Type I collagen in large vessels decreases their elasticity
    • Cross-linking of Type IV collagen in the basement membrane decreases endothelial cell adhesion and makes the vessel more leaky
    • AGE cross-linked proteins are resistant to proteolytic digestion
    • AGE-modified matrix proteins trap nonglycolated plasma or interstitial proteins such as LDL, enhancing deposition of cholesterol in the intima
    • In the glomerulus of the kidney plasma proteins may bind to the glycated basement membrane accounting for the increased thickening of the basement membrane seen in diabetic microangiopathy
    • Modification of circulating plasma proteins by AGE residues
    • These proteins can then bind to AGE receptors on cell types including macrophages, endothelial cells and mesangial cells
    • These cells then release a variety of pro-inflammatory cytokines and growth factors (via NF-kB). Altogether this results in;
      • Release of cytokines and growth factors by macrophages and mesangial cells including, TGF-b, PDGF and VEGF)
      • Increased endothelial permeability
      • Increased procoagulant activity of endothelial cells and macrophages
      • Enhanced proliferation and synthesis of extracellular matrix by fibroblast and SMC
      • AGEs can therefore contribute to both large vessel and microvascular disease

Activation of Protein Kinase C

  • Intracellular hyperglycaemia can stimulate the de novo synthesis of DAG from glycolytic intermediates and hence cause the activation of PKC
  • The effects of PKC include;
  • Production of VEGF implicated in the neovascularisation seen in diabetic retinopathy
  • Increased activity of the vasoconstrictor endothelin-1 and decreased activity of the vasodilator endothelial nitric oxide
  • Production of profibrogenic molecules like TGF-b, leading to increased deposition of a ECM and basement membrane material
  • Production of procoagulant molecule, plasminogen activator inhibitor-1 (PAI-1), leading to reduced fibrinolysis
  • Endothelial cell production of pro-inflammatory cytokines
  • Therapeutic inhibition can retard progression of diabetic retinopathy

Intracellular hyperglycaemia with disturbances in polyol pathways

  • In some tissues which do not require insulin for glucose transport, hyperglycaemia results in an increase in intracellular glucose that is then metabolised to by the enzyme aldose reductase to sorbitol, a polyol and eventually to fructose.
  • This process requires NADPH as a cofactor which is also required by the antioxidant mechanisms mediated by glutathione reductase resulting in the regeneration of reduced glutathione
  • Reduction in this process increases cellular susceptibility to oxidative stress

Clinical features of diabetes

  • In type 1 diabetes the transition from impaired glucose tolerance to overt diabetes can be abrupt and can be heralded by events which increase insulin requirements such as infection
  • Onset it marked by;
    • Polyuria
    • Polydipsia
    • Polyphagia
    • Ketoacidosis
  • Hyperglycaemia exceeds renal threshold for reabsorption resulting in glycosuria
  • Glycosuria induces an osmotic diuresis and thus polyuria causing a profound loss of water and electrolytes
  • Depletion of intracellular water triggers osmoreceptor resulting in polydipsia
  • Catabolism and proteolysis ensues resulting in a negative energy balance, increasing appetite (polyphagia)
  • Diabetic ketoacidosis – adrenalin blocks any residual insulin action and stimulates glucagons, severely exacerbating gluconeogenesis. Again this causes osmotic diuresis and severe dehydration. Insulin deficiency stimulates lipoprotein lipase which breaks down fats into free fatty acids. The free fatty acids are esterified in the liver to fatty acyl CoA, the oxidation of which produces ketone bodies
  • If the urinary excretion of ketone  bodies is accompanied by dehydration, the plasma hydrogen ion concentration increases leading to a metabolic ketoacidosis
  • The diagnosis of type 2 diabetes is most often made after routine blood or urine testing in an asymptomatic person
  • Patients may develop hyperosmolar nonketotic coma, a syndrome resulting from severe dehydration.
  • Long term complications generally develop 15 to 20 years after then onset of hyperglycaemia

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