PATHOPHYSIOLOGY OF DIABETES MELLITUS MUDr. Pavel Maruna.

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Transcript of PATHOPHYSIOLOGY OF DIABETES MELLITUS MUDr. Pavel Maruna.

  • PATHOPHYSIOLOGY OFDIABETES MELLITUSMUDr. Pavel Maruna

  • Diabetes mellitus= chronic endocrine - metabolic disorder,the result of insufficient insulin influence saccharide, lipid, protein metabolism, both water and mineral dysbalance

    Chronic hyperglycemia glykosuria osmotic diuresis

  • = endocrine active part of pancreas1-2,5 mil. islets, 1-2 g, 1-2% mass of pancreas

    B cells ( cells)... 60-80 %, insulinA cells ( cells)... 15-20 % glukagonD cells... 5 % somatostatinG cells... gastrinOther cells... VIP, PP, serotonin ...Islets of Langerhans

  • Islets of Langerhans

  • Insulin synthesis

    preproinsulin (linear chain, 107 AA)A - C - B chain, terminal fragmentcleavage of terminal fragment

    proinsulinA - C - B chaintransport to Golgi complex-SS- bridgesEncapsulationRelease after stimulusIslets of Langerhans

  • Insulin secretion

    insulin + C peptide (in equal amount)C peptide a minimal extraction in liverhINS a pINS - 1 AA difference on position 30(treonin x serin)insulin - 50% extraction in liver during the first passhalf-life of insulin in circulation 4-5 min.specific membrane bound receptors on target cellsIslets of Langerhans

  • Insulin secretion

    basal secretion(plasma levels 5-30 mU/l)after stimulus glcsome AA, glucagon ...sulphonylureaIslets of Langerhans

  • Islets of Langerhans

  • Islets of Langerhans

  • Insulin effects

    Liver- inhibition of glycogenolysis- inhibition of gluconeogenesis- stimulation of glycogenogenesisOther cells (muscles, fat, fibroblasts, brain)- Glc. uptake and utilization- stimulation of anabolic actions- inhibition of catabolic actions(e.g. inhibition of LP lipase)- transport of AA and K+ do cellsIslets of Langerhans

  • Insulin effectsGLUT4

    Insulin dependent Glc uptake into cellsIslets of Langerhans

  • Contraregulatory activities

    Glucagon - activation of hepatic glycogenolysis, activation of ketogenesisEpinephrine - activation of glycogenolysis in liver and muscles, lipid catabolismGH - activation of glycogenolysis in muscles, lipid catabolismCortisol - stimulation of gluconeogenesisT3, T4 - intestinal resorption of Glc, stimulation of both gluconeogenesis and glycogenolysis in liverSomatostatin - inhibition of insulin, glucagon, PP, GH secretionIslets of Langerhans

  • Insulin insufficiency- absolute- relative

    CausesInsulin is not composed in B cells of islets........!!Insulin is composed in defect shapeInsulin is composed OK, but is not released from B cellsInsulin is eliminated from circulation (auto-Ab)Insulin receptor or post-receptor insufficiency........!!! effect of contraregulatory hormones........!

  • Symptoms of insufficient insulin activity

    Glc uptake to cells (fat, muscles) gluconeogenesis in liver and kidneys glycogenolysis... glycaemia, plasma osmolarity... glycosuria due to overrun of renal threshold... osmotic diuresis, dehydration, Na and K loss lipolysis lipogenesis ketoacids production in liver(overpassing and utilising capacity of tissues)... ketoacidosis, acetonuria... acute and chronic diabetic complicationsInsulin insufficiency

  • ClassificationDM 1st type (= insulin-dependent)defect insulin secretion, absolute insulinodeficiency

    DM 2nd type ( non-insulin dependent)Inzulinoresistance + relative insulinodeficiency(impaired dynamics of secretion, delayed secretion ...)

    Secondary DM - in endocrinopathy (Cushing sy, acromegaly, thyrotoxicosis, feochromocytoma)

    Malnutrition-related DM(rare) hereditary syndromesDrugs (diuretics, corticoids)Gestatory DMDM in pancreatic disorders (inflammation, tumors, surgery...)Diabetes mellitus

  • Characteristics

    Absolute insulin insufficiencyTendency to ketoacidosisInsulin-dependent = insulin therapy is necessaryRevealed in children or young age (juvenile diabetes)Quick progression of signs ketoacidotic coma1st type DM

  • Etiology, pathogenesis

    genetic dispositions + acquired factors (viral infection)? autoantigenic presentation of -cells lymphocyte immune control -cell destruction

    Genes disposing for DM 1st type are localized in MHC on 6p chromosome. These genes encode antigens, regulating T-lymphocyte immune supervision (a discernment of own cells)

    1st Class HLA (HLA-A,B,C,D) - expressed on almost all cells2nd Class HLA (HLA-DP,DQ,DR) expressed on immune cells and (possible) on islets cellsE.g.HLA-DR3,DR4,DR1,DR8,DR16 ... higher risk of DM,HLA-DR11,DR15 protection against DM

    Prediction of 1st type DM quantification of risk:Auto-Ab against -cells, insulin, GAD (glutamate-decarboxylase)1st type DM

  • Insulitis

    = disappearance of -cells, inflammatory infiltration, degranulation, hydropic changes, fibrosis in young diabetics1st type DM

  • Insulitis1st type DM

  • LADA

    = latent autoimmune diabetes in adults(diabetes of the 1 1/2 type)

    DM 1st type with manifestation in later age (>30 r.)

    similarity to DM 2nd type (but without obesity),however both C-peptide and insulin levels are lower 0due to destruction of -cells! auto-Ab presented: anti-GAD, ICAs auto-Abtendency to ketoacidosis1st type DM

  • Characteristics

    The most frequent type of DM (80-90 %)

    Relative lack of insulinx ketoacidosisUsually non-insulin-dependentManifestation in middle or older patientsSlow progression, tendency to chronic complications2nd type DM

  • Etiology, pathogenesis

    Genetic dispositions (15-20% population)(marked hereditary dependence, often familiar presence, evidently polygenic transmission)Acquired factors - links to obesity (80 %)(overeating, obesity, stress, age, inactivity) type 2a) without obesity, type 2b) with obesity

    1. Inzulinoresistance = lower sensitivity of muscles, liver and fat to insulin ( receptors, affinity of receptors, or post-receptor blockade)2. Inzulinodeficiency = insufficient maximal insulin secretion (absolute or relative, manifesting together with insulinoresistance)2nd type DM

  • MODY

    = Maturity Onset Diabetes of the Young

    An early manifestation of NIDDM in young patients2nd type DM

  • MODY2nd type DM

  • = Transition between DM and normal glucose metabolism

    Diagnostics: oGTT

    Prognosis: normalization x long-term persistence x progress to DM

    Observation is necessaryImpaired glucose tolerance

  • = PGT or DM manifested firstly in pregnancy

    During pregnancy - physiologically sensitivity to insulin compensatory insulinaemia

    Gestatory DM reveals in women with insufficient compensatory insulinaemia

    After delivery, glucose tolerance is normalized, but there is a risk of DM in future

    Diff. dg.: first manifestation of latent IGT or 1st type DMGestatory DM

  • Glycaemia

    fasting / postprandial / glycaemic profile

    < 5 mmol/l fasting excludes DM> 10 mmol/l in blood (11 mmol/l in plasma) confirms DM7 - 10 mmol/l in blood (8 mmol/l in plasma) repeatedly + typical features suspect DM5 - 7 (8) mmol/l oGTTLaboratory markers of DM

  • oGTT (oral glucose tolerance test)

    75 g Glc per os012 hDM>7>10>10 mmol / l in venous bloodIGT107-10(unconvincing results ? ... decisive fasting glycemia or glycemia after 2 h)Laboratory markers of DM

  • Glycated albuminGlycated hemoglobin (normal levels below 4 %)

    Products of non-enzymatic glycation of proteins

    Glc + H2N-protein Schiffs base ketoamine glycated protein

    Irreversible, non-enzymatic process, dependent on- concentrations of glucose and proteins- half-life of glycated protein(colagens, lens x hemoglobin, albumin)Importance- pathogenesis- diagnostics (markers of long-term compensation of DM)Laboratory markers of DM

  • C peptide above 70-80 pmol/lInsulin (IRI = immunoreactive insulin)

    To distinguish 1st type x 2nd type DMLaboratory markers of DM

  • Urine

    glycosuria55 mmol/l Glc = 1%account of glucose toleranceacetonproteinuriamicroalbuminuria (physiologically 10-20 mg/24 h)U-glucosaminidasean early marker of kidney diseaseLaboratory markers of DM

  • Autoantibodies

    ICAs = against cells (against various cytoplasmic compounds)non-specific (founded in polyglandular syndromes, e.g.)IAAs = against insulinrevealed mostly during insulin therapy,low prognostic impactAnti-GAD = against decarboxylase of glutamate (enzyme for GABA production)highly specific to DM 1 typetheir detection means risk of DM 1st typeAnti-37kD = against 37 kD chain of GADstill higher specificity than anti-GADAnti-BSA = against bovine albuminwhich has (similarly as coxsackie viruses) sequences similar to cytoplasmic antigens of cellsLaboratory markers of DM

  • Markers of DM microangiopathy

    = markers of endothelium activation (beforeclinical signs of angiopathy revealed)

    tPA (tissue plasminogen activator) - marker of fibrinolysis, cleavage of fibronectinPAI-1 (plasminogen activator inhibitor) - antifibrinolytic activityvon Willebrand factorNAG (N-acetyl--glucosaminidase)30 kD N-terminal fibronektin- better than total fibronectin, it reflects an activity of tPALaboratory markers of DM

  • 1. Acute

    a) Hypoglycemia PAD, insulinb) hyperosmolar hyperglycemic coma... 2nd type DMc) ketoacidotic coma... 1st type DM d) lactoacidotic coma biguanidsDM complications

  • 2. Chronic

    a) Specific for DM

    - microangiopathy (diabetic leg)- neuropathy(peripheral symmetric (low extr.), asymmetric (head, extremities), amyotrophy, autonomic visceral)- eye complications (cataracta, glaucoma, paresis, retinopathy)- renal complications (diabetic glomerulosclerosis)Bells form (diffuse) x nodular form Kimmelstiehl-Wilsonmicroalbu