Diabetes mellitus Aetiology and Pathogenesis, Specific complications Darja Krusova II dpt. of internal med. FNUSA Diabetes mellitus chronic metabolic and endocrine disorder «■ due to insuficiency of insulin action «■ blood glucose level -permanent increased hyperglycaemia and glycosuria in Czech Rep.: more than 9,5%=960.000 diabetics -92% DM type 2 1995- 504.000 diabetics, 1975- 250.000 children: 4,3% till 15 y., 6,9% till 6 y. \ M ' USA: 11% > 20r., 28% >65r. (prediab.50% > 65r, 35% > 20r.) Number of treated diabetic patients in Czech rep. 800 000 700 000 600 000 500 000 400 000 300 000 <# J> <# <# <# # c^N # # cČ* □ počet diabetiků celkem □ □ •Č Intrinsic innervation cholinergic, peptidergic PPcell Dcell B cellsN?/ £ Hormones Metabolites Arteriole CI *0 I o • / • Extrinsic innervation adrenergic, cholinergic, Deotideraic Biosynthesis of insulin Gen-11-th chromosoma preproinsulin proinsulin insulin + C peptid (30-120 min) «■ receptors -depends on insulin level, p.o. antidiabetic drugs Rough endoplasmic # reticulunv^^ Golgi apparatus Preproinsulin ,£,eav;?Be * ' A site (dipeptide proinsulin ^ removed) / % V Secretory V „ r granules ^ Ribosome Insulin Cytoplasm A chain pS-S-i tttttt ^ 8 xi^iTir^rir^rir^r^r^r^i? i 1311 i J* 2 £ 5 lo 5 | 1 2 3 4 S 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 __B30 A8 A10 Human Thr Thr lie Porcine Ala Thr lie Bovine Ala Ala Val ' W 1 Insulin secretion ^Basal- cca 20 U/day ^Stimulated- after secretional stimuli & fast, first phase - mediated through hormons (GIP,GLP-1) -5-10 min ©prolonged, second phase - depends on nutritional stimuli, takes all the time of its duration, max 2-3 h. Accessory ampulla Ampulla of Vater Duodenum/ B □ Pancreatic ß cell Insulin D Insulin secretion C-peptide Glucose stimulus A st phase Basal / \ X^"~\ secretion / ^2nd phase 0-5 Time mins Davidson's Principles,Practice of Medicine Lower action of insulin 1 «■ absence of insulin output in B-cells «■ defect in synthesis of ins. /proins., decrease ins.production, output of faulty insulin «■ insulin releasing defect «■ defect due to antibodies «■ defect of ins.action in target organs (receptors) «■ defect in insulin degradation ^increased action of insulin's antagonists hyperglycaemia Lower action of insulin 2 «■ Reduction of intra-cell transport of glucose «■ increase in gluconeogenesis decrease in glycolysis in liver «■ increase in glycogenolysis 1—S hyperglycaemia Insulin action Increased intra-cell transport of glu, aminoacids,K,Mg,Ca ■ of glucose-transporters GLUT-4 ■ 30-60% gl utilized in liver Stimulation of anabolic and block of catabolic processes in organism Insulin actions i Liver: «■ increase in synthesis of glycogen - anabol.effect «■ increased intake of glu into the cells and its utilisation in peripheric «■ decrease in glukoneogenesis a glykogenolysis - anticatabol.effect - decreased glycaemia Insulin actions 2 «■ increase in synthesis of lipids- lipogenesis decreased lipolysis- antilipolytic action antiketogen. action «■ increase in synthesis of proteins-anabol. action increase in RNA syntesis decreased proteolysis- anticatabol. action Glycids glucose anaerob glycolysis 1 pyruvate 1 oxidative decarboxyl. proteins glycerol fatty acids aminoac beta-oxidatioj particular) degradatio Acetyl-Co-A Krehsxvcle lactate aethylalcoholoxaloacet^ zytrate > CO2 + H2O lipids etc. Insulin deficiency i In corporal cells block of glue, and aminoacids - transport intracell. In liver glykogenolysis || glukoneogenesis ||proteolysis occur, of amnoacids peripheral gluc.utilisation R proteosynthesis H production of glu If production of urea production of fat and lipoproteins U production ketoacids Insulin deficiency 2 «" In fatty tissue "Tlipolysis ^lipo genesis In muscle preferential utilisation of proteins and fets ft fatty acids U offer of amino acids and fatty acids for liver Contraregulatory hormones Glukagon-A increases glycogen-splitting in liver STH,GH decreases glucose utilisation ACTH increases glucocort. Glucocorticoids increases glukoneogenesis, stim.of insulin, decreases peripheral glucose utilisation Adrenalin increases glykogenolysis in muscle, decreases insulin secretion Hormons of thyreoid gland Somatostatin -D decreases insulin secretion Pancreatic Polypeptid ,VIP , Amylin -B decreases insulin secretion DM classification i 1 DM type 1 a) immune absolute insulin deficit b) idiopatic LADA, brittle 2 DM type 2 insulin resistance relative insulin deficit DM classification 2 3 Other specific types ► genetic defects of B-cells function: MODY (autosomal domin. inheritance ,younger age,asthenics,without insulin necessity.) ► genetic defects of insulin action ► disease of exocrine part of pancreas ► endocrinopathies ► drugs induced ► viral infection (cong. rubeola, CMV, ...) ► rare immunologically caused ► other genetic sy (Down, Klinefelter, ...) 4 Gestational DM I II asthenic DR3,DR4,DQ -0 -0 + 1 J Age of manifestation childhood-40 habitus haplotyps ins. synthesis insulinaemia autoantibodies response on PAD glycaemia onset of disorder symptoms ketoacidosis insulin therapy vascul.complications brittle quick /weeks/ severe + + micro middle, older, >40 hyperstenic norm, norm, + relat. stable slow (months-years) mild or none ilin-] PAD, diet, insulin-resistance macro Pathogenesis of DM 1 .type EisenbaruYs scheme 1. Genetic susceptibility DR3,DR4 2. Initiating mechanism 3. Incipient insulitis Coxackie B /ICA,ICSA,IA-2,GADA/ mumps, rubeolla, CMV /IAA,PAA,ICSTA/ EBV 4. Full developed insulitis (80%) 5.Manifestation of diabetes 6. No secretion of endogenous insulin 0^> DM 1 .type Normal islet tis ß-cell destruction Environmental triggers and regulators L susceptibility to wmune dysfunction Insulitis Loss 0f fjrst phase Inflammatory cell infiltration of islet ,nsu|m secretion Antibody-mediated (3-cell destruction impaired glucose Autoantibodies present in blood tolerance Overt diabetes Time % 21.4 Pathogenesis of type 1 diabetes. Proposed sequence of events in the development of type 1 diabetes. Environmental triggers Davidson's Principles,Practice of Medicine Pathogenesis of DM 2. type (polygenic type of heredity-except MODY)) overeating^besity leptine Hyperinsulinemi J physical activity fat meal Hyperglycaemia FFA / oxidative stress (a< Glucolipotoxicnty sulin resistance quired and congenital) Decrease of insulin r Overload, exhaustion of B-cells secretion disorder [U. K , ^ DM 2.type DM 2.type -contributing factors fett meals nutrition - overeating high age live style - stress, infection, operation acute endangering situations reduction of movement alcohol - pancreatitis, cirhosis hepatis iatrogenic DM - corticosteroids, thiazids, contraceptivs gravidity endocrine disorders DG criteria Clin, symptoms fasting gly gly/pp. dg thirst,polydipsia, polyuria, weight loss, > 7,0 > 11,1 DM total disability infection (skin, genitals) poorly healing wounds suddenly developed complication <7,0 5,7-11,1 IGT increased FPG, prediabetes No clin. sympt. < 5,6 < 7,8 norm Oral glucose tolerance test oGTT norm. IGT DM fasting value < 5,6 insignificant >7 2-hour value < 7,8 7,8-11,0 >11,1 Laboratory examinations Glycaemia -fasting value glycosuria -postprandial value ketonuria -glycaemic profil Glycated hemoglobin (HbAjC) (fructosamin) C peptid Insulinaemia = IRI insulin antibodies (ia2,gada) biochemistry tests, lipids zdraví Udá: 2&4z mmol/mol ČD5: výborná kompenzace: <45 mmol/mol ADA doporučení: n of MA a)MAU intermitent -after phys.exer. b)MAU perman 30-300 mg/24h duction by the g reduction of Mi U, decrease of C norm, ent ly cont jFR pn 0 rol, mention Stage* Stage of s of di ( Duratioi DM-year iabetic n Mogensen i Laboratory s ephro] 1993 ) GF 3athy Complications 3.Manifest gly control: antihypei 15-20 ireversil tonic dn PU>500 mg/ 24/h Die jgs: deceleral about lmly liiin/nionth ion of pro retinopathy neuropathy gression Stages of diabetic nephropathy (Mogensen 1993 ) Stage ] of I Ouratioi )M-year i Laboratory s GF Complications 4. Chronic renal insuficien >20 t S-krea T S-urea T S-uric acid I progression of vascular compl. End stage kidney ACE inhibitors, RAS blockers Effect: antihypertensive cardioprotective vasoprotective «- in diabetics: action metabolic, antiproliferative, paracrine and specific nephroprotective. Renin-angiotenzinový systém Angiotenzinogen Prostaglandiny renn eninové inhibitory proteázi Angiotenzin I kalikrein ^ Bradykinin ACE —► <«— ACE inhibitory peptiááza=kinináza II Kinináza 1 blokátory receptoru All ▼ III Angiotenzin II_* Receptor All Kinináza II Receptor All aminopeptidáza Angiotenzináza A( inhil ▼ inhibitory Angiotenzin typ ATI Inaktivní kininové fragm Receptor All typ AT2 inaktivní fragmenty? Therapy algoritm in diabetics with MAU Diabetes control N > control correction correct? Y Start of therapy RAS blockers Undesirable effects/ pregnancy-stop. Other antihypert. N J} drugs TK<130/85+decrease MAU-N^therapy of hypert. Y I (add) ▼ Repeat MAU each 3-6 m.^Risk factor elimination GoahstableXrFR. Stable/decreasing MAU. BP. Fig. 60.1 Necrobiosis lipoidica diabeticorum (NLD). (a) An early lesion on an ankle, showing the erythematous stage, (b) A longstanding patch of NLD. Note the typical yellow, atrophic appearance with telangiectasia. Xanthelasma palpebrarum gangraena sicca Dupuytrain's contracture vitreous hemorhagy