Diabetology Diabetes mellitus (DM) nChronic disease nHigh morbidity, mortality, invalidity nMore than 700 000 patients in the Czech Republic nBanting and Best – isolation of insulin (isletin) from canine pancreas Insulin (I) and contrainsular hormones nI – a small protein, chains A, B linked by disulphide bridges nB (beta) cells of the islets of Langerhans nA (alpha) cells: glucagon nD (delta) cells: somatostatin nPP cells: pancreatic polypeptide nC peptide: combination of the A, B chains in proinsulin I - secretion nSynthesis and secretion of I – rise of ATP -glucose nOther nutrients – ketone bodies, FA's, AA's nHormonal and nervous influences nStimulation: growth h., glucagon, GLP-1, gastrointestinal peptide, secretin, gastrin, VIP nInhibition: somatostatin, adrenaline, noradrenaline, prostaglandin E nStimulation: parasympathetic system, beta-adrenerg. I - secretion nTotal daily production of I – 20-40 IU nBasal: 50% (as measured by C peptide on an empty stomach), stimulated 50% (by C peptide after the meals) nEffect of I nInsulin receptor -entry of glucose (G) into the cell -activation of intracellular enzymes n I - effect nStimulation of anabolic and blockade of catabolic processes in the metabolism of glucose, fats, and proteins nTarget tissues: muscles, adipose tissue, liver - - I - effect nLiver: glycogen synthesis, proteosynthesis, lipogenesis, blockade of glycogenolysis, gluconeogenesis, ketogenesis nMuscles: GLUT-4 activation - increased uptake of glucose, glycogen synthesis, proteosynthesis nAdipose tissue: inhibits lipolysis, increased lipogenesis DM classification nType 1 DM nA – autoimmunity conditional nB - idiopathic nType 2 DM nA – predominantly insulin-resistant nB – predominantly insulin-deficient DM classification nThe other specific types of DM nGestational DM (GDM) nCritical disorders of glucose homoeostasis 1.Increased glycaemia on an empty stomach 2.Impaired glucose tolerance (IGT) Type 1 DM nSelective destruction of beta cells = absolute lack of insulin = hyperglycaemia nA- autoimmune – the most frequent in our country, in genetically predisposed people – HLA-DR/DQ n risky DR3,DR4,DQA1,DQB1, protective DR2 n presence of circulating antibodies – 90% DM1 preclinically nB- idiopathic (non-immune) Type 1 DM nTriggering mechanism of autoimmune reaction – infection, most frequently viral; toxic influences nInsulinitis – clinical manifestations only after the disappearance of 40-80% of B cells depending on age nLADA – in older age deceleration up to cessation of the destructive autoimmune process Type 1 DM - clinical picture nTypical symptoms nThirst, polydipsia nNycturia, polyuria nWeight loss nFatigue nDisturbance of consciousness nAcetone odour nBlurred vision nOther symptoms nRecurrent infections nPeriodontitis, cariogenicity nSymptoms of DM complications: polyneuropathic, potency disorders, affection of sight, GIT problems Type 1 DM - clinical picture nHyperglycaemia, dehydration nMetabolic acidosis, ketosis, acidotic Kussmaul respiration nI is missing = increased unused glucosis, escalated gluconeogenesis nIncreased osmolarity = osmotic diuresis, polyuria nRelease of FA's, liver – ketogenesis from acetyl-CoA, acetoacetic acid, 3-hydroxybutyric acid nAbdominal pain up to pseudoperitonitis diabetica Type 1 DM - laboratorial monitoring nGlycaemia: fasting and postprandial, HBA1c, glycosuria, ketonuria nAstrup, Na, K, Cl, Ca, Mg, P nLipids, decreased activity of LPL – increased TG and VLDL nC peptide on an empty stomach and after exertion, IRI nAnti-GAD 65 A, ICA, IAA nMicroalbuminuria, proteinuria, creatinine clearance, examinations: neurology, ophthalmology, vascular Type 1 DM - treatment nInsulin (I) administered exogenously, simulation of physiological secretion nPrandial – preprandially with short-term I before the main meals nBasal – long-acting I, most often in the evening nHuman insulins (HMR, HM NPH), insulin analogues n Type 1 DM - treatment nInsulin pump (CSII) – microdoses of I in a basal and bolus programme nIndication: nUnsatisfactory compensation, repeated hypoglycaemia nProgression of microvascular complications nPregnancy planning nTransplantation of pancreas and/or beta cells Type 1 DM - treatment nDiet nDiabetic diet No. 9 – 275 or 325 g saccharides per day n8400 or 9850 kJ/d n3 main meals, snacks in the meantime. Second supper nRestriction of free saccharides, high-calorie fatty meals nGlucose meter - self-monitoring Type 1 DM - treatment nMovement regimen nBring into harmony the movement regimen with the insulin regimen - danger of severe hypoglycaemias nInadequate acute exhausting stress nAdequate long-time aerobic stress n Type 1 DM - compensation criteria and treatment goals n - ± - nGl.: fasting 4.0-6.0 6.0-7.0 over 7.0 npostprandial 5.0-7.5 7.5-9.0 over 9.0 nHbA1c (%) under 4.5 4.5-6.0 over 6.0 nTotal chol. under 4.5 4.5-5.0 over 5.0 nHDL over 1.1 1.1-0.9 under 0.9 nLDL under 2.6 2.6-3.0 over 3.0 nTG under 1.7 1.7-2.0 over 2.0 Type 1 DM - compensation criteria and treatment goals n + ± - nBMI (kg/m2) nMales 21-25 25-27 over 27 nFemales 20-24 24-26 over 26 nBP under 130/80 - over 130/80 ? n Type 2 DM nOverweight, obesity nLipid spectrum changes nHyperinsulinaemia, insulin resistance nHypertension, increased level of uric acid nHypercoagulation state nMetabolic sy (insulin resistance sy, Reaven syndrome) Type 2 DM - pathogenesis nInsulin resistance (IR) nInsulin deficiency nDiminished utilization of glucose in muscles nResistance of adipose tissue to insulin n Increased FFA's, depositing of fat in the liver and muscles nDisturbance of the incretin system nDisturbance of the alpha cells with hyperglucagonaemia nAltered adaptive response of the kidneys to hyperglycaemia and disturbance of the renal reabsorption of glucose nManifestations of IR in the brain – appetite regulation, thermogenesis DM 2 type – RF ´S nInconspicuous manifestation; complications in 7% on diagnosis nObesity nAge over 40 years nHT nHLP nGestational DM nFoetal macrosomia Comparative Clin. Features of Type 1 and Type 2 DM nType 1 nTypical age at onset nType 2 n Type 2 DM - manifestations nSymptoms of diabetic syndrome nLower metabolic lability nNo inclination to ketoacidosis nAcute hyperglycaemic complication – nhyperglycaemic hyperosmolar coma Type 2 DM - diagnostics nFasting glycaemia higher than 7.0 mmol/l nFasting glycaemia 5.7-7.0 mmol/l – oGTT noGTT (75 g glucose in aqueous solution), n 2 h test higher than 11.1 mmol/l – DM n 7.9 – 11.1 = impaired glucose tolerance n Type 2 DM - therapy nLow-energy diet + movement nFluid intake – 2.5 l minimum nPeroral antidiabetics (PAD) n- Affecting insulin secretion (secretagogues) -Affecting insulin resistance -Affecting absorption of saccharides from the GIT Type 2 DM – medicaments affecting insulin (I) secretion nSulphonylurea derivatives nIncrease insulin secretion, 2nd-generation preparations nGlibenclamide (Maninil), glipizide (Minidiab), gliclazide (Diaprel), gliquidone (Glurenorm), glimepiride (Amaryl) nThe least possible doses 1-2x daily nDrug of choice in non-obese T2DM diabetics Type 2 DM – medicaments affecting insulin (I) secretion nNon-sulphonylurea-type insulin secretagogues (so-called fast insulin secretagogues) (glinides) nThey affect only stimulated (postprandial) secretion of insulin nRepaglinide (Novonorm) nNateglinide ( Starlix) nPreprandially 3x per day in non-obese patients Gliptins (DDP-4 inhibitors) nIncrease in the GLP-1 activity nStimulation of insulin secretion – via beta cells nSuppression of glucagon secretion - alpha cells nInfluence on both fasting and postprandial glycaemia nCombination with SU as well as MTF nSitagliptin (Januvia), Vildagliptin (Galvus) nLinagliptin (Trajenta), Alogliptin (Nesina) n Type 2 DM – medicaments affecting insulin resistance(IR) nBiguanides nInfluence on liver IR, less on peripheral IR nMetformin (Glucophage, Siofor, Metformin) nLactate acidosis nCI – diseases of the liver and kidneys, states associated with a risk for tissue hypoxia = respiratory, circulatory insufficiency n1-2x d, 500-3000 mg/d, obese diabetics n Type 2 DM – medicaments affecting insulin resistance(IR) nInsulin sensitizers nInfluence on peripheral IR nThiazolidinediones – rosiglitazone (Avandia), pioglitazone (Actos) - efficient in muscular and adipose tissues nDemanding in terms of price nIntolerance of metformin nCombined therapy Type 2 DM – medicaments affecting saccharide absorption from the GIT nAlpha-glucosidase inhibitors nDeceleration of the breakdown of disaccharides = deceleration of the postprandial increased glucose level nDisadvantage – fermentative dyspepsias = flatulence, diarrhoea nAcarbose (Glucobay) 3x daily n Type 2 DM – GLP-1 analogues nIncretin antidiabetics, s.c. nGLP-1 agonists: Exenatide (Byetta 2xd, Bydureon 1x per week) nGLP-1 analogues: Liraglutide (Victoza 1xd) nLow risk of hypoglycaemia: hypergl. - stimulated by beta cells, inhibited by alpha cells, normogl.- zero effect nWeight loss – GLP-1 acts in the CNS + deceleration of stomach evacuation nNatriuretic effect - drop of BPs nCombination therapy with MTF, SU, TZD n ‹#› 04.png 14.png 07.png 05.png Gliflozins: a novel, insulin-independent mechanism of lowering hyperglycaemia in type 2 DM1-4 02.png 01.png Proximal tubule 06.png Filtration of glucose 1. Wright EM. Am J Physiol Renal Physiol 2001;280:F10–18; 2. Lee YJ, et al. Kidney Int Suppl 2007;106:S27–35; 3. Hummel CS, et al. Am J Physiol Cell Physiol 2011;300:C14–21; 4. Dapagliflozin. Summary of product characteristics. Dapagliflozin selectively inhibits SGLT 2 in the proximal tubule of the kidneys. SGLT2 Glukóza Dapagliflozin SGLT2 Dapagliflozin inset.png 09.png 12.png 11.png Increased excretion of excessive glucose into urine (~70 g/day, which corresponds to 280 kcal/day) 16.png 17.png 16.png 15.png 16.png 16.png 16.png 16.png 16.png Diminished reabsorption of glucose 01.png Type 2 DM – combination therapy with PAD nEnhancement and supplementation of the effect nFixed combination nGlibenclamid + metformin (Glibomet) nRosiglitazone + metformin (Avandamet) nSitagliptin + MTF (Janumet) nVildagliptin + MTF (Eucreas) Type 2 DM – insulin therapy nCombined therapy nCombination of SU with a dose of intermediate-acting I for the night nCombination of premixed I in two doses + metformin nPreprandially 3x daily administered short-acting I + metformin Secondary DM - the other specific types of DM nDefect of the genetic determinant nImpaired effect of I itself nDisease of tissues associated with the insulinogenic tissue (pancreas) nChemical substances and hormones enhancing IR or blocking insulin secretion Secondary DM - the other specific types of DM nHereditary type of diabetes - MODY n20th to 25th year of life - disturbance of insulin receptors – type A IR nChronic diseases of the pancreas nChronic pancreatitis, ca of the pancreas, cystic fibrosis, haemochromatosis, surgery of the pancreas Secondary DM - the other specific types of DM nEndocrinopathy nOverproduction of counterregulatory hormones: nDiseases of the thyroid, pheochromocytoma, Cushing sy, acromegaly, glucagonoma nGlucocorticoids, diuretics, BB, psychotropic substances n Gestational DM nIntolerance of G in pregnancy, especially in its second half nUsually disappears after childbirth nIncidence 3-4% nIR after 20th week – high concentration of counterinsular hormones – placental lactogen, cortisol, oestrogen Gestational DM nCharacter of type 2 DM, increased postprandial glycaemia nRF's: n DM in family history, obesity, more than 35 years of age, glycosuria in previous pregnancy, delivery of a foetus over 4000 g nFasting oGTT 5.6 and higher; after 2 hrs 7.7 nDiet, insulin ( fasting up to 5.3, postprand. up to 7.8) Critical disorders of glucose homoeostasis nIncreased risk for development of all types of DM nAssociation with MS, thus IR nIncreased risk of cardiovascular complications nFasting G 6.1 – 6.9; G in 2nd hour of oGTT 7.8 - 11.1 mmol/l nDispensing care, diet, weight loss n Acute complications of DM Ketoacidotic hyperglycaemic coma nAcute complication of type 1 DM nMetabolic acidosis with the rise of ketone bodies, hyperglycaemia, deficit in water and ions nPolyuria, polydipsia, dehydration, hypotension nKetoacidosis – nausea vomiting, acetone odour in the breath, dyspnoea Ketoacidotic hyperglycaemic coma nKussmaul respiration, signs of dehydration nK depletion, during therapeutic correction of acidosis, K is shifted intracellularly – a dramatic fall of K nOsmotic diuresis – loss of Cl, Mg, Ca, phosphates Ketoacidotic hyperglycaemic coma nInsulin i.v. a bolus of 8 IU, cont. 4-8 IU/h nFluids + ions nPhys. sol. 1000 ml in 1st hour, then 500 ml for 5-8h nGlycaemia less than 15 mmol/l – 5% G nSupplementation with K: 20 mmol/h nMetabolic acidosis nCorrection with pH less than 7.0, NaHCO3 Non-ketoacidotic hyperosmolar coma nComplication of type 2 DM, serious prognosis nExtreme hyperglycaemia (even more than 50 mmol/l), dehydration nFrequent development of renal insufficiency nHyperosmolality (more than 340 mmol/kg) nFluids i.v., up to 10 l minimum, K, insulin Lactacidotic coma nMetabolic acidosis – lactate accumulation nType A – presence of tissue hypoxia nAnaemia, heart failure, shock nType B without tissue hypoxia nDiseases – DM, liver disorders nToxic influences – alcohol, biguanides nUnsatisfactory treatment – alkalization of NaHCO3, hydrogen carbonate dialysis Hypoglycaemia and hypoglycaemic coma n3.3 mmol/l in the capillary plasma nMild – can be managed by the patient himself/herself nSevere – help from outer environment is necessary nPhysical load, omission of a meal, increase of insulin nTremulousness, cold sweat, tachycardia, hunger nNeuroglycopenic symptoms - headache, affection of fine motor activity, blurred vision nGlucagon 1 mg i.m., 50 ml of 40% G n Chronic complications of DM nDiabetic nephropathy nDiabetic retinopathy nDiabetic neuropathy nMacrovascular complications – ischaemic heart disease, ischaemic diseases of the lower limbs, vascular diseases of the brain Diabetic foot nAffection of lower limbs in DM distally from the ankle nDiabetic gangrene in 5.6%, amputation in 18.5% of diabetic foot patients nHaemorheologic deviations + hypoxia of peripheral tissues nTypes include: neuropathic, angiopathic, mixed Diabetic foot nDiabetic polyneuropathy nThe most frequent cause of ulcerations nDiminished sensation of pain, temperature, pressure nMuscular atrophy, impaired arches of the foot nCharcot's arthropathy nDiabetic angiopathy nMediocalcinosis, microangiopathy, macroangiopathy Moucha1 bzučivka zelená PB130010 PB130001 PB040016 PB040013 PB040012 P8050003 P6020012 P6020011 P4010137 P5270002 P5270001