1. Diabetes mellitus

2. DM – Definition, Prevalence chronic metabolic disease caused by absolute or relative insufficiency of insulin (or their combination) in the world approximately 270 million diabetic patients raising incidence, mainly DM type 2

3. Classification DM DM type 1 DM type 2 Gestational DM Other specific types of DM (e.g. MODY- hereditary forms linked to mitochondrias, drug induced DM - glucocorticoids, β-blockers, thiazides)

4. Acute Complications of DM diabetic ketoacidosis (typical for DM type 1, but can also occur at DM type 2 ) hyperosmolar coma (typical for DM type 2) hypoglycaemic coma

5. Chronic Complications of DM diabetic macroangiopathy = acceleration of atherosclerosis diabetic microangiopathy = damage of retinal and renal vessels diabetic nephropathy diabetic neuropathy = senzo-motoric affection

6. Diabetic foot

7. Prevention of Complications good long-term diabetes controll complex treatment of concomitant risk factors (hypertension, dyslipidemia, obesity...)

8. DM type 1 most often among children genetically determined (allele DQ8, DR3,4) autoimune destruction of B-cells in pancreas by Tc lymphocytes absolute insufficiency of insulin requires whole-life treatment with insulin

9. DM type 1 - Diagnosis clinically: polyuria, polydypsia, loosing of weight, acetone foetor ex ore biochemically:  fasting glycemia >7 mmol/l  oGTT - glycemia 120 min. >11 mmol/l  C-peptide ↓ or 0  urine: + ketonuria, glucose

10. DM type 1 - Treatment nowadays exclusively only human insulins effort to imitate diurnal secretion of insulin (basal + postprandial) important education of parents and also children (selfmonitoring, regimen precaution)

12. Insulins According to Origin 1. Semisynthetic – from porcine insulin by the change of AA (Insuman) 2. Prepared by recombinant DNA method (Humulin - HM) 3. Insulin analogues (exchange, change of sequence or type of AA) = better pharmacocinetic

13. Insulins according to Length of Action A. Short acting :  fast beginning of the effect (15 - 30 min.)  acting 3 - 6 hours  water soluable  s.c. or i.v. administration ( acute states require i.v. administration !!!)

14. Insulins according to Length of Action B. Intermediate acting (NPH) :  slower beginning of the effect (1 - 3 hours)  acting 4 - 12 hours  suspensions  only s.c. administration (after i.v. administration risk of embolisation !!)

15. Insulins according to Lenght of Action B. Insulins with prolonged action :  slow beginning of the effect (3 - 4 hours)  acting 10 - 24 hours  suspensions  only s.c. administration

16. Insulin Analogues Insulins lispro + aspart  beginning of the effect till 15 min., lasts shortly (cca 1 hour)  possible to administer right before meal Insulins glargine + detemir  act 16 – 24 hours  usually enough to administer one time per day

17. Adverse Effects of Insulin hypoglycemia: ↑ dose, insufficient food income, interaction with alcohol lipodystrophy: human ins. rarely weight gain: at ↑ daily doses of insul. at DM type 2 local allergy: rarely

18. Insulin Regimens the conventional regimen 1-2 s.c. injections/day  in some cases at DM 2 after failure of treatment with PAD or + PAD intensified regimen  standard at DM type 1  at DM type 2 after failure of PAD

19. Intensified Regimen the best imitation of physiologic insulin secretion Important is patient education (selfmonitoring) most often 4-5 s.c. injections/day intermediate ins. only at evening or in morning and at evening, short-acting ins. before main meal (morning-noon-evening)

20. Insulin Pump continual s.c. administration of insulin only for good cooperating patients after adequate education the best compensation of diabetes in case of combination with sensor to monitor glycemia, automatic adjustment of doses

22. Aplication Forms of Insulin injection insulin pens ins. pump inhaled insulin (powder) peroral forms = in development

23. Indications of Insulin Therapy DM type 1 DM type 2  loss of PAD effectiveness  surgery, intercurrent diseases gestational DM states after pancreatectomia, pankreatitis

24. Goals of DM Type 1 Therapy prevention of chronic complications by good diabetes compensation  long-term glycemia ≤ 7 mmol/l  HbA1c (glykosyled Hb) < 7% keeping stabilized glycemia  without frequent hypo-hyperglycemias keeping the best possible quality of patient´s lives

25. DM Type 2 insulin resistance at postreceptor level = relative insulin deficiency, later also absolute the same CV risk as patients after MI !!! marked therefore as also „CV disease” frequently part of metabolic syndrome

26. DM Type 2 - Treatment must be complex (hypertension, dyslipidemia, obesity...) important regimen precautions  loss of weight  reduction diet  physical activity

27. Peroral Antidiabetics 1. Stimulators of insulin secretion a. derivates of sulfonylurea b. derivates of meglitinides 2. Insulin sensitisers a. biguanines b. thiazolidindiones (glitazones) 3. Inhibitors of intestine glukosidases 4. New antidiabetics

28. Sulfonylurea Derivatives stimulation of endogenous insulin secretion effect depends on the functional B-cells of pancr. in monotherapy or in combination binding to albumin > 90% = interactions !!! AE - hypoglycemia (carefull, interactions with NSA, alcohol, warfarin), weight gain risk of hypoglycemia mainly glibenclamide, less glipizide and gliklazide

29. Sulfonylurea Derivatives effective – only if functional beta-cells  problem – treatment failure: primary – genet. polymorphisms secondary – loss of pancreatic fuction after treatment  ADRs: hypoglycemia - mortality associated with treatment up to 10%! stimulation of apetite - weight gain

30. Sulfonylurea Derivatives block of ATP sensitive kallium channels high affinity binding to SUR receptors  depolarization - Ca2+ entry  insulin secretion

31. SU RECEPTOR belongs to a family of transmembrane proteins – a group of ABC transporters (ATP-Binding Cassette transporter), is only a regulator of ion channels ATP sensitive kallium channels - K ATP channels: B-cells of pancreas (SUR1) smooth muscle cells – vessels (SUR2B) cardiomyocytes (SUR2A) (animals – slowdown myocardial repolarization, vasoconstriction) Selecitivity of SUR1- the highest gliclazide and meglitinides

32. Derivates of Meglitinide short-lasting stimulation of insulin secretion = influencing postprandial glycemia taking before the main meal metabolism in liver = possibility to give to patients with renal insufficiency mostly in combination with metformin AE - hypoglycemia repaglinide, nateglinide

33. Biguanines - Metformin insulin sensitisers = increase sensitivity of tissues to insulin, ↓ level of TAG, anorectic and antabus effect drug of the 1st choice in the treatment of DM type 2 after treatment failure combination with other PAD AE - GIT intollerance, lactic acidosis (↑ risk among alkoholitics and at chronic renal, hepatal and respiratory diseases, heart failure)

34. Thiazolidindions (Glitazons) – Rosiglitazone, Pioglitazone activators of nuclear receptor PPARy (transkriptional factor) = increase sensitivity of tissues to insulin, ↓ TAG, ↑ HDL AE - ↑ weight (fat redistribution), fluid retention = oedemas, heart failure, among risk patients ↑ CV mortality !! not the 1st choice, only in combination with other PAD

35. Rosiglitazone EMEA: suspension of registration for the potential risk of ischemic CV events (acute myocardial infarction, stroke!!!) FDA: only restriction on the use

37. Inhibitors of Intestine Glukosidases (Acarbose) inhibition of disacharidases in small intestine = slowing down of composite sacharides hydrolysis influencing only postprandial glycemia oft AE - flattulence, diarrhoea, stomach pain less used, only in combination

38. New Antidiabetics on the ground of GLP-1 (glucagon-like peptide 1) = incretin, released in small intestine after stimulation with food, degraded by DPP-4 (dipeptidyl peptidase 4)  stimulates insulin secretion from B-cells  decreases glucagon secretion  has anorectic effect low risk of hypoglycemia don´t lead to weight gain in combination with metformin

39. New Antidiabetics 1. Analogues of GLP-1 = liraglutide, exenatide  s.c. aplication 2. Inhibitors of DPP-4 (gliptins) = sitagliptine  p.o. aplication AE - nasopharyngeal + urinary infections

40. New - Incretin Mimetics and Gliptins stimulation of insulin release incretin, GLP-1  glycemia Exenatid, liraglutid inhibition of glucagon release enzyme DPP-IV (inactivates GLP-1) DPP-IV inhibitors (sitagliptin, vildagliptin)

41. Glucagon like peptid (GLP-1) = insulinotropic peptide: Increases insulin secretion Decreases gastric emptying Increases satiety (weight loss) Stimulates neogenesis of beta-cells Inhibitors of DPP4 (dipeptidyl peptidase): Inhibit degradation of GLP

42. PRAMLINTIDE (?) Injections s.c. Analogue of human amylin – neuroendocrine hormone  – is amyloidogenic, toxicity  postprandial release of glucagon  postprandial release of pancreatic enzymes satiety (hypothamamus)

43. Glucuretics (?) Inhibition of renal glucose transport  glycosuria Phlorizin – the first, nonselective Selective inhibition - SGLT2 (sodium glucose co-transporter) = gliflozines Dapagliflozin Canagliflozin

44. DM Type 2 as the part of Metabolic Syndrome metabolic sy = ↑↑↑ CV risk  abdominal obesity (weist circumference)  insulin resistance (± DM type 2)  hypertension  dyslipidemia  protrombotic state  hyperuricaemia

45. DM Type 2 as the part of Metabolic Syndrome = need of complex therapy of all risk factors hypertension - ACEI, Sartans, CaCB (telmisartan = PPARy agonist) protrombotic state – aspirin??, clopidogrel dyslipidemia - statins obesity - diet, excercise, antiobesitic drugs

46. Obesity key etiologic factor of metabolic sy (ins. resistance) CV risk mainly abdominal obesity (waist circumference > 102 cm men, > 88 cm women- USA; 94 cm and 80cm- Europe without weight loss is good compensation of DM type 2 almost impossible !!!

48. Anti-Obesity Drugs 1. Sibutramine  inhibits reuptake of norepinephrine + serotonin  central anorectic effec 2. Orlistat  inhibitor of intestine lipase  less effective ass sibutramin

49. Anti-Obesity Drugs 3. Rimonabant  blockator of canabinoid recep. (CB1 receptors = hypothalamus, limbic system, visceral region)  anorectic effect  ↑ adiponectin (antiatterogenically, antidiabetically)  makes better lipid profile (TAG, HDL)  lowers insulin resistance  help at quiting of smoking

50. Antio-Obesity Drugs - ADR Rimonabant (Acomplia): suspended registration for suicide risk !!! Sibutramine: reported changes of mood, depressions, panic disorders, FDA doesn´t recommed use for the risk of acute CV events !!! (MI, stroke)

51. Case 13 year old boy, last days is feeling more tired, urinates several times per day also at night, permanently feels thirst despite of drinking more than 2 l fluids per day, fainted at school, before cramp pain of stomach Anamnesis: not seriously ill before, family history without no remarkable Objectively at admission: skin pale, intensificated breathing, signs of dehydration, foetor ex ore after fruit, BP: 90/60, P: 95/min.

52. Case 1. What is susspicious diagnosis? 2. What examinations would you recommend ? 3. What is pseudoperitonitis diabetica? 4. Make pharmacoterapeutic plan