Diabetes mellitus

DM – Definition, Prevalence chronic metabolic disease caused by absolute or relative insufficiency of insulin (or their combination) in the world approximately 370 million diabetic patients raising incidence, mainly DM type 2

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)

Acute Complications of DM diabetic ketoacidosis (typical for DM type 1, but can also occur at DM type 2; breakdown of amino acids and fatty acids in liver to provide energy – ketone bodies) hyperosmolar coma (typical for DM type 2) hypoglycaemic coma

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

Diabetic foot

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

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

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

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)

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

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

Insulin Protein secreted from ß-cells of the islets of Langerhans Secretion induced by a rise in blood glucose and inhibited by a fall in blood glucose Consists of 2 peptid chains (A and B), connected by 2 disulphide bridges Incretins (hormones released from intestine cells in the presence of food) induce insulin secretion

Insulin Metabolic effects – anabolic: Glucose – increasing glycogen storage: active transport of glucose into cells (mostly sceletal muscle, adipose tissue); storage of glucose in the form of glycogen (liver, muscle); inhibits glycogenolysis; inhibits gluconeogenesis in liver. Lipids – reduces plasma free fatty acids and increases adipocyte triglyceride storage. Proteins – inhibition of catabolism of amino acids in liver; increased transport of amino acids into muscle and increased protein synthesis Anabolic effects are inhibited with glucagon, growth hormone, cortisol, catecholamines

Insulins According to Origin 1. Prepared by recombinant DNA method (Humulin - HM) using bacteria or yeast 2. Insulin analogs (exchange, change of sequenceor type of AA) = better pharmacocinetic properties

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Insulins according to Length of Action A. Short-acting insulins: Fast beginning of the effect (30 - 60 min.), acting 5 - 8 hours Has a slower onset and longer duration of action than rapid- acting insulin analogues after s.c. administration Consists of insulin hexamers crystallized around a zinc molecule Water soluable s.c. or i.v. administration (acute states require i.v. administration !!!) i.v. administration only at units equipped to monitor the patient and must be performed by trained personnel; change of therapy only by trained personnel Can be available in biphasic formulations (e.g. regular + NPH)

Insulins according to Lenght of Action B. Insulins with prolonged action: To generate intermediate-acting or long-acting formulations, insulin is complexed with: Protamine Zinc Protamine and zinc

Insulins according to Length of Action B. Intermediate acting (NPH = Neutral Protamine Hagedorn): Slower beginning of the effect (1 - 2 hours), peak (4 - 12 hours), duration (18 – 24 hours) Suspensions, must be gently rolled or inverted before each use to ensure uniform dosage Contains particles of insulin combined with zinc and protamine that slowly dissolve after s.c. administration Is more prone to erratic absorption and intrapatient variability than the long-acting insulin analogues Only s.c. administration (after i.v. administration risk of embolisation !!)

Insulins according to Length of Action C. Rapid-acting insulin analogs: Insulins lispro, aspart, glulisine Very fast beginning of the effect (10 - 20 min.), peak (1 hour), acting (less than 3 hours) Usually given right before meal, but can be given immediately after eating Can be available in biphasic formulations (insulin aspart + insulin aspart protamine; insulin lispro + insulin lispro protamine) s.c. or i.v. administration i.v. administration only at units equipped to monitor the patient and must be performed by trained personnel Can be available in biphasic formulations (e.g. insulin aspart + insulin aspart protamine) – only s.c. administration

Insulins according to Length of Action D. Long-acting insulin analogs: Insulins glargine, detemir, deglutec Beginning of the effect (1 - 2 hours), acting (up to 24 hours) Usually enough to administer one time per day Are slowly absorbed after s.c. administration, which avoids plasma insulin peaks They should not be administered i.v.

Adverse Effects of Insulin Hypoglycemia: the main problem; most people experience warning symptoms, those who not are prone to sudden attack with loss of consciousness, reasons: ↑ dose, insufficient food income, interaction with alcohol Rebound hyperglycaemia: can occur after episode of hypoglycaemia, especially at night (Somogyi effect – compensatory release of hormones, e.g. adrenaline) Insulin resistance: due to production of circulating antibodies, human insulins rarely Weight gain: at ↑ daily doses of insul. at DM type 2 Local allergy: rarely Local fat hypertrophy: can be minimized by rotating the site of injection

Aplication Forms of Insulin injection insulin pens ins. pump inhaled insulin – rapid onset of action, effect lasts 5 – 10 hours (can be used in place of short or rapid-acting insulins) peroral forms = in development

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 the most commonly application of monophasic or biphasic insulin 1/day (usually in the morning) or 2 x/day (morning and evening) intensified regimen 3-5 s.c. injections/day  standard at DM type 1  at DM type 2 after failure of PAD, special situations (severe infection, surgery, metabolic acidosis)

Intensified Regimen the best imitation of physiologic insulin secretion important is patient education (selfmonitoring) most often 3-5 s.c. injections/day administration of prandial insulin (regular, analog) before a meal in combination with basal insulin (NPH, analog)

Insulin Pump continuous s.c. administration of insulin only for good cooperating patients after adequate education the best compensation of diabetes is used if there is a problem with recurrent hypoglycaemia, unpredictable daily lives or hyperglycaemia before breakfast in case of combination with sensor to monitor glycemia, automatic adjustment of doses

Inhaled insulin lower-than-expected sales Exubera problem - the bioavailability 10-15%, is used exclusively for type 2 diabetes, ADR -  vital capacity (!), Ca lungs? was withdrawn from the U.S. market in 2007 due to lack of consumer demand for the product Afrezza FDA 2014 DM type 1 or 2, adults only, non-smokers, not COPD, not lung Ca lower-than-expected sales

Pancreatic cell transplantation necessity of life-long immunosuppression - daclizumab (Zenapax), sirolimus (Rapamune), tacrolimus (Prograf) Edmonton protocol Stem cells, genetic engineering

DM Type 2 occurs in middle and older age (usually after 40yrs of age), it is often associated with overweight the onset of the disease is usually slow, diabetes is often only diagnosed incidentally during tests for other health problems

DM Type 2 A significant proportion of a genetic predisposition Other factors: obesity, stress, low physical activity, inadequate diet composition It can lead to recurrent urinary tract inflammations, badly healing wounds, skin infections, fungal diseases of the genital area, retinopathy

DM Type 2 insulin resistance at postreceptor level = relative insulin deficiency, later also absolute impaired release (secretion) of insulin the same CV risk as patients after MI !!! often part of the metabolic syndrome

INSULIN RESISTANCE

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

Peroral Antidiabetics 1. Stimulators of insulin secretion („hypoglycemic agents“) a. sulfonylureas b. meglitinides (glinides) 2. Insulin sensitisers („antihyperglycemic agents“) a. biguanides b. thiazolidindiones (glitazones) 3. Inhibitors of intestine glukosidase („antihyperglycemic agents“) 4. New antidiabetics

Sulfonylureas stimulation of endogenous insulin secretion effect depends on the functional ß-cells of pancreas in monotherapy or in combination binding to albumin > 90% = interactions !!! AE: the effect increased by: NSAIDs, alcohol, warfarin the effect decreased by: thiazide diuretics, glucocorticoids, β2-agonists, estrogens risk of hypoglycaemia (especially in older patients using preparations with long action) weight gain not suitable for patients with severe renal, hepatic, cardiovascular and respiratory system disorder risk of hypoglycemia mainly glibenclamide (longer duration of action), less glipizide,gliklazide,glimepiride, gliquidon (shorter duration of action).

Sulfonylureas effective – only if functional ß-cells  problem – treatment failure: primary – genet. polymorphisms secondary – loss of pancreatic fuction after treatment reduced basal (prandial) and postprandial blood glucose level and some of them (e.g. gliclazide) have additional beneficial extrapancreatic effects, e.g. antioxidant, anti-atherogenic, resp. increase of insulin sensitivity

Sulfonylureas block of ATP sensitive kallium channels by binding to specific receptors (increase the release of insulin from ß-cells in response to stimulation by glucose) high affinity binding to SUR receptors depolarization - Ca2+ entry  insulin secretion

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 - KATP channels: ß-cells of pancreas (SUR1) smooth muscle cells – vessels (SUR2B) cardiomyocytes (SUR2A) (animals – slowdown myocardial repolarization, vasoconstriction) Selecitivity of SUR1- the highest gliclazide and meglitinides

Meglitinides drugs with similar mechanisms of action and the resulting effects as sulphonylureas short-lasting stimulation of insulin secretion = influencing postprandial glycemia taking before the main meal mostly in combination with metformin AE - hypoglycemia repaglinide, nateglinide, mitiglinide

Biguanides (Metformin) insulin sensitisers = increase sensitivity of tissues to insulin (muscles, adipose tissue), ↓ level of TAG, no weight gain and antabus effect, no hypoglycaemia drug of the 1st choice in the treatment of DM type 2 after treatment failure combination with other PAD AE - GIT intollerance (often), lactic acidosis (potentially fatal; ↑ risk among alkoholitics and at chronic renal, hepatal and respiratory diseases, heart failure)

Thiazolidindiones (Glitazons) – Rosiglitazone, Pioglitazone agonists of nuclear peroxisome proliferator- activated receptor-γ (PPARy) = 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

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

Inhibitors of Intestine Glukosidase (Acarbose) inhibition of disacharidases in small intestine = slowing down of composite sacharides hydrolysis influencing only postprandial glycemia reduce postprandial blood glucose without the risk of hypoglycaemia AE - flattulence, diarrhoea, stomach pain effectiveness in reducing HbA1c is lower than that with other antidiabetic drugs less used, only in combination

New antidiabetics Analogues of GLP-1 (incretin mimetics) and the DPP-4 inhibitors (gliptins) Glucuretics/ SGLT2 inhibitors/Gliflozins Others – only FDA: D2-receptor agonist (bromocryptine with quick-release) bile acid sequestrant (colesevelam) analogue of human amylin (pramlintide)

Incretin mimetics and gliptins Incretins: polypeptides – hormones, secreted by intestinal cells plasmatic half-life 2-7 minutes GLP-1 (glucagon-like peptide-1) and GIP (glucose-dependent insulinotropic polypeptide) Glukagon like peptid (GLP-1): Increases insulin secretion Decreases gastric emptying Increases satiety (weight loss) Stimulates neogenesis of beta-cells Enzyme (DPP-4 dipeptidyl peptidase-4)  inhibits the degradation of the incretins (GLP-1 and GIP).

Incretin mimetics and gliptins 1. Analogues of GLP-1 (incretins) = e.g. exenatide, liraglutide, dulaglutide  s.c. aplication (no peroral antidiabetics) 2. Inhibitors of DPP-4 (gliptins) = e.g. sitagliptin, vidagliptin, alogliptin  p.o. aplication AE - nasopharyngeal + urinary infections

Incretin mimetics and gliptins low risk of hypoglycaemia don´t lead to weight gain many other pleiotropic effects ADRs: nasopharyngeal + urinary infections exenatide: acute pancreatitis !!

Gliflozins = Glucuretics = SGLT2 inhibitors Selective inhibition - SGLT2 (sodium glucose co-transporter) = gliflozins Inhibition of renal glucose transport  glycosuria Phlorizin - the first non-selective E.g.: Dapagliflozin, Canagliflozin, Empagliflozin ADRs – urinary tract infections, fungal Increased excretion of glucose in the urine leads to a reduction of body weight, decrease in blood pressure and also a lower risk of hypoglycaemia as with sulphonylureas

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

Dopamine agonists (Bromocriptine) Has been used for many years in the treatment of hyperprolactinaemia and Parkinson´s disease Research suggest that deficient dopamine neurotransmission in hypothalamus is associated with disturbances in circadian rhythm – it can lead to development of insulin resistance, obesity and diabetes

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

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

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 !!!

Obesity therapy the first line is a combination of a low calorie diet, increased physical activity and behavioral therapy pharmacotherapy – in Slovakia available for the safety only OTC preparations bariatric surgical treatment

Hormonal changes and obesity Hypothyreosis Cushing´s syndrome Deficiency and excess of growth hormone Polycystic ovary syndrome

Anti-Obesity Drugs the possibility of effective pharmacotherapy remains at present limited many new drugs are already at the stage of clinical trials, and many were withdrawn from the market due to adverse reactions the promise to the future is the use of combination therapy

Anti-Obesity Drugs Sibutramine inhibits reuptake of norepinephrine + serotonin central anorectic effec reported changes of mood, depressions, panic disorders, FDA doesn´t recommed use for the risk of acute CV events !!! (MI, stroke)

Anti-Obesity Drugs 2. Dexfenfluramine, fenfluramine, phentermine, sibutramine centrally acting appetite suppressants, withdrawn for increased risk of valvular heart disease and pulmonary hypertension

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 helps at quiting of smoking psychic disturbances, increased risk of suicidal behavior !!!

Anti-Obesity Drugs 4. Orlistat inhibitor of intestine lipase less effective as sibutramin Impaired absorption of fat-soluble vitamins not recommended to use more than for 2 years increase incidence of hypothyroidism liver damage? in Slovakia not on market

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.

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