Diabetes mellitus

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

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)

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 B-cells in

pancreas by Tc lymphocytes absolute insufficiency of insulin requires whole-life treatment with insulin

DM type 1 - Diagnosis

clinically: 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)

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

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 !!!)

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 !!)

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

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

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

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

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)

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

Aplication Forms of Insulin

injection insulin pens ins. pump inhaled insulin (powder) peroral forms = in development

Indications of Insulin Therapy

DM type 1 DM type 2

loss of PAD effectiveness

surgery, intercurrent diseases

gestational DM states after pancreatectomia, pankreatitis

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

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

DM Type 2 - Treatment

must be complex (hypertension, dyslipidemia, obesity...)

important regimen precautions loss of weight

reduction diet

physical activity

Peroral Antidiabetics

1. Stimulators of insulin secretion

a. derivates of sulfonylurea b. derivates of meglitinides2. Insulin sensitisers

a. biguanines b. thiazolidindiones (glitazones)3. Inhibitors of intestine glukosidases4. New antidiabetics

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

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

Sulfonylurea Derivatives

block of ATP sensitive kallium channels 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: 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

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

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)

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

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 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

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

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

New - Incretin Mimetics and Gliptins

stimulation of insulin release

incretin, GLP-1 glycemiaExenatid, liraglutid

inhibition ofglucagon release

enzyme DPP-IV (inactivates GLP-1) DPP-IV inhibitors

(sitagliptin, vildagliptin)

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

PRAMLINTIDE (?) Injections s.c.

Analogue of human amylin – neuroendocrine hormone

– is amyloidogenic, toxicity postprandial release of glucagon postprandial release of pancreatic enzymessatiety (hypothamamus)

Glucuretics (?) Inhibition of renal

glucose transport glycosuria

Phlorizin – the first, nonselective

Selective inhibition - SGLT2 (sodium glucose co-transporter) = gliflozines Dapagliflozin Canagliflozin

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 !!!

Anti-Obesity Drugs

1. Sibutramine

inhibits reuptake of norepinephrine +

serotonin

central anorectic effec

2. Orlistat

inhibitor of intestine lipase

less effective ass sibutramin

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

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)

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