Diabetes mellitus. DM – Definition, Prevalence chronic metabolic disease caused by absolute or...
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Transcript of Diabetes mellitus. DM – Definition, Prevalence chronic metabolic disease caused by absolute or...
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
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.