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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, -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
patients 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 meglitinides
2. Insulin sensitisers
a. biguanines
b. thiazolidindiones (glitazones)
3. Inhibitors of intestine glukosidases
4. 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
dont 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 glycemia


Exenatid, liraglutid
inhibition of
glucagon
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 enzymes
satiety (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 doesnt
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

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