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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
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DM type 1
DM type 2
Gestational DM
Other specific types of DM (e.g. MODYhereditary 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

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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
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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
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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


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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



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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
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
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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
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injection
insulin pens
ins. pump
inhaled insulin (powder)
peroral forms = in development
Indications of Insulin Therapy
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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


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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
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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

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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
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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)
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smooth muscle cells – vessels (SUR2B)
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cardiomyocytes (SUR2A)

(animals – slowdown myocardial repolarization,
vasoconstriction)
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Selecitivity of SUR1- the highest gliclazide and meglitinides
Derivates of Meglitinide

short-lasting stimulation of insulin secretion =
influencing postprandial glycemia
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taking before the main meal
metabolism in liver = possibility to give to
patients with renal insufficiency
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mostly in combination with metformin
AE - hypoglycemia
repaglinide, nateglinide
Biguanines - Metformin
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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
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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)
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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)
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 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
Exenatid, liraglutid
enzyme DPP-IV
(inactivates GLP-1)
 glycemia
inhibition of
glucagon
release
DPP-IV inhibitors
(sitagliptin,
vildagliptin)
Glucagon like peptid (GLP-1) = insulinotropic peptide:
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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 (?)
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Injections s.c.
Analogue of human amylin –
neuroendocrine hormone
– is amyloidogenic, toxicity
 postprandial release of glucagon
 postprandial release of pancreatic enzymes
satiety (hypothamamus)
Glucuretics (?)
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Inhibition of renal
glucose transport  glycosuria
Phlorizin – the first, nonselective
Selective inhibition - SGLT2
(sodium glucose co-transporter)
= gliflozines
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Dapagliflozin
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Canagliflozin
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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)
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protrombotic state – aspirin??, clopidogrel
dyslipidemia - statins
obesity - diet, excercise, antiobesitic drugs
Obesity
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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 !!!
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Sibutramine: reported changes of mood,
depressions, panic disorders, FDA doesn´t
recommed use for the risk of acute CV
events !!! (MI, stroke)
Case
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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