Diabetes mellitus
Practicals – experimental diabetes mellitus in laboratory animal بايو كمستري (م 4) / د . احمد الطويلثاني اسنان موصل 23 / 11 / 2015Definition of DM
DM is a group of metabolic disorders characterized by hyperglycemia as a reason of impaired effect of insulin absolute relative chronic hyperglycemia leads to cell & tissue damage (complications) retina kidney nervesDiagnosis of DM
classical symptoms of diabetes + random plasma glycemia 11.1 mmol/lany time of the day symptoms include polyuria, polydipsia and rapid loose of weightFPG (fasting plasma glucose) 7.0 mmol/lfasting means at least 8 h from the last meal2-h PG (postprandial glucose) 11.1 mmol/l during oGTTaccording to WHO standard load of 75g of glucoseInterpretation of glycemia
FPG: <6.1 mmol/l = normal glycemia6.1-7.0 mmol/l = IGT (impaired glucose tolerance) 7.0 mmol/l = diabetesoGTT – 2h PG: <7.8 mmol/l = normal glucose tolerance7.8 - 11.1 mmol/l = IGT11.1 mmol/l = diabetesOral glucose tolerance test
normalIGT
diabetes mellitus
Practicals
i.p. ANESTEZIA
repeated measurement of glycemia on glucometr in 30 a 90 min time intervals determination of glukosuria in urine sample
1 week before 1/2 animals ALLOXAN i.v. 30 mg/kg
results: graph FPG - 30mPG - 90mPG comparison of DM x non-DM
blood sample from a tail vein measurement of FPG on glucometr
application of 20% glucose 1ml/100g i.p.
Pathophysiology of DM
Regulation of glycemiahumoral principal insulin glucagon auxiliary glucocorticoids adrenalin growth hormone neural sympaticus hyperglycemia parasympaticus hypoglycemia
GLUCOSE
glucose-6-Ppyruvate
ATP
lactate
ATP
acetyl-CoA
citrate cycle
respiratory chain and oxidative phosphorylation
CO2
H2O
lactate cycle in liver
glycolysis
GLYCOGEN
glucose-1-phosphate
liver, muscle
glycogenesis, glycogenolysis
glycerol glucogennic aminoacids
gluconeogenesis
liver, kidney, intestine
free fatty acids
-oxidation keton bodies
ATP
Insulin
preproinsulin proinsulin insulin + C-peptideexocytosis into portal circulation50% degraded during first pass through liver total daily production 20 - 40 U 1/2 basal secretion, 1/2 stimulatedbasal secretion pulsatile5 - 15 min intervalsstimulated – glucose, amino acids, FFA, GIT hormonesearly phase (ready insulin)late phase (synthesis de novo)Diabetes mellitus
heterogeneous syndrome characterized by hyperglycemia due to deficiency of insulin action (as a result of complete depletion or peripheral resistance) prevalence of DM in general population 5%, over the age of 65 already 25%Causes of insulin deficiency
absolutedestruction of the -cells of the islets of Langerhanґs relative insulin abnormal molecule of insulin (mutation) defective conversion of preproinsulin to insulin circulating antibodies against insulin or receptor insulin resistance in peripheral tissue receptor defect post-receptor defectClassification of DM
I. DIABETES MELLITUSDiabetes mellitus of type 1 (T1DM)
Diabetes mellitus of type 2 (T2DM)
Gestational diabetes mellitus
Other specific types - genetic defects of β cell function (MODY)- genetic abnormalities of insulin receptor- exocrine pancreas disorders- endocrinopathies- iatrogenic- rare genetic syndromes II. IMPAIRED GLUCOSE TOLERANCE (IGT)
Type 2 DM (formerly NIDDM)
imbalance between secretion and affect of insulingenetic predisposition – polygenicinsulin resistance impairment of secretionclinically manifested T2DM has concomitant insulin resistance and impairment of secretiondue to epigenetic factorstypically in older adults 90% of subjects is obese – metabolic syndrome!!!Insulin resistance
physiologic amount of insulin does not cause adequate response compensatory hyperinsulinism further worsening by down-regulation of insulin receptors
Clinical presentation of manifest DM
due to the increase of blood osmolality, osmotic diuresis and dehydratation classical polyuria thirst polydipsia weight loss temporary impairment of visus cutaneous infectionsacute hyperglycemic coma ketoacidotic non-ketoticidotic