17. Insulin and other antidiabetics Flashcards
In what species does diabetes mellitus occur most frequently?
Dogs and cats (0,2-0,5%)
What are 2 types of DM?
- Type 1: (IDDM - insulin dependent DM) - beta cells are not able to produce enough insulin to maintain normal blood glucose level
- Type 2: (NIDDM - non-insulin dependent DM) - insulin resistance of body tissues -› organism produces more insulin -› beta cells hypertrophy and hyperplasia -› over time dysfunction, hypoplasia and death of beta cells
What type of DM is most frequent among diabetic animals
Type 1 - insulin deficiency
Synthesis of insulin
- Produced by beta-cells of the islets of Langerhans in the endocrine pancreas
- preproinsulin in endoplasmic reticulum -› proinsulin -› transportation to the Golgi complex -› insulin -› storage in secretory granules in a complex form with zinc
How is insulin secreted normally?
In beta cells ATP-sensitive K+ channels and Ca++ channels are present. Typically K channels are open -› K goes outside of the cells. And Ca channels are normally closed.
When glucose is present in the blood it gets transported into the cell via GLUT-2 transporter, glucose is eventually metabolised into ATP -› K channels are sensitive to ATP -› when ATP level rises K channels close -› increase of K concentration inside of the pancreatic cells -› depolarisation -› opening of the voltage-gated Ca channels -› Ca rushes into the cell -› increased Ca conc inside of the cell activates calcium-calmodulin-responsive protein kinases -› exocytosis (fusion of the secretory granules filled with insulin with the plasma) membrane)
Action of insulin:
- increased IC uptake of glucose, AAs, FAs, K+
- increased protein synthesis, deposition of fat and glycogen
- decreased glycogenolysis, GNG, lipolysis
Lack of insulin leads to:
(Signs of DM)
- hyperglycaemia, glucosuria
- polyuria, polydipsia (PU/PD)
- weight loss
- incomplete fat metabolism -› increase of plasma FAs conc -› ketoacidosis -› coma
Metabolism and use of insulin
Degradation of insulin by a relatively specific insulin-degrading enzyme (insulinase) is rapid (half-life 5 min)
Use:
- to treat DM
- ketosis and fatty liver in cattle which are non-responsive to glucose or GCC therapy alone
Forms of insulin drugs
-
regular
Can be given IV. Rapid onset, duration of action short (4-8h) -
insulin zinc suspension (lente insulin)
12-24h -
protamine zinc insulin (PZI)
24-36h -
isophane insulin (NPH = Neutral Protamine Hagedorn)
12-30h
Mainly SC administration!
Adverse effects and interactions of insulin:
Adverse effects:
- acute hypoglycaemia
- Somogyi rebound effect - hypoglycaemia induced hyperglycaemia due to compensatory release of insulin-antagonist hormones
- allergic reaction
Interactions:
- drugs reducing hypoglycaemic activity: GCCs, dobutamin, oestrogen/progesterone, xylazine, thiazide diuretics
- drugs increasing hypoglycaemic activity: anabolic steroids, beta-adrenergic blockers (propranolol), MAO inhibitors, phenylbutazone, salicylates
What antidiabetic drugs are used orally? In what case?
In type 2 DM - non-insulin dependent DM
- acarbose
- sulnonylureas (glipizide - preferred in cats)
Acarbose mechanism of action
inhibition of alpha-glycosidase (e.g. amylase) activity in GI -› less rapid elevation of blood sugar level after food consimption. Also with insulin in dogs and cats
Mechanism of action of sulfonylureas. Side effects
- insulin secretion↑
- sencitivity of the cells to insulin↑
- number of receptors↑
- binding of insulin to plasma proteins↓
- glucagon release↓
side effects: liver toxicity, elevated CYP-enzyme activity
What are other oral antidiebetic groups (beside acarbose and glipizide) that are not in the drug list?
- glinides: (nateglinide) - increased insulin secretion
- biguanides: (fenformine, buformine, methformine) - simulation of the action of insulin, decreased oral absorption of glucose
- sulfonylureas (gliclazide, glibenclamide)
