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INSULIN
By
Arijit ChakrabortyM-Pharm (Pharmacology)
09/10/20121
Diabetes Mellitus
Diabetes mellitus is a metabolic disorder characterized by hyperglycemia, glucosourea, hyperlipaemia, negative nitrogen balance and sometimes ketonaemia.
Two major types of diabetes mellitus: i) Insulin-dependent diabetes
mellitus (IDDM). ii) Non-Insulin-dependent
diabetes mellitus (NIDDM). Various symptoms are: Feeling very thirsty and tired,
high level of glucose in urine, constant hunger etc.
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Insulin-dependent diabetes mellitus : There is β cell destruction in pancreatic islets; majority of cases are autoimmune antibodies that destroy β cell are detectable in blood, but some are idiopathic, there are no β cell antibody are found. In all cases circulating insulin levels are low.
Noninsulin-dependent diabetes mellitus : There is no loss or moderate reduction in β cell mass, insulin in circulation is low, normal or even high, no anti-β-cell antibody is demonstrable; has a high degree of genetic predisposition, generally has a late onset.
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Treatment
IDDM : Insulin must be injected or inhaled
NIDDM : Food control, exercise, medicines:
i) Which increase insulin secretion;
ii) Which increase the sensitivity of
target organs to insulin;
iii) Which decrease glucose absorption.
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INSULIN Insulin was the first protein for
amino acid sequence which consists of two peptides chains (21 and 30 amino acid residues) linked by disulfide bonds.
Secretion : β-cell in pancreatic islet.
Degradation : Liver & kidney. Endogenous: Liver (60 %) &
kidney (35 %-40 %) Exogenous: Liver (35 %-40 %) &
kidney (60 %)
Half life : 3-5 min in plasma.5
Physiological & pharmacological actions
Sugar metabolism : Stimulates glucose
uptake & use by cells; inhibits gluconeogenesis
→blood sugar↓
Fatty metabolism : Improves fatty acid
transportation & fat anabolism; inhibits fat
catabolism & fatty acid,
Protein metabolism : Improves a
transportation & protein anabolism; inhibits protein
catabolism & an utilization in liver, 6
Physiological & pharmacological actions
Potassium : Stimulates K+ entering cells → blood
K+↓
Long-term action : Improves or inhibits the
synthesis of some enzymes.
Mechanism of action : i) Insulin receptor in cell membrane
mediates the effect;
ii) Insulin receptor is consisted by 2α-
subunits, which constitutes the recognition site, and
2β-subunits, which contains a tyrosine kinase.8
Mechanism of action of insulin
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Effect of insulin on glucose uptake and metabolism.
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Clinical use Diabetes mellitus : Insulin is effective in all forms of diabetes
mellitus and is a must for IDDM cases, as well as for post pancreatectomy diabetes and gestational diabetes. Many NIDDM cases can be controlled by diet, reduction in body weight and appropriate exercise.
Insulin needed by some such patients: i) Not controlled by diet and exercise
or when these are not practicable. ii) Primary or secondary failure of oral
hypoglycemic or when these drugs are not tolerated.
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iii) Under weight patients. iv) Temporarily to tide over
infections, trauma, surgery, pregnancy. v) Any complication of diabetes, e.g.
Ketoacidosis, nonketotic hyperosmolar coma, gangrene of extremities.
Other :
i) Hyperkalemia
ii) A component of GIK solution
which is for limiting myocardial infarction &
arrhythmias.12
Adverse reaction Insulin allergy : Itching, redness,
swelling, anaphylaxis shock Hypoglycemia : Nausea, hungry, tachycardia, sweating, and tremulousness.
Insulin resistance : i) Acute : Diabetic ketoacidoisis,
Nonketotic hyperosmolar coma. ii) Chronic : Microvascular disease: impotence
& poor wound healing Atherosclerosis : Strokes,
coronary heart disease Renal failure, retinal damage,
nerve damage Infective disease: Tuberculosis
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Oral Hypoglycemic Drugs
Classification:
Sulfonylureas
Thiazolidinediones
Biguanides
α-glucosidase inhibitors
Meglitinides
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Sulfonylureas
Representative Drugs: 1st generation: tolbutamide chlorpropamide
tolazamide 2nd generation: glybenclamide glyburide glipizide glymepride 3rd generation: glyclazipe
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Pharmacological effects:
1. Hypoglycemic effect:
2. Anti-diuretic effect:
chlorpropamide & glybenclamide
3. Anti-platelete aggregation effect:
glyclazipe
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Hypoglycemic MechanismRapid mechanism: Stimulation of insulin
secretion Sulfonylurea receptor in β-cell
membrane activated
ATP-sensitive K+-channel inhibited
Cellular membrane depolarized
Ca2+ entry via voltage-dependent Ca2+ channel
Insulin release
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Long term profit involved mechanism: Inhibition of glucagon secretion by
pancreas α cells; Ameliorating insulin resistance Increase insulin receptor number & the
affinity to insulin
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Clinical use: 1. Type 2 diabetes mellitus 2. Diabetes insupidus, chlorpropamide
Adverse reactions: 1. Gastrointestinal disorders 2. Allergy 3. Hypoglycemia Chlorpropamide forbidden for ageds &
patients with functional disorder in liver or kidney.
4. Granulocytopenia, cholestasis & hepatic injury 1
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Thiazolidinediones
Representative Drugs:
rosiglitazone, troglitazone, pioglitazone, ciglitazone
Pharmacological effects:
Improving function of pancreas β cells.
Ameliorating insulin resistance.
Ameliorating fat metabolic disorder.
Preventing and treating type 2 diabetes mellitus and their cardiovascular complications.
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Mechanism (possible):Per-oxisome proliferator-activated receptor-
γ(PPAR-γ) activated
Nuclear genes involved in glucose & lipid metabolism and adipocyte differentiation activated
Clinical use: Insulin resistance & type 2 diabetes
mellitus
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Thank you