2. Insulin Discovered by Banting and Best in 1921 . First obtained in crystalline form in 1926 and later structure worked upon by Sanger. Insulin is two chain polypeptide having 51 amino acids and mol.wt around 6000. The peptide hormones directly involved in responding to and controlling blood glucose levels are located in the islets of Langerhans in the pancreas; insulin is secreted by β-cells and glucagon by α2 cells.
3. Insulin Human insulin consists of 51 AA in two chains connected by 2 disulfide bridges (a single gene product cleaved into two chains during post-translational modification). T1/2 ~5-10 minutes, degraded by glutathione-insulin transhydrogenase (insulinase) which cleaves the disulfide links. Bovine insulin differs by 3 AAs, pork insulin differs by 1 AA. Insulin is stored in a complex with Zn+2 ions.
4. What is diabetes??? Diabetes is a heterogeneous group of syndromes characterized by the elevation of glucose levels due to a relative or absolute deficiency of insulin; frequently inadequate insulin release is complicated by excess glucagon release. Diabetes is a disorder of inadequate insulin activity it is associated with episodes of both hyper- and hypo-glycaemia. It is the episodes of hyperglycemia that are associated with long-term complications.
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6. Classifications of complications The long term complications of diabetes may be divided into two large groups: 1. Macrovascular: These complications are associated with pathology of the large & medium sized vessels; this includes CHD, stroke, PVD 2. Microvascular: These complications are due to vascular pathology of the small vessels and include neuropathy, nephropathy, retinopathy
9. Normal Glucose Control In the post-absorptive period of a normal individual, low basal levels of circulating insulin are maintained through constant β cell secretion. This suppresses lipolysis, proteolysis and glycogenolysis. After ingesting a meal a burst of insulin secretion occurs in response to elevated glucose and amino acid levels. When glucose levels return to basal levels, insulin secretion returns to its basal level. Type I DM: Lack of functional β-cells prevents mitigation of elevated glucose levels and associated insulin responses. The onset and progression of neuropathy, nephropathy and retinopathy are directly related to episodic hyperglycemia. Type II DM: The pancreas retains some β-cell function but effective insulin response is inadequate for the glucose level. Actual insulin levels may be normal or supra-normal but it is ineffective (insulin resistance).
10. Treatment: Type I: Type 1s depend on exogenous insulin to prevent hyperglycemia and avoid ketoacidosis. The goal of type 1 therapy is to mimic both the basal and reactive secretion of insulin in response to glucose levels avoiding both hyper- and hypo-glycemic episodes. Type II: The goal of treatment is to maintain glucose concentrations within normal limits to prevent long term complications. Weight reduction, exercise (independent of weight reduction) and dietary modification decrease insulin resistance and are essential steps in a treatment regimen. For many this is inadequate to normalize glucose levels, the addition of hypoglycemic agents is often required, often insulin therapy is required.
11. Insulin secretion: Insulin secretion is regulated by glucose levels, certain amino acids, hormones and autonomic mediators. Secretion is most commonly elicited by elevated glucose levels; increased glucose levels in β-cells results in increased ATP levels, this results in a block of K+ channels causing membrane depolarization which opens Ca+2 channels. The influx of Ca results in a pulsatile secretion of insulin; continued Ca influx results in activation of transcription factors for insulin. Oral glucose elicits more insulin secretion than IV glucose; oral administration elicits gut hormones which augment the insulin response. Insulin is normally catabolized by insulinase produced by the kidney.
14. Mechanism of Insulin Action Insulin binds to specific high affinity membrane receptors with tyrosine kinase activity. Phosphorylation cascade results in translocation of Glut-4 (and some Glut1) transport proteins into the plasma membrane. It induces the transcription of several genes resulting in increased glucose catabolism & inhibits the transcription of genes involved in gluconeogenesis. Insulin promotes the uptake of K+ into cells.
17. Insulin Degradation Hydrolysis of the disulfide linkage between A&B chains. 60% liver, 40% kidney(endogenous insulin) 60% kidney,40% liver (exogenous insulin) Half-Life 5-7min (endogenous insulin) Delayed-release form( injected one) Category B ( not teratogenic) Usual places for injection: upper arm, front& side parts of the thighs& the abdomen. Not to inject in the same place ( rotate) Should be stored in refrigerator& warm up to room temp before use. Must be used within 30 days.
22. 22 3. Intermediate - acting insulins (contd.) Lente and NPH insulins Are roughly equivalent in biological effects. They are usually given once or twice a day. Note: They are not used during emergencies (e.g. diabetic ketoacidosis).
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24. More safe than NPH&Lenteinsulins due to reduced risk of hypoglycemia(esp.nocturnal hypoglycemia).
27. 26 COMPLICATIONS OF INSULIN THERAPY 1. Severe Hypoglycemia (< 50 mg/dl )– Life threatening Overdose of insulin Excessive (unusual) physical exercise A meal is missed How it is treated ? 2. Weight gain 3. Local or systemic allergic reactions (rare) 4. Lipodystrophy at injection sites 5. Insulin resistance 6. Hypokalemia
