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Uploaded byRasel Mahbub JNU
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Diabetes and insulin

This document summarizes different aspects of diabetes mellitus (DM) and insulin. It defines DM as characterized by elevated blood sugar levels due to lack of insulin. It describes the two main types of DM, and discusses HbA1c levels, insulin secretion, the conversion of proinsulin to insulin, and the storage and metabolic effects of insulin. The document also outlines the mechanisms of insulin action in the liver, muscle, and adipose tissue, describes various insulin preparations and their durations of action, and discusses potential adverse effects and mechanisms to reduce blood sugar levels, including sulfonylureas, biguanides, thiazolidinediones, alpha-glucosidase inhibitors, GLP-1 analogs, and D

Health & Medicine◦
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 Presented by  Rasel Mahbub  Dept of pharmacy  Jagannath University 
DM is characterized by elevated blood sugar levels due to absolute or relative lack of insulin. Type 1 diabetes - -cell failure at outset •Insulin dependent Type 2 diabetes - Gradual -cell deterioration •Early stages: Diet and Oral agents •Late-stage: Insulin therapy
Glycosylated hemoglobin Hb-A1c : It is used to monitor the plasma glucose concentration over prolonged periods of time (4-6 weeks). Insulin secretion is promoted by ↑ blood glucose levels, amino acids, GI hormones and by β-2 agonist.
Proinsulin is converted to insulin and C peptide. Insulin is referred as the storage hormone as it promotes anabolism and inhibits catabolism of carbohydrates, fatty acids and protein. In the absence of insulin, most tissues cannot use glucose and fats/proteins are broken down to provide energy.
Mechanism of action : Insulin binds to insulin receptors on the plasma membrane and activates tyrosine kinase – primarily in adipose tissue, liver and skeletal muscle. The Nerves, RBC’s, Kidney, and Lens of the eye do not require insulin for glucose transport.
Liver : Insulin increase the storage of glucose as glycogen in the liver. It inserts the GLUT-2 glucose transport molecule in the cell membrane. It inhibits gluconeogenesis – thus significantly ↓ glucose output by the liver. It decrease the protein catabolism.
Muscle : Insulin stimulates the glycogen synthesis and protein synthesis. Glucose transport into the cells is facilitated by GLUT-4 into the cell membrane. It inhibits the protein catabolism.
Adipose tissue : Insulin facilitates the storage of triglyceride by activating plasma lipoprotein lipase and inhibiting intracellular lipolysis. It increase the glucose uptake by GLUT-4 insertion into the cell membrane.
Insulin is a 51 AA peptide Not active orally. Insulin is inactivated by insulinase found mainly in liver and kidney. Dose reduced in renal insufficiency Sources of Insulin : • Beef pancreas / Pork pancreas • Human insulin: recombinant DNA origin
Human Insulin : Do not contain measurable amounts of proinsulin or contaminants. Diminished antibody Less allergic reactions Less lipodystrophy Preferred in gestational diabetes
Insulin preparations : Rapid acting insulin : Lispro, Aspart and Glulisine Short acting insulin: Regular (crystalline) Intermediate acting insulin: NPH (isophane) and Lente (insulin zinc) Long acting insulin: Ultralente, Detimir and Glargine
Insulin Duration Route Features Lispro 3 – 5 hrs I.V or S.C Onset within 15 minutes Regular (crystalline) 7 – 10 hrs I.V or S.C common NPH (Neutral protamine hagedorn) 16 – 20 hrs S.C NPH can mix with regular Ultralente 24 – 30 hrs S.C Basal level
Insulin
Adverse effects of Insulin : Hypoglycemia Allergic reactions Lipodystrophy Others includes • Seizures • Coma
Mechanisms to reduce blood sugar : Stimulation of pancreatic insulin release – Sulfonylureas, Meglitinide Reduce the bio-synthesis of glucose in liver – Biguanides (Metformin) Increase the sensitivity of target cells to insulin -- Thiazolidinediones Retard the absorption of sugars from the GI tract – Acarbose, Miglitol
Sulfonylureas : First generation : Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide Second generation : Glipizide, Glyburide – more potent, more efficacious and fewer adverse effects. Third generation : Glimiperide
Sulfonylureas
Sulfonylureas Dose (mg) Duration (h) First Generation Tolbutamide (Orinase) 1000-1500 6-8 Chlorpropamide (Diabinese) 250-375 24-60 Tolazamide (Tolinase) 250-375 12-24 Second generation Glipizide (Glucotrol) 10 10-24 Glyburide (Micronase) (Glibenclamide) Third generation 5 16-24 Glimepiride (Amaryl) 1-2 24
Sulfonylureas : Adverse effects : Hypoglycemia Cholestatic jaundice Weight gain Cross placenta – fetal hypoglycemia. Chlorpropamide : It can cause water retention by ↑ release of ADH (SIADH) Disulfiram-like reaction with alcohol.
Repaglinide, Nateglinide : More rapidly acting insulin enhancers and shorter duration than sulfonylurea. Hypoglycemia is the common adverse effect. Less weight gain
Repaglinide, Nateglinide The drug has minimal renal excretion thus useful in patients with DM and impaired renal function. It is designed to be taken with each meal to stimulate insulin release with meal. If a meal is skipped, so is the repaglinide.
Biguanides (Metformin): Inhibits gluconeogenesis. Does not promote insulin secretion. It increase the sensitivity of liver and muscle to insulin. It causes modest weight loss.
Metformin (Glucophage) : It does not cause hypoglycemia. It produces a significant ↓ TG and LDL, and ↑HDL. There is a serious concern about lactic acidosis especially in patients with kidney disease.
Thiazolidinediones Enhance glucose and lipid metabolism through action on Peroxisome Proliferator Activated Receptor (PPAR–γ) Enhance sensitivity to insulin in muscle and fat by increasing the GLUT 4 glucose transporters. E.g. ; Pioglitazone Actos, Rosiglitazone Avandia
Thiazolidinediones : Beneficial effects on serum lipid; ↓TG and ↑HDL. Troglitazone is associated with hepatitis. Edema.
Alpha-Glucosidase Inhibitors: It inhibits -glucosidase which converts dietary starch and complex carbohydrates into simple sugars It reduces absorption of glucose after meals. The main side effects includes flatulence and diarrhea. Acarbose (Glucobay) , Miglitol (Glyset)
Glucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) : GLP is an incretin released from the small intestine which increase the glucose dependent insulin secretion. Xenatide suppress glucagon release and reduce appetite It is administered by SC injection.
Glucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :
Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN (januvia) Xenatide (Byetta) inj Sitagliptin (januvia)
Sitagliptin (Januvia) is an oral anti- diabetic drug. It inhibit the dipeptidyl peptidase 4 (DPP- 4), an enzyme which inactivates the incretins GLP-1 and GIP, that are released in response to a meal. It potentiates the secretion of insulin and suppress the release of glucagon by the pancreas.
Glucagon : It has positive inotropic action and chronotropic action on the heart. It acts by stimulation of glucagon receptors and not through beta 1 receptors. This is the basis for using glucagon in beta blocker overdose.