Types and treatment of diabetes mellitus
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Types and treatment of diabetes mellitus
- 1. Diabetes mellitus • DM is characterized by elevated blood sugar levels due to absolute or relative lack of insulin. • Type 1 diabetes - β-cell failure at outset – Insulin dependent • Type 2 diabetes - Gradual β-cell deterioration – Early stages: Diet and Oral agents – Late-stage: Insulin therapy
- 2. Diabetes mellitus • 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.
- 3. Insulin • 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.
- 4. Insulin 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.
- 5. Insulin 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.
- 7. Insulin 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.
- 8. Insulin 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.
- 9. Insulin
- 10. Insulin • 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
- 11. Insulin Human Insulin : • Do not contain measurable amounts of proinsulin or contaminants. • Diminished antibody • Less allergic reactions • Less lipodystrophy • Preferred in gestational diabetes
- 12. Insulin 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
- 13. 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
- 14. Insulin
- 15. Insulin Adverse effects of Insulin : • Hypoglycemia • Allergic reactions • Lipodystrophy • Others includes – Seizures – Coma
- 16. Oral Anti-diabetic drugs 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
- 18. Oral Anti-diabetic drugs Sulfonylureas : • First generation : Acetohexamide, Chlorpropamide, Tolbutamide, Tolazamide • Second generation : Glipizide, Glyburide – more potent, more efficacious and fewer adverse effects. • Third generation : Glimiperide
- 19. Sulfonylureas
- 20. 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
- 21. Oral Anti-diabetic drugs 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.
- 22. Oral Anti-diabetic drugs Repaglinide, Nateglinide : • More rapidly acting insulin enhancers and shorter duration than sulfonylurea. • Hypoglycemia is the common adverse effect. • Less weight gain
- 23. Oral Anti-diabetic drugs 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.
- 24. Oral Anti-diabetic drugs Biguanides (Metformin): • Inhibits gluconeogenesis. • Does not promote insulin secretion. • It increase the sensitivity of liver and muscle to insulin. • It causes modest weight loss.
- 25. Oral Anti-diabetic drugs 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.
- 26. Oral Anti-diabetic drugs 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
- 27. Anti-diabetic drugs Thiazolidinediones : • Beneficial effects on serum lipid; ↓TG and ↑HDL. • Troglitazone is associated with hepatitis. • Edema.
- 28. Anti-diabetic drugs 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. • AcarboseAcarbose (Glucobay)(Glucobay) , Miglitol, Miglitol (Glyset)(Glyset)
- 30. Anti-diabetic drugs 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.
- 31. Anti-diabetic drugs Glucagon like Peptide : GLP-1 analog : Xenatide : (Byetta) :
- 32. Anti-diabetic drugs Dipeptidyl peptidase 4 (DPP-4) inhibitors: SITAGLIPTIN (januvia) Xenatide (Byetta) inj Sitagliptin (januvia)
- 33. Anti-diabetic drugs • 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.
- 34. Endocrine 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.
Hinweis der Redaktion
- 1 mmol/L of glucose = 18 mg/dl. In europe mmpl/l is used where as in USA mg/dl is used for measuring blood sugar level
- Increased potassium uptake – forces cells to absorb serum potassium; lack of insulin inhibits absorption. Thus lowers potassium levels in blood.
- Effect of insulin on glucose uptake and metabolism. Insulin binds to its receptor (1) on the cell membrane which in turn starts many protein activation cascades (2). These include: translocation of Glut-4 transporter to the plasma membrane and influx of glucose (3), glycogen synthesis (4), glycolysis (5) and fatty acid synthesis (6).
- Inhalable insulin was available from September 2006 to October 2007 in the United States as a new method of delivering insulin , a drug used in the treatment of diabetes , to the body. After the withdrawal of the only inhalable formulation, all currently available insulin formulations are administered by subcutaneous or intravenous injection . [1] The first such product to be marketed was Exubera, a powdered form of recombinant human insulin, delivered through an inhaler into the lungs where it is absorbed. [2] [3] [4] Once it has been absorbed, it begins working within the body over the next few hours. Diabetics still need to take a longer acting basal insulin by injection. [5] A systematic review concluded that inhaled insulin "appears to be as effective, but no better than injected short-acting insulin. The additional cost is so much more that it is unlikely to be cost-effective." [6] In October 2007, Pfizer announced that it would be discontinuing the production and sale of Exubera due to poor sales. [7] Several other companies are developing inhaled forms of the drug to reduce the need for daily injections among diabetics.
- Insulin glargine (Lantus), an insulin analog which is suitable for once-daily dosing.
- Tolbutamide can be used in renal failure. Glipizide dose should be reduced in liver dysfunction whereas glyburide dose should be reduced in kidney function.
- Mechanism of Action : Sulfonylureas Stimulates release of insulin from beta cells. Reduction of insulin resistance by increasing insulin receptor binding and postreceptor activity in liver, muscle and adipose tissue. Reduction of glucagon level.
- Chlorpropamide may also enhance antidiuretic hormone secretion and very rarely cause hyponatraemia (hyponatraemia is also reported with glimepiride and glipizide).
- “ Glucagon-like-peptide-1” or GLP-1 is hormone is produced by the intestine. This hormone stimulates the insulin secreting cells in the pancreas . Type 2 diabetics have a substantial deficiency in GLP-1 and this is one of the reasons that they do not have enough insulin. The advantages of exanatide includes: 1. A slowing of gastric emptying thereby contributing to a decreased hunger. This slowing of gastric emptying also slows the rate at which food gets into the blood stream and the blood sugar does not go up as high. 2. Exenatide use was associated with a definite weight loss. On average, patients lost 1-2 pounds per month without personal effort. There are now reports in the literature of individuals losing sixty pounds in the course of a year in response to this drug. 3. It was associated with a significant drop in the A1C indicating much better control of the person’s diabetes. 4. It decreased the secretion of a hormone called glucagon. . 5. exanatide has an insulin secreting cell stimulatory effect. Exenatide (also Exendin-4, marketed as Byetta) is the first of a new class of medications approved for the treatment of type 2 diabetes . It is to be used in conjunction with oral medications such as metformin and/or a sulfonylurea to improve glucose control. The medication is injected twice per day using a specially designed pen. The typical human response is both an improvement of the release of internal insulin by the pancreas and suppression of pancreas glucagon release.
- “ Glucagon-like-peptide-1” or GLP-1 is hormone is produced by the intestine. This hormone stimulates the insulin secreting cells in the pancreas . Type 2 diabetics have a substantial deficiency in GLP-1 and this is one of the reasons that they do not have enough insulin. The advantages of exanatide includes: 1. A slowing of gastric emptying thereby contributing to a decreased hunger. This slowing of gastric emptying also slows the rate at which food gets into the blood stream and the blood sugar does not go up as high. 2. Exenatide use was associated with a definite weight loss. On average, patients lost 1-2 pounds per month without personal effort. There are now reports in the literature of individuals losing sixty pounds in the course of a year in response to this drug. 3. It was associated with a significant drop in the A1C indicating much better control of the person’s diabetes. 4. It decreased the secretion of a hormone called glucagon. . 5. exanatide has an insulin secreting cell stimulatory effect. Exenatide (also Exendin-4, marketed as Byetta) is the first of a new class of medications approved for the treatment of type 2 diabetes . It is to be used in conjunction with oral medications such as metformin and/or a sulfonylurea to improve glucose control. The medication is injected twice per day using a specially designed pen. The typical human response is both an improvement of the release of internal insulin by the pancreas and suppression of pancreas glucagon release.
- Mode of action Thiazolidinediones or TZDs act by binding to PPARs (peroxisome proliferator-activated receptors), a group of receptor molecules inside the cell nucleus , specifically PPARγ (gamma). The normal ligands for these receptors are free fatty acids (FFAs) and eicosanoids . When activated, the receptor migrates to the DNA , activating transcription of a number of specific genes . Genes upregulated by PPARγ can be found in the main article on peroxisome proliferator -activated receptors . By activating PPARγ: Insulin resistance is decreased Adipocyte differentiation is modified VEGF -induced angiogenesis is inhibited [1] Leptin levels decrease (leading to an increased appetite ) Levels of certain interleukins (e.g. IL-6) fall Adiponectin levels rise The insulin sensitizer rosiglitazone, one of the thiazolidinediones (TZDs), activates peroxisome proliferator-activated receptor- (PPAR ), an adipocyte transcription factor. This stimulates adipocyte differentiation to adipocytes in which adiponectin is secreted ( 17 – 20 ). Adiponectin improves glucose transport into cells and insulin sensitivity (21). The TZDs also inhibit inflammatory cytokine production and thereby the development of atherosclerosis (22). The beneficial effect of rosiglitazone on adiponectin secretion and insulin sensitivity has been demonstrated in subjects with type 2 diabetes mellitus and with impaired glucose tolerance. Rosiglitazone treatment significantly decreased plasma resistin levels in overweight women with PCOS. A similar effect of rosiglitazone has been reported in type 2 diabetic patients (35) and in HIV-positive subjects with insulin resistance (34). The role of resistin in humans is not well understood. It has been found to be correlated with insulin resistance (26) and to have proinflammatory regulatory properties in human monocytes in vitro (56) and in diabetic patients (28). Furthermore, elevated levels of resistin have been associated with coronary atherosclerosis (29). The present data suggest that rosiglitazone, by decreasing plasma resistin levels, may have beneficial effects in the prevention of atherosclerosis and cardiovascular diseases in women with PCOS. In conclusion, rosiglitazone treatment increased plasma levels of adiponectin and decreased plasma levels of resistin in overweight women with PCOS, suggesting that these adipocytokines may contribute to the improvement in insulin sensitivity observed during rosiglitazone treatment.
- Thiazolidinediones expand body fluid volume through PPARgamma stimulation of ENaC -mediated renal salt absorption. The reasons for fluid retention and peripheral edema with TZD use are not fully understood and are likely to be multifactorial. The increase in plasma volume related to TZDs has already been cited and may result from a reduction in renal excretion of sodium and an increase in sodium and free water retention. 30 TZDs may interact synergistically with insulin to cause arterial vasodilatation, leading to sodium reabsorption with a subsequent increase in extracellular volume, and thereby resulting in pedal edema. Increased sympathetic nervous system activity, 31 altered interstitial ion transport, 32 alterations in endothelial permeability, 33 and peroxisome proliferator–activated receptor- –mediated expression of vascular permeability growth factor 34 represent other possible mechanisms for edema with these agents.
- The incretin hormones GLP-1 (glucagon-like peptide-1) and GIP are produced by the endocrine cells of the intestine following ingestion of food. Exenatide is believed to facilitate glucose control in at least four ways: Exenatide augments pancreas response (i.e. increases insulin secretion) in response to eating meals; the result is the release of a higher, more appropriate amount of insulin that helps lower the rise in blood sugar from eating. Once blood sugar levels decrease closer to normal values, the pancreas response to produce insulin is reduced; Exenatide also suppresses pancreatic release of glucagon in response to eating, which helps stop the liver from overproducing sugar when it is unneeded, which prevents hyperglycemia (high blood sugar levels). Exenatide helps slow down gastric emptying and thus decreases the rate at which meal-derived glucose appears in the bloodstream. Exenatide has a subtle yet prolonged effect to reduce appetite and thus may prevent weight gain. Most people using Exenatide slowly lose weight, and generally the greatest weight loss is achieved by people who are the most overweight at the beginning of exenatide therapy. Clinical trials have demonstrated that the weight reducing effect continues at the same rate through 2.25 years of continued use. When separated into weight loss quartiles, the highest 25% experience substantial weight loss, and the lowest 25% experience no loss or small weight gain. Exenatide reduces liver fat content. Fat accumulation in the liver or non-alcoholic fatty liver disease (NAFLD) is strongly related with several metabolic disorders, in particular low HDL cholesterol and high triglycerides, present in patients with type 2 diabetes. It became apparent that exenatide reduced liver fat in mice and more recently in man. The main disadvantage of these GLP-1 analogs is that they must be administered by subcutaneous injection.
- Several DPP-4 inhibitors that can be taken orally, by mouth, as a tablet have been developed. One of them, Januvia ( sitagliptin ) was approved by the FDA on October 18, 2006 . Sitagliptin ( INN ; previously identified as MK-0431 , trade name Januvia ) is an oral antihyperglycemic ( anti-diabetic drug ) of the dipeptidyl peptidase-4 (DPP-4) inhibitor class. This enzyme-inhibiting drug is used either alone or in combination with other oral antihyperglycemic agents (such as metformin or a thiazolidinedione ) for treatment of diabetes mellitus type 2 . The benefit of this medicine is its lower side-effects (e.g., less hypoglycemia, less weight gain) in the control of blood glucose values.
- The two main candidate molecules that fulfil criteria for an incretin are glucagon -like peptide-1 (GLP-1) and Gastric inhibitory peptide (aka glucose-dependent insulinotropic peptide or GIP). Both GLP-1 and GIP are rapidly inactivated by the enzyme dipeptidyl peptidase 4 (DPP-4).
- Pramlintide acetate (Symlin) is a relatively new adjunct treatment for diabetes . It is derived from amylin , a hormone that is released into the bloodstream , in a similar pattern as insulin , after a meal. Like insulin, amylin is deficient in individuals with diabetes. By substituting for amylin, pramlintide aids in the absorption of glucose by slowing gastric emptying , promoting satiety , and inhibiting inappropriate secretion of glucagon , a catabolic hormone that opposes the effects of insulin and amylin. Symlin has been approved for use by the FDA by type 1 and type 2 diabetics who use insulin. Symlin results in weight loss, allows patients to use less insulin, lowers average blood sugar levels, and substantially reduces what otherwise would be a large unhealthy rise in blood sugar that occurs in diabetics right after eating. Symlin is the only drug approved by the FDA to lower blood sugar in type 1 diabetics since insulin's discovery in the early 1920s.