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As diabetes cases are in the raise these days , there is a need of new treatment for diabetes mellitus. there are new treatments available which i tried to list down here. By this we may obtain a better knowledge in treating diabetes mellitus.
Titre original
Recent Developments in the Treatment of Diabetes Mellitus
As diabetes cases are in the raise these days , there is a need of new treatment for diabetes mellitus. there are new treatments available which i tried to list down here. By this we may obtain a better knowledge in treating diabetes mellitus.
As diabetes cases are in the raise these days , there is a need of new treatment for diabetes mellitus. there are new treatments available which i tried to list down here. By this we may obtain a better knowledge in treating diabetes mellitus.
RECENT DEVELOPMENTS IN THE TREATMENT OF DIABETES MELLITUS.
INTRODUCTION: DEFINITION: Diabetes mellitus is a group of metabolic diseases characterized by hyperglycemia resulting from defects in insulin secretion, insulin action, or both. The chronic hyperglycemia of diabetes is associated with long-term damage, dysfunction, and failure of various organs, especially the eyes, kidneys, nerves, heart, and blood vessels. 1
It is of two types: 1.diabetes mellitus type-1( DM-1) 2.diabetes mellitus type-2 . (DM-2) . ETIOLGY: DIABETES MELLITUS TYPE -1 : This form of diabetes results from autoimmune destruction of the cells of the pancreas . Markers of immune destruction of the cell are present at the time of diagnosis in 90% of individuals and include islet cell antibodies ,antibodies to glutamic acid decarboxylase , and antibodies to insulin. While this form of diabetes usually occurs in children and adolescents, it can occur at any age . Younger individuals typically have a rapid rate of cell destruction and present with ketoacidosis , while adults often maintain sufficient insulin secretion to prevent ketoacidosis for many years , which is often referred to as latent autoimmune diabetes in adults . 2 2. Certain drugs and chemicals may also play a role in the development of type-1 diabetes by destroying the pancreatic beta cells. These include chemicals such as pyrinuron (Vacor, N-3-pyridylmethyl-N'-p-nitrophenyl urea) which is used as a rat poison and is no longer used in the USA. An anticancer and antibiotic agent called streptozotocin used to treat pancreatic cancer also destroys the pancreatic beta cells. 6
DIABETES MELLITUS TYPE-2 : The etiology of type 2 diabetes mellitus appears to involve complex interactions between environmental and genetic factors.The disease develops when a diabetogenic lifestyle 2
(ie, excessive caloric intake, inadequate caloric expenditure, obesity) is superimposed on a susceptible genotype. 1.The body mass index (BMI) at which excess weight increases risk for diabetes varies with different racial groups. For example, compared with persons of European ancestry, persons of Asian ancestry are at increased risk for diabetes at lower levels of overweight.
2.Hypertension and prehypertension are associated with a greater risk of developing diabetes in whites than in African Americans. 3.In addition, an in utero environment resulting in low birth weight may predispose some individuals to develop type 2 diabetes mellitus.
4. Infant weight velocity has a small, indirect effect on adult insulin resistance, and this is primarily mediated through its effect on BMI and waist circumference. 5.About 90% of patients who develop type 2 diabetes mellitus are obese. 6. However, a large, population-based, prospective study has shown that an energy- dense diet may be a risk factor for the development of diabetes that is independent of baseline obesity. 7.Some studies suggest that environmental pollutants may play a role in the development and progression of type 2 diabetes mellitus.
8.Secondary diabetes may occur in patients taking glucocorticoids or when patients have conditions that antagonize the actions of insulin (eg, Cushing syndrome, acromegaly, pheochromocytoma). 3 9. History of impaired fasting glucose or impaired fasting glucose tolerance. 10. Compromised function of the pancreatic -cell such that insulin secretion is insufficient to match the degree of insulin resistance. 11. Elevated levels of triglycerides levels in muscle(intra myocellular lipids) also cause insulin resistance. And these are considered most important cause nowadays i;e even more important than BMI. 4
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PATHOPHYSIOLOGY: PHYSIOLOGY: Mechanisms by which various classes of extracellular signals regulate insulin secretion are discussed regarding their cellular and molecular actions. Under physiological circumstances, the small postprandial changes in plasma glucose concentrations (4.46.6 mM) primarily serve as a conditional modifier of insulin secretion and dramatically alter the responsiveness of islets to a combination of neurohumoral agonists. These agonists have two functions. Cholecystokinin (CCK) and acetylcholine activate the hydrolysis of polyphosphoinositides, and gastric inhibitory polypeptide (GIP) and glucagon like peptide 1 activate adenylate cyclase. These two functional classes of neurohumoral agonists act synergistically to enhance insulin secretion when plasma glucose is >6.0 mM but not when it is 4 mM. On the other hand, an increase in plasma glucose concentration to 810 mM induces an increase in insulin secretory rate in the absence of any of the neurohumoral agonists. Remarkably, high glucose leads to an increase in the same intracellular signals, as does a combination of acetylcholine and GIP. The regulation of insulin secretion occurs in three stages: cephalic, early enteric, and later enteric. In this view, the crucial event occurring during the first two phases is the agonist induced translocation of protein kinase C (PKC) to the plasma membrane under conditions in which an increase in Ca 2+ influx does not occur. PKC is now in a cellular location and a Ca 2+ -sensitive conformation such that an increase in Ca 2+ influx rate occurring during the third phase leads to its immediate activation and an enhanced rate of insulin secretion. Furthermore, under physiological circumstances, an optimal insulin secretory response is dependent on a correct temporal pattern of signals arising from neural and enteric sources. If this pattern is deranged, an abnormal pattern of insulin secretion is observed. An important new insight is provided by the observation that agonists (e.g., CCK or acetylcholine) that act to stimulate the hydrolysis of phosphatidylinositides, when acting for a short period (1020 min), induce an enhanced responsiveness of islets to glucose, i.e., proemial sensitization. However, when acting unopposed for several hours, these agonists will induce a time- dependent suppression of responsiveness to glucose and other agonists. Optimal insulin secretion is dependent on periodic rather than continuous exposure to the correct pattern of extracellular signals. The clinical implications of these new observations are 4
discussed regarding glucose toxicity, the possible role of interleukin 1 in the pathogenesis of insulin-dependent diabetes, sulfonylurea therapy, and the abnormalities of insulin secretion seen in non-insulin-dependent diabetes. 5 PATHOGENESIS: Diabetes mellitus type -1 : Diabetes mellitus type 1 is an autoimmune disease. The autoimmune process begins many years before clinical detection and presentation. It is directly against beta cell of the islets of Langerhans. The destruction must be very heavy, more than 90 percent of beta cells must be destroyed for clinical symptoms to develop. The speed of the beta cell destruction is variable. What is a trigger for autoimmune destruction is not known. Autoantibody presence in serum are: ICA (Islet cell antibodies) - against the antigen present in the cytoplasm of the endocrine cells in pancreatic islets. IAA (Insulin auto antibodies) GAD auto antibodies to glutamic acid decarboxylas. IA-2A (Insulinoma associated 2 auto antibodies) - against the protein tyrosine phosphatase. 7 Diabetes mellitus type-2 : In type 2 diabetes the body either produces inadequate amounts of insulin to meet the demands of the body or insulin resistance has developed. Insulin resistance refers to when cells of the body such as the muscle, liver and fat cells fail to respond to insulin, even when levels are high. In fat cells, triglycerides are instead broken down to produce free fatty acids for energy; muscle cells are deprived of an energy source and liver cells fail to build up glycogen stores. This also leads to an overall rise in the level of glucose in the blood. Glycogen stores become markedly reduced and there is less glucose available for release when it may be needed. Obesity and lack of physical activity are thought to be major causes of insulin resistance. 8, 9
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TREATMENT: Diabetes type-1: 1. Early treatment of non obese diabetic (NOD) rats with CTLA4Ig prevents the diabetes development. This development of autoimmune disease in the NOD mouse begins at between 2 to 4 weeks of age due to infiltration of islets of langerhans by lymphocytes. This insulitis leads to development of complete diabetes at 8 to 10 weeks of age. So, the animals were injected with hCTLA4Ig which interacts with anti B7 -2antibody which helps in preventing the disease. 10
2. Recent introduction to the insulin market has been insulin glargine, which functions as a very long acting insulin (peakless basal insulin). Combinations of engineered very long acting insulins and rapid acting insulins can provide control and convenience similar to that obtained with insulin pumps. 3. Islet transplantation with modified immunosuppressive regimens can cure type 1 diabetes. Islet transplantation is a consideration for the limited but important subset of patients with recurrent severe hypoglycaemic episodes not responsive to medical management. Inability to control autoimmunity and alloimmunity and a lack of donor organs limit the application of islet transplantation. 11
Treatment of diabetes type-2: 1.Dipeptidyl peptidase-4 inhibitors : These protect a natural compound in the body glucagon like peptide-1(GLP-1) from breaking down. GLP-1 helps lower blood glucose. Drugs: 1.Januvia 2. Nesina. 3. Onglyza 4. Tradjenta. 6
5.Alogliptin 15
2.Incretin mimetics or GLP analogs: They use the bod. y's own signaling system to boost insulin after meals. Drugs : Injected drugs 1. Byetta 2. Victoza 3.Sodium-glucose co-transporter 2 (SGLT2) inhibitors: They work by blocking glucose from being reabsorbed by the kidneys. That raises the amount of glucose urinated, and lowers the amount of glucose in the blood. Currently, Invokana (canaglifozin) is the only drug in this class that's approved by the FDA. More SGLT2 inhibitors are being developed. 14 4.Other drugs : It helps lower blood sugar after meals in people with diabetes who use insulin. Drugs: 1. Symilin, an injectable synthetic hormone. 5.Combination drugs: They join different medications in one pill ; often metformin and a sulfonylurea, a meglitinide, a DPP4 inhibitor, a thiazolidinedione, or a thiazolidinedione in combination with a sulfonylurea. Combination drugs include Actoplus MET, Avandamet, Duetact, Glucovance, Metaglip, Kazano, Oseni, and PrandiMet. 6.New types of insulin : They allow some people to take just one injection of a long-acting insulin each day. That can be much easier than multiple injections of standard insulin such asinsulin releasing glucokinase. 12,13,16 7
REFRENCE(S): 1. http://care.diabetesjournals.org/content/32/Supplement_1/S62.full 2. Pharmacotherapy: A Pathophysiologic Approach, 8e.Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey 3. http://emedicine.medscape.com/article/117853-overview#aw2aab6b2b3 4. http://diabetesdiabetesjournals.needdiets.com/cgi/content/full/51/1/7 5. http://care.diabetesjournals.org/content/13/6/655.abstract 6. http://www.news-medical.net/health/Diabetes-Mellitus-Type-1- Pathophysiology.aspx 7. http://autoimmune.pathology.jhmi.edu/diseases.cfm?systemID=3&DiseaseID=23 8. http://www.news-medical.net/health/Diabetes-Mellitus-Type-2- Pathophysiology.aspx 9.Pharmacotherapy: A Pathophysiologic Approach, 8e.Joseph T. DiPiro, Robert L. Talbert, Gary C. Yee, Gary R. Matzke, Barbara G. Wells, L. Michael Posey