Novel treatment for Type II Diabetes - Essay Example

Novel treatment for Type II Diabetes Introduction Diabetes mellitus has assumed pandemic proportions worldwide and the estimates of the growth inits prevalence suggest that it is likely to present a public health crisis for the world. It is estimated that by the year 2025, the prevalence of diabetes is likely to increase to 2 million in the developed countries and 228 million in the developing, demonstrating a strikingly high rate of rise in its prevalence. 90% to 95% of these cases are likely to be made up of Type 2 diabetes (Pratley, 2008). Type II Diabetes and Traditional Treatment The better understanding of the pathophysiology of Type 2 Diabetes that has evolved over time show that many components are involved in the pathophysiology of Type 2 Diabetes, in addition to obesity. These components cause progressive worsening in glycaemic control and the ability of the beta cells to produce adequate quantities of insulin, with the consequences of uncontrolled hyperglycaemia. Uncontrolled hyperglycaemia accelerates the progress of the disease, emphasizing the requirement for adequate management of hyperglycaemia and the other compounding factors of dyslipidemia and hypertension (Horton, 2008). Type 2 Diabetes has a multi-factorial basis. Inappropriate secretion insulin and elevated resistance to insulin are two key characteristics of Type 2 Diabetes among the several other defects that contribute to hyperglycaemia. Another key characteristic in Type 2 Diabetes is the demonstration of elevated fasting plasma glucagon levels. Clinical evidence shows that these elevated levels of glucagon do not decrease, and in some cases may even increase on ingestion of carbohydrates, resulting in excessive glucose production in the liver. It is this profile that makes Type-2 Diabetes a complicated disease and poses a problem in the management of the disease (Vilsboll, 2008). Oral anti-diabetic drugs are the essential means of the traditional therapeutic regimen in the management of Type 2 Diabetes. Traditionally the Oral anti-diabetic drugs used have been metformin and the sulphonylureas. The traditional oral anti-diabetic have proven to be insufficient in adequately addressing the treatment requirements in Type 2 Diabetes, leading to progress of the disease and ultimate dependence on insulin injections (Horton, 2008). The limitations in the traditional treatment can be summed as inadequate efficacy in lowering of blood glucose levels; limited period of the glycaemic response to the drugs, inconvenient dosing regimens, lower safety levels and issues of tolerance that include hypoglycaemia, weight gain and gastro-intestinal intolerance. These limitations have caused the exploration for novel means to treat Type 2 Diabetes that offer better efficacy in the control of hyperglycaemia, more convenient dosage schedule, enhanced safety levels and better tolerability profile (Vilsboll, 2008). Novel Treatments for Type 2 Diabetes There have been some advances in the treatment availability for Type 2 Diabetes, like the dipeptidyl peptidase (DPP)-IV inhibitor sitagliptin and the glucagon-like peptide (GLP)-1 hormone analog exenatide. However, while these offer some advantages over the traditional oral anti-diabetic drugs, they do not remove in total the deficits of the traditional oral anti-diabetic drugs. Table – 1 provides lists most of the current advances in availability of drugs for the treatment of Type 2 Diabetes. Table – 1 Current Treatments for Type 2 Diabetes Drug/Class Mode of Action Side Effects Limitations/Contraindications Metformin Reduces hepatic glucose production Nausea, diarrhoea (5% to 10% intolerant) Contraindicated in renal impairment; caution in heart failure, liver impairment SUs/non-SU secretagogues Stimulate insulin secretion via Na/K channel activation Hypoglycemia, weight gain   Acarbose Alpha-glucosidase inhibitor GI disturbance Poorly tolerated, limited efficacy Thiazolidinediones PPAR-gamma activation Weight gain, fluid retention Contraindicated in heart failure; rosiglitazone not recommended in IHD DPP-IV inhibitors Enhancement of incretin action, by inhibiting breakdown of GLP-1 and GIP Hypoglycemia in combination with SU. Skin rashes   Exenatide GLP-1 mimetic, simulates insulin secretion Nausea, vomiting Hypoglycemia in combination with SU. pancreatitis Injectable SU = sulfonylurea; DPP-IV = dipeptidyl peptidase IV; PPAR = peroxisome proliferator-activated receptor; GLP-1 = glucagon-like peptide 1; GIP = gastric inhibitory polypeptide; GI = gastrointestinal; IHD = ischemic heart disease (Sodium-Glucose Transporter 2 Inhibitors: New Therapeutic Targets, New Therapeutic Options in the Treatment of Type 2 Diabetes Mellitus). The Incretin Inhibitors and the Incretin Mimetics Studies of the physiological action of the incretin hormones have led to an increase in knowledge of the actions of incretin hormones glucagons-like peptide -1 (GLP-1) and the glucose-dependent insulinotropic polypeptide (GIP), which have led to novel means to address hypoglycaemia in Type 2 Diabetes. Evidence emerging from studies has shown that these hormones increase meal-induced insulin production and have trophic effects on the beta cells that produce insulin. In addition to this GLP-1 has been found to reduce glucagons secretion and reduce food intake through the suppression of appetite. Another feature that has emerged from studies is that Dipeptidyl peptidase 4 (DPP-4) has been found to be the enzyme that is responsible for the quick degradation of the incretin hormones. This understanding provides the basis for the development of two new classes of drugs for the treatment of Type-2 Diabetes. The first is the class of incretin mimetics or the long acting analogues of GLP-1 to provide prolonged effect of GLP-1, and the second are the so called incretin enhancers that inhibit the action of the enzyme DPP-4, thereby preventing the quick degradation of GLP-1 (Deacon, Carr & Holst, 2008). GLP-1 is an endogenous hormone that has an insulinotropic or glucagonostatic action, but this action occurs in a self-limiting with a self-limiting mechanism. It is a multi-functional hormone that produces the effect of insulin release stimulation, suppression of the breakdown of glucagons in the liver, up regulation of the islet cell proliferation, neogenesis and delaying the emptying of the stomach. The short half-life of GLP-1 and its quick clearance through the renal pathway by the action of DPP -4, reduce the effect of thus hormone to a large extent. To overcome this long-acting analogues of GLP-1 and inhibitors of DPP-4 have been developed that raise the possibility of more effective means of treatment for Type 2 Diabetes (Al-Omar & Al-Arifi, 2005). GLP-1-(7-36) amide in human beings gets degraded to the metabolite GLP -1-(9-36) amide. Meirr et al, 2006 compared the physiological activity of GLP-1-(7-36) amide and its metabolite GLP -1-(9-36) amide. GLP-1-(7-36) reduces fasting and postprandial glucose concentrations and retards gastric emptying. Such action was not seen with GLP-1-(9-36). Glucagon levels were found to be reduced by GLP -1-(7-36), but not by its metabolite. Comparison between GLP-1-(7-36) and its metabolite GLP-1-(9-36), show that there is great diminishing in the glucose-lowering effect between GLP-1-(7-36) and its metabolite GLP-1-(9-36), (Meirr et al, 2006). (Val8)GLP-1 is an enzyme resistant GLP-1 analogue. Green et al 2006 compared its physiological activity in obese mice in comparison with GLP-1. These animal studies show that (Val8) GLP-1 improves glucose tolerance, reduces glycaemic excursion subsequent to food intake, enhances plasma insulin response to a stimulus of glucose, and improves sensitivity to glucose. Furthermore it was found that these effects were more prolonged than in the case of GLP-1 (Green et al, 2006). Several incretin enhancers that inhibit the action of the enzyme DPP-4, thereby increasing the levels of GLP-1 are in the clinical evaluation stage. Most of the studies relate to sitagliptin from Merck and vildagliptin from Novartis. Results from these clinical evaluations show that the inhibition of the activity of enzyme DPP-4 by the use of these novel therapeutic agents, results in an increase in the levels of GLP-1, which lowers glucose levels through the increase in insulin secretion and the reduction in glucagons secretion (Ahren, 2007). Drucker and Nauck, 2006, based on the findings on the evaluation of incretin mimetics and incretin enhancers, point out that the incretin mimetics and the incretin enhancers besides increasing insulin and reducing glucagons secretion, also demonstrate the capacity to expand the mass of beta cells in studies. Based on a systematic review of evidence available on DPP-4 inhibitors or incretin enhancers Richter et al, 2008, advice caution in the use of DPP-4 inhibitors, as their safety has not been fully established through credible evidence, particularly with respect to cardiovascular outcomes. Acarbose A treatment option for Type 2 Diabetes is the k-glucosidase inhibitor acarbose. Acarbose binds in a reversible manner with the oligosaccharide binding site of k-glucosidase enzymes within the small intestine mucosa and through this action retards the enzymatic breakdown of carbohydrates. This results in reduction in the rate of glucose absorption after the intake of food, leading to reduced postprandial serum levels of glucose and lack of adequate insulin in Type-2 diabetic patients (Neuser et al, 2005). Ogawa, Takeuchi and Ito, 2004, after studying the effects of acarbose point out that acarbose provided two beneficial effects. It lowers insulin resistance and through this action has the beneficial impact of reducing triglyceride levels in patients with Type 2 Diabetes. This provides the second benefit of helping to reduce cardiovascular problems associated with Type 2 Diabetes. Thiazolidinediones (TZDs) TZDs reduce fasting and postprandial blood glucose levels through the action of increased insulin sensitivity in the cells of fat, muscle and the liver. This action occurs through the binding to peroxisome-proliferator-activated receptor-y (PPAR-y) that is a regulator of gene expression, cell differentiation, insulin signal transduction and the metabolism of glucose, lipids and proteins. This activation of PPAR-y by TZDs is responsible for the up-regulation of insulin-mediated glucose-transporter-4 expression and is also associated with improved beta cell function in the pancreas (Granberry, Hawkins & Franks, 2007). Bailey 2005 evaluated the combined use of metformin and TZDs in the treatment of Type-2 Diabetes. Based on the findings the author recommends the combined use of metformin and TZDs in Type-2 Diabetes, because they do not interfere in each other’s pharmacokinetics. This feature makes it possible to dosage reduction of the two drugs to reduce the side effects of these drugs. However, there is the continuing need to maintain caution in the combined use of these drugs, because of renal, cardiac and hepatic implications with the use of both drugs Small Molecule Inhibitors of PTP1B A family of diverse molecules with a significant role to play in the activation and signalling of a broad range of cellular responses are the protein tyrosine phosphates (PTPs). There is clear evidence to show that one of these phosphatases in the form of protein tyrosine phosphatase 1B (PTP1B) has a definite role to play to play in attenuating insulin signalling (Tobin & Tam, 2002). PTB1B is believed tom have a role to play as a negative regulator of insulin receptor signalling and this makes it a potential drug in the treatment of Type 2 Diabetes. Findings of studies show that it is on the surface of the endoplasmic reticulum that the PT1B inhibitors bind to and colocalize and have a negative influence on insulin signalling upstream of phosphatidylinesitol 3-kinase and MEK1. Cells treated with PTB1B inhibitors in the presence or absence of insulin demonstrate a marked enhancement of lRbeta and IRS-1 phosphorylation, Akt and ERK1/2 activation, Glut4 translocation, glucose uptake as well as Elk1 transcriptional activation and cell proliferation. Such a demonstration suggests that small molecule inhibitors, which target PTB1B, provide both insulin mimetic and insulin sensitizing activity (Xie et al, 2003). However, the challenge that is faced is the conversion of potent and selective small molecule PTB1B inhibitors into orally viable drugs that have the desired physiochemical properties and required levels of efficacy to treat Type 2 Diabetes (Zhang & Lee, 2003). Conclusion Novel treatments have emerged from the increased understanding of the pathophysiology of Type 2 Diabetes. The enhanced knowledge of its pathophysiology has led to the development of new approaches to the treatment of Type-2 Diabetes with the objective of overcoming the limitations of the traditional oral anti-diabetes to prevent the progress of the disease. The novel pathways for treatment include development of analogues of DLP-1 with prolonged activity, inhibition of the action of DPP-4 to enhance the plasma levels of GLP-1, reduction in the rate of glucose absorption, increasing insulin sensitivity. An evaluation of these novel treatments show that they do not remove in total the deficits of the traditional oral anti-diabetic drugs and more evidence on their efficacy and safety is required, before they can be used as replacements to the traditional oral anti-diabetics or in conjunction with them for the treatment of Type 2 Diabetes. Literary References Ahren, B. 2007, ‘Dipeptidyl Peptidase-4 Inhibitors: Clinical Data and Clinical Implications’, Diabetes Care, vol.30, no.6, pp.1344-1350. Al-Omar, M. A. & Al-Arifi, M.N. 2005, ‘Glucagon-like peptide-1 derivatives and dipeptidyl peptidase-IV inhibitors. New hope for the treatment of type-2 diabetes’, Saudi medical journal, vol.26, no.10, pp.1511-1515. Bailey, C. J. 2005, ‘Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones’, Diabetes, obesity & metabolism, vol.7, no.6, pp.675-691. Deacon, C. F., Carr, R. D., & Holst, J. J. 2008, ‘DPP-4 inhibitor therapy: new directions in the treatment of type 2 diabetes’, Frontiers in bioscience, vol.13, pp.1780-1794. Drucker, D. J. & Nauck, M. A. 2006, ‘The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes’, Lancet, vol.368, no.9584, pp.1606-1705. Granberry, M. C., Hawkins, J. B. & Franks, M. A. 2007, ‘Thiazolidinediones in Patients With Type 2 Diabetes Mellitus and Heart Failure’, American Journal of Health-System Pharmacy, vol.64, no.9, pp.931-936. Green, B. D., Lavery, K. S., Irwin, N., O’hart, F. P., Harriott, P., Greer, B., Bailey, C. J. & Flatt, P. R. 2006, ‘Novel glucagon-like peptide-1 (GLP-1) analog (Val8)GLP-1 results in significant improvements of glucose tolerance and pancreatic beta-cell function after 3-week daily administration in obese diabetic (ob/ob) mice, The Journal of pharmacology and experimental therapeutics, vol.318, no.2, pp.914-921. Horton, E. 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