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Initially described in 1902 by Bayliss and Starling, incretins refer to the hormones produced by the gastro-intestinal tract in response to nutrient entry, which then stimulate insulin secretion in a glucose-dependent manner. In the later part of the 20th century, GLP-1 (glucagon-like peptidea€“1) and GIP (glucose-dependent insulinotropic polypeptide) were discovered to be the incretin hormones which are responsible for this gut-derived insulin response. In addition to glucose-dependent stimulation of insulin secretion, incretins have other effects that help to lower blood glucose and contribute to glycaemic control. Diabetes is associated with defects in the incretin axis, and these defects may contribute to the development of Type 2 diabetes. Both endogenous GLP-1 and GIP are rapidly inactivated by the enzyme DPP-4 (dipeptidyl peptidase-4). Two pharmacological approaches have been taken to augment the incretin effect in Type 2 diabetes. The other approach is to administer GLP-1 analogues (GLP-1 receptor agonists) that are resistant to cleavage by DPP-4. DPP-4 inhibitors act as incretin enhancers by preventing the inactivation of endogenous incretins by DPP-4, thereby elevating active incretin levels. The DPP-4 inhibitors are orally bioavailable, small molecular weight drugs that act via competitive, reversible inhibition of DPP-4, providing up to 90% inhibition of plasma DPP-4 activity over 24 hours.
Clinical data indicate that DPP-4 inhibitors are effective antidiabetic agents, providing HbA1c reductions of approximately 1% when used as monotherapy and additional reductions in HbA1c when used as part of combination therapy, especially with metformin. DPP-4 inhibitors have been approved for use as monotherapy and combination therapy with other classes of anti-diabetic agents.
GLP-1R agonists show the same myriad effects of endogenous GLP-1: increase in insulin secretion, increase in proinsulin synthesis in beta cells, suppression in glucagon secretion from alpha cells, slower gastric emptying, increased feeling of satiety, decrease in food intake, increase in proliferation and delay in apoptosis of pancreatic cells. Exenatide is derived from the saliva of the Gila monster, the largest venomous lizard native to the United States. Pancreatitis has been reported in a very small number of patients taking both exenatide and liraglutide. Liraglutide is an analogue of endogenous human GLP-1, in which Lys34 has been substituted with Arg34 at the N-terminal and a fatty acid chain added to Lys26.
In the LEAD (Liraglutide Effect and Action in Diabetes) trial programme, liraglutide used as monotherapy or in combination with one or two oral antidiabetic drugs provided significant reductions in HbA1c.
Similar to exenatide, its main side-effects are nausea and vomiting, which usually resolve within a few weeks. Acting on several of the mechanisms that contribute to Type 2 diabetes, DPP-4 inhibitors and GLP-1R agonists increase insulin secretion, decrease glucagon secretion, and enhance beta-cell function. Majority of patients with diabetes have difficulties in achieving optimal glycaemic control despite being aware of the risk of developing diabetic complications. Incretin-based therapy may overcome the limitations with current therapies and help to address the unmet clinical needs of patients with Type 2 diabetes. If left unchecked, the growing problem of diabetes will exact a heavy toll on patients and healthcare systems. Despite the availability of well-validated treatments of diabetes, such as metformin, sulphonylureas and insulin, there are still important unmet needs in the treatment of diabetes.


This phenomenon has been coined the a€?incretin effecta€? and is estimated to account for approximately 50% to 70% of the total insulin secreted following oral glucose administration. The incretin hormones not only stimulate glucose-induced insulin secretion, but do so in a highly glucose-dependent manner, thus preventing GLP-1 alone from provoking hypoglycaemia. In recent years, incretin-based therapies have been introduced and are currently the newest class of anti-diabetic agents available for the treatment of Type 2 diabetes mellitus. This effectively increases the half-life and therefore the circulating concentrations of the incretins. Thus, the efficacy of DPP-4 inhibitors is dependent upon endogenous incretin secretory capacity. They have been demonstrated to facilitate two to three-fold enhancements in the levels of active GLP-1 and GIP, improve impaired insulin secretion and reduce glucagon levels in patients with Type 2 diabetes.
Unlike the majority of anti-diabetic agents, these incremental reductions in HbA1c are not associated with significant hypoglycaemia or weight gain. Hypoglycaemia and gastrointestinal side effects are infrequent in patients who take DPP-4 inhibitors. They increase the concentrations of GLP-1 receptor (GLP-1R) agonists to supraphysiological levels, leading to concentrations up to 10-fold that of the physiological ones found in the postprandial state.
Exenatide shares a 53% sequence homology with human GLP-1 and is resistant to degradation by the DPP-4 enzyme.
Nevertheless, a definitive causal relationship between GLP-1R agonists and pancreatitis has not been proven.
In rats and mice, exposure to liraglutide has resulted in thyroid c-cell stimulation, but no evidence of such an effect has been seen in humans. Accordingly, they are effective in improving all measures of glycaemic control: HbA1C, fasting plasma glucose, and post-prandial glucose levels.
His areas of specialty include diabetes, thyroid disorders, lipid disorders, weight management, osteoporosis, adrenal and pituitary disorders and other endocrine disorders. Potent derivatives of glucagon-like peptide-1 with pharmacokinetic properties suitable for once daily administration. Content and images are meant for practicing medical doctors, allied health care professionals and other establishments in the medical industry. In Singapore, the prevalence of diabetes in our adult populations has increased from 2% in 1975 to 11.3% in 2010. Currently available agents fail to demonstrate prolonged efficacy in reducing hyperglycaemia and to be disease-modifying. GLP-1 is secreted by the L cells in the ileum and colon, while GIP is secreted by the K cells in the duodenum. Glucagon is a hormone that works oppositely to insulin, increasing blood glucose by stimulating glucose production by the liver. These novel agents exert their glucose lowering effect by incretin-related mechanisms and are able to achieve improved glucose control with fewer side-effects, in terms of less hypoglycaemia and no weight gain.
DPP-4 inhibitors act as a€?incretin enhancersa€? by preventing the inactivation of endogenous incretins by DPP-4, thereby elevating active incretin levels.


GLP-1 receptor agonists are also known as a€?incretin mimeticsa€? because they directly affect the incretin system by mimicking the effects of endogenous GLP-1.
Most DPP-4 inhibitors with the exception of linagliptin, are primarily secreted via renal elimination.
The GLP-1R agonists, but not DPP-4 inhibitors, have been shown to slow gastric emptying and to promote satiety.
Compared to liraglutide, exenatide is associated with greater antibody production, but this does not appear to be clinically significant. However, because of this animal data, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or Multiple Endocrine Neoplasia syndrome type 2B. With the use of these agents, the occurrence of hypoglycaemia is low and severe hypoglycaemia is infrequent. Dr Liew pursued subspecialty training in Endocrinology at National University Hospital, Singapore and the Oxford Centre of Diabetes and Metabolism, United Kingdom.
Most anti-diabetic agents, with the exception of insulin, are only able to reduce HbA1c by approximately 1%.
GLP-1A delays stomach emptying, which helps to spread glucose absorption out over time, and thus limit hyperglycaemia. As a consequence, the dosage should be adjusted lower in patients with moderate-to-severe renal impairment.
In addition to glycaemic effects, GLP-1R agonists have a beneficial effect on weight, due to their inhibitory effect on appetite via the gut-brain axis. Other contraindications include pregnancy, severe renal impairment, and paediatric patients. As a consequence, the longer exposure time to high blood sugar levels can lead to more patients developing chronic diabetes complications.
Furthermore, studies in animals have suggested that GLP-1 canA increase the number of pancreatic beta cells, either through promoting growth or by inhibiting apoptosis.
As renal excretion is only a minor route of linagliptin elimination (5% to 7%), no dosage adjustment is necessary in patients with renal impairment.
The majority of this weight loss occurred primarily in the first 16 weeks and was maintained throughout the 52-week study period. While studies have shown the importance of good glycaemic control in the prevention of diabetes complications, most patients with diabetes are still not achieving optimal diabetes control. For instance, higher doses of sulphonylureas and insulin are limited by the side-effects of hypoglycaemia and weight gain. Dipeptidyl peptidase IV inhibitors: a promising new therapeutic approach for the management of type 2 diabetes.



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