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Incretin Axis in Type 1 Diabetes Mellitus

2016-04-03 10:54:39 | BioPortfolio

Summary

Type 1 diabetes is an autoimmune disorder characterized by beta cell destruction resulting in insulinopenia. Currently it is being treated with insulin. Dipeptidylpeptidase inhibitors (DPP4 inhibitors e.g. linagliptin & sitagliptin) has been used for type 2 diabetes mellitus (T2DM) traditionally. Previous studies has shown that it is also effective in type 1 diabetes mellitus (T1DM), but the mechanism of action not well understood. This study will evaluate possible mechanism of action of linagliptin in T1DM patients.

Description

Glucose is the most important physiologic substance involved in the regulation of insulin release. The effect of glucose on the beta cell is dose related. Dose-dependent increases in concentrations of insulin and C-peptide and in rates of insulin secretion have been observed after oral and intravenous glucose loads with 1.4 units of insulin, on average, being secreted in response to an oral glucose load as small as 12 g. The insulin secretory response is greater with oral compared to intravenous glucose administration. This difference in insulin secretion is known as the incretin effect. This enhanced response to oral glucose has been interpreted as an indication that absorption of glucose by way of the gastrointestinal tract stimulates the release of hormones and other mechanisms that ultimately enhance the sensitivity of the beta cell to glucose. The release of insulin from the beta cell after a meal is facilitated by a number of gastrointestinal peptide hormones, including GIP (Glucose dependent insulinotropic peptide), cholecystokinin, and GLP1 (Glucagon like peptide 1). These hormones are released from small-intestinal endocrine cells postprandialy and travel in the bloodstream to reach the beta cells, where they act through second messengers to increase the sensitivity of these islet cells to glucose. In general, these hormones are not themselves secretagogues, and their effects are evident only in the presence of hyperglycemia. This incretin effect could account for the greater beta-cell response observed after oral as opposed to intravenous glucose administration.

GLP1, the most potent of the incretin peptides, lowers glucose in patients with T2DM by stimulating endogenous insulin secretion and perhaps by inhibiting glucagon secretion and gastric emptying. Treatment with supra physiologic doses of GIP during hyperglycemia has been shown to augment insulin secretion in normal humans but not in individual with diabetes mellitus. Although cholecystokinin has the ability to augment insulin secretion in humans, it is not firmly established whether it is an incretin at physiologic levels. Its effects are also seen largely at pharmacological doses.

Type 1 diabetes (T1DM) is characterized by autoimmune pancreatic β cell destruction and insulin deficiency resulting in hyperglycemia. Insulin is the mainstay of treatment in T1DM. There are few study which showed effectiveness of OHA (oral hypoglycemic agents) in T1DM.

Linagliptin is a dipeptidyl peptidase 4 (DPP4) inhibitor. It increases endogenous glucagon like peptide 1 levels by inhibiting its rapid metabolism through the dipeptidyl peptidase 4 enzyme. It is currently Food and Drug Administration (FDA) approved for the treatment of Type 2 diabetes (T2DM ) as mono therapy or in combination with insulin or other oral hypoglycemic agents. Increasing endogenous glucagon like peptide 1 levels in patients with T2DM has been shown to significantly improve postprandial glucose levels by both increasing glucose-dependent insulin release and reducing glucagon levels.

Studies had shown that sitagliptin, a DPP4 inhibitor is effective in T1DM. But the mechanism of action is unknown. In this study the investigators want to investigate the effect of linagliptin, another DPP4 inhibitor on the glycaemic profile, HbA1C and glycaemic variability in patients with T1DM. The investigators also will assess the GLP1 and glucagon response during mixed meal test to identify the potential mechanism of this novel form of therapy. These out come parameters will be compared with placebo treated T1DM patients. During this study patients will be monitored for any adverse effect like nausea, vomiting, pancreatitis. Serum urea, creatinin, amylase and lipase will be monitored monthly.

Study Design

Allocation: Randomized, Endpoint Classification: Pharmacodynamics Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment

Conditions

Type 1 Diabetes Mellitus

Intervention

Linagliptin, Placebo

Location

Department of Endocrinology, PGIMER
Chandigarh
India
160012

Status

Recruiting

Source

Postgraduate Institute of Medical Education and Research

Results (where available)

View Results

Links

Published on BioPortfolio: 2016-04-03T10:54:39-0400

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Medical and Biotech [MESH] Definitions

A purine and quinazoline derivative that functions as an INCRETIN and DIPEPTIDYL-PEPTIDASE IV INHIBTOR. It is used as a HYPOGLYCEMIC AGENT in the treatment of TYPE II DIABETES MELLITUS.

A subclass of DIABETES MELLITUS that is not INSULIN-responsive or dependent (NIDDM). It is characterized initially by INSULIN RESISTANCE and HYPERINSULINEMIA; and eventually by GLUCOSE INTOLERANCE; HYPERGLYCEMIA; and overt diabetes. Type II diabetes mellitus is no longer considered a disease exclusively found in adults. Patients seldom develop KETOSIS but often exhibit OBESITY.

The time period before the development of symptomatic diabetes. For example, certain risk factors can be observed in subjects who subsequently develop INSULIN RESISTANCE as in type 2 diabetes (DIABETES MELLITUS, TYPE 2).

A subtype of DIABETES MELLITUS that is characterized by INSULIN deficiency. It is manifested by the sudden onset of severe HYPERGLYCEMIA, rapid progression to DIABETIC KETOACIDOSIS, and DEATH unless treated with insulin. The disease may occur at any age, but is most common in childhood or adolescence.

A type of diabetes mellitus that is characterized by severe INSULIN RESISTANCE and LIPODYSTROPHY. The latter may be generalized, partial, acquired, or congenital (LIPODYSTROPHY, CONGENITAL GENERALIZED).

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