Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.

Incretinomimetics and inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for diabetes. Previous retrospective studies have shown that these treatments induced an increase in pancreatic mass with potentially a risk for pancreatitis and development of precancerous lesions. The aim of our study is to provide a better understanding of the pathophysiological mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain treatment of type 2 diabetes.

The incretinomimetics and the inhibitors of dipeptidyl peptidase-4 (DPP-4) are new treatments for diabetes. The incretinomimetics are analogs of Glucagon Like Peptide 1 (GLP-1), secreted from endocrine L-cells of the colon and terminal ileum peptide. Serum GLP-1 increase rapidly after a meal. But its degradation is also fast. It acts on the hypothalamus by reducing appetite and food intake, on the stomach by delaying gastric emptying and the level of beta islet cells by inducing the synthesis and secretion of insulin (1). The incretinomimetics currently marketed in Belgium (March 2014) are exenatide (Byetta ®), liraglutide (Victoza ®), lixisenatide (Lyxumia ®) and very soon (April 2014) extended-release exenatide (Bydureon ®). The DPP-4 prevent the degradation of GLP-1. The DPP-4 currently marketed (March 2014) are sitagliptin (Januvia ®), vildagliptin (Galvus ®), saxagliptin (Onglyza ®) and (Trajenta ®) linagliptin. In diabetic patients, these treatments allow a significant reduction in fasting plasma glucose and postprandial, with a low risk of hypoglycemia and no weight gain (and sometimes weight loss) (2). Their place in the management of type 2 diabetes is considered or in combination with metformin, when diabetes is inadequately controlled despite maximal dose of the latter, or when patients are intolerant to metformin. A study to evaluate the safety of 'incretinomimetics therapy "showed an increase in pancreatic weight of 40% (3). Indeed, in a cohort of 34 pancreatic organ donors from brain death, 20 patients were diabetic and 8 as incretin mimetics for over 1 year. An increase in pancreatic mass on average 40% was observed compared to diabetic patients without this treatment. This study also demonstrated an increase in the mass of beta cells without restoring insulin function. The advanced for this mass increase without a significant increase of cell size is a hypothesis decreased apoptosis of beta cells. Furthermore there is also an increase in the mass of cells producing α intraductulaire cell proliferation. This would be responsible for the onset of pancreatitis but also the appearance of endocrine microadenomas. The same study (3) also observed an increase in cell proliferation in the exocrine compartment of the pancreas (ductal and acinar cells) induced by incretinomimetic and an increased frequency of lesions potentially pre-cancerous PanIN 1 and 2 with this treatment. Another study (4) by the same group of researchers showed that GLP-1 induced ductal cell growth in rats treated with high-dose exenatide for 12 weeks. It could therefore, by ductal obstruction induce pancreatitis. All of these studies therefore warns about these new treatments potentially inducers of different pancreatic lesions. The aim of our study is to provide a better understanding of the pathophysiological mechanisms of increased volume and / or pancreatic exocrine secretion when exposed to certain treatment of type 2 diabetes.

- exenatide (Byetta®), - liraglutide (Victoza®), - lixisenatide (Lyxumia®), - exenatide extended-release (Bydureon®).

- sitagliptine (Januvia®), - vildagliptine (Galvus®), - saxagliptine (Onglyza®), - linagliptine (Trajenta®).

A RMN will be done before and 1 year after the treatment. A comparative mesure of pancreatic volume will be performed.

A RMN with injection of secretin will be done before and after the treatment. A quantitative evaluation of secretin response will be performed.

Inclusion Criteria: Type 2 diabetes inadequately controlled or intolerant to metformin Obtaining informed consent Aged between 18 and 70 years BMI between 20 and 45 kg / m² Exclusion Criteria: Contraindication to nuclear magnetic resonance (NMR): Carrying a metallic foreign body (pacemaker, valve, intraocular equipment, clips) Allergy to Gadolinium / Secretin Pregnancy or breastfeeding Contraindication to treatment with incretinomimetic: Hypersensitivity to the active substance or to any of the excipients Severe Gastroparesis Severe renal impairment History of Surgery (gastroduodenal, pancreatic or ileocecal) Presence or history of pancreatic disease Active alcoholism

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