Pathophysiological Study of the Increase in Pancreatic Volume in Type 2 Diabetes Treatments.
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
N/A |
Detailed Description
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.
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: Sulfonylurea Patient will received metformine with sulfonylurea |
Drug: Incretinomimetics
Other Names:
Drug: DPP-4 inhibitors
Other Names:
|
| Active Comparator: Incretinomimectics Patients will received metformin with sulfonylurea with GLP-1 analogue |
Drug: DPP-4 inhibitors
Other Names:
|
| Active Comparator: DPP-4 inhibitors Patients will received metformin with DPP-4 inhibitors |
Drug: Incretinomimetics
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Volumetric measurement of the pancreas [1 year]
A RMN will be done before and 1 year after the treatment. A comparative mesure of pancreatic volume will be performed.
Secondary Outcome Measures
- Quantitative response to secretin [1 year]
A RMN with injection of secretin will be done before and after the treatment. A quantitative evaluation of secretin response will be performed.
Other Outcome Measures
- Fasting glycemia [1 year]
Quarterly during 1 years a blood analysis will be done.
- C-Peptide [1 years]
Quarterly during 1 year a blood analysis will be done.
- HbA1c [1 year]
Quarterly during 1 year a blood analysis will be done.
- Cholesterol [1 year]
Quarterly during 1 year a blood analysis will be done.
- Calcium [1 year]
Quarterly during 1 year a blood analysis will be done.
- Phosphorus [1 year]
Quarterly during 1 year a blood analysis will be done.
- Urea [1 year]
Quarterly during 1 year a blood analysis will be done.
- Creatininemia [1 year]
Quarterly during 1 year a blood analysis will be done.
- Bilirubinemia [1 year]
Quarterly during 1 year a blood analysis will be done.
- Alcaline phosphatase [1 year]
Quarterly during 1 year a blood analysis will be done.
- Gamma GT [1 year]
Quarterly during 1 year a blood analysis will be done.
- Alanine aminotransferase [1 year]
Quarterly during 1 year a blood analysis will be done.
- Asparate aminotransferase [1 year]
Quarterly during 1 year a blood analysis will be done.
- Lipasemia [1 year]
Quarterly during 1 year a blood analysis will be done.
Eligibility Criteria
Criteria
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):
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Carrying a metallic foreign body (pacemaker, valve, intraocular equipment, clips)
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Allergy to Gadolinium / Secretin
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Pregnancy or breastfeeding
-
Contraindication to treatment with incretinomimetic:
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Hypersensitivity to the active substance or to any of the excipients
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Severe Gastroparesis
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Severe renal impairment
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History of Surgery (gastroduodenal, pancreatic or ileocecal)
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Presence or history of pancreatic disease
-
Active alcoholism
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Gastroenterology Department Erasme Hospital | Brussels | Belgium | 1070 |
Sponsors and Collaborators
- Erasme University Hospital
Investigators
- Principal Investigator: Vincent Huberty, MD, Gastroenterology Department Erasme Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- Incretine study