Role of Endoplasmic Reticulum Stress in the Pathophysiology of Type 2 Diabetes

Study Overview
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Brief Summary
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The purpose of this study is to investigate whether Endoplasmic Reticulum (ER) stress pathway is activated in peripheral tissues (adipose tissue) in insulin resistant diabetic patients compared to healthy subjects normoglycemic matched for age and sex an to investigate whether ER stress pathway can be activated in response to insulin. Indeed, some preliminar on rates studies shows that ER stress pathway is activated by insulin in liver and adipose tissue showing that hyperinsulinemia might help trigger stress path ER. For this, we propose a case control study of type 2 diabetic patients vs control subjects in which markers of ER stress will be evaluated from abdominal subcutaneous adipose tissue obtained before and after euglycemic hyperinsulinemic. We chose to consider adipose tissue subcutaneous rather than visceral adipose tissue for obvious reasons of lesser invasiveness.

Official Title
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Role of Endoplasmic Reticulum Stress in the Pathophysiology of Type 2 Diabetes

Conditions
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Diabetes Mellitus, Type 2, Endoplasmic Reticulum Stress

Intervention / Treatment
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* Other: No intervention


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Specific criteria for diabetic patients: Having type 2 diabetes for at least 6 months HbA1c ≤ 8% Treated by lifestyle and dietary rules associated or not to a hypoglycemic therapy (metformin and / or sulfamid) and / or insulin secretors dependent glucose as inhibitors of DPP4 (dipeptidyl peptidase-4): Vildagliptin, Sitagliptin, Saxagliptin No modification of hypoglycemic therapy and / or insulin secretors for at least 3 months Specific criteria for control subjects: Nondiabetic subjects (fasting blood glucose <7.0 mmol / l without hypoglycemic treatment). The control subjects should be matched to patients for age (± 5 years), sex, and BMI (± 2 kg/m2). Common criteria for patients and control subjects: Aged 18 to 60 years Body Mass Index between 25 and 35 kg/m2 Accepting the constraints of the protocol and who signed the informed consent Systolic blood pressure < 160 mmHg, diastolic blood pressure < 90 mm Hg (with or without antihypertensive treatment) Resting heart rate between 55 and 100 beats/min. Normal laboratory tests or not clinically significant abnormality for NFS platelets, PT, aPTT, fibrinogen ALT, AST, GGT, Serum electrolytes, urea, creatinine, Uric acid Triglycerides, total cholesterol, HDL cholesterol HCG negative blood (for female subjects) Affiliated to the Social Security. Exclusion Criteria: Current infections or recent infections (<10 days) Neoplastic disorders (with the exception of carcinoma in situ of the cervix or cutaneous epithelioma), haematological, cardiovascular, psychiatric, neurological Poisoning smoking (>10 cigarettes per day, what ever the duration of intoxication) Treatment with insulin or glitazones Pregnancy, Breastfeeding Body Mass Index > 35 kg/m2 Any drug taken for less than 8 days without the inclusion of minor analgesics (aspirin, paracetamol), anti-hypertensive medications, oral hypoglycemic (metformin and sulphonylureas) and insulin secretors dependent glucose as inhibitors of DPP4 (dipeptidyl peptidase-4) and oral contraceptives.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 60 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| control<br>control subjects with : Nondiabetic subjects (blood glucose <7.0 mmol/l without hypoglycemic treatment). The control subjects should be matched to patients for age (± 5 years), sex, and BMI (± 2 kg/m2). | Other: No intervention<br> <br> |
| case<br>Diabetic patients with : Having type 2 diabetes for at least 6 months HbA1c ≤ 8% Treat by lifestyle and dietary rules associated or not to a hypoglycemic therapy (metformin and / or sulfamid) and / or insulin secretors dependent glucose as inhibitors of DPP4 (dipeptidyl peptidase-4): Vildagliptin, Sitagliptin, Saxagliptin No modification of hypoglycemic therapy and / or insulin secretors for at least 3 months | Other: No intervention<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Show an increase in markers of ER stress in fasting patients with type 2 diabetes | Protein expression markers of ER stress pathway BiP / GRP 78, CHOP, ATF4 EDEM and XBP-1 | 2 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assess whether insulin induces an increase in markers of ER stress | Insulin sensitivity | 2 days | 
| Insulin secretion in response to glucose infusion |  | 2 days | 
| Insulin secretion in response to arginine infusion |  | 2 days | 
| Lipolysis on insulin |  | 2 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Endoplasmic Reticulum