The Impact of Glucotoxicity on Gastric Emptying in Chinese Patients With Newly Diagnosed Type 2 Diabetes

Study Overview
=================
Brief Summary
-----------------
Gastric emptying is now recognized as a major determinant of the blood glucose response to carbohydrate in both health and type 2 diabetes (T2D). While patients with longstanding diabetes exhibit a high prevalence of delayed gastric emptying, i.e. gastroparesis, patients with fewer complications are often associated with accelerated gastric emptying, which exacerbates postprandial glycaemic excursions. Moreover, gastric emptying appears to be more rapid in Han Chinese patients with T2D, as compared to Caucasian patients with T2D. The proposed study will (i) compare the rate of gastric emptying in newly diagnosed, Chinese patients with T2D to non-diabetic controls, (ii) evaluate the relationship between gastric emptying and glycaemic indices, including measures of glucose variability, and (iii) determine whether gastric emptying is altered by glucose-lowering therapies.

Detailed Description
-----------------
A total of 100 newly diagnosed Han Chinese patients with type 2 diabetes will be recruited into the study through the Department of Endocrinology, Nanjing first Hospital. Following enrolment, patients will receive either an intensive insulin pump therapy for a months, or a combination of oral glucose-lowering agents (including metformin, DPP-4 inhibitors and/or sodium-glucose co-transporter-2 inhibitors), or a combination of oral glucose-lowering agents and injectable glucagon-like peptide-1 (GLP-1) receptor agonists for 3 months. Before the commencement of the therapy and on days 30 and 90, patients will attend the hospital for continuous glucose monitoring over 24 hours and measurement of gastric emptying using a 75 g oral glucose tolerance test (OGTT). During their hospital stay, patients will consume 3 standard meals (i.e. breakfast, lunch and dinner) provided by the Department of Clinical Nutrition, with their glucose levels tracked by continuous glucose monitoring system (CGMS). Following the dinner, subjects will be asked to fast from solids and liquids (other than water) until the following morning, when they will be subjected to an OGTT at  0900h. An intravenous cannula will be placed into a vein on the forearm. Subjects will be asked to consume a glucose drink containing 75 g glucose and 150mg 13C-acetate, within 5 min for the assessment of gastric emptying, postprandial glycemic and hormonal responses. Breath samples will be collected immediately before, and every 15 minutes after the drink for 3 hours for the measurement of gastric emptying. Venous blood samples will be taken at t = 0, 30, 60, 90, 120, 150 and 180 min for the measurements of plasma glucose, serum insulin, C-peptide, glucagon, total GLP-1, GIP and bile acids concentrations. Blood pressure and heart rate will be measured before and every 15 min after the drink for 3 hours.

Official Title
-----------------
The Impact of Glucotoxicity on Gastric Emptying in Chinese Patients With Newly Diagnosed Type 2 Diabetes

Conditions
-----------------
Type 2 Diabetes

Intervention / Treatment
-----------------
* Drug: Anti-Diabetics


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Patients newly diagnosed of type 2 diabetes as defined by published Criteria of World Health Organization in 1999; with HbA1c ≥ 7%, age ≥ 18 years of age and ≤ 80 years old, and willing to receive anti-diabetic treatments, Non-diabetic controls, with BMI and age matched to patients with type 2 diabetes Exclusion Criteria: Patients with a fasting blood glucose ≤ 3.9mmol/L; Patients with insulin allergy; Patients with severe gastrointestinal symptoms and diseases; Patients with gastrointestinal surgery history; Use of any medication that may influence gastrointestinal motor function, body weight or appetite (opiates, anticholinergics, levodopa, clonidine, nitrates, tricyclic antidepressants, selective serotonin re-uptake inhibitors, phosphodiesterase type 5 inhibitors, sumatriptan, metoclopramide, domperidone, cisapride, prucalopride, or erythromycin); Patients with major cardiovascular disease event (e.g., stroke, symptomatic peripheral artery disease, myocardial infarction, percutaneous coronary or peripheral artery angioplasty or coronary artery bypass surgery) in the previous 6 months; Patients with liver dysfunction (aspartate aminotransferase or alanine aminotransferase level of more than two times the upper limit of normal range) or renal dysfunction (creatinine > 150 μmol/L or GFR < 60 mL/min/1.73m2); Patients with severe anemia and hemoglobin disorders (Hb < 60 g/L); Patients with infected injection site or coagulation disorders; Patients who are pregnant.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 80 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| patients with newly diagnosed type 2 diabetes<br>Newly diagnosed, drug-naïve, Chinese patients with type 2 diabetes. | Drug: Anti-Diabetics<br>* The anti-diabetic treatments include insulin glargine, insulin aspart, GLP-1 receptor agonist, DPP-4 inhibitor, SGLT-2 inhibitor, metformin, sulfonylureas and/or gliclazide. Therapeutic dose of each drug follows recommendation by the treating doctor.<br>|
| Non-diabetic control subjects<br> | |

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change in Gastric-half emptying time of the 75 g glucose drink | The Change in gastric-half emptying time (min) before and after the treatment | Baseline, 1 month and 3 months in diabetic group | 
| Gastric-half emptying time of the 75 g glucose drink | The difference in gastric-half emptying time (min) between subjects with and without type 2 diabetes | Baseline in both diabetic and non-diabetic group | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The mean blood glucose level | The mean blood glucose level (mmol/L) during the 24 hours continuous glucose monitoring. | Baseline, 1 month and 3 months in the diabetic group | 
| The mean amplitude of glycemic excursion | The mean amplitude of glycemic excursion (mmol/L) during the 24 hours continuous glucose monitoring. | Baseline, 1 month and 3 months in the diabetic group | 
| The percentage of blood glucose levels within the target range | The percentage of blood glucose levels within the target range (%) during the 24 hours continuous glucose monitoring. | Baseline, 1 month and 3 months in the diabetic group | 
| Serum insulin concentrations | The differences in the incremental under the curve from 0 to 180 min (iAUC0-180min) for serum insulin (mU/L) in response to a 75 g glucose drink before and after the treatment. The incremental area under the curve (iAUC) is calculated using the trapezoidal rule. | t = 0, 30, 60, 120 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Serum C-peptide concentrations | The differences in the incremental area under the curve from 0 to 180 min (iAUC0-180min) for serum C-peptide (ng/mL) in response to a 75 g glucose drink before and after the treatment. | t = 0, 30, 60, 120 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Serum total GLP-1 concentrations | The differences in the incremental under the curve from 0 to 180 min (iAUC0-180min) for serum total GLP-1 (pmol/L) in response to a 75 g glucose drink before and after the treatment. | t = 0, 30, 60, 120 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Serum total GIP concentrations | The differences in the incremental under the curve from 0 to 180 min (iAUC0-180min) for serum total GIP (pmol/L) in response to a 75 g glucose drink before and after the treatment. | t = 0, 30, 60, 120 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Serum bile acid concentrations | The differences in the fasting serum bile acid concentrations (μmol/L) before and after the treatment. | Baseline, 1 month and 3 months in the diabetic group | 
| Systolic blood pressure | The differences in systolic blood pressure (mmHg) in response to the 75 g glucose drink before and after the treatment. | t = 0, 15, 30, 45, 60,75, 90, 105, 120, 135, 150, 165 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Diastolic blood pressure | The differences in diastolic blood pressure (mmHg) in response to the 75 g glucose drink before and after the treatment. | t = 0, 15, 30, 45, 60,75, 90, 105, 120, 135, 150, 165 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 
| Heart rate | The differences in heart rate (beats/min) in response to the 75 g glucose drink before and after the treatment. | t = 0, 15, 30, 45, 60,75, 90, 105, 120, 135, 150, 165 and 180 min (t = 0 is when 75 g glucose drink is given) on baseline, 1 month and 3 months in the diabetic group | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
type 2 diabetes, gastric emptying, gut hormones, blood glucose, bile acid, glycaemia variability