Effects of SGLT2 Inhibitors on Islet Cell Function and Insulin Sensitivity in Patients of Type 2 Diabetes Mellitus

September 20, 2019 updated by: Peking Union Medical College Hospital
The main pathogenesis of type 2 diabetes mellitus is insulin resistance and insufficient secretion of insulin by pancreatic beta cells. SGLT2 (sodium-glucose synergistic transporter 2) inhibitor is a kind of newly developed hypoglycemic medicine, which increases urinary glucose excretion and lowers blood glucose in an insulin-independent manner. The mechanisms of its effects on insulin resistance, insulin secretion by pancreatic beta cells and glucagon secretion by pancreatic alpha cells, are not well studied in domestic and foreign, and there is no unified conclusion. A few studies concerning SGLT2 inhibitors have observed that insulin resistance and islet beta cell secretion function can be improved by the improvement of glucotoxicity and lipotoxicity, but its effect on pancreatic alpha cell function to increase glucagon level, thereby increasing liver glucose output, may be one of the mechanisms of its side effects. In this study, patients with type 2 diabetes mellitus were treated with three domestic listed SGLT2 inhibitors (dapagliflozin, empagliflozin and canagliflozin) for one week, which were expected to improve the glucotoxicity, but excluding the effects on lipotoxicity and body weight, to observe the changes of islet beta cell and alpha cell function and insulin sensitivity. Three different SGLT2 inhibitors were used in order to make clear whether this effect is the unique effect of different structure of drugs or the similar effect of this kind of drugs.

Study Overview

Status

Unknown

Conditions

Intervention / Treatment

Detailed Description

In this study, type 2 diabetes patients were treated with three kinds of SGLT2 inhibitors (dapagliflozin, empagliflozin and canagliflozin) for one week. With routine dose applied, (dapagliflozin 10mg/d, empagliflozin 10mg/d, canagliflozin 100mg/d), blood glucose level could be improved with small expected effect on body weight and no effect in lipid metabolism after the treatment period of one week. Normal glucose tolerance subjects (diagnosed of OGTT) were included as the control group.According to previous studies in three major SGLT2 inhibitors currently on the market, an increase in urinary glucose excretion and a decrease in blood glucose within three days after application in mice and human could be observed. Therefore, the short-term treatment cycle in this study is intended to be set at one week, and can be extended to two weeks if there is no significant decrease in blood glucose.

The insulin sensitivity, islet beta cell secretion function and islet alpha cell function of diabetic patients were measured at baseline (before taking SGLT2 inhibitors) and one week after taking SGLT2 inhibitors, of normal glucose tolerance subjects were measured only at baseline. The effect of SGLT2 inhibitors on islet cell function and insulin sensitivity would be evaluated in order to study the extrarenal action mechanism of SGLT2 inhibitors.

Study Type

Interventional

Enrollment (Anticipated)

40

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact Backup

  • Name: Tao Yuan, MD
  • Phone Number: +86 13671067042
  • Email: t75y@sina.com

Study Locations

  • China
    • Beijing
      • Beijing, Beijing, China, 100730
        • Recruiting
        • Peking Union Medical College Hospital
        • Contact:
        • Contact:
          • Tao Yuan, MD
          • Phone Number: +86 13671067042
          • Email: t75y@sina.com

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years to 70 years (Adult, Older Adult)

Accepts Healthy Volunteers

Yes

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • (1)According to the diagnostic criteria of World Health Organization (WHO) in 1999, type 2 diabetes mellitus was diagnosed clinically. The age ranged from 18 to 70 years (including 18 and 70 years). There was no limit to the duration of diabetes mellitus and gender.
  • (2)Basic antidiabetic therapy is not limited.
  • (3)HbA1c ≥ 7%.
  • (4)eGFR ≥60 ml/min；without contraindications to SGLT2 Inhibitors.
  • (5)Sign written consent form voluntarily.

Exclusion Criteria:

  • (1)Other types of diabetes mellitus.
  • (2)Unstable control of blood glucose(fasting blood glucose > 11.1 mmol/L).
  • (3)Acute complications of diabetes mellitus within 6 months.
  • (4)History of myocardial infarction or stroke within 6 months, or existing severe cardiovascular disease and risk.
  • (5)Abnormal liver function [i.e. serum alanine aminotransferase (ALT) or aspartate aminotransferase (AST) is 1.5 times higher than the upper limit of normal value].
  • (6)Severe hypertension that defined as systolic blood pressure ≥160 mmHg, diastolic blood pressure ≥90 mmHg with drug therapy, or hypotension (resting seat blood pressure < 90/50 mmHg).
  • (7)psychosis, alcohol dependence or history of drug abuse, lactation women, participation in other studies three months before the trial, allergic constitution or allergic to a variety of drug and those researchers think inappropriate to the research.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Experimental: Dapagliflozin Group
10mg/d for one week
Drug: Dapagliflozin
Treated with dapagliflozin 10mg/d for one week.
Experimental: Empagliflozin Group
10mg/d for one week
Drug: Empagliflozin
Treated with empagliflozin 10mg/d for one week.
Experimental: Canagliflozin Group
100mg/d for one week
Drug: Canagliflozin
Treated with canagliflozin 100mg/d for one week.
No Intervention: Normal Glucose Tolerance Group

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change from baseline to post-treatment in insulin sensitivity.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)

Insulin sensitivity is calculated by the following formula according to blood glucose and insulin levels in OGTT (Oral Glucose Tolerance Test).

1.1 OGTT Matsuda and De Fronzo Insulin Sensitivity Index（ISOGTT）：10000/square root(Gluc0×Ins0×mean Gluc×mean Ins)。Mean gluc and mean Ins are average values calculated by each value in 0, 60, 120 and 180 minutes of OGTT.

1.2 QUICKI（quantitative insulin sensitivity check index）model：1/(log[Ins0]+ log[Gluc0]) 1.3 HOMA-IR：(Gluc0×Ins0)/22.5
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in islet beta cell secretory function.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)

Islet beta cell secretory function is calculated by area under the curve of blood glucose、 insulin、C-peptide in OGTT and following formula above.

2.1 Stumvoll first phase insulin secretion：1,194+4.724×Ins0-117.0 ×Gluc60 + 1.414×Ins60 2.2 Stumvoll second phase insulin secretion：295+0.349×Ins60-25.72×Gluc60+1.107×Ins0 2.3 HOMA-β：(20×Ins0)/(Gluc0-3.5)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in islet alpha cell secretory function.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Islet Alpha Cell secretory function is calculated by area under the curve of blood glucose、glucagon level in OGTT.
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)

Secondary Outcome Measures

Outcome Measure
Time Frame
Change from baseline to post-treatment in weight.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in fasting blood glucose and non-fasting blood glucose.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in fasting insulin level.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in blood lipid including cholesterol, triglycerides, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in urine volume and urine glucose level.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Change from baseline to post-treatment in urinary output of uric acid, sodium, calcium, and phosphorus.
Time Frame: Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)
Baseline, Week 1(extended to Week 2 if without significantly decrease in blood glucose)

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Peking Union Medical College Hospital

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

September 1, 2019

Primary Completion (Anticipated)

July 31, 2020

Study Completion (Anticipated)

July 31, 2020

Study Registration Dates

First Submitted

July 7, 2019

First Submitted That Met QC Criteria

July 7, 2019

First Posted (Actual)

July 10, 2019

Study Record Updates

Last Update Posted (Actual)

September 24, 2019

Last Update Submitted That Met QC Criteria

September 20, 2019

Last Verified

August 1, 2019

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

  • Yuan-SGLT2

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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