Effects of Rosiglitazone and Metformin on Metabolism in Type 2 Diabetes (ROSI)

Comparison of Effects of Rosiglitazone and Metformin on Myocardial, Skeletal Muscle, Liver and Adipose Tissue Insulin Stimulated Glucose Uptake in Patients With Type 2 Diabetes Mellitus

The objectives of this study are to compare the effects of rosiglitazone and metformin on insulin stimulated glucose uptake in subjects with type 2 diabetes. Whole body, and skeletal muscle, heart and adipose tissue insulin stimulated glucose uptake is measured during euglycemic hyperinsulinemic clamp and positron-emission tomography scanning before and 26 weeks after treatment in 48 newly diagnosed subjects with type 2 diabetes. Subjects will be randomized to receive either rosiglitazone or metformin or placebo, according to a simple randomization procedure with double blinding.

Study Overview

• Status: Completed
• Conditions: Type 2 Diabetes; Insulin Sensitivity
• Intervention / Treatment: Drug: Placebo; Drug: Metformin; Drug: Rosiglitazone

Detailed Description

Insulin resistance is a pivotal underlying metabolic abnormality in most subjects with type 2 diabetes. Clinical experience has proved metformin to be efficacious treatment in patients with type 2 diabetes. Rosiglitazone is a novel antidiabetic agent, which has been shown to decrease fasting plasma glucose concentrations in animal models and in clinical trials. There are no previous studies that compare the effects of rosiglitazone and metformin on insulin stimulated glucose uptake in subjects with type 2 diabetic in different organs.

PET is very sensitive in detecting changes in glucose uptake and blood flow and, is the method of choice to investigate the effects of medical interventions. Due to sensitivity of these functional parameters only moderate or small number of subjects need to be studied. This makes it feasible to perform tightly controlled intervention studies in a very cost-effective way.

The objectives of this study are to compare the effects of rosiglitazone and metformin on insulin stimulated glucose uptake in subjects with type 2 diabetes. PET measurements on myocardium, skeletal muscle and subcutaneous and visceral fat are performed at baseline and at the end of the treatment period. Furthermore, the effect of exercise on skeletal muscle blood flow and glucose uptake is studied.

The study consists of 48 newly diagnosed subjects with type 2 diabetes. Subjects will be randomized to receive either rosiglitazone or metformin or placebo, according to a simple randomization procedure with double blinding. The investigators will also study ten age-matched non-diabetic control subjects, who will undergo the same PET study procedure as subjects with type 2 diabetes.

A study of the effects of antidiabetic oral medication in newly diagnosed subjects with type 2 diabetes is of great importance for the understanding of the differences in mode of action of the different antidiabetic drugs. Such a study would contribute to elucidate advantages and disadvantages with certain drugs and potential additive effects in combination therapy.

• Study Type: Interventional
• Enrollment (Actual): 48
• Phase: Phase 4

Contacts and Locations

Study Locations

• Finland
  • Turku, Finland, 20520
    • Turku PET Centre
  • Turku, Finland, 20520
    • Turku university hospital, PET center
  • Turku, Finland, 20521
    • Turku PET Centre (Turku University Hospital)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 38 years to 73 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Age 40-75 years,
• BMI 25-35 kg/m2,
• WHO criteria for type 2 diabetes fasting plasma glucose>=7.0 mmol/l on at least 2 separate occasions,
• C-peptide>0.2 nmol/l

Exclusion Criteria:

• plasma glucose < 6.1 or >10 mmol/l after the screening period
• cardiac heart failure
• diagnosed coronary heart disease
• severe aortic, mitral or tricuspidal valve disease
• blood pressure > 160/ 100 mg Hg
• any previous or present hepatic (GT >100, alanine amino transferase >3 x upper limit of the reference range) or renal (S-creatinine > 130) disease
• pregnancy or lactation
• proliferative retinopathy
• microalbuminuria
• subjects with history of lactate acidosis
• symptomatic polyneuropathy
• antidiabetic medication
• changes in antihypertensive medication or beta-blockers in medication
• metal objects in region of imaging
• anemia with Hb < 100 in mean or < 90 in women
• oral corticosteroid treatment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; placebo, 2 tablets per day	Drug: Placebo; Patients received either placebo, metformin or rosiglitazone
Active Comparator: Metformin; 500mg 1 tablet 2 times per day for the first 2 weeks, then after that 2 tables 2 times per day	Drug: Metformin; Patients received either placebo, metformin or rosiglitazone
Active Comparator: Rosiglitazone; 2 mg 1 tablets 2 times per day for the first 2 weeks, then after that 2 tablets 2 times per day	Drug: Rosiglitazone; Patients received either placebo, metformin or rosiglitazone; Other Names: Avandia

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
insulin sensitivity in skeletal muscle	pre and at 26 weeks measured with euglycemic clamp and 18-F-2-fluoro-2-deoxy-D-glucose scanning skeletal muscle	26 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
skeletal muscle blood flow	measured using PET scanning	26 weeks
insulin signaling pathways in skeletal muscle	measured from muscle biopsies taken before and after intervention	26 weeks
insulin sensitivity of bone marrow fat	measured using PET images	26 weeks
insulin stimulated intestinal glucose uptake	measured using PET images	26 weeks

Collaborators and Investigators

• Sponsor: Turku University Hospital
• Collaborators: SmithKline Beecham
• Investigators: Principal Investigator: Pirjo Nuutila, MD, PhD, Turku University Hospital

Publications and helpful links

General Publications

• Koffert JP, Mikkola K, Virtanen KA, Andersson AD, Faxius L, Hallsten K, Heglind M, Guiducci L, Pham T, Silvola JMU, Virta J, Eriksson O, Kauhanen SP, Saraste A, Enerback S, Iozzo P, Parkkola R, Gomez MF, Nuutila P. Metformin treatment significantly enhances intestinal glucose uptake in patients with type 2 diabetes: Results from a randomized clinical trial. Diabetes Res Clin Pract. 2017 Sep;131:208-216. doi: 10.1016/j.diabres.2017.07.015. Epub 2017 Jul 20.

Study record dates

Study Major Dates

• Study Start: October 1, 2000
• Primary Completion (Actual): December 1, 2001
• Study Completion (Actual): December 1, 2001

Study Registration Dates

• First Submitted: August 11, 2015
• First Submitted That Met QC Criteria: August 14, 2015
• First Posted (Estimate): August 18, 2015

Study Record Updates

• Last Update Posted (Estimate): August 18, 2015
• Last Update Submitted That Met QC Criteria: August 14, 2015
• Last Verified: August 1, 2015

More Information

Terms related to this study

• Keywords: muscle; metformin; rosiglitazone
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Hyperinsulinism; Diabetes Mellitus; Diabetes Mellitus, Type 2; Insulin Resistance; Hypoglycemic Agents; Physiological Effects of Drugs; Metformin; Rosiglitazone
• Other Study ID Numbers: TurkuUH-ROSI