This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The progression to type 2 diabetes represents an evolution, resulting from a vicious cycle where both glucotoxicity and lipotoxicity act to reduce insulin secretion and insulin action. In this study, we will focus on obese subjects with history of gestational diabetes (GDM) who are at risk of developing diabetes. We will examine insulin secretion, insulin action, hepatic glucose production, and muscle lipid metabolism in response to two insulin sensitizers with two different modes of action. We propose that thiazolidinediones will improve cell function by reversing lipotoxicity as reflected by reduced muscle lipid accumulation. Our hypotheses and specific aims are the followings: 1) In subjects with history of gestational DM who are at risk of developing diabetes, thiazolidinediones, but not biguanides, improve cell function. cell function will be evaluated by measuring changes in acute insulin response to glucose and non-glucose secretagogues in subjects with IGT and it will be compared in response to treatment with pioglitazone versus metformin. 2) In subjects with history of gestational DM, thiazolidinediones, but not biguanides, decrease the accumulation of fat in non-adipose tissues including muscle, pancreas, liver and myocardium. The muscle fat content will be evaluated as the surrogate measure for lipotoxicity and overaccumulation of fat in non-adipose tissue. From the muscle biopsy specimens, we will measure the amount of intramyocellular triglyceride before and after treatment with pioglitazone versus metformin. This study examines the mechanisms of effects and the potential benefits of two widely used insulin sensitizing drugs, pioglitazone and metformin. If one drug were shown to have an advantage over the other in the care of patients, then there would eventually be a cost saving, either by choosing the less expensive drug, or by using the drug that delays the progression of the disease, and improves the care of the patient. In addition, this study will provide mechanistic information that will help guide the choice of drug for prevention of diabetes. This will be a pilot study involving 20 subjects who had gestational diabetes in the previous 3 years. Subjects with body mass index range between 28 and 38, and age older than 18 y/o will be treated with either metformin or pioglitazone for ten weeks. Exclusion criteria will be a contraindication to the use of either medication or nursing. Hepatic glucose production, insulin secretion and sensitivity will be measured in response to either metformin or rosiglitazone treatment. Effects of these two insulin sensitizers on body composition will be assessed using DXA and on distribution of subcutaneous and visceral fat will be evaluated by CT scan of abdomen. Muscle fat content will be evaluated in response to different treatments using CT scanning of thigh and microscopic measurement of intramyocellular triglyceride from muscle biopsy specimens. Both muscle and fat biopsies will be performed in response to treatment. The specimens will be also stored for our future studies. Our long-term goal is to gather preliminary data to expand the study. Considering the feasibility of completing the study within one year, we would not be able to explore the modulation of the gene expression in fat and muscle by pioglitazone or metformin during this time. This experiment will give us an opportunity to study the pattern of altered gene expression in human adipose tissue and muscle by using microarray or RT-PCR for specific genes. We will be able to determine whether the pattern of altered gene expression in the fat and muscle is specific to pioglitazone therapy or will also be found in the subjects treated with metformin. This study may result in the identification of novel genes involved in the adipose tissue muscle response to insulin
Showing the most recent 10 out of 164 publications
