Modulation of Insulin Secretion and Insulin Sensitivity in Bangladeshi Type 2 Diabetic Subjects by an Insulin Sensitizer Pioglitazone and T2DM Association With PPARG Gene Polymorphism.

1. Introduction Thiazolidinediones and metformin are known drugs and especially metformin is widely used medicine to treat people with T2DM. Though pioglitazone has been suspended in many countries, its safety and efficacy is a matter of research for the drug investigators. Thiazolidinediones had been introduced in 1997 as an oral anti-diabetic drug (OAD). Metformin has been used as the key compound to treat T2DM for many years and is the most prescribed OAD worldwide. Both metformin and thiazolidinediones are considered as "insulin sensitizer". The ß-cell dysfunction and insulin resistance are the core defects in the progression of T2DM with associated metabolic syndrome. Evidence suggests that pioglitazone lowers glucose in blood by increasing glucose uptake into cell and metformin by decreasing glucose production. However, there are many controversies in clinical study specially about the improvement of insulin action of metformin. In contrast, a research recommended pioglitazone as the most appropriate OAD for the South Asian population. The key to this argument is that since pioglitazone is a proliferator-activated receptor gamma (PPAR-γ or PPARG) [a group of nuclear receptor proteins that function as transcription factors regulating the expression of genes] agonist and decreases insulin resistance, overall glycemic control seems to be better with this thiazolidinedione. However, there are very few published documents on the efficacy and safety of these drugs in South Asians. To the best of our knowledge, there is no published paper that examined and compared the efficacy and safety of these two drugs in Bangladeshi patients T2DM. This double-blind trail therefore examined the efficacy and safety of pioglitazone and metformin in T2DM individuals and also the association of the effects of pioglitazone and the variants of PPARG. We have compared the effects of pioglitazone with metformin on biomedical variables in T2DM patients who were eligible for oral hypoglycaemic therapy and then we also analyzed the association among the effects of pioglitazone and PPARG variants.

2. Methodology

3. Study Setting:

The study was conducted between November 2008 and September 2010. The participants for this study were recruited from the outdoor, BIRDEM Hospital in Dhaka,Bangladesh. 2. Subjects I.Individuals who had been diagnosed with T2DM treating with diet/exercise or Metformin 850 mg or Pioglitazone 30mg once daily, and were attending Outdoor Patient Department (OPD) of BIRDEM for consultation were approached by the researcher and invited to participate in the study. The patients were diagnosed already and registered in BIRDEM. T2DM was ascertained based on World Health Organization recommended criteria two repeated measures of fasting (plasma glucose ≥7.0 mmol ⁄ l or 2-h plasma glucose ≥11.1 mmol ⁄ l.)

II.We screened a total of 130 patients for eligibility and selected 80 patients for enrollment based of our inclusion and exclusion criteria. But 77 T2DM patients with HbA1c level < 7.5 %, BMI kg/m2 ≥ 25, SGPT≤ 100 IU/L , creatinine ≤ 1.2 mg/dl) of both sexes, aged between 40-50, treated by monotherapy of pioglitazone or metformin received the drug for the trial according to inclusion and exclusion criteria. 53 patients were screening failure as some did not match eligibility criteria (n=39), some refused to take part(n=11)and some were unable to take part (n=03)due to unknown cause. 3. Patient Preparation:

I.Written informed consent was obtained from all participants before study entry. Patients were instructed to follow adhere to a disease- and weight-orientated diet throughout the study as before.