Efficacy Study of Pioglitazone and Metformin and Association Between Pioglitazone Response and Peroxisome Proliferator-activated Receptor Gamma Gene Variants in Bangladeshi Type 2 Diabetes Mellitus Subjects (T2DMCT)

• ClinicalTrials.gov Identifier: NCT01589445
• Recruitment Status: Completed
• First Posted: May 2, 2012
• Results First Posted: February 27, 2014
• Last Update Posted: February 28, 2014
• Sponsor: University of Dhaka
• Collaborators: Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders; University of Dundee
• Information provided by (Responsible Party): Dr. Masuma Parvin, University of Dhaka

Study Description

Brief Summary:

• The present study was undertaken to assess the efficacy and safety of two different insulin sensitizers (namely Pioglitazone and Metformin) among subjects with type 2 diabetes mellitus (T2DM) in Bangladesh.
• A prospective, double-blind, single group, 'within-subject' designed clinical trial of 77 diagnosed T2DM patients out of 130 patients with glycosylated haemoglobin (HbA1c) ≥7.2±1.5%, aged 46±6.4 years and registered for diabetes treatment in Bangladesh Institute of Research and Rehabilitation in Diabetes Endocrine and Metabolic Disorders (BIRDEM) was carried out.
• The study was conducted between November 2008 and September 2010.
• Baseline data, included case history of the patients,anthropometric measurement, biomedical parameters psychosocial factors, were collected from each subject and then enrolled to receive treatment with 001 drug once daily for three months, then the patients were left for wash out with metformin 850mg once daily for one month; then they received 002 drug once daily for further three months.
• Dietary chart was remained as before.

• DNA was isolated by Chelex method using the primers and control DNA,restriction Digestion Enzyme Endonuclease Hae 111 for genotyping PPARγ-(Peroxisome Proliferator Activated Receptor gamma)Pro12Pro

  • (Proline12Proline)/Pro12Ala-(Proline12 Alanine))/Ala12Ala-(Alanine12Alanine).
• The blinded drugs were decoded after analyzing results, 001 tablet was pioglitazone (30 mg once daily) and 002 tablets was metformin (850mg once daily). Bio-medical outcomes were measured to assess the efficacy of both the drugs each month. After finishing the treatment period the effects of two drugs were compared using SPSS.And the association between the pioglitazone drug effects and genetic polymorphism was also assessed.
• The metformin effects was assessed also using the response rate of HbA1c <7.0% after 3 months treatment to the patients.

Condition or disease	Intervention/treatment	Phase
Type 2 Diabetes Mellitus	Drug: Pioglitazone hydrochloride; Drug: Metformin hydrochloride	Phase 4

Detailed Description:

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

   1. 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.

      II.Each case history was documented in the case report form. The study was approved by the National Medical Ethics Review Boards (NMERB) of Bangladesh Medical Research Council (BMRC).The investigations were carried out in accordance with the principles of the Declaration of Helsinki as revised in 2000.

   4. Treatment:

      The patients were to receive treatment pioglitazone tablet 001 (30mg once per day) for 3 months followed by one month "metformin wash-out period", then to the alternative treatment regimen for further 3 months with metformin tablet 002 (850mg once per day). The drugs were supplied by the Aristopharma Pharmaceutical Ltd., Bangladesh.

   5. Anthropometric Measurements I.Height: Standing height was measured using appropriate scales (Detect-Medic, Detect scales INC, USA) without shoes.

      II.Weight: Weight was measured with the balance was placed on a hard flat surface and checked for zero balance before measurement. The subjects were in the center of the platform wearing light cloths without shoes.

      III.BMI: Body mass indexes (BMI) of the subjects were calculated using standard formula: BMI= Weight (kg)/[Height (m)] 2.

      IV.Blood Pressure: Systemic and Diastolic pressure was measured according to WHO-IHS.

   6. Blood Sample Collection for Biochemical analysis :

      I. During the appointed date the patients came in the fasting condition. Fasting blood samples (10 ml) were drawn from the antecubital vein. The time was mentioned as 0 hour. Then the patients received drug. They were requested to swallow the tablet and have their breakfast according to their diet charts. Next blood sample had been drawn at 30 min and 2 hour and then they were provided the drugs for the whole month.

      II.The patients were requested to take the drug just before the breakfast every day for 29 days.

      III.From the fasting blood sample 1ml of blood was transferred in an EDTA containing tube for measurement of HbA1C and the rest of the blood was taken in an EDTA containing tube and centrifuged immediately.

      IV.Samples after processing were divided into two aliquots under sterile condition;one aliquot was sent for biochemical analysis for Fasting glucose, Lipid profile, Cholesterol, ALT, Insulin, Creatinine and another one was stored at -80 0C for further verification of results in case of any necessity.

   7. Biochemical Test Methods:

      I. Serum glucose (fasting, 1 and 2 hours) by Glucose Oxidase (GOD-PAP) method (Randox Laboratories Ltd., UK).

      II.Serum triglyceride by enzymatic colorimetric (GPO-PAP) method (Randox Laboratories Ltd., UK).

      III.Serum total cholesterol by enzymatic endpoint (Cholesterol Oxidase/ Peroxidase) method (Randox Laboratories Ltd., UK).

      IV.Serum HDL cholesterol by enzymatic colorimetric (Cholesterol CHOD-PAP) method (Randox Laboratories Ltd., UK) using micro-plate reader (Bio-Tec, ELISA).

      V.Serum creatinine by enzymatic colorimetric (GPO-PAP) method (Randox Laboratories Ltd., UK).

      VI.Serum alanine amino transferase (ALT) by UV method using ALT (GPT) opt.kit (Randox Laboratories Ltd., UK).

      VII.Serum insulin by enzyme linked immunosorbent assay (ELISA) method (Linco Research Inc., USA).

      VIII.Glycosylated Haemoglobin (HbA1c) by High Performance Liquid Chromatographic (HPLC) method.

   8. Blood sample collection for DNA analysis (PPARG gene):

   I.At the end of 3rd month of each treatment 1.5 ml of blood was taken in EDTA containing tube for genetic analysis and the whole blood specimen was collected in the vacuum collection tube containing EDTA, stored at -20 0C to - 80 0C.

   II.DNA was isolated by Chelex method, identified by electrophoresis method and amplified by using primers. We used a published document to select the primers for genotyping PPARγ Pro12Ala/Pro12Pro. The primers for the Pro12Ala SNP genotype, we amplified exon B using the reverse primer 5' CTG GAA GAC AAA CTA CAA GAG 3' and the forward primer 5' ACT CTG GGA GAT TCT CCT ATT GGC 3'. (Sigma product, Order No. SIGMA 03/11/09 4152936-F/185 PPARG-R 8006875247-1).

   III.Control DNA: Professor Colin Palmer Laboratory, Biomedical Research Institute ,University of Dundee Medical School, University of Dundee, Scotland, UK sent six control samples of 3 types control DNA genotyped for PPARG SNP rs 1801282 (Pro12Ala).

   IV.Restriction Digestion Enzyme Endonuclease Hae 111 was used to identify the cutting site(Sigma Product No. R 5628).

3. Response Rate:

1. The response rate was defined by the decrease of ≥10% FBG or by the decrease of ≥1% HbA1c from the baseline values.

ll.There was another response group was defined by the the HbA1c rate <7.0% after 3 months treatment with metformin only to find out the secondary failure rate of metformin.

4) Statistical Analysis: I.Statistical analysis was performed using SPSS (Statistical Package for Social Science) software for Windows version 18 (SPSS Inc, Chicago, Illinois, USA). Data were expressed as mean + SD (Standard Deviation).

II. Effects of drugs after 3 months treatment were analyzed using t pair tests. The groups were compared using one way ANOVA. If the p value was <0.05, the groups were compared using the student's t test for unpaired samples or χ2 test through univariate analysis for further verification. Correlation coefficient among the variables was tested using Pearson's test. Multivariate logistic regression analysis was performed to obtain the odds ratios and independent influencing factor for finding possible association between PPARγ genotypes and drug response in case of genetic analysis.

III.A p value <0.05 was considered significant for all tests. lv. The statistical analysis for within group study like PPARG response group and metformin secondary failure group has not been displayed here.

5) List of Abbreviations

AEs Adverse Events

ALT Alanine aminotransferase

BMI Body Mass Index

BMRC Bangladesh Medical Research Council

BIRDEM Bangladesh Institute of Research and Rehabilitation in Diabetes,Endocrine and Metabolic Disorder

BP Blood Pressure

DNA Deoxynucleic Acid

DBP Diastolic Blood Pressure

DM Diabetes Mellitus

EASD European Association for the Study of Diabetes

EDTA Ethylene Diamine Tetra Acetic acid

ELISA Enzyme Linked Immunosorbent Assay

FBG/FSG Fasting Blood Glucose/Fasting Serum Glucose

FSI Fasting Serum Insulin

2hBG 2 hours Blood Glucose

HbA1c Glycosylated Haemoglobin

HOMA percent B Homeostasis Model Assessment percentage of beta cell function HOMA percent S Homeostasis Model Assessment percentage of sensitivity

HOMA IR Homeostasis Model Assessment Insulin Resistance

HDL-C High Density Lipid Cholesterol

IU/L International Unit/Litre

LDL-C Low Density Lipid Cholesterol

ml millilitre

mm millimetre

mg/dl milligram/ decilitre

MLR Multiple Logistic Regression

OPD Outdoor Patient Department

OMIM Online Mendelian Inheritance in Man

OR Odds Ratio

PPARγ Peroxisome Proliferator Activated Receptor gamma

Pro12Pro Proline12Proline

Pro12Ala Proline 12 Alanine

Ala12Ala Alanine12Alanine

PCR Polymerase Chain Reaction

QUICKI Quantitative Insulin sensitivity Check Index

SD Standard Deviation

SPSS Statistical Package for Social Science

SBP Systolic Blood Pressure

TC Total Cholesterol

TG Triglyceride

T2DM Type 2 Diabetes Mellitus

TZD Thiazolidinedione

µl Microliter

WHO World Health Organization

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 77 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: 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.
• Study Start Date: November 2008
• Actual Primary Completion Date: December 2009
• Actual Study Completion Date: June 2010

Arms and Interventions

Arm	Intervention/treatment
Experimental: Pioglitazone (001 group); The patients received pioglitazone hydrochloride tablet 30 mg (001 drug)once daily for first three months	Drug: Pioglitazone hydrochloride; 77 patients were treated with pioglitazone hydrochloride (B001) for 3 months.Biomedical parameters were measured each month.; Other Names: GLUCOZON; 30 mg tablet, once, daily; Coded as B001(Preparation Date:Jun 08); Aristopharma LTD.,Bangladesh; Drug: Metformin hydrochloride; After the treatment with pioglitazone(001) for 3 months first and then patients were on one month washout period;in the washout period they were given metformin tablet 850mg once daily,then treated with 002 (metformin) for further 3 months. The same biomedical measurements were assayed.; Other Names: GLUCOMET; 850 mg tablet, once, daily; Coded as B002 (Preparation date: Jun 08); Aristopharma LTD.,Bangladesh
Experimental: Metformin (002 group); The patients received metformin hydrochloride tablet 850 mg (002 drug)once daily for next three months.	Drug: Pioglitazone hydrochloride; 77 patients were treated with pioglitazone hydrochloride (B001) for 3 months.Biomedical parameters were measured each month.; Other Names: GLUCOZON; 30 mg tablet, once, daily; Coded as B001(Preparation Date:Jun 08); Aristopharma LTD.,Bangladesh; Drug: Metformin hydrochloride; After the treatment with pioglitazone(001) for 3 months first and then patients were on one month washout period;in the washout period they were given metformin tablet 850mg once daily,then treated with 002 (metformin) for further 3 months. The same biomedical measurements were assayed.; Other Names: GLUCOMET; 850 mg tablet, once, daily; Coded as B002 (Preparation date: Jun 08); Aristopharma LTD.,Bangladesh

Outcome Measures

Primary Outcome Measures :

1. Comparison of Changes in Fasting Serum Glucose (FSG)With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]
   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.
2. Comparison of Changes in Glycosylated Hemoglobin (HbA1c)With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]
   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.
3. Comparison of Changes in Insulin Levels (HOMA IR,QUICKI) With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]

   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.

   Analysis 1: Homeostasis Model Assessment Insulin Resistance(HOMA IR) Analysis 2: Quantitative Insulin sensitivity Check Index(QUICKI)

4. Comparison of Changes in HOMA Percent B and HOMA Percent S With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]

   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.

   Analysis 1: Homeostatic Model Assessment of Beta cell function(HOMA percent B) Analysis 2: Homeostatic Model Assessment of Insulin Sensitivity (Homa percent S)

5. Comparison of Changes in Fasting Serum Insulin (FSI)With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]
   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.

Secondary Outcome Measures :

1. Comparison of Changes in Lipid Profiles With Pioglitazone and Metformin [ Time Frame: 3 months for each drug ]

   Response rate was defined by ≥10% decrease of FSG or/and ≥1% decrease of HbA1c from the baseline values after 3 months treatment.48 responded to pioglitazone and 32 responded to metformin.

   Analysis 1:Total Cholesterol(TC) Analysis 2:Triglyceride(TG) Analysis 3:High Density Lipoprotein(HDL) Analysis 4:Low Density Lipoprotein(LDL)

Eligibility Criteria

• Ages Eligible for Study: 40 Years to 50 Years (Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Type 2 DM patients (with HbA1c level < 8.5 %, 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.

Exclusion Criteria:

• Patients with diabetes secondary to another cause.
• Patients suffering from serious incurrent illness requiring systemic treatment.
• Patients suffering from any other infectious diseases.
• Patients with impaired kidney function (serum creatinine level more than 1.2mg/dl)
• Patients with impaired hepatic function (SGPT ≥ 100 IU/L).
• Patients with pulmonary insufficiency with hypoxaemia.
• Triglyceriadiamea (TG ≥ 150mg/dl).
• Bloodpressure > 180 mmHg (Systolic) or > 110 mmHg (diastolic).
• Positive history of drug or alcohol abuse.
• Pregnant women and willing to be pregnant shortly.

Contacts and Locations

Locations

Bangladesh

Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM)

Dhaka, Bangladesh, 1000

Sponsors and Collaborators

University of Dhaka

Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders

University of Dundee

Investigators

• Study Chair: AK Azad Chowdhury, PhD; University of Dhaka, Bangladesh
• Principal Investigator: Masuma Parvin, PhD; University of Dhaka, Bangladesh
• Study Director: Begum Rokeya, PhD; BIRDEM,Dhaka,Bangladesh
• Study Director: Colin Palmer, PhD; University of Dundee

More Information

Additional Information:

Bangladesh Medical Research Council 

Bangladesh Institute of Research &amp; Rehabilitation in Diabetes, Endocrine and Metabolic Disorders (BIRDEM) 

Publications:

Laakso M. Hyperglycemia and cardiovascular disease in type 2 diabetes. Diabetes. 1999 May;48(5):937-42. Review.

Zimmet P, Alberti KG, Shaw J. Global and societal implications of the diabetes epidemic. Nature. 2001 Dec 13;414(6865):782-7. Review.

Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: estimates for the year 2000 and projections for 2030. Diabetes Care. 2004 May;27(5):1047-53.

Trivedi B, Mazumdar JD, Bhatt, Hemavathi KG. Effect of Shilajit on blood glucose and lipid profile in alloxan-induced diabetic rats. Indian J Pharmacol 2004; 36: 373-376.

Michael J, Fowler MD. Microvascular and Macrovascular Complications of Diabetes. Clinical Diabetes 2008; 26 : 77-82.

Mahtab H, Khan AR, Latif ZA, Pathan F, Ahmed T. Guideline for care of Type 2 Diabetes Mellitus in Bangladesh. BIRDEM Clinical Research Group Publishing 2003.

Silink M. The diabetes epidemic: The case for a resolution on diabetes. Diabetic Endocrine Journal 2006; 34:3-4.

Krall LP. The wide world of diabetes. In: World book of diabetes in practice. Krall LP. (ed) v2 Amsterdam: Elsevier Science publishing; 1986.

Diabetes Statistics -Diabetes help. http://www.diabetes.org.uk/Professionals/ Publications-reports-and-resources/Reports-statistics-and-case-studies/Reports/ Diabetes-prevalance-2010

Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010 Jan;87(1):4-14. doi: 10.1016/j.diabres.2009.10.007. Epub 2009 Nov 6.

American Diabetes Association. Diagnosis and classification of diabetes mellitus. Diabetes Care. 2005 Jan;28 Suppl 1:S37-42.

Flórez H. [Steps toward the primary prevention of type II diabetes mellitus. Various epidemiological considerations]. Invest Clin. 1997 Mar;38(1):39-52. Review. Spanish.

Health Survey for England. http://www.heartstats.org/datapage.

National Service Framework for Diabetes: Standards http:// www. technology adoptioncentre.nhs.uk/assets/_files/documents/mar_10/nhs__1268044698_Diabetes_NSF.pdf

Abdella N, Al Arouj M, Al Nakhi A, Al Assoussi A, Moussa M. Non-insulin-dependent diabetes in Kuwait: prevalence rates and associated risk factors. Diabetes Res Clin Pract. 1998 Dec;42(3):187-96.

Singh RB, Bajaj S, Niaz MA, Rastogi SS, Moshiri M. Prevalence of type 2 diabetes mellitus and risk of hypertension and coronary artery disease in rural and urban population with low rates of obesity. Int J Cardiol. 1998 Sep 1;66(1):65-72.

Ramachandran A, Snehalatha C, Latha E, Manoharan M, Vijay V. Impacts of urbanisation on the lifestyle and on the prevalence of diabetes in native Asian Indian population. Diabetes Res Clin Pract. 1999 Jun;44(3):207-13.

Pan XR, Li GW, Hu YH, Wang JX, Yang WY, An ZX, Hu ZX, Lin J, Xiao JZ, Cao HB, Liu PA, Jiang XG, Jiang YY, Wang JP, Zheng H, Zhang H, Bennett PH, Howard BV. Effects of diet and exercise in preventing NIDDM in people with impaired glucose tolerance. The Da Qing IGT and Diabetes Study. Diabetes Care. 1997 Apr;20(4):537-44.

Ramachandran A, Snehalatha C, Mary S, Mukesh B, Bhaskar AD, Vijay V; Indian Diabetes Prevention Programme (IDPP). The Indian Diabetes Prevention Programme shows that lifestyle modification and metformin prevent type 2 diabetes in Asian Indian subjects with impaired glucose tolerance (IDPP-1). Diabetologia. 2006 Feb;49(2):289-97. Epub 2006 Jan 4.

McKeigue PM, Shah B, Marmot MG. Relation of central obesity and insulin resistance with high diabetes prevalence and cardiovascular risk in South Asians. Lancet. 1991 Feb 16;337(8738):382-6.

McKeigue PM, Miller GJ, Marmot MG. Coronary heart disease in south Asians overseas: a review. J Clin Epidemiol. 1989;42(7):597-609. Review.

West KM, Kalbfleisch JM. Glucose tolerance, nutrition, and diabetes in Uruguay, Venezuela, Malaya, and East Pakistan. Diabetes. 1966 Jan;15(1):9-18.

Sayeed MA, Banu A, Haq JA, Khanam PA, Mahtab H, Azad Khan AK. Prevalence of hypertension in Bangladesh: effect of socioeconomic risk factor on difference between rural and urban community. Bangladesh Med Res Counc Bull. 2002 Apr;28(1):7-18.

Sayeed MA, Hussain MZ, Banu A, Rumi MA, Azad Khan AK. Prevalence of diabetes in a suburban population of Bangladesh. Diabetes Res Clin Pract. 1997 Jan;34(3):149-55.

Abu Sayeed M, Banu A, Khan AR, Hussain MZ. Prevalence of diabetes and hypertension in a rural population of Bangladesh. Diabetes Care. 1995 Apr;18(4):555-8.

Sayeed MA, Mahtab H, Khanam PA, Latif ZA, Banu A, Khan AK. Prevalence of diabetes and impaired fasting glucose in urban population of Bangladesh. Bangladesh Med Res Counc Bull. 2007 Apr;33(1):1-12.

Diabetic Association of Bangladesh. Statistical Year Book. July 2009-June 2010; p 250. web version is available at www.dab-bd.org.

Gyas M. Interviewed by: Parvin M. 16 October 2011.

Kahn SE, Porte DJ. The pathophysiology of type II (noninsulindependent) diabetes mellitus: implications for treatment. In: Porte D Jr, Sherwin RS editor(s). Ellenberg & Rifkin's Diabetes Mellitus. 5th ed. Stamford, Conneticut (U.S.A.): Appleton & Lange, 1997.

Richter B, Bandeira-Echtler E, Bergerhoff K, Clar C, Ebrahim SH. Pioglitazone for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006 Oct 18;(4):CD006060. Review.

DeFronzo RA. Lilly lecture 1987. The triumvirate: beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes. 1988 Jun;37(6):667-87. Review.

DeFronzo RA. Pathogenesis of type 2 diabetes: metabolic and molecular implication for identifying diabetes genes. In: American Diabetes Association, eds (Annual Review Of Diabetes), AlexandriaVA: American Diabetes 1998; 1-93.

Kain K, Catto Aj. Trans-Cultural Medicine: Insulin Resistance Syndrome In South Asians. The British Journal of Diabetes & Vascular Disease 2002; 2: 398.

WHO Expert Consultation. Appropriate body-mass index for Asian populations and its implications for policy and intervention strategies. Lancet. 2004 Jan 10;363(9403):157-63. Review. Erratum in: Lancet. 2004 Mar 13;363(9412):902.

Mathur SK, Rathore R, Chandra S, Sharma BB, Sharma L, Mathur P, Mathur M. Primary pioglitazone failure in Asian Indian diabetics is not related to common Pro12Ala polymorph of PPAR-gamma gene. Indian J Physiol Pharmacol. 2009 Apr-Jun;53(2):175-80.

Zinnat R. Role of Insulin Defficiency and Insulin Resistance in the Pathogenesis of Type 2 Diabetes in Young Bangladesh Subjects. M.Phil thesis. Bangladesh Institute of Research and Rehabilitation in Diabetes, Endocrine and Metabolic Disorders; 1999.

Alhossainy K. (kalhossainy@gmail.com). As per our database. Parvin M (acmasuma@gmail.com) 21 July 2011.

Thiazolidinedione http://en.wikipedia.org/wiki/Thiazolidinedione

Blüher M, Lübben G, Paschke R. Analysis of the relationship between the Pro12Ala variant in the PPAR-gamma2 gene and the response rate to therapy with pioglitazone in patients with type 2 diabetes. Diabetes Care. 2003 Mar;26(3):825-31.

Patlak M. New weapons to combat an ancient disease: treating diabetes. FASEB J. 2002 Dec;16(14):1853.

DeFronzo RA, Goodman AM. Efficacy of metformin in patients with non-insulin-dependent diabetes mellitus. The Multicenter Metformin Study Group. N Engl J Med. 1995 Aug 31;333(9):541-9.

Goodman & Gilmans'. The Pharmacological basis of Therapeutics. 10th ed. International Edition, McGraw Hill; 2001: p1701, 1704, 1706.

Lasker SP, McLachlan CS, Wang L, Ali SMK , Jelinek HF. Discovery, treatment and management of diabetes (Review Article). Journal of Diabetology Feb 2010; 1:1 http://www.journalofdiabetology.org/

MacCracken J, Hoel D. From ants to analogues. Puzzles and promises in diabetes management. Postgrad Med. 1997 Apr;101(4):138-40, 143-5, 149-50.

Pickup JC, Willium G. The history of diabetes mellitus. In Textbook of diabetes. 3rd ed. Vol-1.Oxford London: Blackwell Science Limited; 2003.

Kahn CR. Banting Lecture. Insulin action, diabetogenes, and the cause of type II diabetes. Diabetes. 1994 Aug;43(8):1066-84. Review.

Dabson M. Experiments and observations on the urine in diabetes. Med Obs Inq 1776; 5: 298-316.

Barnett DM, Krall LP. The History of diabetes. In Joslin's diabetes Mellitus, 14th ed. Boston MA. Lipincott William and Wilkins; 2005.

Stuart AR. Insulin and related medication. In Pharmacologic aspects of nursing. Paghiro, AM and Pagliaro, LA (eds). USA. The C.V. Mosby Company; 1988.

Von Mering J, Minowski O. Diabetes mellitus nach pancreas extripation. Arch Exper Path Pharmacol Leipzig 1890; 26: 371-87.

De Meyer J. Sur la signification physiologique de la secretion interne du pancreas. Zbl Physiol 1904;18:S826.

Classification and diagnosis of diabetes mellitus and other categories of glucose intolerance. National Diabetes Data Group. Diabetes. 1979 Dec;28(12):1039-57.

World Health Organization. Definition, Diagnosis, Classification of Diabetes Mellitus and its Complications. Geneva: WHO 1999. Report of a WHO Consultation. Part1: Diagnosis and Classification of Diabetes Mellitus.

Newman B, Selby JV, King MC, Slemenda C, Fabsitz R, Friedman GD. Concordance for type 2 (non-insulin-dependent) diabetes mellitus in male twins. Diabetologia. 1987 Oct;30(10):763-8.

O'Rahilly SP, Nugent Z, Rudenski AS, Hosker JP, Burnett MA, Darling P, Turner RC. Beta-cell dysfunction, rather than insulin insensitivity, is the primary defect in familial type 2 diabetes. Lancet. 1986 Aug 16;2(8503):360-4.

Taylor SI, Accili D, Imai Y. Insulin resistance or insulin deficiency. Which is the primary cause of NIDDM? Diabetes. 1994 Jun;43(6):735-40. Review.

DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol. 1979 Sep;237(3):E214-23.

Matthews DR, Hosker JP, Rudenski AS, Naylor BA, Treacher DF, Turner RC. Homeostasis model assessment: insulin resistance and beta-cell function from fasting plasma glucose and insulin concentrations in man. Diabetologia. 1985 Jul;28(7):412-9.

Rizza RA, Mandarino LJ, Gerich JE. Mechanism and significance of insulin resistance in non-insulin-dependent diabetes mellitus. Diabetes. 1981 Dec;30(12):990-5.

Sherwin RS, Hendler RG, Felig P. Effect of diabetes mellitus and insulin on the turnover and metabolic response to ketones in man. Diabetes. 1976 Sep;25(9):776-84.

DeFronzo RA, Ferrannini E. Insulin resistance. A multifaceted syndrome responsible for NIDDM, obesity, hypertension, dyslipidemia, and atherosclerotic cardiovascular disease. Diabetes Care. 1991 Mar;14(3):173-94. Review.

Luzi L, DeFronzo RA. Effect of loss of first-phase insulin secretion on hepatic glucose production and tissue glucose disposal in humans. Am J Physiol. 1989 Aug;257(2 Pt 1):E241-6.

O'Rahilly S, Hattersley A, Vaag A, Gray H. Insulin resistance as the major cause of impaired glucose tolerance: a self-fulfilling prophesy? Lancet. 1994 Aug 27;344(8922):585-9.

Lang DA, Matthews DR, Burnett M, Turner RC. Brief, irregular oscillations of basal plasma insulin and glucose concentrations in diabetic man. Diabetes. 1981 May;30(5):435-9.

Polonsky KS, Given BD, Hirsch LJ, Tillil H, Shapiro ET, Beebe C, Frank BH, Galloway JA, Van Cauter E. Abnormal patterns of insulin secretion in non-insulin-dependent diabetes mellitus. N Engl J Med. 1988 May 12;318(19):1231-9.

Olefsky JM. Insulin resistance. In: Rifkin H, porte D Jr, eds. Ellenberg and Rifkin's diabetes mellitus: theory and practice. NewYork: Elsvier 1997: 513-52.

Kolterman OG, Gray RS, Shapiro G, Scarlett JA, Griffin J, Olefsky JM. The acute and chronic effects of sulfonylurea therapy in type II diabetic subjects. Diabetes. 1984 Apr;33(4):346-54.

Lillioja S, Mott DM, Zawadzki JK, Young AA, Abbott WG, Knowler WC, Bennett PH, Moll P, Bogardus C. In vivo insulin action is familial characteristic in nondiabetic Pima Indians. Diabetes. 1987 Nov;36(11):1329-35.

Garvey WT, Olefsky JM, Griffin J, Hamman RF, Kolterman OG. The effect of insulin treatment on insulin secretion and insulin action in type II diabetes mellitus. Diabetes. 1985 Mar;34(3):222-34.

Katsilambros N, Tentolouris N. Type 2 diabetes: an overview. In: Textbook of Diabetes, 3rd ed. Pickup JC and Williams G, Eds, Blackwell Science; 2003: pp 4.1-4.19.

Gerich JE, Smith TM. beta-cell defects and pancreatic abnormalities in type 2 diabetes. In: Textbook of Diabetes, 3rd ed, Pickup JC & Williams G, Eds, Blackwell Science 23; 2003: 1-23.11.

Armour T, Norris S, Brown D, Zhang X, Caspersen C. Initiating and maintaining physical activity for type 2 diabetes mellitus. Cochrane Database of Systematic Reviews 2004.

Orozco LJ, Buchleitner AM, Gimenez-Perez G, Roqué I Figuls M, Richter B, Mauricio D. Exercise or exercise and diet for preventing type 2 diabetes mellitus. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003054. doi: 10.1002/14651858.CD003054.pub3. Review. Update in: Cochrane Database Syst Rev. 2017 Dec 04;12 :CD003054.

Nield L, Summerbell CD, Hooper L, Whittaker V, Moore H. Dietary advice for the prevention of type 2 diabetes mellitus in adults. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD005102. doi: 10.1002/14651858.CD005102.pub2. Review. Update in: Cochrane Database Syst Rev. 2016;1:CD005102.

Thomas DE, Elliott EJ, Naughton GA. Exercise for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2006 Jul 19;(3):CD002968. Review.

Black C, Donnelly P, McIntyre L, Royle PL, Shepherd JP, Thomas S. Meglitinide analogues for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2007 Apr 18;(2):CD004654. Review.

Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 2005 Jul 20;(3):CD002966. Review. Update in: Cochrane Database Syst Rev. 2015;9:CD002966.

Salpeter S, Greyber E, Pasternak G, Salpeter E. Risk of fatal and nonfatal lactic acidosis with metformin use in type 2 diabetes mellitus. Cochrane Database Syst Rev. 2003;(2):CD002967. Review. Update in: Cochrane Database Syst Rev. 2006;(1):CD002967.

Meriden T. Progress with thiazolidinediones in the management of type 2 diabetes mellitus. Clin Ther. 2004 Feb;26(2):177-90. Review.

Misso ML, Egberts KJ, Page M, O'Connor D, Shaw J. Continuous subcutaneous insulin infusion (CSII) versus multiple insulin injections for type 1 diabetes mellitus. Cochrane Database Syst Rev. 2010 Jan 20;(1):CD005103. doi: 10.1002/14651858.CD005103.pub2. Review.

Richter B, Neises G. 'Human' insulin versus animal insulin in people with diabetes mellitus. Cochrane Database Syst Rev. 2005 Jan 25;(1):CD003816. Review.

Roberts D, Van NW, Chang H, Pohula W, MCheang, Moffatt M, et al. Glargine versus other basal insulins (NPH, Lente, or Ultralente) for the treatment of type 1 diabetes mellitus. Cochrane Database of Systematic Reviews 2005.

Charlotte E, Mathis G. Inhaled insulin. Diabetes Health Center 2007, http://diabetes. webmd.com/inhaledinsulin.

Dunn C, Curran MP. Inhaled human insulin (Exubera): a review of its use in adult patients with diabetes mellitus. Drugs. 2006;66(7):1013-32. Review.

Smith U. Pioglitazone: mechanism of action. Int J Clin Pract Suppl. 2001 Sep;(121):13-8. Review.

Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004 Sep 9;351(11):1106-18. Review.

Seda O, Sedová L. PPARs: molecular targets in the pharmacogenomics era. Prague Med Rep. 2004;105(3):223-36. Review.

Kim H, Haluzik M, Asghar Z, Yau D, Joseph JW, Fernandez AM, Reitman ML, Yakar S, Stannard B, Heron-Milhavet L, Wheeler MB, LeRoith D. Peroxisome proliferator-activated receptor-alpha agonist treatment in a transgenic model of type 2 diabetes reverses the lipotoxic state and improves glucose homeostasis. Diabetes. 2003 Jul;52(7):1770-8.

Tonelli J, Li W, Kishore P, Pajvani UB, Kwon E, Weaver C, Scherer PE, Hawkins M. Mechanisms of early insulin-sensitizing effects of thiazolidinediones in type 2 diabetes. Diabetes. 2004 Jun;53(6):1621-9. Erratum in: Diabetes. 2005 Feb;54(2):587.

Ferré P. The biology of peroxisome proliferator-activated receptors: relationship with lipid metabolism and insulin sensitivity. Diabetes. 2004 Feb;53 Suppl 1:S43-50. Review.

Mayerson AB, Hundal RS, Dufour S, Lebon V, Befroy D, Cline GW, Enocksson S, Inzucchi SE, Shulman GI, Petersen KF. The effects of rosiglitazone on insulin sensitivity, lipolysis, and hepatic and skeletal muscle triglyceride content in patients with type 2 diabetes. Diabetes. 2002 Mar;51(3):797-802.

Miyazaki Y, Mahankali A, Matsuda M, Mahankali S, Hardies J, Cusi K, Mandarino LJ, DeFronzo RA. Effect of pioglitazone on abdominal fat distribution and insulin sensitivity in type 2 diabetic patients. J Clin Endocrinol Metab. 2002 Jun;87(6):2784-91.

Hundal RS, Krssak M, Dufour S, Laurent D, Lebon V, Chandramouli V, Inzucchi SE, Schumann WC, Petersen KF, Landau BR, Shulman GI. Mechanism by which metformin reduces glucose production in type 2 diabetes. Diabetes. 2000 Dec;49(12):2063-9.

Metformin. http://en.wikipedia.org/wiki/Metformin (accessed on 20 October 2011)

Hamman RF. Genetic and environmental determinants of non-insulin-dependent diabetes mellitus (NIDDM). Diabetes Metab Rev. 1992 Dec;8(4):287-338. Review.

Avogaro A. Insulin resistance: trigger or concomitant factor in the metabolic syndrome. Panminerva Med. 2006 Mar;48(1):3-12. Review.

Parikh H, Groop L. Candidate genes for type 2 diabetes. Rev Endocr Metab Disord. 2004 May;5(2):151-76. Review.

Lohmueller KE, Pearce CL, Pike M, Lander ES, Hirschhorn JN. Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet. 2003 Feb;33(2):177-82. Epub 2003 Jan 13.

Stumvoll M, Goldstein BJ, van Haeften TW. Type 2 diabetes: principles of pathogenesis and therapy. Lancet. 2005 Apr 9-15;365(9467):1333-46. Review.

Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005 Aug;54(8):2460-70. Review.

Spiegelman BM. PPAR-gamma: adipogenic regulator and thiazolidinedione receptor. Diabetes. 1998 Apr;47(4):507-14. Review.

Dubuquoy L, Dharancy S, Nutten S, Pettersson S, Auwerx J, Desreumaux P. Role of peroxisome proliferator-activated receptor gamma and retinoid X receptor heterodimer in hepatogastroenterological diseases. Lancet. 2002 Nov 2;360(9343):1410-8. Review.

Olefsky JM. Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest. 2000 Aug;106(4):467-72. Review.

Fajas L, Auboeuf D, Raspé E, Schoonjans K, Lefebvre AM, Saladin R, Najib J, Laville M, Fruchart JC, Deeb S, Vidal-Puig A, Flier J, Briggs MR, Staels B, Vidal H, Auwerx J. The organization, promoter analysis, and expression of the human PPARgamma gene. J Biol Chem. 1997 Jul 25;272(30):18779-89.

Auwerx J. PPARgamma, the ultimate thrifty gene. Diabetologia. 1999 Sep;42(9):1033-49. Review.

Gouda HN, Sagoo GS, Harding AH, Yates J, Sandhu MS, Higgins JP. The association between the peroxisome proliferator-activated receptor-gamma2 (PPARG2) Pro12Ala gene variant and type 2 diabetes mellitus: a HuGE review and meta-analysis. Am J Epidemiol. 2010 Mar 15;171(6):645-55. doi: 10.1093/aje/kwp450. Epub 2010 Feb 23. Review.

Stumvoll M, Häring H. The peroxisome proliferator-activated receptor-gamma2 Pro12Ala polymorphism. Diabetes. 2002 Aug;51(8):2341-7. Review.

Altshuler D, Hirschhorn JN, Klannemark M, Lindgren CM, Vohl MC, Nemesh J, Lane CR, Schaffner SF, Bolk S, Brewer C, Tuomi T, Gaudet D, Hudson TJ, Daly M, Groop L, Lander ES. The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes. Nat Genet. 2000 Sep;26(1):76-80.

Deeb SS, Fajas L, Nemoto M, Pihlajamäki J, Mykkänen L, Kuusisto J, Laakso M, Fujimoto W, Auwerx J. A Pro12Ala substitution in PPARgamma2 associated with decreased receptor activity, lower body mass index and improved insulin sensitivity. Nat Genet. 1998 Nov;20(3):284-7.

Paracchini V, Pedotti P, Taioli E. Genetics of leptin and obesity: a HuGE review. Am J Epidemiol. 2005 Jul 15;162(2):101-14. Epub 2005 Jun 22. Review.

Vigouroux C, Fajas L, Khallouf E, Meier M, Gyapay G, Lascols O, Auwerx J, Weissenbach J, Capeau J, Magré J. Human peroxisome proliferator-activated receptor-gamma2: genetic mapping, identification of a variant in the coding sequence, and exclusion as the gene responsible for lipoatrophic diabetes. Diabetes. 1998 Mar;47(3):490-2.

Mori H, Ikegami H, Kawaguchi Y, Seino S, Yokoi N, Takeda J, Inoue I, Seino Y, Yasuda K, Hanafusa T, Yamagata K, Awata T, Kadowaki T, Hara K, Yamada N, Gotoda T, Iwasaki N, Iwamoto Y, Sanke T, Nanjo K, Oka Y, Matsutani A, Maeda E, Kasuga M. The Pro12 -->Ala substitution in PPAR-gamma is associated with resistance to development of diabetes in the general population: possible involvement in impairment of insulin secretion in individuals with type 2 diabetes. Diabetes. 2001 Apr;50(4):891-4.

Ek J, Andersen G, Urhammer SA, Hansen L, Carstensen B, Borch-Johnsen K, Drivsholm T, Berglund L, Hansen T, Lithell H, Pedersen O. Studies of the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-gamma2 (PPAR-gamma2) gene in relation to insulin sensitivity among glucose tolerant caucasians. Diabetologia. 2001 Sep;44(9):1170-6.

Chuang LM, Hsiung CA, Chen YD, Ho LT, Sheu WH, Pei D, Nakatsuka CH, Cox D, Pratt RE, Lei HH, Tai TY. Sibling-based association study of the PPARgamma2 Pro12Ala polymorphism and metabolic variables in Chinese and Japanese hypertension families: a SAPPHIRe study. Stanford Asian-Pacific Program in Hypertension and Insulin Resistance. J Mol Med (Berl). 2001 Nov;79(11):656-64.

Hara K, Yamauchi T, Kubota N, Tobe K, Yamazaki T, Nagai R, Kadowaki T. [The role of PPARgamma in the onset of type 2 diabetes]. Nihon Yakurigaku Zasshi. 2003 Oct;122(4):317-24. Review. Japanese.

Koch M, Rett K, Maerker E, Volk A, Haist K, Deninger M, Renn W, Häring HU. The PPARgamma2 amino acid polymorphism Pro 12 Ala is prevalent in offspring of Type II diabetic patients and is associated to increased insulin sensitivity in a subgroup of obese subjects. Diabetologia. 1999 Jun;42(6):758-62.

Globerman H, Zauberman Y, Makarov T, Beamer BA, Yen CJ, Shuldiner AR, Harel C, Karnieli E. Analysis of the peroxisome proliferator activated receptor gamma (PPARgamma) gene in HAIRAN syndrome with obesity. Clin Endocrinol (Oxf). 2000 Apr;52(4):479-85.

Masugi J, Tamori Y, Mori H, Koike T, Kasuga M. Inhibitory effect of a proline-to-alanine substitution at codon 12 of peroxisome proliferator-activated receptor-gamma 2 on thiazolidinedione-induced adipogenesis. Biochem Biophys Res Commun. 2000 Feb 5;268(1):178-82.

Werman A, Hollenberg A, Solanes G, Bjorbaek C, Vidal-Puig AJ, Flier JS. Ligand-independent activation domain in the N terminus of peroxisome proliferator-activated receptor gamma (PPARgamma). Differential activity of PPARgamma1 and -2 isoforms and influence of insulin. J Biol Chem. 1997 Aug 8;272(32):20230-5.

Stumvoll M, Wahl HG, Löblein K, Becker R, Machicao F, Jacob S, Häring H. Pro12Ala polymorphism in the peroxisome proliferator-activated receptor-gamma2 gene is associated with increased antilipolytic insulin sensitivity. Diabetes. 2001 Apr;50(4):876-81.

Boden G. Role of fatty acids in the pathogenesis of insulin resistance and NIDDM. Diabetes. 1997 Jan;46(1):3-10. Review. Erratum in: Diabetes 1997 Mar;46(3):536.

U.K. prospective diabetes study 16. Overview of 6 years' therapy of type II diabetes: a progressive disease. U.K. Prospective Diabetes Study Group. Diabetes. 1995 Nov;44(11):1249-58. Erratum in: Diabetes 1996 Nov;45(11):1655.

Brown JB, Conner C, Nichols GA. Secondary failure of metformin monotherapy in clinical practice. Diabetes Care. 2010 Mar;33(3):501-6. doi: 10.2337/dc09-1749. Epub 2009 Dec 29.

Holstein A, Seeringer A, Kovacs P. Therapy With Oral Antidiabetic Drugs: Applied pharmacogenetics. British Journal of Diabetes & Vascular Disease 2011;11:10. DOI: 10.1177/1474651410397583 (accessed on 20 October 2011).

Cavaghan MK, Ehrmann DA, Byrne MM, Polonsky KS. Treatment with the oral antidiabetic agent troglitazone improves beta cell responses to glucose in subjects with impaired glucose tolerance. J Clin Invest. 1997 Aug 1;100(3):530-7.

Kubo K. Effect of pioglitazone on blood proinsulin levels in patients with type 2 diabetes mellitus. Endocr J. 2002 Jun;49(3):323-8.

Li J, Tian H, Ren Y, et al. Effect of pioglitazone on first phase insulin secretion in type 2 diabetes mellitus and impaired glucose tolerance. Diabetes. 2003 (Abstract No 1212-P); 52 : A281.

Diani AR, Sawada G, Wyse B, Murray FT, Khan M. Pioglitazone preserves pancreatic islet structure and insulin secretory function in three murine models of type 2 diabetes. Am J Physiol Endocrinol Metab. 2004 Jan;286(1):E116-22. Epub 2003 Oct 7.

Al-Shali KZ, House AA, Hanley AJ, Khan HM, Harris SB, Zinman B, Mamakeesick M, Fenster A, Spence JD, Hegele RA. Genetic variation in PPARG encoding peroxisome proliferator-activated receptor gamma associated with carotid atherosclerosis. Stroke. 2004 Sep;35(9):2036-40. Epub 2004 Jul 29.

Power AC. Diabetes mellitus.In: KasperDL, Fauci AS, Longo DL,Braunwald E, Hauser SL, Jameson JL (Eds). Harrison's Principles of Internal Medicine, 16th ed. McGraw-Hill; 2005: 2152-79.

Kaku K. Efficacy and safety of therapy with metformin plus pioglitazone in the treatment of patients with type 2 diabetes: a double-blind, placebo-controlled, clinical trial. Curr Med Res Opin. 2009 May;25(5):1111-9. doi: 10.1185/03007990902820816 .

Bailey CJ. Treating insulin resistance in type 2 diabetes with metformin and thiazolidinediones. Diabetes Obes Metab. 2005 Nov;7(6):675-91. Review. Erratum in: Diabetes Obes Metab. 2005 Nov;7(6):769.

Kahn SE, Haffner SM, Heise MA, Herman WH, Holman RR, Jones NP, Kravitz BG, Lachin JM, O'Neill MC, Zinman B, Viberti G; ADOPT Study Group. Glycemic durability of rosiglitazone, metformin, or glyburide monotherapy. N Engl J Med. 2006 Dec 7;355(23):2427-43. Epub 2006 Dec 4. Erratum in: N Engl J Med. 2007 Mar 29;356(13):1387-8.

Schernthaner G, Matthews DR, Charbonnel B, Hanefeld M, Brunetti P; Quartet [corrected] Study Group. Efficacy and safety of pioglitazone versus metformin in patients with type 2 diabetes mellitus: a double-blind, randomized trial. J Clin Endocrinol Metab. 2004 Dec;89(12):6068-76. Erratum in: J Clin Endocrinol Metab. 2005 Feb;90(2):746.

Nagasaka S, Aiso Y, Yoshizawa K, Ishibashi S. Comparison of pioglitazone and metformin efficacy using homeostasis model assessment. Diabet Med. 2004 Feb;21(2):136-41.

Tan MH, Glazer NB, Johns D, Widel M, Gilmore KJ. Pioglitazone as monotherapy or in combination with sulfonylurea or metformin enhances insulin sensitivity (HOMA-S or QUICKI) in patients with type 2 diabetes. Curr Med Res Opin. 2004 May;20(5):723-8.

Ceriello A, Johns D, Widel M, Eckland DJ, Gilmore KJ, Tan MH. Comparison of effect of pioglitazone with metformin or sulfonylurea (monotherapy and combination therapy) on postload glycemia and composite insulin sensitivity index during an oral glucose tolerance test in patients with type 2 diabetes. Diabetes Care. 2005 Feb;28(2):266-72. Erratum in: Diabetes Care. 2005 May;28(5):1272.

Yoon KH, Shin JA, Kwon HS, Lee SH, Min KW, Ahn YB, Yoo SJ, Ahn KJ, Park SW, Lee KW, Sung YA, Park TS, Kim MS, Kim YK, Nam MS, Kim HS, Park IeB, Park JS, Woo JT, Son HY. Comparison of the efficacy of glimepiride, metformin, and rosiglitazone monotherapy in korean drug-naïve type 2 diabetic patients: the practical evidence of antidiabetic monotherapy study. Diabetes Metab J. 2011 Feb;35(1):26-33. doi: 10.4093/dmj.2011.35.1.26. Epub 2011 Feb 28.

Vilar L, Canadas V, Arruda MJ, Arahata C, Agra R, Pontes L, Montenegro L, Vilar CF, Silva LM, Albuquerque JL, Gusmão A. Comparison of metformin, gliclazide MR and rosiglitazone in monotherapy and in combination for type 2 diabetes. Arq Bras Endocrinol Metabol. 2010 Mar;54(3):311-8.

Ito H, Ohno Y, Yamauchi T, Kawabata Y, Ikegami H. Efficacy and safety of metformin for treatment of type 2 diabetes in elderly Japanese patients. Geriatr Gerontol Int. 2011 Jan;11(1):55-62. doi: 10.1111/j.1447-0594.2010.00635.x.

Kaku K, Tajima N, Kawamori R. Melbin observational research (MORE) study of metformin therapy in patients with type 2 diabetes mellitus. J Japan Diab Soc 2006; 49: 325-331 (in Japanese).

Miyazaki Y, Matsuda M, DeFronzo RA. Dose-response effect of pioglitazone on insulin sensitivity and insulin secretion in type 2 diabetes. Diabetes Care. 2002 Mar;25(3):517-23.

Matthews DR, Charbonnel BH, Hanefeld M, Brunetti P, Schernthaner G. Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Diabetes Metab Res Rev. 2005 Mar-Apr;21(2):167-74.

de Winter W, DeJongh J, Post T, Ploeger B, Urquhart R, Moules I, Eckland D, Danhof M. A mechanism-based disease progression model for comparison of long-term effects of pioglitazone, metformin and gliclazide on disease processes underlying Type 2 Diabetes Mellitus. J Pharmacokinet Pharmacodyn. 2006 Jun;33(3):313-43. Epub 2006 Mar 22.

Rasouli N, Raue U, Miles LM, Lu T, Di Gregorio GB, Elbein SC, Kern PA. Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue. Am J Physiol Endocrinol Metab. 2005 May;288(5):E930-4. Epub 2005 Jan 4.

Summerson JH, Bell RA, Konen JC. Coronary heart disease risk factors in black and white patients with non-insulin-dependent diabetes mellitus. Ethn Health. 1996 Mar;1(1):9-20.

Langenfeld MR, Forst T, Hohberg C, Kann P, Lübben G, Konrad T, Füllert SD, Sachara C, Pfützner A. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: results from a controlled randomized study. Circulation. 2005 May 17;111(19):2525-31. Epub 2005 May 9.

Greene ME, Blumberg B, McBride OW, Yi HF, Kronquist K, Kwan K, Hsieh L, Greene G, Nimer SD. Isolation of the human peroxisome proliferator activated receptor gamma cDNA: expression in hematopoietic cells and chromosomal mapping. Gene Expr. 1995;4(4-5):281-99.

Elbrecht A, Chen Y, Cullinan CA, Hayes N, Leibowitz Md, Moller DE, Berger J. Molecular cloning, expression and characterization of human peroxisome proliferator activated receptors gamma 1 and gamma 2. Biochem Biophys Res Commun. 1996 Jul 16;224(2):431-7.

Matthaei S, Stumvoll M, Kellerer M, Häring HU. Pathophysiology and pharmacological treatment of insulin resistance. Endocr Rev. 2000 Dec;21(6):585-618. Review.

Perriello G, Misericordia P, Volpi E, Santucci A, Santucci C, Ferrannini E, Ventura MM, Santeusanio F, Brunetti P, Bolli GB. Acute antihyperglycemic mechanisms of metformin in NIDDM. Evidence for suppression of lipid oxidation and hepatic glucose production. Diabetes. 1994 Jul;43(7):920-8.

Zhou G, Myers R, Li Y, Chen Y, Shen X, Fenyk-Melody J, Wu M, Ventre J, Doebber T, Fujii N, Musi N, Hirshman MF, Goodyear LJ, Moller DE. Role of AMP-activated protein kinase in mechanism of metformin action. J Clin Invest. 2001 Oct;108(8):1167-74.

Moser M, Sowers JR. Clinical Management of Cardiovascular Risk Factors in Diabetes. 4th ed. USA: Professional Communications Publishing; 2011 : p 230.

Nissen SE, Nicholls SJ, Wolski K, Nesto R, Kupfer S, Perez A, Jure H, De Larochellière R, Staniloae CS, Mavromatis K, Saw J, Hu B, Lincoff AM, Tuzcu EM; PERISCOPE Investigators. Comparison of pioglitazone vs glimepiride on progression of coronary atherosclerosis in patients with type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008 Apr 2;299(13):1561-73. doi: 10.1001/jama.299.13.1561. Epub 2008 Mar 31.

Wulffelé MG, Kooy A, de Zeeuw D, Stehouwer CD, Gansevoort RT. The effect of metformin on blood pressure, plasma cholesterol and triglycerides in type 2 diabetes mellitus: a systematic review. J Intern Med. 2004 Jul;256(1):1-14. Review.

Seidell JC, Hautvast JG, Deurenberg P. Overweight: fat distribution and health risks. Epidemiological observations. A review. Infusionstherapie. 1989 Dec;16(6):276-81. Review.

O'Moore-Sullivan TM, Prins JB. Thiazolidinediones and type 2 diabetes: new drugs for an old disease. Med J Aust. 2002 Apr 15;176(8):381-6. Review. Erratum in: Med J Aust 2002 Oct 7;177(7):396.

Shihara N, Kitaoka M, Inagaki N, Kadowaki T, Koumoto S, Satoh J, Terauchi Y, Nunoi K, Yamada Y, Sakamaki H, Seino Y. Randomized controlled trial of single-agent glimepiride and pioglitazone in Japanese patients with type 2 diabetes: A comparative study. J Diabetes Investig. 2011 Oct 7;2(5):391-8. doi: 10.1111/j.2040-1124.2011.00115.x.

Kang ES, Park SY, Kim HJ, Kim CS, Ahn CW, Cha BS, Lim SK, Nam CM, Lee HC. Effects of Pro12Ala polymorphism of peroxisome proliferator-activated receptor gamma2 gene on rosiglitazone response in type 2 diabetes. Clin Pharmacol Ther. 2005 Aug;78(2):202-8.

Beamer BA, Yen CJ, Andersen RE, Muller D, Elahi D, Cheskin LJ, Andres R, Roth J, Shuldiner AR. Association of the Pro12Ala variant in the peroxisome proliferator-activated receptor-gamma2 gene with obesity in two Caucasian populations. Diabetes. 1998 Nov;47(11):1806-8.

Ek J, Urhammer SA, Sørensen TI, Andersen T, Auwerx J, Pedersen O. Homozygosity of the Pro12Ala variant of the peroxisome proliferation-activated receptor-gamma2 (PPAR-gamma2): divergent modulating effects on body mass index in obese and lean Caucasian men. Diabetologia. 1999 Jul;42(7):892-5.

Nicklas BJ, van Rossum EF, Berman DM, Ryan AS, Dennis KE, Shuldiner AR. Genetic variation in the peroxisome proliferator-activated receptor-gamma2 gene (Pro12Ala) affects metabolic responses to weight loss and subsequent weight regain. Diabetes. 2001 Sep;50(9):2172-6.

Iwata E, Matsuda H, Fukuda T, Fukuen S, Motomura T, Igarashi T, Yamamoto I, Azuma J. Mutations of the peroxisome proliferator-activated receptor gamma (PPAR gamma) gene in a Japanese population : the Pro12Ala mutation in PPAR gamma 2 is associated with lower concentrations of serum total and non-HDL cholesterol. Diabetologia. 2001 Oct;44(10):1354-5.

Oh EY, Min KM, Chung JH, Min YK, Lee MS, Kim KW, Lee MK. Significance of Pro12Ala mutation in peroxisome proliferator-activated receptor-gamma2 in Korean diabetic and obese subjects. J Clin Endocrinol Metab. 2000 May;85(5):1801-4.

Snitker S, Watanabe RM, Ani I, Xiang AH, Marroquin A, Ochoa C, Goico J, Shuldiner AR, Buchanan TA; Troglitazone in Prevention of Diabetes (TRIPOD) study. Changes in insulin sensitivity in response to troglitazone do not differ between subjects with and without the common, functional Pro12Ala peroxisome proliferator-activated receptor-gamma2 gene variant: results from the Troglitazone in Prevention of Diabetes (TRIPOD) study. Diabetes Care. 2004 Jun;27(6):1365-8.

• Responsible Party: Dr. Masuma Parvin, Research fellow, University of Dhaka
• ClinicalTrials.gov Identifier: NCT01589445
• Other Study ID Numbers: BS-67/2008-09; BMRC/ERC/2007-2010/2024 ( Other Identifier: Bangladesh Medical Research Council )
• First Posted: May 2, 2012
• Results First Posted: February 27, 2014
• Last Update Posted: February 28, 2014
• Last Verified: February 2014

Keywords provided by Dr. Masuma Parvin, University of Dhaka:

Bangladesh; T2DM; Pioglitazone; Metformin; Insulin secretion and Sensitivity

Additional relevant MeSH terms:

Diabetes Mellitus; Diabetes Mellitus, Type 2; Glucose Metabolism Disorders; Metabolic Diseases; Endocrine System Diseases; Metformin; Pioglitazone; Hypoglycemic Agents; Physiological Effects of Drugs