Beyond BMI: Why Pioglitazone Deserves a Place in Managing 'Thin-Fat' Type 2 Diabetes in India

Thin-Fat Paradox in Indian T2DM - A Distinct Metabolic Challenge: In the Indian population, the 'thin-fat' phenotype-normal BMI with excess visceral and reduced peripheral fat-represents a distinct metabolic risk. Nearly one-third of Indian adults with a BMI <25 kg/m² may exhibit this profile, with a 2.7-fold higher risk of type 2 diabetes.(1) As BMI inadequately reflects adipose dysfunction, integrating pathophysiologic insights into risk assessment is essential. (1,2) Targeting insulin resistance and ectopic fat-using agents such as pioglitazone, which acts through PPAR-γ activation-may benefit metabolically selected individuals.

Unveiling Metabolic Pathways in Thin-Fat T2DM: Insulin Resistance and Ectopic Fat: The thin-fat or MUNO (metabolically unhealthy non-obese) phenotype is marked by reduced adipose tissue expandability, leading to ectopic fat deposition and insulin resistance via lipotoxicity. This contributes to the high prevalence of NAFLD/MASLD, with hepatic steatosis as an early marker of metabolic dysfunction. Hepatic insulin resistance, glucagon resistance, and DPP4 overexpression further exacerbate metabolic complications. (3)

Clinical Approach and Practical Considerations in Thin-Fat T2DM Early recognition of the thin-fat phenotype is crucial, especially in Indian individuals with normal BMI but increased visceral adiposity, insulin resistance, or early-onset metabolic disease.(1) Screening may include BMI, waist circumference, liver enzymes, lipid profile, HOMA-IR, and hepatic imaging, with ultrasound or CT/MRI (where feasible) or to quantify hepatic and visceral fat.

Pioglitazone, a selective PPAR-γ agonist, enhances insulin sensitivity in adipose tissue, liver, and skeletal muscle, while promoting the redistribution of lipids from ectopic depots (e.g., liver, muscle) into subcutaneous adipose tissue. These mechanisms are particularly relevant in thin-fat T2DM, where impaired adipose expandability and ectopic fat accumulation contribute to insulin resistance, β-cell dysfunction, and chronic inflammation. (5) This mechanistic rationale forms the basis for pioglitazone’s observed clinical benefits across diverse patient populations.

Clinical Evidence Supporting Pioglitazone in Thin-Fat and Insulin-Resistant Phenotypes

Pioglitazone-Anti-inflammatory and Cardiometabolic Benefits: In the IRIS V study (n=1,170; glitazone-naïve T2DM patients in routine care), pioglitazone significantly reduced systemic inflammation as shown by hsCRP decline (3.3 → 2.8 mg/L, p<0.01). Glycemic markers improved, with HbA1c decreasing from 7.5% to 6.8% (p<0.001), alongside reductions in fasting glucose, triglycerides, LDL cholesterol, and blood pressure. HDL increased significantly (p<0.001), indicating improved lipid homeostasis. (6)

Pioglitazone-Improved Insulin Sensitivity and β-Cell Function: In a 16-week study of 68 drug-naïve lean and obese T2DM patients, pioglitazone significantly enhanced insulin sensitivity (via euglycemic clamp), first-phase insulin secretion, and β-cell glucose sensitivity (p<0.001). HbA1c dropped by >1%, and adiponectin levels increased in obese participants, highlighting pioglitazone’s impact on adipose function and endocrine signaling. (7)

Pioglitazone Led to Reduction of Ectopic Fat: In a mechanistic trial (n=23) with adults having impaired glucose tolerance, pioglitazone (vs. metformin) reduced 2-hour glucose (172.8 → 109.8 mg/dL), increased insulin sensitivity by 65%, and lowered intramyocellular lipid (IMCL) by 34% (p≤0.002). These effects occurred without increased lipid oxidation, suggesting improved lipid partitioning. (8)

Pioglitazone’s Durable Glycemic Control in Indian Patients: An Indian observational study (n=958; T2DM uncontrolled on OADs) showed that pioglitazone (7.5–30 mg) led to sustained reductions in FBG (~27 mg/dL), PPG (up to ~60 mg/dL), and HbA1c (8.4% → 7.7%; p<0.0001) over 2 years. (9)

Pioglitazone Reduced Proteinuria in Diabetic Kidney Disease(DKD): In a double-blind trial (n=76; T2DM with proteinuria >250 mg/day), pioglitazone 15 mg/day for 2 months reduced proteinuria by 32% (p=0.005), along with improvements in HbA1c and triglycerides. (10)

Comparing Pioglitazone with SGLT2i and GLP-1 RAs: Pioglitazone is one of the few antidiabetic agents with consistent RCT evidence showing MASH resolution and potential fibrosis improvement, unlike SGLT2 inhibitors, which lack histological data despite benefits in steatosis and liver enzymes. (11) While GLP-1 receptor agonists have shown promise in improving liver outcomes primarily via weight reduction, pioglitazone remains a cost-effective option with direct histological efficacy, particularly relevant in resource-limited settings. (12)

Recommendations from RSSDI and ADA: The RSSDI 2022 guidelines recommend pioglitazone as an insulin sensitizer in patients with type 2 diabetes who exhibit features of insulin resistance, including central obesity, NAFLD, or PCOS, and note its particular relevance in lean individuals with high insulin resistance or the thin-fat phenotype. (13) Similarly, the ADA 2025 recommends considering thiazolidinediones (such as pioglitazone) for adults with cost-related barriers or suboptimal glycemic control, particularly when high insulin doses are required, while weighing potential risks. (14)

Pioglitazone has a well-characterized safety profile. Common adverse effects include fluid retention, dose-dependent and more likely with insulin, which may trigger heart failure in those with cardiac dysfunction. Weight gain is common, but it is often associated with an increase in subcutaneous fat and a shift of fluid away from visceral fat. Fracture risk is modestly increased in women, and recent analyses do not support a causal link with bladder cancer.(12)

Take-Home Messages

• The thin-fat phenotype is common in Indians with normal BMI and carries a significantly elevated risk for type 2 diabetes, necessitating risk assessment beyond BMI.
• Ectopic fat accumulation and impaired adipose function are central to the pathogenesis of insulin resistance and NAFLD/MASLD in thin-fat T2DM.
• Pioglitazone targets key pathophysiologic mechanisms by enhancing insulin sensitivity, reducing ectopic fat, and supporting β-cell function.
• Evidence from diverse T2D populations supports the durable glycemic, metabolic, and renal benefits of pioglitazone in appropriately selected patients.

Reference

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2. Misra A, Soares MJ, Mohan V, Anoop S, Abhishek V, Vaidya R, Pradeepa R. Body fat, metabolic syndrome and hyperglycemia in South Asians. J Diabetes Complications. 2018 Nov;32(11):1068-1075. doi: 10.1016/j.jdiacomp.2018.08.001. Epub 2018 Aug 4. PMID: 30115487.

3. Godoy-Matos, A.F., Silva Júnior, W.S. & Valerio, C.M. NAFLD as a continuum: from obesity to metabolic syndrome and diabetes. Diabetol Metab Syndr 12, 60 (2020). https://doi.org/10.1186/s13098-020-00570-y

4. Gorgojo-Martínez, Juan J. “Adipocentric Strategy for the Treatment of Type 2 Diabetes Mellitus.” Journal of clinical medicine vol. 14,3 678. 21 Jan. 2025, doi:10.3390/jcm14030678

5. Yki-Järvinen, Hannele. “Thiazolidinediones.” The New England journal of medicine vol. 351,11 (2004): 1106-18. doi:10.1056/NEJMra041001

6. Karagiannis, Efstrathios et al. “The IRIS V study: pioglitazone improves systemic chronic inflammation in patients with type 2 diabetes under daily routine conditions.” Diabetes technology & therapeutics vol. 10,3 (2008): 206-12. doi:10.1089/dia.2008.0244

7. Qian, Xin et al. “Pioglitazone Improved Insulin Sensitivity and First Phase Insulin Secretion Among Obese and Lean People with Diabetes: A Multicenter Clamp Study.” Diabetes therapy : research, treatment and education of diabetes and related disorders vol. 9,2 (2018): 815-826. doi:10.1007/s13300-018-0401-9

8. Rasouli, Neda et al. “Pioglitazone improves insulin sensitivity through reduction in muscle lipid and redistribution of lipid into adipose tissue.” American journal of physiology. Endocrinology and metabolism vol. 288,5 (2005): E930-4. doi:10.1152/ajpendo.00522.2004

9. Balaji, Vijayam. “Efficacy and safety of pioglitazone in type 2 diabetes in the Indian patients: Results of an observational study.” Indian journal of endocrinology and metabolism vol. 17,4 (2013): 709-15. doi:10.4103/2230-8210.113766

10. Pourshabanan, Pejman et al. “Effect of pioglitazone on decreasing of proteinuria in type 2 diabetic patients with nephropathy.” Diabetes & metabolic syndrome vol. 13,1 (2019): 132-136. doi:10.1016/j.dsx.2018.04.013

11. Isaacs SD, Farrelly FV, Brennan PNRole of anti-diabetic medications in the management of MASLDFrontline Gastroenterology 2025;16:239-249.

12. DeFronzo, Ralph A et al. “Pioglitazone: The forgotten, cost-effective cardioprotective drug for type 2 diabetes.” Diabetes & vascular disease research vol. 16,2 (2019): 133-143. doi:10.1177/1479164118825376

13. RSSDI (Research Society for the Study of Diabetes in India). RSSDI Clinical Practice Recommendations 2022: Summary Document for Training. RSSDI, 2022.

14. American Diabetes Association Professional Practice Committee; 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Care in Diabetes—2025. Diabetes Care 1 January 2025; 48 (Supplement_1): S181–S206. https://doi.org/10.2337/dc25-S009

Abbreviations: T2DM – Type 2 Diabetes Mellitus, BMI – Body Mass Index, PPAR-γ – Peroxisome Proliferator-Activated Receptor Gamma, NAFLD – Non-Alcoholic Fatty Liver Disease, MASLD – Metabolic Dysfunction-Associated Steatotic Liver Disease, MUNO – Metabolically Unhealthy Non-Obese, HOMA-IR – Homeostatic Model Assessment of Insulin Resistance, hsCRP – High-Sensitivity C-Reactive Protein, LDL – Low-Density Lipoprotein, HDL – High-Density Lipoprotein, FBG – Fasting Blood Glucose, PPG – Postprandial Glucose, OADs – Oral Antidiabetic Drugs, IMCL – Intramyocellular Lipid, DPP4 – Dipeptidyl Peptidase 4, ADA- American Diabetes Association, RSSDI- Research Society for the Study of Diabetes in India