Obesity-Prediabetes Duo: Why Clinicians Must Intervene Early?
Prediabetes is alarmingly common, with the IDF 2025 Atlas estimating nearly 90 million Indians are affected. [1] Escalating obesity, urbanization, sedentary lifestyles, and high-calorie diets are intensifying metabolic dysfunction. An Indian study found nearly 80% of prediabetics are overweight or obese [2],while the recent ICMR study (n=1,13,043) revealed India's growing metabolic burden: 43.3% metabolically obese non-obese (MONO), 28.3% metabolically obese obese (MOO), 26.6% metabolically healthy non-obese (MHNO), and only 1.8% metabolically healthy obese (MHO) [3] with obesity increasing CV risk substantially and diabetes risk by 4-fold [4,5] ,highlighting the urgent need to prioritise prediabetes management in India’s increasingly obese population.
Insulin Resistance – At Crossroads of Obesity, Prediabetes, and Diabetes
Obesity and prediabetes share an insulin resistance pathway but differ by phenotype. Normoglycemic obesity involves primarily adipose-driven insulin resistance, while obesity with prediabetes exhibits genetically determined muscular insulin resistance that accelerates beta-cell stress, inflammation, and glucotoxicity. Rapid prediabetes-to-diabetes conversion in South Asians stems from their distinctive phenotype: abdominal obesity, low muscle mass, ectopic liver fat, elevated post-prandial glucose, and early β-cell failure, which intensifies insulin resistance and hastens β-cell exhaustion. These mechanisms explain the swift deterioration in obese Indian prediabetics and highlight the need for early, targeted intervention.[6,7]
Risk Factors Associated with Obesity and Insulin Resistance-Related Implications
Risk Factor | Associations & Clinical Implications |
| Family History [8] | Family history of obesity increases risk 2-fold (OR 2.09; 95% CI: 2.01–2.16), highlighting the genetic and familial burden of obesity-related insulin resistance. |
| NAFLD/NASH [9] | Patients with obesity have a 2–3-fold higher risk of developing NASH, with 30% affected, reflecting the strong adipose-hepatic axis; adiposopathy (dysfunctional adipose tissue) drives NAFLD, which in turn contributes to insulin resistance and dyslipidaemia. |
| PCOS [10] | In PCOS, 38–88% of women are overweight/obese and 50–90% are insulin resistant due to PI3-kinase post-receptor defect, while an intact MAP-kinase pathway promotes insulin-driven steroidogenesis, hyperandrogenaemia, and reproductive dysfunction via compensatory hyperinsulinaemia. |
Obstructive Sleep Apnoea (OSA) [11] | Every 10% weight gain increases OSA risk 6-fold. OSA independently causes insulin resistance and abnormal glucose metabolism, serving as an independent prediabetes risk factor, with AHI positively linked to glycaemic variability. |
Metformin: Evidence in Obesity-Linked Prediabetes & Related Clinical Issues
Pharmacotherapy plays an important role in slowing diabetes progression in high-risk obese prediabetic individuals. [12] Metformin reduces hepatic gluconeogenesis, decreases intestinal glucose absorption, and enhances glucose uptake in the liver and skeletal muscle through AMPK activation, the central regulator of energy homeostasis. It also modulates obesity-induced meta-inflammation by affecting immune cells in adipose tissue and the liver. [13]
An observational study of obese prediabetic patients (n=304; mean BMI 39.40 kg/m², HbA1c 5.89%) demonstrated that metformin reduced HbA1c by 0.22% (5.95% to 5.73%) and BMI by 1.46 kg/m² (39.77 to 38.31 kg/m²), indicating favorable outcomes. [14] In overweight/obese adults with symptomatic knee osteoarthritis, RCT data showed metformin produced greater pain reduction at 6 months (−31.3 mm on the 100-mm Visual Analog Scale (VAS) vs −18.9 mm with placebo; difference −11.4 mm; P=.01). [15]
Metformin in Maintenance Therapy Post GLP-RA: EASD 2025 Conference Spotlight A real-world study presented at the 61st EASD 2025 Annual Meeting showed that patients who achieved weight loss with GLP-1 RAs were able to maintain their results after discontinuation by transitioning to generic anti-obesity medications, with metformin used in 80% of cases. This study confirms that patients transitioning from GLP-1 RA therapy to metformin-based generic therapy maintained weight loss at 20 months. The benefit of metformin post GLP-RA seems a valid concept. However, more large, randomized controlled studies are needed in this direction. [16] |
Global and Indian recommendations
Globally, metformin has been approved for prediabetes in at least 66 countries, reinforcing its established role in diabetes prevention. [17]
The Indian Expert Group Consensus Statement supports the use of metformin in individuals with prediabetes, particularly those with BMI >35 kg/m², age <60 years, and women with prior gestational diabetes, and when lifestyle intervention is insufficient. [18] Similarly, the RSSDI–ESI advises initiating metformin in younger individuals with risk factors—either one or more risks regardless of BMI, or in those who are overweight or obese with IFG plus IGT, or IFG plus HbA1c >5.7%. [19]
Key Messages:
- Prediabetes and obesity share an insulin-resistance pathway, with South Asians showing rapid conversion to diabetes due to abdominal obesity, low muscle mass, ectopic liver fat, and early β-cell failure.
- Obesity-linked risks such as family history, NAFLD/NASH, PCOS, and OSA intensify insulin resistance and metabolic deterioration, accelerating the risk of progression to T2D.
- Metformin delivers broad benefits in obesity-linked prediabetes, improving glycaemia, reducing BMI, a consideration supported by Indian guidelines in high-risk patients. The emerging role of metformin in sustaining GLP-1 RA–induced weight loss as a maintenance therapy appears promising.
Abbreviations: IDF = International Diabetes Federation; ICMR = Indian Council of Medical Research; MONO = Metabolically Obese Normal Weight; MOO = Metabolically Obese Overweight; MHNO = Metabolically Healthy Normal Weight; CV = Cardiovascular; FPG = Fasting Plasma Glucose; IFG = Impaired Fasting Glucose; IGT = Impaired Glucose Tolerance; HbA1c = Glycated Hemoglobin A1c; NAFLD = Non-Alcoholic Fatty Liver Disease; NASH = Non-Alcoholic Steatohepatitis; PCOS = Polycystic Ovary Syndrome; OSA = Obstructive Sleep Apnoea; AHI = Apnea–Hypopnea Index; FHS = Family History Score; PRS = Polygenic Risk Score; AMPK = AMP-Activated Protein Kinase; ATP = Adenosine Triphosphate; RCT = Randomized Controlled Trial; VAS = Visual Analog Scale; SD = Standard Deviation; GLP-1 RA = Glucagon-Like Peptide-1 Receptor Agonist; AOM = Anti-Obesity Medication; RSSDI–ESI = Research Society for the Study of Diabetes in India–Endocrine Society of India; ADA = American Diabetes Association; EASD = European Association for the Study of Diabetes; T2D = Type 2 Diabetes.
