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Aims-A common variant, rs9939609, in the FTO (fat mass and obesity) gene is associated with adiposity in Europeans, explaining its relationship with diabetes. However, data are inconsistent in South Asians. Our aim was to investigate the association of the FTO rs9939609 variant with obesity, obesity-related traits and Type 2 diabetes in South Asian individuals, and to use metaanalyses to attempt to clarify to what extent BMI influences the association of FTO variants with diabetes in South Asians.Methods-We analysed rs9939609 in two studies of Pakistani individuals: 1666 adults aged ≥ 40 years from the Karachi population-based Control of Blood Pressure and Risk Attenuation (COBRA) study and 2745 individuals of Punjabi ancestry who were part of a Type 2 diabetes case-control study (UK Asian Diabetes Study/Diabetes Genetics in Pakistan; UKADS/DGP). The main outcomes were BMI, waist circumference and diabetes. Regression analyses were performed to determine associations between FTO alleles and outcomes. Summary estimates were combined Results-In the 4411 Pakistani individuals from this study, the age-, sex-and diabetes-adjusted association of FTO variant rs9939609 with BMI was 0.45 (95% CI 0.24-0.67) kg/m 2 per A-allele (P = 3.0× 10 −5 ) and with waist circumference was 0.88 (95% CI 0.36-1.41) cm per A-allele (P = 0.001). The A-allele (30% frequency) was also significantly associated with Type 2 diabetes [per A-allele odds ratio (95% CI) 1.18 (1.07-1.30); P = 0.0009]. A meta-analysis of four South Asian studies with 8091 subjects showed that the FTO A-allele predisposes to Type 2 diabetes [1.22 (95% CI 1.14-1.31); P = 1.07× 10 −8 ] even after adjusting for BMI [1.18 (95% CI 1.10-1.27); P = 1.02× 10 −5 ] or waist circumference [1.18 (95% CI 1.10-1.27); P = 3.97× 10 −5 ].Conclusions-The strong association between FTO genotype and BMI and waist circumference in South Asians is similar to that observed in Europeans. In contrast, the strong association of FTO genotype with diabetes is only partly accounted for by BMI.

The prevalence of diabetes mellitus and impaired glucose tolerance (IGT) and their relationship to age and obesity was estimated in the rural town of Shikarpur in Sindh Province, Pakistan by a population-based survey in 1994. Oral glucose tolerance tests were performed in a stratified random sample of 967 adults (387 men, 580 women) aged 25 years and above. The diagnoses of diabetes and IGT were made on the basis of WHO criteria. The response rate was 71% for men and 80% for women. The prevalence of diabetes was 16.2% (9.0% known, 7.2% newly diagnosed) in men, and 11.7% (6.3% known, 5.3% newly diagnosed) in women. The prevalence rose with age to a peak of 30% and 21% in 65-74 year-old men and women respectively. IGT was detected in 8.2% of men and 14.3% of women. Thus, total glucose intolerance (diabetes and IGT combined) was present in 25% of subjects examined. These results indicate that glucose intolerance in South Asians can no longer be regarded as a problem confined to migrant communities. Of the 72 subjects previously known to have diabetes, none was using insulin treatment, but 57 (79%) took oral hypoglycaemic agents. Central obesity and positive family history were strongly associated with diabetes, as was prevalence of hypertension. The association with central obesity was greater for women than for men, and suggests important, modifiable risk factor(s) related to lifestyle.

Over the past two decades, there has been a striking increase in the number of people with metabolic syndrome. The prevalence of metabolic syndrome varies due to lack of an internationally agreed upon definition. Considering the increased cardiovascular risk among Asian people, a lower cutoff for waist circumference is defined. Obesity in terms of waist circumference is found to be 46-68% of the Pakistani population, with a strong association found between arm fat and insulin insensitivity. In studying dyslipidemia, hypertriglyceridemia is found in 27-54% of the population, whereas 68-81% have low levels of high-density lipoprotein (HDL). Fifty percent were found to be at high risk of metabolic syndrome and as being hypertensive. With the high prevalence of all of these metabolic risk factors, the prevalence of metabolic syndrome in Pakistan according to different definitions is reported to be from 18% to 46%, comparable to the data from other South Asian countries. Thus, metabolic syndrome should be considered as a prime target for preventive medicine. The primary management goals for metabolic syndrome are to reduce the risks of cardiovascular disease and diabetes. Lifestyle-related risk factors are associated with the metabolic syndrome and diabetes. Unless preventive programs are properly designed and implemented, we will continue to treat the majority of the cases after they have already developed the complications. A prospective primary prevention study is underway in Pakistan that will help to create a base for public awareness strategies and nationwide surveillance and prevention programs against noncommunicable diseases.