Progressive increases in adiposity and ectopic fat surrogates across glycaemic states highlight weight reduction as a key target for type 2 diabetes prevention, especially in younger people

Aims: To determine whether there are progressive changes in weight and ectopic fat surrogates in individuals comparing normoglycaemia, prediabetes and undiagnosed type 2 diabetes, and whether these increments differ by age. Materials and methods: Cross-sectional analysis of UK Biobank White participants without baseline cardiovascular disease or known diabetes (n = 287 987). Participants were classified based on glycated haemoglobin (HbA1c): normal (<5.7% [38.9 mmol/mol]), prediabetes1 (5.7-5.9% [39.0-41.9 mmol/mol]), prediabetes2 (6%-6.2% [42.0-44.9 mmol/mol]), prediabetes3 (6.3%-6.4% [45-47.9 mmol/mol]) and undiagnosed diabetes (6.5%-9% [48-75 mmol/mol]). Ordered logistic and linear regressions were used to test associations between HbA1c groups and differences in body mass index (BMI), waist-to-height ratio (WHtR), alanine aminotransferase (ALT; a surrogate of liver fat with known limitations) and triglycerides (circulating fat), adjusting for age, sex, deprivation status and statin use. The impact of age was also considered. Results: BMI exhibited a stepwise increase across groups with the prediabetes1, prediabetes2, prediabetes3 and undiagnosed diabetes groups having 1.47, 2.86, 3.82 and 4.09 kg/m2 higher BMI, respectively, compared to the normal group; WHtR followed a similar trend, rising by 0.024, 0.047, 0.062 and 0.065 across groups, as did ALT levels by 2.45, 4.05, 6.11 and 10.28 U/L and triglycerides by 0.25, 0.42, 0.50 and 0.67 mmol/L, respectively. Such increments were greater in younger versus older people. Conclusions: Deteriorating glycaemic status was marked by progressively higher levels of adiposity and circulating and hepatic ectopic fat markers. Findings were more pronounced in younger individuals, suggesting a greater role for ectopic fat in their diabetes and reinforcing the importance of weight intervention for preventing the progression from normoglycaemia to prediabetes to frank diabetes.