Impact of overweight and obesity on fasting insulin secretion in men and women without diabetes: effect sizes and mechanisms.

Fat mass and waist circumference were the strongest adiposity predictors of fasting insulin secretion among all adiposity indices examined.

• Fat mass had a standardised β coefficient (Stβ) of 0.27 (p<0.0001)
• Waist circumference had a Stβ of 0.21 (p<0.0001)
• Other adiposity indices including BMI, body fat percentage, and WHR were also evaluated
• Analysis was performed in 1250 healthy participants (547 men, 703 women) from the EGIR-RISC cohort

Fasting insulin secretion increased 2.4-fold across BMI deciles in the study population.

• The impact of obesity on fasting insulin secretion (FIS) was continuous across the full spectrum of BMI values
• The dose-response relationship was also continuous across the full spectrum of WHR values
• Participants had BMI ranging from 18.5 to 40.0 kg/m²
• Age range was 30–60 years

The effect of obesity on fasting insulin secretion was greater in men than in women.

• Sex-related differences in the relationship between body mass and insulin secretion were observed
• The cohort included 547 men and 703 women
• Multivariable regression models and stratifications for BMI, body fat percentage, WHR, and fat mass were used to evaluate these effects

Adiposity-associated insulin hypersecretion appeared to be driven by the combination of hyperglycaemia and an increase in insulin secretion rate at 5 mmol/l glucose (ISR@5).

• ISR@5 is a specific beta cell function variable representing insulin secretion rate at 5 mmol/l glucose
• Beta cell function was modelled from an OGTT combined with clamp-derived insulin sensitivity
• This combination of hyperglycaemia and upregulated beta cell secretion sustained the observed fasting hyperinsulinaemia

Weight gain over 3.5-year follow-up was associated with increases in fasting insulin secretion and fasting glucose, while weight loss reduced both.

• Weight gainers had a mean ± SD Δweight of +5.1 ± 3.8 kg and showed increased FIS and fasting glucose (+0.20 ± 0.63 mmol/l, p<0.03)
• Weight losers had a mean Δweight of −4.7 ± 2.8 kg and showed reduced FIS and fasting glucose (+0.06 ± 0.55 mmol/l, p<0.006)
• ISR@5 declined in both weight losers (−0.17 ± 1.9 U/h, p<0.002) and those with stable weight (−0.16 ± 1.0 U/h, p<0.002) but not in weight gainers (−0.06 ± 1.1 U/h)
• Follow-up duration was 3.5 years

Peripheral insulin resistance, plasma NEFA, and leptin accounted for only part of obesity's effect on fasting insulin secretion.

• These typical hormonal and metabolic consequences of obesity did not fully explain the observed insulin hypersecretion
• Clamp-derived insulin sensitivity was used to assess peripheral insulin resistance
• The analysis was conducted in the full cohort of 1250 participants

Subset analysis of endogenous glucose production (EGP) data suggested progressive hepatic glucose overproduction across fat mass quintiles despite a preserved hepatic insulin response.

• EGP was measured in a subset of 368 participants using fasting and clamp methods
• The data indicated a rightward shift in the dose-response curve across fat mass quintiles
• This pattern was interpreted as progressive hepatic glucose overproduction despite preserved hepatic insulin response
• The authors suggest hepatic glucose overproduction contributes to fasting hyperinsulinaemia in obesity