This study shows that obese Hispanic young adults have higher pancreatic fat accumulation than obese African Americans and that this ethnic difference becomes greater with increasing age. Pancreatic fat was positively associated with VAT volume and liver fat deposition, as well as increased concentrations of plasma FFA.
Previous studies have consistently reported that Hispanics accumulate more VAT and HFF than African Americans, whereas the latter have higher levels of SAT (11
). VAT is known to be more deleterious than SAT, because of its high rate of lipolysis and delivery of portal inflammatory cytokines (18
). This may contribute to higher liver fat deposition, a strong predictor of insulin resistance (18
). Our results support these ethnic differences in fat partitioning and further underline the fact that they are detected early in life. Furthermore, we show that pancreatic fat deposition is higher in Hispanics than African Americans. Pancreatic fat has recently been identified as a novel obesity-related fat depot (6
). It is higher in males than females and linearly increases with age and BMI (6
), consistent with our results. In this study, we further show that ethnic differences in PFF are exacerbated with increased age even in young populations, with a twofold higher PFF in Hispanics versus African Americans from the 19–25 year group. This suggests that in Hispanic populations, PFF may cluster with high amounts of VAT and liver fat, thus possibly contributing to their increased risk for type 2 diabetes and related metabolic disorders as they grow up.
We therefore addressed the relationships between these various fat depots. HFF increases with obesity, and more specifically VAT (19
). VAT has a high rate of lipolysis, which allows direct delivery of fatty acids into the portal vein, leading to hepatic lipid accumulation (18
). Similar relationships exist in regard to pancreatic fat: recent imaging studies showed that both pancreatic volume and fat content increased with BMI (6
), waist:hip ratio (6
), and VAT deposition (9
). We further extend this finding and show that PFF positively correlates with both VAT and HFF, independently of BMI, total fat, and SAT content in an at-risk minority population. A previous study also reported simultaneous occurrence of fatty liver and fatty pancreas in overweight individuals (23
), suggesting a common etiology to fat accumulation in these two organs. These results contrast with those from the Tushuizen study (8
), who did not report any relationship between PFF and HFF. These contradictory results may possibly arise from methodology differences since Tushuizen et al. used magnetic resonance spectropscopy or from differences in population age and ethnicity. Because Hispanics are highly prone to visceral and liver fat accumulation, they may be genetically predisposed to altered fat partitioning in ectopic tissues as a whole.
We subsequently addressed whether PFF was related to abnormal endocrine function. PFF has been linked to low insulin sensitivity, measured by 2-h postchallenge glucose concentration (6
) or homeostasis model assessment of insulin resistance (23
), as well as insulin secretion (8
). However, this last observation was found in healthy individuals but not in type 2 diabetic patients. In contrast, Heni et al. reported an inverse relationship between PFF and insulin secretion in individuals with impaired fasting glucose or impaired glucose tolerance but not normoglycemic participants (9
). The authors postulated that PFF may have adverse metabolic effects when insulin resistance is present. Our results support this hypothesis: despite being overweight, all study participants were normoglycemic. Moreover, this study involved adolescents and young adults, who may be at more heterogeneous stages in the progression of β-cell failure, compared with older adults. Taken together, these results suggest that pancreatic fat is negatively correlated with insulin secretion in individuals with impaired glucose tolerance but not in normoglycemic individuals or type 2 diabetic patients. Thus pancreatic fat accumulation may play a pivotal role during the intermediary step of the disease and negatively affect insulin secretion only by persistent insulin resistance, when β-cells cannot anymore compensate for the increased insulin demand.
To further identify metabolic perturbations linked to PFF, we assessed the relationship between PFF and FFA. FFA are elevated in obese patients and are strong predictors of hepatic fat deposition (4
). We show that in a multiple stepwise regression analysis, FFA and VAT were the strongest predictors of PFF. Several animal studies have assessed the effect of lipotoxicity on β-cell function. In Zucker diabetic fatty rats, plasma FFA were elevated 3 to 4 weeks before they became diabetic (22
). The elevated FFA concentrations were followed within 2 weeks by islet triglyceride accumulation and impaired insulin secretion. Interestingly, these alterations were reversed by reducing plasma FFA, suggesting a causal role of high plasma FFA on altered β-cell function. The authors proposed that high circulating FFA may lead to β-cell lipid accumulation, which may subsequently impair β-cell function, possibly by stimulation of ceramide production, similarly to what has been described in the skeletal muscle (2
) and liver (3
Finally, markers of chronic inflammation have been associated with type 2 diabetes, β-cell dysfunction (24
), and hepatic fat accumulation. We found that PFF was associated with proinflammatory cytokines MCP-1, IL-8, TNF-α, HGF, and thrombogenic factor PAI-1. These markers are usually elevated in obese patients and are linked to insulin resistance and liver fat. However, when adjusted for VAT, these relationships were no longer significant. This suggests that in our population, inflammatory markers merely reflect VAT-related inflammation rather than cytokine production by the pancreas. We therefore cannot state that there is a direct relationship between PFF and inflammation either as a cause or consequence.
A limitation of our study includes the assessment of insulin secretion by IVGTT. Although IVGTT is the gold-standard method to evaluate glucose-mediated insulin secretion, it does not allow measurement of incretin-stimulated insulin secretion that physiologically occurs after meal consumption, which potentiates insulin secretion (25
). It remains therefore possible that pancreatic fat may affect specifically meal-induced insulin secretion.
Collectively, these results raise concern about the effects of pancreatic fat accumulation in humans. Hispanics accumulate more pancreatic fat than African Americans. Pancreatic fat is closely related to other deleterious fat depots, such as VAT and liver fat, which are elevated in Hispanics, a population at high risk for metabolic disease. Pancreatic fat is also positively related to circulating FFA, which may trigger lipotoxicity and affect pancreatic function in the long run.