Background: Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance. Methods: We included study participants from the Jackson Heart Study, a prospective cohort of adult African Americans in Jackson, Mississippi, that were free of T2D at the baseline Exam 1. Incident T2D was defined as new cases at Exam 2 or Exam 3. We created separate Cox regression models (hazard ratios per log-transformed ng/mL of leptin and adiponectin) with and without insulin resistance, HOMA-IR. Mediation by insulin resistance was analyzed. Several interactions were assessed, including by sex, HbA1c, and obesity. Results: Among our 3363 participants (mean age 53 years, 63% women), 584 developed incident T2D. Leptin was directly associated with incident T2D when modeled without HOMA-IR (HR = 1.29, 95% CI = 1.05-1.58). This direct association between leptin and T2D was significant among men (HR = 1.33, 95% CI = 1.05-1.69), but nonsignificant among women (HR = 1.24, 95% CI = 0.94-1.64); statistical interaction with sex was nonsignificant (p = 0.65). The associations in all participants and in men were nullified by HOMA-IR (HR = 0.99, 95% CI = 0.80-1.22; HR = 1.00, 95% CI = 0.78-1.28, respectively), indicating mediation through insulin resistance (proportion mediated: 1.04), and were not observed in abdominally obese participants. Adiponectin was inversely associated with T2D even after adjustment for HOMA-IR in women (HR = 0.68, 95% CI = 0.55-0.84), but not in men (HR = 0.80, 95% CI = 0.62-1.04). The inverse association was present only among abdominally obese participants, and persisted after adjustment for HOMA-IR. (Continued on next page)Conclusions: Among African Americans in the Jackson Heart Study the association of leptin with incident type 2 diabetes was mediated by insulin resistance. This association was present only among abdominally non-obese participants. Differences by sex appeared: men showed a significant association mediated by insulin resistance. Among abdominally obese participants, adiponectin was inversely associated with incident T2D even after adjustment for HOMA-IR. Our results should inform future clinical trials that aim to reduce the burden of type 2 diabetes through the modification of serum levels of leptin and adiponectin.

Background: Growing evidence suggests that leptin is critical for glycemic control. Impaired leptin signaling may also contribute to low adiponectin expression in obese individuals. We assessed the association of leptin and adiponectin with incident type 2 diabetes (T2D), their interactions with sex and obesity status, and mediation by insulin resistance.Methods: Study participants from the Jackson Heart Study, a prospective cohort of adult African Americans in Jackson, Mississippi, included those free of T2D at the baseline Exam 1. Incident T2D was defined as new cases at Exam 2 or Exam 3. We created separate Cox regression models (hazard ratios per log-transformed ng/mL of leptin and adiponectin) with and without insulin resistance, HOMA-IR. Mediation by insulin resistance was analyzed. Several interactions were assessed, including by sex, HbA1c, and obesity.Results: Among 3,363 participants (mean age 53 years, 63% women), 584 developed incident T2D. Leptin was associated with incident T2D when modeled without HOMA-IR (HR=1.29, 95% CI=1.05-1.58). Among men, this positive association between leptin and T2D was significant (HR=1.33, 95% CI=1.05-1.69), but it was nonsignificant among women (HR=1.24, 95% CI=0.94-1.64); statistical interaction with sex was nonsignificant (p=0.65). The associations in all participants and in men were nullified by HOMA-IR (HR=0.99, 95% CI=0.80-1.22; HR=1.00, 95% CI=0.78-1.28, respectively), indicating mediation through insulin resistance (proportion mediated: 1.04), and were not observed in abdominally obese participants. Adiponectin was inversely associated with T2D even after adjustment for HOMA-IR in women (HR=0.68, 95% CI=0.55-0.84), but not in men (HR=0.80, 95% CI=0.62-1.04). The inverse association was present only among abdominally obese participants, and persisted after adjustment for HOMA-IR.Conclusions: Among African Americans in the Jackson Heart Study the association of leptin with incident T2D was explained by HOMA-IR. The association of leptin and incident T2D was mediated by insulin resistance and observed only among abdominally non-obese. Differences by sex appeared: men showed a significant association mediated by insulin resistance. Among abdominally obese participants, adiponectin was inversely associated with incident T2D even after adjustment for HOMA-IR.

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Introduction: Directly proportional to body fat leptin influences the regulation of blood glucose through several mechanisms some of them influenced by adiponectin. In population studies high leptin levels have been associated with the development of type 2 diabetes mellitus (T2D), with differences by sex. Because African Americans have high prevalence of obesity and T2D, we assessed the association of leptin with T2D and its interaction with adiponectin in a large ongoing cohort study. The hypothesis was a direct association between leptin and T2D, with differences by sex and modulated by adiponectin. Methods: We included participants who were free of T2D (ADA 2004) at the baseline examination (Exam 1) from the Jackson Heart Study (JHS), a single-site, prospective cohort of risk factors of heart disease in African Americans in Jackson, Mississippi. Incident T2D was defined as new T2D cases among Exam 2 or Exam 3 participants. Separate logistic regression models (odds ratios per log-transformed unit of biomarker) included a minimally adjusted model for age, sex and BMI; a model with addition of systolic blood pressure, antihypertension medication, triglycerides, HDL-cholesterol and antihyperlipidemic medication, smoking, alcohol intake, physical activity and education level; and a full model with addition of insulin resistance, HOMA-IR, on top of these variables. Several interactions were assessed such as by sex and glycated hemoglobin, HgA1c. Results: Among our 3083 participants (mean age 53 years, 63% women) there were 584 incident T2D cases. Significant correlations were present among women for leptin with BMI (0.64) and HOMA-IR (0.30), and for adiponectin with HOMA-IR (-0.32) and HDL-cholesterol (0.39). Among men, significant correlations were found for leptin with BMI (0.76) and HOMA-IR (0.53); and for adiponectin with HOMA-IR (-0.28) and HDL-cholesterol (0.38). Leptin was directly associated with incident T2D in the minimally adjusted model (OR= 1.46; 95% C.I. 1.21, 1.77). The association remained in the additional model (OR=1.43, 95% C.I. 1.15-1.78). However the fully adjusted model showed no association between leptin and T2D (OR=0.97, 95% C.I. 0.76-1.24), indicative of a mediation through insulin resistance. The direct association between leptin and T2D was present in men (OR=1.54, 95% C.I. 1.18-1.99; association nullified by insulin resistance), but not in women (OR=1.30, 95% C.I. 0.96-1.76); although no statistical interaction was present (p=0.96). Adiponectin did not interact with leptin in their association with incident T2D (p=0.08). Effect modification was not present for HgA1c and leptin or adiponectin. Conclusion: Among our African American participants there was an association between leptin and incident T2D, explained by insulin resistance but not modulated by adiponectin. Differences by sex were present, men showing an association nullified by HOMA-IR.