Leptin and incident type 2 diabetes: risk or protection?

Abstract

Aims/hypothesis The aim of this study was to investigate the association of leptin levels with incident diabetes in middle-aged adults, taking into account factors purportedly related to leptin resistance. Subjects and methods We conducted a case-cohort study (570 incident diabetes cases and 530 non-cases) representing the 9-year experience of 10,275 participants of the Atherosclerosis Risk in Communities Study. Plasma leptin was measured by direct sandwich ELISA. Results In proportional hazards models adjusting for age, study centre, ethnicity and sex, high leptin levels (defined by sex-specific cut-off points) predicted an increased risk of diabetes, with a hazard ratio (HR) comparing the upper with the lower quartile of 3.9 (95% CI 2.6-5.6). However, after further adjusting additionally for obesity indices, fasting insulin, inflammation score, hypertension, triglycerides and adiponectin, high leptin predicted a lower diabetes risk (HR=0.40, 95% CI 0.23-0.67). Additional inclusion of fasting glucose attenuated this protective association (HR=0.59, 95% CI 0.32-1.08, p<0.03 for linear trend across quartiles). In similar models, protective associations were generally seen across subgroups of sex, race, nutritional status and smoking, though not among those with lower inflammation scores or impaired fasting glucose (interaction p=0.03 for both). Conclusions/interpretation High leptin levels, probably reflecting leptin resistance, predict an increased risk of diabetes. Adjusting for factors purportedly related to leptin resistance unveils a protective association, independent of adiponectin and consistent with some of leptin's described protective effects against diabetes.

The relationship between adipokines and the onset of type 2 diabetes in middle-aged men: The PRIME study

“…Instead, they reported that obesity and insulin resistance explained most of the association between leptin and subsequent diabetes risk. Other studies also suggest that abdominal adiposity may modulate the association between leptin and type 2 diabetes [9,12,14,15,25].…”

“…The relationship between adipokines and the onset of type 2 diabetes in middle-aged men: The PRIME study. Diabetes Research and Clinical Practice, 120,[24][25][26][27][28][29][30] Publisher rights © 2016 Elsevier Ltd. This manuscript version is made available under the CC-BY-NC-ND 4.0 license http://creativecommons.org/licenses/bync-nd/4.0/which permits distribution and reproduction for non-commercial purposes, provided the author and source are cited.…”

Response to comment on: Schmidt MI, Duncan BB, Vigo A et al. (2006) Leptin and incident type 2 diabetes: risk or protection? Diabetologia 49:2086–2096

“…In contrast, the ARIC study was based on a total of 581 cases (229 men and 352 women) [2]. Small sample size also increases the risk of multicollinearity.…”

“…To the Editor: We thank Snijder et al for sharing their data from the Hoorn Study [1] and for their interpretation of the protective associations we reported between leptin and incident diabetes in middle-aged adults from the Atherosclerosis Risk in Communities (ARIC) study [2].…”

“…Another possibility is that the two study samples differ in important ways. For example, the Hoorn Study had more current smokers and considerably fewer black participants than the ARIC study [1,2], and protective associations tended to be stronger in black subjects and in non-smokers in ARIC (see Figs 2 and 3 of the original publication) [2]. In addition, the Hoorn Study did not include all the covariates that were used in ARIC, omitting markers of inflammation and quadratic terms.…”