Aim The incidence of type 2 diabetes has increased rapidly on a global scale. beta-cell function, with beta-coefficients of -0.24 (p = 0.038) and -0.25 (p = 0.028) for beta-cell function/HOMA-IR, and disposition index respectively. Comparable results were obtained using a third measure for beta-cell function. experiments revealed that this RA index was a potent regulator of acute insulin secretion where a high RA index (20ng ml-1 resistin, 5nmol l-1 g-adiponectin) significantly decreased insulin secretion whereas a low RA index (10ng ml-1 resistin, 10nmol l-1 g-adiponectin) significantly increased insulin secretion. The RA index was successfully validated in a second human cohort with beta-coefficients of -0.40 (p = 0.006) and -0.38 (p = 0.008) for beta-cell function/ HOMA-IR, and disposition index respectively. Conclusions Waist-to-hip ratio Rabbit Polyclonal to SHIP1 and RA index were identified as significant modulators of beta-cell function. The ability of the RA index to modulate insulin secretion was confirmed in mechanistic studies. Future work should identify strategies to alter the RA index. Introduction The prevalence of type 2 diabetes (T2D) has increased rapidly on an international scale, with pancreatic beta-cell dysfunction and failure at the core of its development [1]. Where hyperglycaemia exists, pancreatic beta-cells must function to a greater capacity in order to produce 1174043-16-3 IC50 more insulin to maintain glucose homeostasis [2]. Beta-cells have an ability to functionally adapt to allow for this compensatory response of further insulin production. Beta-cell dysfunction is commonly seen in T2D, where compensation of the beta-cells to produce insulin, often due to insulin resistance, leads to the gradual failure of beta-cells [3]. With this in mind, there is 1174043-16-3 IC50 a need to investigate factors related to pancreatic beta-cell function in humans. Glucose stimulates insulin secretion, triggering and amplifying signals in pancreatic beta-cells [4C6]. Challenge tests such as the oral glucose tolerance test (OGTT) have been used to investigate how effective individuals are at maintaining glucose homeostasis, thus assessing beta-cell function [7]. Progression into T2D status can be categorised by examining alterations in metabolic parameters and beta-cell function. Weir & Bonner-Weir proposed five stages of evolving beta-cell dysfunction during the progression into T2D [8]. Stage 1 is usually described as and extreme beta-cell failure with advancement to ketosis, with blood glucose levels above 22mmol/L. Movement between stages 1C4 can be in either direction, with diet and exercise interventions having strong potential to return individuals back to stage 2 [8]. It is important to identify parameters which influence the function of beta-cells, in order to optimise beta-cell functionality and potentially identify markers of disease progression or targets for intervention. Body mass index (BMI) and an increased energy intake are recognised as major risk factors for conditions associated with beta-cell dysfunction, and although the evidence of a direct effect of BMI on pancreatic beta-cell function is still largely undefined, the association between BMI and T2D has been well established [9C12]. Strong evidence also exists that 1174043-16-3 IC50 an 1174043-16-3 IC50 excess of visceral fat is usually closely related to insulin resistance and T2D risk [13]. The above studies did not have beta-cell dysfunction as their primary aim; therefore further research is needed to determine the exact phenotypic and biochemical parameters that influence specific steps of beta-cell function. A number of recent studies have highlighted a link between beta-cell function and high density lipoprotein (HDL) cholesterol [14C16]. Several studies have found links between certain anthropometric and biochemical parameters associated with T2D, with fewer studies examining the determinants of specific steps of beta-cell function in human cohorts. Beta-cell dysfunction is at the core of T2D, therefore it is paramount to understand factors which influence beta-cell function. In contrast to insulin resistance, beta-cell dysfunction continues to be difficult to measure and monitor, due to factors such as inaccessibility to the endocrine pancreas and incretin effects [17]. There is a clear need for the identification of markers that could be assessed in a fasting biological sample, to allow for the assessment of beta-cell function. Therefore, the aim of this study was to investigate and identify potential factors related to beta-cell function steps in a human cohort and to further investigate these where possible. Materials and Methods Study populace This research focuses on data obtained from the Metabolic Challenge (MECHE) study which is a part of a national research program by the Joint Irish Nutrigenomics Organisation, as previously 1174043-16-3 IC50 described [18]. The MECHE study recruited 214 healthy participants aged between 18C60 years. Individuals were informed about the purpose of the study and the experimental procedures, prior to giving written consent. Good health was defined as the.