Journal of Diabetes Research & Clinical Metabolism Research Article Open Access Non-linear Modelling of Fasting Plasma Glucose Concentration and Peak 2-hour Insulin Response to Glucose Challenge in Australian Aboriginal People Mark Daniel 1,2,3* , Geng Zang 3 , Kevin G. Rowley 2,4 , Robyn McDermott 1 , Shona J. Kelly 1 and Kerin O’Dea 1,2 Correspondence: mark.daniel@unisa.edu.au 1 Sansom Institute for Health Research, University of South Australia, Adelaide, Australia. 2 Department of Medicine, St. Vincent’s Hospital, The University of Melbourne, Australia. 3 Centre hospitalier de l’Université de Montréal, Université de Montréal, Canada. 4 Onemda VicHealth Koori Health Unit, Centre for Health and Society, Melbourne School of Population Health, The University of Melbourne, Australia. Abstract Background: The aim of this study was to investigate the relationship between 2-hour insulin concentration and fasting plasma glucose concentration (FPG) in a population-based sample of Indigenous Australians. Methods: Data collected from 2930 adults with unknown diabetic status were analyzed using three non-linear modeling methods: locally weighted regression (LOESS), generalized additive models (GAM), and fractional polynomial (fracpoly) regression procedures. Results: Log fasting insulin and log 2-hour insulin had nonlinear relationships with FPG. All models indicated a consistent ft for 2-hour insulin response across FPG values of 3.5–5.8 mmol/l. GAM and fracpoly regressions overlapped across FPG values of 3.5–13 mmol/l. The LOESS model had a slightly diferent pattern from FPG of 5.8-17 mmol/l. For all models, log 2-hour insulin concentration increased across FPG values from 3.5–7.0 mmol/l and decreased for FPG >7.0 mmol/l. Conclusions: The 7.0 mmol/l FPG diagnostic cut-of represents the start of a diminishing second-phase insulin response to glucose, indicating that pancreatic output begins to decline at this FPG level. These results provide strong physiological rationale, beyond rising rates of clinical complications, for the revised fasting glucose diagnostic criterion of 7.0 mmol/l. Further research is needed to evaluate whether similar relationships exist for other high- and low-risk populations. keywords: epidemiology; biostatistics; screening, Australian Aboriginal people, insulin © 2012 Daniel et al; licensee Herbert Publications Ltd. Tis is an open access article distributed under the terms of Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0),Tis permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited Introduction The current American Diabetes Association recommended diagnostic criterion for type 2 diabetes mellitus of fasting plasma glucose (FPG) ≥7.0 mmol/l is based on the point at which risk for macrovascular and microvascular complications substantially increases [ 1, 2]. The WHO continues to recommend assessment of plasma glucose level by oral glucose tolerance test (OGTT) with a 75g glucose load and the diagnostic criterion of a 2-hour post-challenge plasma glucose ≥11.1mmol/l [2]. The OGTT with glucose loading and two venipunctures is unpopular with patients and screening test participants, and is difficult to implement in field settings. This is so for Australian Aboriginal peoples who, with diabetes prevalence rates of 15-30% [3,4] and incidence rates of 20-23 cases per 1,000 person-years [5,6], are at elevated risk for having and developing the disease. Specific aetiologies of type 2 diabetes mellitus and the exact contributions that insulin secretion and insulin sensitivity play in hyperglycaemia associated with type 2 diabetes, are not fully understood [ 1 ]. The relationship is hyperbolic: at early stages of type 2 diabetes, insulin secretion increases as the body responds to elevated blood glucose levels and then, as blood glucose levels continue to be elevated or increase further, insulin secretion decreases (i.e., “Starling’s curve of the pancreas”) [ 7-9]. This evidence has shaped the theory that the primary abnormality in type 2 diabetes is insulin resistance and β-cell dysfunction is a secondary impairment [ 7]. Insulin secretory response to oral glucose challenge has been shown to correlate with 2-hour plasma glucose levels. Previous studies have indicated that insulin responses rise and peak between 2-hour plasma glucose levels of 7.8-11.1 mmol/l and become progressively lower for 2-hour plasma glucose levels greater than 11.1 mmol/l [ 10, 11 ]. Such data have provided physiological support for the WHO-recommended type 2 diabetes diagnostic criterion of plasma glucose ≥11.1