CLINICAL STUDY Lack of association of liver fat with model parameters of b-cell function in men with impaired glucose tolerance and type 2 diabetes Maarten E Tushuizen 1 , Mathijs C Bunck 1 , Petra J W Pouwels 2 , Saskia Bontemps 1 , Andrea Mari 3 and Michaela Diamant 1 1 Department of Endocrinology/Diabetes Centre, 2 Department of Physics and Medical Technology and 3 Institute of Biomedical Engineering, National Research Council, I-35127, Padova, Italy (Correspondence should be addressed to M Diamant who is now at Department of Endocrinology/Diabetes Centre, VU University Medical Centre, PO Box 7057, 1007 MB Amsterdam, The Netherlands; Email: m.diamant@vumc.nl) Abstract Objective: Hepatic steatosis and obesity are components of the metabolic syndrome and risk factors for developing type 2 diabetes (T2DM). We studied how liver fat and body fat distribution relate to various aspects of b-cell function. Methods: In 12 men with T2DM, 10 men with impaired glucose tolerance (IGT), and 14 age- and body mass index-matched controls, we measured body fat distribution and liver fat by magnetic resonance imaging and spectroscopy. An oral glucose tolerance test was performed to calculate insulin secretory rate (ISR) by C-peptide deconvolution, and b-cell function using a mathematical model that describes ISR as a function of absolute glucose levels (insulin secretory tone and glucose sensitivity), the glucose rate of change (rate sensitivity), and a potentiation factor. Results: Waist circumference and the various body fat compartments did not differ among groups. IGT had the highest total and late phase insulin secretion (P!0.001), whereas patients had the lowest insulinogenic index adjusted for insulin resistance (PZ0.006). In spite of the hypersecretion, IGT had b-cell glucose sensitivity, rate sensitivity, and potentiation similar to controls. Liver fat content was highest in diabetic patients (PZ0.004) and showed the strongest association with total and late phase of insulin secretion in the IGT group (rZ0.657, PZ0.039 and rZ0.732, PZ0.016 respectively). Model b-cell function variables showed no association with liver fat or body fat compartments. Conclusions: These data suggest that, in spite of the association of central adiposity and liver fat with T2DM risk, additional, hitherto unknown factors may contribute to b-cell dysfunction in susceptible humans. European Journal of Endocrinology 159 251–257 Introduction Central adiposity and liver steatosis are considered key features underlying the insulin resistance or metabolic syndrome and its associated cardiometabolic abnormal- ities (1). Furthermore, central obesity and liver steatosis are associated with a high risk for the development of type 2 diabetes (T2DM) (1, 2). However, evidence indicates that T2DM only develops in insulin-resistant subjects with the onset of b-cell dysfunction (3–5). In addition, recent data from the Relationship between Insulin Sensitivity and Cardiovascular risk (RISC) study demonstrate that each of obesity, insulin resistance, abdominal obesity, and insulin response can be found in isolation despite their strong tendency to cluster (6). The relationship of insulin sensitivity and b-cell function is therefore not unequivocal, confirming the notion that T2DM is a heterogeneous disease. Thus, the mechanisms that link central obesity and liver fat content to b-cell dysfunction are at present incompletely understood. Chronic exposure of pancreatic islets to high circulating levels of non-esterified fatty acids (NEFA), due to unsuppressed lipolysis in insulin-resistant adipose tissue, is considered as a potential primary cause of b-cell dysfunction (4). Recently, we reported that fat localized in the pancreas was inversely associated with dynamic measures of b-cell function in non-diabetic men (7). Previous reports described an association of intra-abdominal fat with b-cell function (8, 9); however, this was not confirmed by others (10–12). This seeming discrepancy may be due to the differences in populations studied and the methods by which b-cell function parameters were estimated. In particular, if the magnitude of the insulin secretory response to acute glucose stimulation is used to estimate b-cell function, an association with visceral adipose tissue (VAT) may rather reflect impaired insulin sensitivity (11). Similarly, although liver steatosis is associated with hepatic insulin resistance and inflammation, and was European Journal of Endocrinology (2008) 159 251–257 ISSN 0804-4643 q 2008 European Society of Endocrinology DOI: 10.1530/EJE-08-0424 Online version via www.eje-online.org