Aims/hypothesis. Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Methods. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.Results. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. IntroductionThe respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3]. The first occurs as an immediate response to a rise in blood glucose concentrations. Low first-phase insulin release is an early abnormality in deteriorating glucose homeostasis and predicts the subsequent development of Type 2 diabetes [4,5,6,7]. Late-phase insulin release is more prolonged, but of lesser amplitude. It includes the progressively increasing second phase of insulin secretion seen in response to sustained hyperglycaemia [3], and also the compensatory insulin secretion that is the feedback response to a continued increase in circulating glucose. This late-phase insulin secretion may seem to be preserved even when glucose metabolism is defective,In the course of this work, our colleague and co-author James Jeffs died unexpectedly after a short illness. His contribution will be greatly missed.
Aims/hypothesis: We assessed the impact of ethnic origin on metabolism in women following gestational diabetes mellitus (GDM). Materials and methods: Glucose regulation and other features of the metabolic syndrome were studied at 20.0 (18.2-22.1) months (geometric mean [95% CI]) post-partum in women with previous GDM (185 European, 103 Asian-Indian, 80 African-Caribbean). They were compared with the same features in 482 normal control subjects who had normal glucose regulation during and following pregnancy. Results: Impaired glucose regulation or diabetes by WHO criteria were present in 37% of women with previous GDM (diabetes in 17%), especially in those of African-Caribbean and Asian-Indian origin (50 and 44%, respectively vs 28% in European, p=0.009). BMI, waist circumference, diastolic blood pressure, fasting triglyceride and insulin levels, and insulin resistance by homeostatic model assessment (HOMA), were increased following GDM (p<0.001 for all, vs control subjects).Where glucose regulation was normal following GDM, basal insulin secretion (by HOMA) was high (p<0.001 vs control subjects). Irrespective of glucose regulation in pregnancy, Asian-Indian origin was associated with high triglyceride and low HDL cholesterol levels, and AfricanCaribbean with increased waist circumference, blood pressure, and insulin levels, together with insulin resistance and low triglyceride concentrations. Nonetheless, the GDMassociated features were consistent within each ethnic group. The metabolic syndrome by International Diabetes Federation criteria was present in 37% of women with previous GDM, especially in non-Europeans (Asian-Indian 49%, African-Caribbean 43%, European 28%, p=0.001), and in 10% of controls. Conclusions/interpretation: Following GDM, abnormal glucose regulation and the metabolic syndrome are common, especially in non-European women, indicating a need for diabetes and cardiovascular disease prevention strategies.
MUC1 mucin is transcriptionally regulated by estrogen, progesterone, and glucocorticoids. Our objective was to determine whether androgen receptor (AR) activation regulates expression of MUC1. The following breast and prostatic cell lines were phenotyped and grouped according to AR and MUC1 protein expression: 1) AR+MUC1 + [DAR17+19 (AR transfectants of DU-145), ZR-75-1, MDA-MB-453, and T47D]; 2) AR-MUC1 + [DZeo1 (AR-vector control), DU-145, BT20, MDA-MB-231, and MCF7]; 3) AR+MUC1 - (LNCaP and LNCaP-r). Cell proliferation was determined using the MTT assay in the presence of synthetic androgen R1881, 0.1 microM to 1 microM. Cell surface MUC1 expression was determined by flow cytometry in the presence or absence of oestradiol, medroxy progesterone acetate or R1881, with and without 4 hydroxy-flutamide (4-OH), a nonsteroidal AR antagonist. The functional significance of MUC1 expression was investigated with a cell-cell aggregation assay. Only AR+MUC1 + cell lines showed a significant increase in MUC1 expression with AR activation (P (range) =.01 to .0001), reversed in the presence of 4-OHF. Cell proliferation was unaffected. Increased expression of MUC1 was associated with a significant (P (range) = .002 to .001) reduction in cell-cell adhesion. To our knowledge, this is the first description of androgen-dependent regulation of MUC1 mucin. This is also functionally associated with decreased cell-cell adhesion, a recognised feature of progressive malignancy. These findings have important implications for physiological and pathological processes.
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