BARTHA, JOSE L., PATRICIA MARÍN-SEGURA, NIEVES L. GONZÁ LEZ-GONZÁ LEZ, FERNANDO WAGNER, MANUEL AGUILAR-DIOSDADO, AND BLAS HERVIAS-VIVANCOS. Ultrasound evaluation of visceral fat and metabolic risk factors during early pregnancy. Obesity. 2007;15:2233-2239. Objective: The objective was to study the relationships between ultrasound estimated visceral fat and metabolic risk factors during early pregnancy. Research Methods and Procedures: Thirty consecutive healthy pregnant women at 11 to 14 weeks of gestation were studied. Maximum subcutaneous fat thickness (SFT) and visceral fat thickness (VFT) were successfully measured by ultrasound. Fasting plasma glucose, insulin, triglycerides, total cholesterol, high-density lipoprotein cholesterol (HDL-C), and blood pressure were measured. Insulin resistance was calculated by using the homeostasis model assessment (HOMA). Results: VFT significantly correlated with diastolic blood pressure (r ϭ 0.37, p ϭ 0.04), glycemia (r ϭ 0.37, p ϭ 0.04), insulinemia (r ϭ 0.59, p ϭ 0.001) insulin sensitivity (HOMA; r ϭ 0.59, p ϭ 0.001), triglycerides (r ϭ 0.58, p ϭ 0.03), HDL-C (r ϭ Ϫ0.39, p ϭ 0.03), and total cholesterol/ HDL-C ratio (p ϭ 0.002), whereas SFT was significantly correlated with only diastolic blood pressure (p ϭ 0.03). VFT better significantly correlated with the metabolic risk factors than pre-gestational BMI [r ϭ 0.39, p ϭ 0.03 for insulinemia, r ϭ 0.42, p ϭ 0.02 for insulin sensitivity (HOMA), and r ϭ 0.49, p ϭ 0.01 for triglycerides and not significant for the rest]. Discussion: Visceral fat thickness can be easily measured by ultrasound at early pregnancy and correlates better than BMI with metabolic risk factors.

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Pancreatic b-cell homeostasis is a balance between programmed cell death (apoptosis) and regeneration. Although autoimmune diabetes mellitus type 1 (DM1) is the most-studied cause of b-cell mass loss by pro-inflammatory cytokineinduced apoptosis, influences of a pro-inflammatory environment on b-cell regenerative response have been poorly studied. In this study, we assess the anti-proliferative effect of pro-inflammatory cytokines and glucose concentration on rat pancreatic b cells and the potential protective role of glucagon-like peptide (GLP-1). Apoptotic and proliferating islet cells were stained using the DeadEnd Fluorimetric TUNEL System and 5-bromo-2 0 -deoxyuridine label respectively, in the presence-absence of varying concentrations of glucose, pro-inflammatory cytokines, and GLP-1. The potential signaling pathways involved were evaluated by western blot. Considerable anti-proliferative effects of pro-inflammatory cytokines interleukin (IL)-1b, interferon (IFN)-g, and tumour necrosis factor-a (TNF-a) were observed. The effects were synergistic and independent of glucose concentration, and appeared to be mediated by the inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activation, the signaling pathway involved in b-cell replication. GLP-1 completely reversed the cytokine-induced inhibition of ERK phosphorylation and increased b-cell proliferation threefold in cytokine-treated cultures. While pro-inflammatory cytokines reduced islet cell ERK1/2 activation and b-cell proliferation in pancreatic islet culture, GLP-1 was capable of reversing this effect. These data suggest a possible pharmacological application of GLP-1 in the treatment of early stage DM1, to prevent the loss of pancreatic b cells as well as to delay the development of overt diabetes.

HMG20A (also known as iBRAF) is a chromatin factor involved in neuronal differentiation and maturation. Recently small nucleotide polymorphisms (SNPs) in the HMG20A gene have been linked to type 2 diabetes mellitus (T2DM) yet neither expression nor function of this T2DM candidate gene in islets is known. Herein we demonstrate that HMG20A is expressed in both human and mouse islets and that levels are decreased in islets of T2DM donors as compared to islets from non-diabetic donors. In vitro studies in mouse and human islets demonstrated that glucose transiently increased HMG20A transcript levels, a result also observed in islets of gestating mice. In contrast, HMG20A expression was not altered in islets from diet-induced obese and pre-diabetic mice. The T2DM-associated rs7119 SNP, located in the 3′ UTR of the HMG20A transcript reduced the luciferase activity of a reporter construct in the human beta 1.1E7 cell line. Depletion of Hmg20a in the rat INS-1E cell line resulted in decreased expression levels of its neuronal target gene NeuroD whereas Rest and Pax4 were increased. Chromatin immunoprecipitation confirmed the interaction of HMG20A with the Pax4 gene promoter. Expression levels of Mafa, Glucokinase, and Insulin were also inhibited. Furthermore, glucose-induced insulin secretion was blunted in HMG20A-depleted islets. In summary, our data demonstrate that HMG20A expression in islet is essential for metabolism-insulin secretion coupling via the coordinated regulation of key islet-enriched genes such as NeuroD and Mafa and that depletion induces expression of genes such as Pax4 and Rest implicated in beta cell de-differentiation. More importantly we assign to the T2DM-linked rs7119 SNP the functional consequence of reducing HMG20A expression likely translating to impaired beta cell mature function.

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