Compared with healthy controls, the presence of functional HMGA1 gene variants in individuals of white European ancestry was associated with type 2 DM.

Krüppel-like transcription factors (KLFs) have elicited significant attention because of their regulation of essential biochemical pathways and, more recently, because of their fundamental role in the mechanisms of human diseases. Neonatal diabetes mellitus is a monogenic disorder with primary alterations in insulin secretion. We here describe a key biochemical mechanism that underlies neonatal diabetes mellitus insulin biosynthesis impairment, namely a homozygous mutation within the insulin gene (INS) promoter, c.-331C>G, which affects a novel KLF-binding site. The combination of careful expression profiling, electromobility shift assays, reporter experiments, and chromatin immunoprecipitation demonstrates that, among 16 different KLF proteins tested, KLF11 is the most reliable activator of this site. Congruently, the c.-331C>G INS mutation fails to bind KLF11, thus inhibiting activation by this transcription factor. Klf11−/− mice recapitulate the disruption in insulin production and blood levels observed in patients. Thus, these data demonstrate an important role for KLF11 in the regulation of INS transcription via the novel c.-331 KLF site. Lastly, our screening data raised the possibility that other members of the KLF family may also regulate this promoter under distinct, yet unidentified, cellular contexts. Collectively, this study underscores a key role for KLF proteins in biochemical mechanisms of human diseases, in particular, early infancy onset diabetes mellitus.

Background: Liraglutide is the first glucagon-like peptide-1 receptor agonist (GLP-1 RA) based on the human GLP-1 sequence, with potential weight loss benefits, approved for the treatment of type 2 diabetes (T2D) mellitus. Herein, we aimed to assess the 5-year effectiveness of Liraglutide in the management of weight and glycometabolic control in a Southern Italian cohort of overweight/obese T2D patients, who were naïve to GLP-1 RAs. Patients and Methods: Forty overweight or obese patients treated with Liraglutide at doses up to 1.8 mg/day, in combination with one or more oral antidiabetic agents, were retrospectively assessed at baseline, during, and after 60 months of continuous therapy. Results: After 5 years of Liraglutide treatment, body weight decreased from 92.1 ± 20.5 kg to 87.3 ± 20.0 Kg (p < 0.001), with a mean reduction of 5.0 ± 7.0 Kg and a body mass index (BMI) decrement of −2.0 ± 3.1 Kg/m2. On Spearman’s univariate analysis, change in body weight was correlated with female gender and baseline BMI. Hemoglobin A1c (HbA1c) decreased from 7.9 ± 0.9% at baseline to 7.0 ± 0.7% at the end of the study period (p < 0.001), followed by a significant reduction in fasting plasma glucose. No significant differences emerged in other biochemical parameters, despite a trend toward improvement in lipid profile. Notwithstanding encouraging effects on several markers of cardiovascular disease (CVD), increments in the 5- and 10-year risk for the first atherosclerotic cardiovascular event were documented, as four incident cases of myocardial infarction. Conclusions: Prolonging treatment with Liraglutide can lead to durable benefits in relation to weight and glycemic control, with a greater impact on women. These results extend and corroborate previous observations, suggesting that gender per se may modulate the response to Liraglutide. Despite favorable effects on some established CVD risks factors, the long-term role of Liraglutide in primary prevention of CVD in patients with T2D remains controversial.

Insulin resistance (IR) is a condition which refers to individuals whose cells and tissues become insensitive to the peptide hormone, insulin. Over the recent years, a wealth of data has made it clear that a synergistic relationship exists between IR, type 2 diabetes mellitus, and cancer. Although the underlying mechanism(s) for this association remain unclear, it is well established that hyperinsulinemia, a hallmark of IR, may play a role in tumorigenesis. On the other hand, IR is strongly associated with visceral adiposity dysfunction and systemic inflammation, two conditions which favor the establishment of a pro-tumorigenic environment. Similarly, epigenetic modifications, such as DNA methylation, histone modifications, and non-coding RNA, in IR states, have been often associated with tumorigenesis in numerous types of human cancer. In addition to these observations, it is also broadly accepted that gut microbiota may play an intriguing role in the development of IR-related diseases, including type 2 diabetes and cancer, whereas potential chemopreventive properties have been attributed to some of the most commonly used antidiabetic medications. Herein we provide a concise overview of the most recent literature in this field and discuss how different but interrelated molecular pathways may impact on tumor development.

The metabolic syndrome (MetS) is a common disorder, where systemic insulin-resistance is associated with increased risk for type 2 diabetes (T2D) and cardiovascular disease. Identifying genetic traits influencing risk and progression of MetS is important. We and others previously reported a functional HMGA1 gene variant, rs146052672, predisposing to T2D. Here we investigated the association of rs146052672 variant with MetS and related components. In a case-control study from Italy and Turkey, increased risk of MetS was seen among carriers of the HMGA1 variant. In the larger Italian cohort, this variant positively correlated with BMI, hyperglycemia and insulin-resistance, and negatively correlated with serum HDL-cholesterol. Association between rs146052672 variant and MetS occurred independently of T2D, indicating that HMGA1 gene defects play a pathogenetic role in MetS and other insulin-resistance-related conditions. Overall, our results indicate that the rs146052672 variant represents an early predictive marker of MetS, as well as a predictive tool for therapy.

The apolipoprotein A-V gene (APOA5) plays an important role in determining plasma triglyceride levels. We studied the effects of APOA5 polymorphisms on plasma triglyceride levels in Turks, a population with low levels of HDL cholesterol and a high prevalence of coronary artery disease. We found 15 polymorphisms, three of which were novel. Seven haplotype-tagging single nucleotide polymorphisms (SNPs) were chosen and genotyped in z3,000 subjects. The rare alleles of the -1464T.C, -1131T.C, S19W, and 1259T.C SNPs were significantly associated with increased triglyceride levels (19-86 mg/dl; P , 0.05) and had clear gene-dose effects. Haplotype analysis of the nine common APOA5 haplotypes revealed significant effects on triglyceride levels (P , 0.001). Detailed analysis of haplotypes clearly showed that the -1464T.C polymorphism had no effect by itself but was a marker for the -1131T. C, S19W, and 1259T.C polymorphisms. The -1131T. C and 1259T.C polymorphisms were in a strong but incomplete linkage disequilibrium and appeared to have independent effects. Thus, the APOA5 -1131T.C, S19W, and 1259T.C rare alleles were associated with significant increases in plasma triglyceride levels. At least one of these alleles was present in z40% of the Turks. Similar associations were observed for -1131T.C and S19W in white Americans living in San Francisco, California. Atherogenic dyslipidemia, including hypertriglyceridemia, is a risk factor for coronary artery disease (CAD) (1, 2). Family and twin studies have shown that triglyceride levels are controlled by genetic factors, although heritability estimates vary widely (3-5). Recently, the multinational Genetic Epidemiology of Metabolic Syndrome project (6) conducted a genome scan for atherogenic dyslipidemia and found significant evidence for linkage to triglyceride levels near the apolipoprotein A-V gene (APOA5), on chromosome 11q22, only in Turkish families (7). ApoA-V is an important regulator of plasma triglyceride levels (8, 9). Triglyceride levels are 4-fold higher in Apoa5 knockout mice and significantly lower in transgenic mice (8) or in adenovirus-treated mice expressing human APOA5 (9) than in wild-type mice. ApoA5 may decrease plasma triglyceride levels by increasing lipoprotein lipase activity (10, 11) and reducing hepatic levels of very low density lipoprotein triglyceride (11).Several single nucleotide polymorphisms (SNPs) within the APOA5 locus (-1131T.C, -3A.G, S19W, IVS31 476G.A, 1259T.C, and G185C) have been identified, and their rare alleles are associated with increased plasma triglyceride levels in different populations (8, 12 -22). The -1131T.C, -3A.G, IVS3+476G.A, and 1259T.C SNPs (haplotype APOA5*2) were in almost complete linkage disequilibrium (LD) in European populations (17,20). Therefore, any one of these polymorphisms might serve as a marker for the others in these populations. The frequencies of the rare alleles of -1131T.C and S19W vary greatly among populations (8,(12)(13)(14)(15)(16)(17)(18)(19)(20)(21)(22). The plasma triglyceride in...

A patient with an intrasellar germinoma leading to pituitary stalk thickening is reported. The patient, a 24-year old woman, presented with hyperprolactinemia, secondary hypothyroidism, and hypogonadotropic hypogonadism with no evidence of diabetes insipidus. Cerebrospinal fluid (CSF) examination revealed an increased number of lymphocytes and histiocytes. Although beta-HCG concentration was normal (<2 mIU/mL) in the CSF, increased beta-HCG concentration was detected in the serum. Systemic glucocorticoid treatment led to a decrease in CSF cell count, but no regression of the sellar mass was noted. A diagnostic biopsy was performed and showed an intrasellar germinoma. The patient underwent conventional radiotherapy. Complete resolution of the mass lesion and normalization of beta-HCG concentration in the serum were observed three months after radiotherapy. The presence of intrasellar mass lesion in association with pituitary stalk thickening may cause difficulties in the differential diagnosis. Histopathological examination is essential in equivocal cases in order to reach accurate diagnosis and apply the most appropriate therapy.

The ectoenzyme ENPP1 (also termed membrane glycoprotein PC-1 or ENPP1/PC-1) is an inhibitor of insulin-induced activation of the insulin receptor. There is evidence from previous studies that coding variants of ENPP1/PC-1 (K121Q) are associated with type 2 diabetes (T2D) and obesity. Studies in the general Turkish population have demonstrated: unique plasma lipid characteristics; a high prevalence of cardiovascular risk factors; and an increased prevalence of obesity and T2D. We investigated, therefore, the association of ENPP1/PC-1 variants with obesity and T2D in Turkish individuals. The TaqMan allelic discrimination assay was used for genotyping the relationship of ENPP1/PC-1 variants to obesity and T2D in a genetic association study of 1553 genotyped, randomly selected subjects from the Turkish Heart Study. The K121Q (rs1044498) variant, and other previously reported variants (rs997509, rs1799774, rs1044548, rs11964389, rs7754561) were analyzed. In this cohort, the minor allele frequency of the K121Q variant was associated with obesity in male, but not female, subjects (male, OR 1.64, CI%95 1.004-2.698, p = 0.048; female, OR 1.003, CI%95 0.684-1.471, p=ns.). In addition, the previously reported ENPP1/PC-1 “risk haplotype” [Q (rs1044498), delT (rs1799774), and G (rs7754561) alleles] was found to be associated with obesity in male, but not female, subjects (p = 0.035). In contrast, there was no association of either the K121Q variant or the ENPP1/PC-1 haplotype with T2D. We find evidence that variants of ENPP1/PC-1 are associated with obesity in the male Turkish population and thus these variants may contribute to the development of the obesity in these individuals.