Protein phosphatase 1 (PP-1)-dependent inhibition of insulin secretion by leptin in INS-1 pancreatic β-cells and human pancreatic islets

Leptin inhibits insulin secretion from pancreatic beta-cells, and in turn, insulin stimulates leptin biosynthesis and secretion from adipose tissue. Dysfunction of this adipoinsular feedback loop has been proposed to be involved in the development of hyperinsulinemia and type 2 diabetes mellitus. At the molecular level, leptin acts through various pathways, which in combination confer inhibitory effects on insulin biosynthesis and secretion. The aim of this study was to identify molecular mechanisms of leptin action on insulin secretion in pancreatic beta-cells. To identify novel leptin-regulated genes, we performed subtraction PCR in INS-1 beta-cells. Regulated expression of identified genes was confirmed by RT-PCR and Northern and Western blotting. Furthermore, functional impact on beta-cell function was characterized by insulin-secretion assays, intracellular Ca(2+) concentration measurements, and enzyme activity assays. PP-1alpha, the catalytic subunit of protein phosphatase 1 (PP-1), was identified as a novel gene down-regulated by leptin in INS-1 pancreatic beta-cells. Expression of PP-1alpha was verified in human pancreatic sections. PP-1alpha mRNA and protein expression is down-regulated by leptin, which culminates in reduction of PP-1 enzyme activity in beta-cells. In addition, glucose-induced insulin secretion was inhibited by nuclear inhibitor of PP-1 and calyculin A, which was in part mediated by a reduction of PP-1-dependent calcium influx into INS-1 beta-cells. These results identify a novel molecular pathway by which leptin confers inhibitory action on insulin secretion, and impaired PP-1 inhibition by leptin may be involved in dysfunction of the adipoinsular axis during the development of hyperinsulinemia and type 2 diabetes mellitus

Genetic differentiation across North America in the generalist moth Heliothis virescens and the specialist H. subflexa

The two moth species Heliothis virescens (Hv) and H. subflexa (Hs) are closely related, but have vastly different feeding habits. Hv is a generalist and an important pest in many crops in the USA, while Hs is a specialist feeding only on plants in the genus Physalis. In this study, we conducted a comparative population genetic analysis to assess whether and how generalist and specialist life styles are reflected in differences in population structures. In Hv 98% of the total variation occurred within populations. The overall differentiation (F(ST)) between regions was 0.006 and even lower between years (0.0039) and hosts (0.0028). Analyses of population structure suggest that all individuals form one genetically homogeneous population, except for at most 12 individuals (6%) that diverged from this cluster. Population homogeneity likely results from the high mobility of Hv and its generalist feeding behaviour. Hs exhibited substantially more population structure. Even though 96% of the total variation was attributable to within-population variability, F(ST)-values between Hs populations were 10 times higher than between Hv populations. Hs populations showed significant isolation by distance. Analyses of Hs population structure suggest at least two subpopulations and thus some degree of metapopulation structure. We speculate that the patchy distribution of Physalis - the exclusive food source of Hs - contributes to differences in population structure between these closely related species. The finding that the specialist shows more population differentiation than the generalist corroborates the notion that host specialization is not an evolutionary dead end but a dynamic trait

The Incidence of Cancer Among Acromegaly Patients: Results From the German Acromegaly Registry

Context: Acromegaly is a rare disease characterized by high serum levels of GH and IGF-1. Animal studies have demonstrated links between these hormones and cancer, but data regarding cancer incidence among acromegaly patients are inconsistent. Moreover, therapy options have changed considerably since many of the aforementioned data were collected. Objective: The objective was to determine whether the overall and site- specific incidence of cancer is comparable to that of the general population. Design and Setting: Data from the German Acromegaly Registry for 446 patients (6656 person-years from diagnosis) treated in seven specialized endocrine centers were analyzed. Main Outcome Measure: Standard incidence ratios (SIRs) were calculated as compared to the general population. Results: Overall cancer incidence was slightly but not significantly lower than in the general population (SIR, 0.75; 95% confidence interval, 0.55 to 1.00; P = .051) and was not significantly higher for colorectal, breast, thyroid, prostate, and lung cancers. The SIRs of those with GH in the ranges = 2.5 ng/mL were 0.75, 0.44, and 0.92, respectively (P = .94). There was not a significant dependence on normal vs elevated IGF-1 (P = .87), radiation therapy (P = .45), disease duration (P = .96), age at diagnosis (P = .15), or during a period of high GH and IGF-1 from 8 years before to 2 years after diagnosis of acromegaly (P = .41). Conclusions: Cancer screening strategies need to take incidence into account, which does not seem to be substantially higher in treated acromegaly patients than in the general population for any site of cancer