Diabetes caused by insulin gene (INS) deletion: clinical characteristics of homozygous and heterozygous individuals

Background: Mutations of the preproinsulin gene (INS) account for both permanent neonatal diabetes (PND) and adult-onset diabetes. The molecular mechanism of complete INS deletion has recently been published and we now add clinical data of homozygous and heterozygous subjects as well as the detailed mapping of the 646 bp deletion of the INS gene. Methods: Location and size of the INS deletion was mapped in one case with PND and INS genotype of the whole family was further characterized by breakpoint-spanning PCR. The phenotype of monoallelic loss of INS was studied in 33 adult family members of a large consanguineous kindred with INS deletion. Results: The 646 bp deletion was found in two individuals with PND that included exons 1 and 2 of the INS gene (chr11: g.2138434_2139080del646) and results in loss of approximately half of the preproinsulin protein. The two boys with homozygous INS deletion (D/D) presented with reduced birth weight, PND within the first 24 h of life and complete absence of C-peptide. Adult family members with the N/D had diabetes onset with earliest 25 years, while the oldest subject without diabetes was 45 years. INS-deletion-diabetes was initially treated with oral antidiabetic drugs but then transferred to insulin within 5-16 years. Overall, N/D-subjects (n=11) had a higher risk to develop insulin-dependent diabetes up to the fifth decade, if compared with normal subjects (n=22). Conclusion: Complete loss of the human INS gene results in neonatal diabetes, while heterozygous INS deletion is a strong risk factor for developing insulin-dependent diabetes at adult age

Long-term lanreotide treatment in six patients with congenital hyperinsulinism

BACKGROUND: Medical treatment is a substantial therapeutic measure to achieve glycemic control and prevent hypoglycemic brain damage without surgery in patients with congenital hyperinsulinism (CHI). However, only few drugs are available and even fewer are approved as a medical therapy to maintain normal blood glucose levels. The established therapies are demanding for caregivers and complicated by different side effects such as gastrointestinal symptoms, hypertrichosis, and obesity. Therefore, it is important to develop new strategies to improve blood glucose control. METHODS: We report the use of the very-long-acting somatostatin analogue lanreotide autogel in 6 patients with CHI over a mean duration of 40.8 months. Blood glucose levels before and after the start and dosage titration of lanreotide in these patients are compared. RESULTS: In 3 of 6 patients, switching to lanreotide raised mean blood glucose levels and reduced individually as well as overall the risk for hypoglycemic episodes (odds ratio 0.38) significantly. CONCLUSION: Lanreotide autogel can be used as an alternative pharmacological treatment and may be beneficial in conservatively treated patients with CHI

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

Begrenzung der Schadstoffemission von Maschinen zum Bearbeiten asbesthaltiger Materialien

TIB: RN 8492 (1984,2) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekSIGLEDEGerman

Erfassung von Schwermetallstroemen in landwirtschaftlichen Tierproduktionsbetrieben und Erarbeitung einer Konzeption zur Verringerung der Schwermetalleintraege durch Wirtschaftsduenger tierischer Herkunft in Agraroekosysteme

The overall objectives of the project were to assess heavy metal flows on livestock farms and to develop a strategy to reduce heavy metal inputs into animal manures. For the experiments 20 farms with animal husbandry in various regions of Germany were selected. On the farms the inputs and outputs of the elements copper and zinc, as well as lead, cadmium, chromium and nickel were balanced at the stable level. The effect of abatement measures was evaluated using a calculation tool for stable balances. It is shown, the main input pathways for heavy metals into animal manures are, apart from copper disinfectants, feeding stuffs and feed supplements. Home grown feeds are the major source of heavy metal input into the stable because they are fed in large quantities. However, the heavy metal content of the home grown feeds in particular of roughages for ruminants is low. Purchased feed stuffs (supplementary feeding stuffs and complete feeding stuffs) were found to have a higher content of heavy metals (due to supplementation with trace elements) compared to home grown feeds. Thus, pig and poultry husbandry rather than ruminant husbandry is susceptible to heavy metal accumulation of manures. Heavy metals are cycling within the farm which is of importance when discussing the environmental impact. The turnover within the farm can hardly be controlled by the farmer. Thus, effective strategies have to be targeted at the inputs, e. g. the purchased feed stuffs. A main option to reduce the heavy metal input is to lower the trace element concentrations in supplementary feed stuffs either by legislation of maximum threshold values (e. g. EG 1334/2003) or by volunteer agreements of the feed industry and agriculture. In addition, the absorption of copper and zinc by the animals should be improved using better absorbable trace element compounds and phytase. (orig.)SIGLEAvailable from TIB Hannover: RN 8422(2004,6) / FIZ - Fachinformationszzentrum Karlsruhe / TIB - Technische InformationsbibliothekBundesministerium fuer Umwelt, Naturschutz und Reaktorsicherheit, Berlin (Germany)DEGerman