Genetische Formen von extremer Insulinresistenz

• Research unit: COST
• Project number: C96.0027

Key words (English)

INSULIN RESISTANCE; GENETIC

Research programs (English)

COST-Action B5 - Molecular mechanisms in the etiology of non-insulin dependant diabetes mellitus (NIDDM)

Short description (English)

See abstract

Further information (English)

Full name of research-institution/enterprise: Universitätsspital Zürich Departement Innere Medizin Abteilung für Endokrinologie und Diabetologie

Partners and International Organizations (English)

B, CZ, CH, D, DK, E, F, H, I, IRL, N, NL, S, SI, SK, UK

Abstract (English)

In a first project, we established cell lines from patients with extreme insulin resistance, and showed sequence abnormalities in the insulin receptor of all studied patients. One patient carries a maternally inherited in-frame deletion of exon 2 leading to decreased insulin binding and reduced mRNA expression. The three other studied subjects revealed two different point mutations that are located within the tyrosine kinase domain of the insulin receptor and abolish its enzymatic function. In a second project, we studied the effect of insulin-like growth factor I (IOF-I) and growth hormone (OH) on leptin and insulin levels. IOF-I enhances insulin sensitivity, but OH causes insulin resistance in humans. In addition IGF-I is regulated by OH, and the latter is inhibited by IOF-I via negative feedback mechanism. To examine the effects of IGF-I and OH without interference of endogenous OH we used either hypophysectomised rats or OH-deficient patients for our studies. Treatment of the patients with OH increased serum leptin levels along with increased C-peptide levels but serum leptin increase lagged behind the rise of C-peptide. In contrast, OH did not affect leptin and insulin levels significantly in hypophysectomised rats. In normal rats IOF-I infusion had profound effects on fat tissue: The fat pad weight, and leptin insulin levels were markedly reduced when compared to controls although food consumption and body weight were unaltered. Therefore we assume that alterations in leptin levels are secondary effects of the availability of free fatty acids caused by variations in the size of fat tissues. In OH-deficient humans IGF-I infusion significantly suppressed serum leptin levels after 3 days of treatment. Fasting C-peptide and serum insulin levels were diminished already 1 day after treatment. In a third project that was recently initiated we started to identify new components of the insulin signaling pathways. We approached to clone the genes of proteins that interact with known signaling components from cDNA expression libraries. For screening we currently adapt a M13 phage display system to be able to efficiently express cDNA fragments on the phage surface. Simultaneously, proteins interacting with insulin receptor substrate-I (IRS-I) are screened in the yeast two-hybrid system. So far we have identified four potential new components of the insulin receptor-signaling pathway. Currently, we are studying their function in the 3T3-LI adipocytes using a newly developed adenovirus system.

References in databases (English)

Swiss Database: COST-DB of the State Secretariat for Education and Research Hallwylstrasse 4 CH-3003 Berne, Switzerland Tel. [phone] Swiss Project-Number: C96.0027