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Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes.

journal contribution
posted on 2023-06-08, 08:54 authored by I Huang-Doran, LS Bicknell, FM Finucane, N Rocha, KM Porter, YCL Tung, F Szekeres, A Krook, JJ Nolan, Mark O'DriscollMark O'Driscoll, M Bober, S O'Rahilly, AP Jackson, R.K Semple
OBJECTIVE Genetic defects in human pericentrin (PCNT), encoding the centrosomal protein pericentrin, cause a form of osteodysplastic primordial dwarfism that is sometimes reported to be associated with diabetes. We thus set out to determine the prevalence of diabetes and insulin resistance among patients with PCNT defects and examined the effects of pericentrin depletion on insulin action using 3T3-L1 adipocytes as a model system. RESEARCH DESIGN AND METHODS A cross-sectional metabolic assessment of 21 patients with PCNT mutations was undertaken. Pericentrin expression in human tissues was profiled using quantitative real-time PCR. The effect of pericentrin knockdown on insulin action and adipogenesis in 3T3-L1 adipocytes was determined using Oil red O staining, gene-expression analysis, immunoblotting, and glucose uptake assays. Pericentrin expression and localization also was determined in skeletal muscle. RESULTS Of 21 patients with genetic defects in PCNT, 18 had insulin resistance, which was severe in the majority of subjects. Ten subjects had confirmed diabetes (mean age of onset 15 years [range 5-28]), and 13 had metabolic dyslipidemia. All patients without insulin resistance were younger than 4 years old. Knockdown of pericentrin in adipocytes had no effect on proximal insulin signaling but produced a twofold impairment in insulin-stimulated glucose uptake, approximately commensurate with an associated defect in cell proliferation and adipogenesis. Pericentrin was highly expressed in human skeletal muscle, where it showed a perinuclear distribution. CONCLUSIONS Severe insulin resistance and premature diabetes are common features of PCNT deficiency but are not congenital. Partial failure of adipocyte differentiation may contribute to this, but pericentrin deficiency does not impair proximal insulin action in adipocytes.

History

Publication status

  • Published

Journal

Diabetes

ISSN

00121797

Publisher

American Diabetes Association Inc

Issue

3

Volume

60

Page range

925-935

Department affiliated with

  • Sussex Centre for Genome Damage Stability Publications

Full text available

  • No

Peer reviewed?

  • Yes

Legacy Posted Date

2012-02-06

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