Key result
Protein kinase D inhibition protects against diet-induced glucose intolerance and enhances insulin secretion in mice.
Why the study?
Insulin is the principal factor regulating lipoprotein lipase activity in adipose tissue, but the specific signaling mechanisms by which insulin controls lipoprotein lipase expression were unknown.
PKD inhibition may enhance insulin secretion in mice; leaves open translation to human metabolic disease.
Lipoprotein lipase (LPL) hydrolyzes the triacylglycerol component of circulating lipoprotein particles, mediating the uptake of fatty acids into adipose tissue and muscle. Insulin is the principal factor responsible for regulating LPL activity in adipose tissue, yet the mechanisms whereby insulin controls LPL expression are unknown. The current studies used wortmannin, a specific inhibitor of phosphatidylinositol (PI) 3-kinase, and rapamycin, a specific inhibitor of activation of phosphoprotein 70 ribosomal protein S6 kinase (p70s6k), to explore some of the components of the insulin signaling pathway controlling LPL activity in adipose cells. Preincubation of isolated rat adipose cells with wortmannin completely abrogated the stimulation of LPL activity by insulin, while preincubation with rapamycin caused approximately a 60% inhibition of insulin-stimulated LPL activity. Thus, the current studies show that the regulation of adipose tissue LPL by insulin is mediated via a wortmannin-sensitive pathway, most likely PI 3-kinase, and that a rapamycin-sensitive pathway, most likely p705s6k, constitutes an important downstream component in the insulin signaling pathway through which LPL is regulated.
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Kraemer et al. (1998) studied Pancreatic beta-cell aging and high-fat diet-induced insulin resistance (preclinical mouse and rat adipose cell models). Protein kinase D (PKD) inhibition (transgenic dominant-negative PKDkd-EGFP expression or pharmacological pan-PKD inhibitor CRT0066101) / Wortmannin and rapamycin in rat adipocytes vs. Control (ntg/+/-) mice, carrier control (5% dextrose in 0.9% NaCl), or low-fat diet (LFD) was evaluated on Glucose tolerance, glucose-stimulated insulin secretion (GSIS), and beta-cell senescence hallmarks (or insulin-stimulated lipoprotein lipase activity in abstract). Genetic or pharmacological inhibition of protein kinase D (CRT0066101) induces beta-cell senescence hallmarks, enhances insulin secretion, and protects mice against diet-induced glucose intolerance.
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