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Cdk5-dependent regulation of glucose-stimulated insulin secretion


Tight glycemic control in individuals with diabetes mellitus is essential to prevent or delay its complications1. Present treatments to reduce hyperglycemia mainly target the ATP-sensitive K+ (KATP) channel of pancreatic beta cells to increase insulin secretion. These current approaches are often associated with the side effect of hypoglycemia. Here we show that inhibition of the activity of cyclin-dependent kinase 5 (Cdk5) enhanced insulin secretion under conditions of stimulation by high glucose but not low glucose in MIN6 cells and pancreatic islets. The role of Cdk5 in regulation of insulin secretion was confirmed in pancreatic beta cells deficient in p35, an activator of Cdk5. p35-knockout mice also showed enhanced insulin secretion in response to a glucose challenge. Cdk5 kinase inhibition enhanced the inward whole-cell Ca2+ channel current and increased Ca2+ influx across the L-type voltage-dependent Ca2+ channel (L-VDCC) upon stimulation with high glucose in beta cells, but had no effect on Ca2+ influx without glucose stimulation. The inhibitory regulation by Cdk5 on the L-VDCC was attributed to the phosphorylation of loop II-III of the α1C subunit of L-VDCC at Ser783, which prevented the binding to SNARE proteins and subsequently resulted in a decrease of the activity of L-VDCC. These results suggest that Cdk5/p35 may be a drug target for the regulation of glucose-stimulated insulin secretion.

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Figure 1: Cdk5 inhibition enhances glucose-stimulated insulin secretion in MIN6 cells.
Figure 2: Effect of Cdk5 inhibition on Ca2+ mobilization in beta cells.
Figure 3: Effect of phosphorylation of the LII-III domain on interactions with syntaxin and SNAP-25.
Figure 4: p35 deficiency promotes insulin secretion in isolated islets and in vivo.

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We thank V. Lilla (Louis-Jeantet Research Laboratory, University Medical Center) for providing the MIN6 B1 cell line, H. Noguchi for the technical advice, and T. Ogawa and A. Kemori for technical assistance. This work was supported by a Grant-in-Aid for Scientific Research on Priority Areas “Membrane Traffic” from the Ministry of Education, Science, Sports and Culture of Japan.

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Correspondence to Kazuhito Tomizawa.

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Supplementary information

Supplementary Fig. 1

Suppression of Cdk5 expression level by siRNA enhanced insulin secretion in MIN6 cells. (PDF 152 kb)

Supplementary Fig. 2

Reduced phosphorylation level of Ser783 of αlc in the brain and islets of p35-deficient mice. (PDF 184 kb)

Supplementary Fig. 3

Immunostaining of islets in wild-type and p35-knockout mice. (PDF 1086 kb)

Supplementary Fig. 4

Islet mass of wild-type and p35-deficient mice. (PDF 2126 kb)

Supplementary Methods (PDF 72 kb)

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Wei, FY., Nagashima, K., Ohshima, T. et al. Cdk5-dependent regulation of glucose-stimulated insulin secretion. Nat Med 11, 1104–1108 (2005).

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