Editors' ChoiceDiabetes

Clocks stop sugar shock

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Science Translational Medicine  05 Apr 2017:
Vol. 9, Issue 384, eaan2772
DOI: 10.1126/scitranslmed.aan2772


The circadian clock orchestrates the timing of insulin and glucagon secretion, which is important for glycemic control.

When we eat, insulin and glucagon stabilize our blood sugar through a system of counter-regulation. Insulin, produced by pancreatic β-cells, stimulates cellular uptake of glucose from the blood, while glucagon produced by pancreatic α-cells prevents hypoglycemia by stimulating glucose release from the liver. For this yin-yang arrangement to work, insulin and glucagon secretion must be carefully spaced to avoid episodes of high blood sugar or low blood sugar (“sugar shock”). The traditional view is that the lag between insulin and glucagon secretion reflects the time needed for α-cells to sense dropping glucose levels. In a recent paper, Petrenko et al. demonstrate an additional mechanism at work involving the circadian clock.

The circadian clock is a genetic mechanism for producing circadian rhythms in mammals. While clock genes are expressed in almost all nucleated cells in the body and carry out tissue-specific programs, the physiologic role of “peripheral clocks” is not well understood. To understand circadian clock function within α- and β-cells, Petrenko et al. used a fluorescence-based cell sorting approach to isolate pure populations of these cells from mouse pancreas at various times of day and analyzed their differential transcriptomes. Expression of insulin and glucagon genes themselves was not circadian, but genes associated with their secretion were expressed in a rhythmic manner. Unexpectedly, clock genes in α-cells tended to peak a few hours later in the day than those in β-cells, mirroring a lag between insulin and glucagon secretion seen in vivo. Synchronized cultures of α- and β-cells showed a similar lag between insulin and glucagon secretion, as well as the clock gene expression. Why the clock of α-cells is phase-delayed relative to that of β-cells, despite their physical proximity in the pancreatic islet, remains unclear. The authors suggest differences in adrenergic receptor gene expression as one potential explanation, but more investigation is needed. Overall, these results illustrate a new role for circadian clocks in optimizing the joint action of counter-regulatory hormones. It may be that drugs targeting clock genes will someday prove useful for certain forms of diabetes by enhancing the coordination between insulin and glucagon secretion.

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