Loss ofmPer2increases plasma insulin levels by enhanced glucose‐stimulated insulin secretion and impaired insulin clearance in mice

Abstract

a b s t r a c tThe existence of peripheral oscillators has been shown, and they are critically important for organizing the metabolism of the whole body. Here we show that mice deficient in mPer2 markedly increase circulatory levels of insulin compared with wild type mice. Insulin secretion was more effectively stimulated by glucose, and alloxan, a glucose analogue, induced more severe hyperglycemia in mPer2-deficient mice. Hepatic insulin degrading enzyme (Ide) displayed an obvious day and night rhythm, which was impaired in mPer2-deficient mice, leading to a decrease in insulin clearance. Deficiency in mPer2 caused increased Clock expression and decreased expression of Mkp1 and Ide1, possibly underlying the observed phenotypes and suggesting that mPer2 plays a role in regulation of circulating insulin levels.

Circadian rhythms in glucose and lipid metabolism in nocturnal and diurnal mammals

“…Disruption of Per2 expression results in reduced fasting glycemia, altered glycogen accumulation in the liver, enhanced glucose-induced insulin secretion and impaired gluconeogenesis (Schmutz et al, 2010;Zani et al, 2013;Zhao et al, 2012), although Feillet et al (2006) detected no change in the daily variations of liver glycogen in Per2 mutant mice. Mice deficient in Per2 also may have dampened corticosterone rhythms ), but other investigations reported unaltered or increased corticosterone rhythms in Per2 mutants (Dallmann et al, 2006).…”

Endocrine regulation of circadian physiology

“…tissue-specifically deleting Clock or Bmal1) results in hypoinsulinemia (Marcheva et al 2010, Sadacca et al 2011, whereas deletion of the clock's negative regulators (i.e. the Pers or Crys) is associated with hyperinsulinemia (Barclay et al 2012, Zhao et al 2012. In rodent and human pancreatic beta cells, the main functional targets of the clock machinery are a number of CCGs involved in peptide secretory pathways (Perelis et al 2015, Saini et al 2016.…”

Immunometabolism: Is it under the eye of the clock?

“…Il-6 and Tnf˛ RNA. Lower NF-B activation [147] Cry1 (AP-Tg) Global • Elevated glucose levels in serum and urine [161] • Common symptoms of diabetes mellitus, polydipsia and polyuria [161] Per2 Global • Reduced levels of triacylglycerol and non-sterified fatty acids [139] • Enhanced adipocyte differentiation [139] • Increased plasma insulin and impaired gluconeogenesis [142,143] • Protected from sepsis-induced death [144] • Lower IL-1␤ and IFNϒ in serum [144] • Lower Tlr9 expression [82] Per3 Global • Enhanced adipogenesis [139] • Increased adipose tissue and decreased muscle tissue mass [139] Rev-erb˛ Global • Increased adiposity and mild hyperglycemia [119] • Altered lipid and glucose metabolism [119] • Increase in G6Pase and PEPCK [120] • Increased IL-6 in serum [124] ROR˛ sg/sg Global • Reduced adiposity and protection from obesity [128] • Lower serum and liver triglyceride levels [128] • Impaired Th17 cell development [133] • Highly susceptible to LPS induced sepsis [136] ROR Global • Enhanced production of insulin sensitive adipocytes.…”

“…Global Per3 knock out mice exhibit increased deposits of adipose tissue and reduced muscle tissue in comparison to wild-type mice [140]. PER proteins have also been linked to glucose storage with Per2-/-mice exhibiting a loss of rhythmic glycogen accumulation in the liver, impaired gluconeogenesis and elevated plasma insulin levels [141][142][143].…”