Increase of Calcium Sensing Receptor Expression Is Related to Compensatory Insulin Secretion during Aging in Mice

PLoS One. 2016 Jul 21;11(7):e0159689. doi: 10.1371/journal.pone.0159689. eCollection 2016.


Type 2 diabetes is caused by both insulin resistance and relative insulin deficiency. To investigate age-related changes in glucose metabolism and development of type 2 diabetes, we compared glucose homeostasis in different groups of C57BL/6J mice ranging in age from 4 months to 20 months (4, 8, 12, 16 and 20 months). Interestingly, we observed that non-fasting glucose levels were not significantly changed, but glucose tolerance gradually increased by 20 months of age, whereas insulin sensitivity declined with age. We found that the size of islets and glucose-stimulated insulin secretion increased with aging. However, mRNA expression of pancreatic and duodenal homeobox 1 and granuphilin was decreased in islets of older mice compared with that of 4-month-old mice. Serum calcium (Ca2+) levels were significantly decreased at 12, 20 and 28 months of age compared with 4 months and calcium sensing receptor (CaSR) mRNA expression in the islets significantly increased with age. An extracellular calcium depletion agent upregulated CaSR mRNA expression and consequently enhanced insulin secretion in INS-1 cells and mouse islets. In conclusion, we suggest that decreased Ca2+ levels and increased CaSR expression might be involved in increased insulin secretion to compensate for insulin resistance in aged mice.

MeSH terms

  • Aging / genetics
  • Aging / metabolism*
  • Animals
  • Blood Glucose / metabolism
  • Body Weight
  • Calcium / blood
  • Cell Line
  • Fasting
  • Gene Expression
  • Glucose Tolerance Test
  • Immunohistochemistry
  • Insulin / metabolism*
  • Insulin Resistance
  • Insulin Secretion
  • Islets of Langerhans / metabolism
  • Male
  • Mice
  • RNA, Messenger
  • Receptors, Calcium-Sensing / genetics
  • Receptors, Calcium-Sensing / metabolism*


  • Blood Glucose
  • Insulin
  • RNA, Messenger
  • Receptors, Calcium-Sensing
  • Calcium

Grant support

This study was supported by grants from the Innovative Research Institute for Cell Therapy (A062260) and the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (grant number: HI14C1135).