Abstract
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.
Highlights
With the global population aging, there has been an increase in the prevalence of impaired glucose tolerance and type 2 diabetes [1,2,3]
This resulted in a significant decrease in the area under the curve (AUC) in 16- and 20-month-old mice compared with 4-month-old mice (Fig 2B)
We examined mRNA expression levels of genes which are involved in insulin expression and insulin secretion, such as pancreatic and duodenal homeobox 1 (Pdx-1), glucose transporter 2 (Glut-2) and granuphilin in islets from these mice
Summary
With the global population aging, there has been an increase in the prevalence of impaired glucose tolerance and type 2 diabetes [1,2,3]. A compensatory increase of beta cell function and beta cell mass to adapt to metabolic stress associated with aging and insulin resistance can maintain normal glucose levels. When beta cells fail and can no longer compensate, type 2 diabetes develops [4]. Insulin secreted by the pancreatic beta cells is the key hormone in regulating glucose metabolism. There exists a close relationship between insulin secretion and insulin sensitivity in the maintenance of normal glucose tolerance, such that insulin secretion as well as beta cell mass.
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