Deletion of pancreatic β‐cell adenosine kinase improves glucose homeostasis in young mice and ameliorates streptozotocin‐induced hyperglycaemia

Abstract

Severe reduction in the β‐cell number (collectively known as the β‐cell mass) contributes to the development of both type 1 and type 2 diabetes. Recent pharmacological studies have suggested that increased pancreatic β‐cell proliferation could be due to specific inhibition of adenosine kinase (ADK). However, genetic evidence for the function of pancreatic β‐cell ADK under physiological conditions or in a pathological context is still lacking. In this study, we crossed mice carrying LoxP‐flanked Adk gene with Ins2‐Cre mice to acquire pancreatic β ‐cell ADK deficiency (Ins2‐Cre ± Adk fl/fl ) mice. Our results revealed that Ins2‐Cre +/‐ Adk fl/fl mice showed improved glucose metabolism and β‐cell mass in younger mice, but showed normal activity in adult mice. Moreover, Ins2‐Cre ± Adk fl/fl mice were more resistant to streptozotocin (STZ) induced hyperglycaemia and pancreatic β‐cell damage in adult mice. In conclusion, we found that ADK negatively regulates β‐cell replication in young mice as well as under pathological conditions, such as STZ induced pancreatic β‐cell damage. Our study provided genetic evidence that specific inhibition of pancreatic β‐cell ADK has potential for anti‐diabetic therapy.

FAM3A plays crucial roles in controlling PDX1 and insulin expressions in pancreatic beta cells

“…To directly evaluate the roles of FAM3A in insulin expression and secretion, β cell specific FAM3A knockout mice (BKO mice) were generated by crossing FAM3A‐Loxp mice with Ins2‐Cre mice (Supplemental Figure 3A,B). Although there is concern that Cre may impact β cell functions, it had also been reported that Ins2‐Cre mice (RIP‐Cre) exhibited normal insulin secretion and glucose metabolism as flox/flox (Loxp) and wild‐type mice, and Loxp mice had been widely used as control mice in studies involving RIP‐Cre‐triggered β cell specific knockout of genes . Our preliminary experiments revealed that there was no significant difference in OGTT between Loxp mice and RIP‐Cre mice (Supplemental Figure 3C), so the Loxp mice had been used as control mice in the current study.…”

“…66,67 At present, some study used RIP-Cre mice as controls. 68 However, a number of studies had also shown that RIP-Cre have comparable glucose tolerance tests and insulin secretion as Loxp mice, and Loxp mice and even wild-type mice had been widely used as control mice [40][41][42][43][44][45][46][47][48][69][70][71] in study involving β cell specific knockout of genes triggered by RIP-Cre. In addition, although FAM3A-deficience impairs while FAM3A overexpression increases insulin secretion in primary mouse islets and β cell lines under basal glucose concentration, BKO mice has comparable insulin and blood glucose levels in fasting status as control mice.…”

“…PCR and agarose gel electrophoresis assays were used to characterize mouse genotypes. It had been reported that Ins2‐Cre mice (RIP‐Cre) exhibited normal insulin secretion and glucose metabolism as flox/flox and wild‐type mice, which had been widely used as control mice in studies involving Ins2‐triggered β cell specific knockout of genes. In the current study, the flox/flox mice had been used as control mice.…”

“…Although there is concern that Cre may impact β cell functions, it had also been reported that Ins2-Cre mice (RIP-Cre) exhibited normal insulin secretion and glucose metabolism as flox/ flox (Loxp) and wild-type mice, 40,[42][43][44][45] and Loxp mice had been widely used as control mice in studies involving RIP-Cre-triggered β cell specific knockout of genes. 42,[44][45][46][47][48][49] Our preliminary experiments revealed that there was no significant difference in OGTT between Loxp mice and RIP-Cre mice (Supplemental Figure 3C), so the Loxp mice had been used as control mice in the current study. BKO mice had similar body weight as control mice during the growth (Supplemental Figure 3D).…”

Adenosine-Metabolizing Enzymes, Adenosine Kinase and Adenosine Deaminase, in Cancer

“…The protective effect of ADK inhibitors has been shown [114]. Lately, new data have appeared on the role of ADK-L in the regulation of cellular proliferation in the pancreas [58,115] and nervous system [52] as well the involvement of ADK-L in mitogenesis, carcinogenesis, and tumor invasion [62]. Besides, the epigenetic role of ADK-L has been shown and is actively studied.…”