Genetic Disruption of Adenosine Kinase in Mouse Pancreatic β-Cells Protects Against High-Fat Diet–Induced Glucose Intolerance

Abstract

Islet β-cells adapt to insulin resistance through increased insulin secretion and expansion. Type 2 diabetes typically occurs when prolonged insulin resistance exceeds the adaptive capacity of β-cells. Our prior screening efforts led to the discovery that adenosine kinase (ADK) inhibitors stimulate β-cell replication. Here, we evaluated whether ADK disruption in mouse β-cells affects β-cell mass and/or protects against high-fat diet (HFD)–induced glucose dysregulation. Mice targeted at the Adk locus were bred to Rip-Cre and Ins1-Cre/ERT1Lphi mice to enable constitutive (βADKO) and conditional (iβADKO) disruption of ADK expression in β-cells, respectively. Weight gain, glucose tolerance, insulin sensitivity, and glucose-stimulated insulin secretion (GSIS) were longitudinally monitored in normal chow (NC)–fed and HFD-fed mice. In addition, β-cell mass and replication were measured by immunofluorescence-based islet morphometry. NC-fed adult βADKO and iβADKO mice displayed glucose tolerance, insulin tolerance and β-cell mass comparable to control animals. By contrast, HFD-fed βADKO and iβADKO animals had improved glucose tolerance and increased in vivo GSIS. Improved glucose handling was associated with increased β-cell replication and mass. We conclude that ADK expression negatively regulates the adaptive β-cell response to HFD challenge. Therefore, modulation of ADK activity is a potential strategy for enhancing the adaptive β-cell response.

Opposing effects of intracellular versus extracellular adenine nucleotides on autophagy: implications for β-cell function

“…Inhibition of ADK in β-cells has been shown to increase β-cell proliferation in vitro (Annes et al, 2012). Moreover, it has recently been shown that β-cell ADK knockout mice exhibit increased β-cell proliferation and insulin secretion in vivo, resulting in improvement of glycemia in mice exposed to the metabolic stress of a high-fat diet (Navarro et al, 2017). On the other hand, insulin secretion of islets from aged A 1 adenosine receptor knockout mice was enhanced compared with age-matched controls; this was associated with reduced oxidative stress and inflammation (Yang et al, 2015).…”

Dysregulation of adenosine kinase isoforms in breast cancer

“…Metabolic removal of adenosine occurs either through its deamination by adenosine deaminase (ADA) to be converted to inosine or via phosphorylation by adenosine kinase (ADK) to form adenosine monophosphate [12,13]. As ADK plays a major role in adenosine removal and its availability for downstream effects, this adenosine-ADK balance is strictly regulated in healthy cells [14]. ADK has two isoforms: a long isoform, ADK-L, dominantly located in the nucleus [15]; and a short isoform, ADK-S, located in the cytoplasm [16].…”

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

“…4 Recently, the screening of small compounds using a primary β-cell replication assay or a human MYC (transcriptional regulator Myc-like) expression system identified that inhibition of at least two kinase targets, ADK and DYRK1A, can compensate for β-cell loss during type 1 or type 2 diabetes. 4 23 It is worth noting that whereas no glucose metabolism difference was found in adult mice, young-aged (4-week-old) Ins2-Cre ± Adk fl/fl mice improved glucose metabolism significantly. This difference in the observed glucose metabolism and β-cell mass between 4 and 9-12 weeks might be due to their age difference.…”

“…Our results exhibited that Ins2-Cre ± Adk fl/fl mice were more resistance to STZ-induced hyperglycaemia compared with their littermates. This resistance to STZ-induced hyperglycaemia was explained by significant increase of β-cell proliferation which was accompanied by Importantly, the Rip-Cre/Adk fl/fl and Ins1-Cre/ERT1 Lphi /Adk fl/ fl mice showed significantly improved glucose homeostasis under high-fat diet conditions, 23 which mostly mimic type 2 diabetes. In our study, we found that the specific loss of ADK in a β-cell causes Ins2-Cre ± Adk fl/fl mice to be more resistant to STZ treatment, a pathological model generally for type 1 diabetes.…”