Title

Prediabetes Linked To Excess Glucagon In Transgenic Mice With Pancreatic Active Akt1

Keywords

Glucagon; Glucose metabolism; Insulin signaling; Oncogenes; Pancreas

Abstract

Protein kinase B/AKT has three isoforms (AKT1-3) and is renowned for its central role in the regulation of cell growth and proliferation, due to its constitutive activation in various cancers. AKT2, which is highly expressed in insulin-responsive tissues, has been identified as a primary regulator of glucose metabolism as Akt2 knockout mice (Akt2-/-) are glucoseintolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1Myr) expressed through a bicistronic Pdx1-TetA and TetO-MyrAkt1 system were susceptible to islet cell carcinomas, and in this study we characterized an early onset, prediabetic phenotype. Beginning at weaning (3 weeks of age), the glucose-intolerant AKT1Myr mice exhibited non-fasted hyperglycemia, which progressed to fasted hyperglycemia by 5 months of age. The glucose intolerance was attributed to a fasted hyperglucagonemia, and hepatic insulin resistance detectable by reduced phosphorylation of the insulin receptor following insulin injection into the inferior vena cava. In contrast, treatment with doxycycline diet to turn off the transgene caused attenuation of the non-fasted and fasted hyperglycemia, thus affirming AKT1 hyperactivation as the trigger. Collectively, this model highlights a novel glucagon-mediated mechanism by which AKT1 hyperactivation affects glucose homeostasis and provides an avenue to better delineate the molecular mechanisms responsible for diabetes mellitus and the potential association with pancreatic cancer.

Publication Date

1-1-2016

Publication Title

Journal of Endocrinology

Volume

228

Issue

1

Number of Pages

49-59

Document Type

Article

Personal Identifier

scopus

DOI Link

https://doi.org/10.1530/JOE-15-0288

Socpus ID

84953255247 (Scopus)

Source API URL

https://api.elsevier.com/content/abstract/scopus_id/84953255247

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