Prediabetes linked to excess glucagon in transgenic mice with pancreatic active AKT1.

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 glucose-intolerant and insulin-resistant. However, the role of AKT1 in glucose metabolism is not as clearly defined. We previously showed that mice with myristoylated Akt1 (AKT1(Myr)) 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 AKT1(Myr) 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.

• Authors: Toya M Albury-Warren, Veethika Pandey, Lina P Spinel, Michal M Masternak, Deborah A Altomare
• Journal: The Journal of endocrinology (J Endocrinol) Vol. 228 Issue 1 Pg. 49-59 (Jan 2016) ISSN: 1479-6805 [Electronic] England
• PMID: 26487674 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: © 2016 Society for Endocrinology.

Chemical References

• Blood Glucose
• Insulin
• Myristic Acids
• Glucagon
• Akt1 protein, mouse
• Proto-Oncogene Proteins c-akt
• Glucose

Topics

• Animals
• Blood Glucose (analysis)
• Diabetes Mellitus (etiology)
• Enzyme Activation
• Fasting
• Genotype
• Glucagon (blood)
• Glucose (metabolism)
• Glucose Intolerance
• Homeostasis
• Hyperglycemia
• Insulin (blood)
• Insulin Resistance
• Mice
• Mice, Transgenic
• Myristic Acids
• Pancreas (enzymology)
• Prediabetic State (blood)
• Proto-Oncogene Proteins c-akt (chemistry, genetics, physiology)