PTEN Deletion in Adult Mice Induces Hypoinsulinemia With Concomitant Low Glucose Levels.

Maria Crespo-Masip,Carla Guzmán,Nuria Doladé,José Manuel Valdivielso,Alicia García-Carrasco,Sandra Rayego,Aurora Pérez-Gómez,Ramiro Jover

doi:10.3389/fendo.2022.850214

Abstract

The PI3K/AKT pathway, negatively regulated by PTEN, plays a paramount role in glucose metabolism regulation due to its activation by the insulin receptor signaling pathway. We generated a PTEN-KO mouse to evaluate the systemic effect of the overactivation of the PI3K/AKT pathway in insulin signaling and glucose homeostasis. Our results demonstrate that PTEN-KO mice show very low glucose levels in the fasted state, which poorly respond to glucose and pyruvate administration. Insulinemia decreased without alterations in pancreatic islets. Among the possible reasons, we uncover the deregulation of the expression of proximal tubule glucose transporter and consequent glycosuria. Moreover, we evidence an altered activation of hepatic gluconeogenesis-related genes. In addition, the expression of several genes related to β-oxidation showed a delayed or even absent response to fasting, suggesting that the lack of PTEN not only impairs glucose metabolism but also slows down the use of lipids as a metabolic fuel. We conclude that the inducible full PTEN-KO mice could be a good model to study the metabolic interactions between glycidic and lipidic metabolism in hypoinsulinemic hypoglycemia and that PTEN could be an important mediator in the disease and/or a potential drug target.

Highlights

Hypoglycemia can be induced by many causes, especially by an overdose of oral hypoglycemic agents or insulin in diabetic patients, leading to hyperinsulinemic hypoglycemia
After 7 hours offasting, the glucose levels of control mice were similar to their basal levels, in contrast to Phosphatase and tensin homolog (PTEN)-KO mice in which blood glucose levels were significantly lower than the ones measured at the basal time point
The glucose tolerance test (GTT) showed that PTEN knock-out model (PTEN-KO) mice responded with a smaller peak in serum glucose, which returned to basal values after 40 minutes, in contrast to control mice in which glucose levels returned to basal values after 120 minutes (Figure 1B)

Summary

Introduction

Hypoglycemia can be induced by many causes, especially by an overdose of oral hypoglycemic agents or insulin in diabetic patients, leading to hyperinsulinemic hypoglycemia. In rare cases, hypoglycemia can be found together with low levels of insulin in non-diabetic patients, in the so-called hypoinsulinemic hypoglycemia. Liver injury-induced hypoglycemia is one of the causes of hypoinsulinemic hypoglycemia [1]. In those cases, hypoglycemia seems to be secondary to a depletion of glycogen in the liver. Hypoinsulinemic hypoglycemia has been reported in DoegePotter syndrome, a rare paraneoplastic condition characterized by a solitary fibrous tumor. This tumor causes hypoglycemia by the secretion of a prohormone form of insulin-like growth factor II (IGFII) [2]. Episodes of hypoglycemia are usually recurrent and refractory to conventional treatment, and they can cause lifethreatening consequences [9, 10]

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Results

Conclusion