More News About NUCB2/Nesfatin-1: A New Factor in the Hypothalamic Control of Glucose Homeostasis?

  1. Andrew A. Butler
  1. Department of Metabolism and Aging, The Scripps Research Institute, Jupiter, Florida
  1. Corresponding author: Andrew A. Butler, abutler{at}scripps.edu.

Insulin resistance and declining insulin production define a spectrum of metabolic diseases afflicting a growing portion of the population (1). Current estimates suggest that 26 million Americans have diabetes, with the incidence of type 2 diabetes involving insulin resistance and β-cell decompensation far exceeding that of type 1 diabetes. Treatment of type 2 diabetes involves secretagogues that increase insulin secretion and insulin sensitizers to improve insulin receptor (INSR) action (and likely include other effects on glucose production) (1). These drugs exhibit a short duration of efficacy in many patients and often require a multidrug approach as the disease progresses and insulin injections when other treatment options fail. A clear need exists for continued research aimed at developing more effective strategies for maintaining glycemic control.

In this issue, Yang et al. (2) report that intracerebroventricular (ICV) infusion of nesfastin-1 improves glucose homeostasis in diet-induced obese rats by inhibiting hepatic glucose production. Improved insulin action is one mechanism for the reduction in hepatic glucose production. Increased phosphorylation of the INSR and insulin receptor substrate-1 was observed in lean and obese rats following ICV administration of nesfatin-1. Tyrosine phosphorylationof multiple residues in the insulin receptor substrate-1 coding sequence is an important early event following INSR activation. This leads to an intracellular signaling cascade that facilitates changes in energy metabolism by regulating gene transcription and enzymatic activity (3). The changes in phosphorylation of AKT, AMP-dependent protein kinase, mammalian target of rapamycin, and mammalian target of rapamycin complex 2 that were also observed were consistent with improved actions of these important downstream effectors in the INSR signaling cascade. Activity of phosphoenolpyruvate carboxykinase, the rate-limiting enzyme in gluconeogenesis, was also reduced in livers of lean and diet-induced obese rats administered nesfatin-1 ICV. Finally, a …

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