Summary The Forkhead transcription factor Foxo1 regulates expression of genes involved in stress resistance and metabolism. To assess the contribution of Foxo1 to metabolic dysregulation during hepatic insulin resistance, we disrupted Foxo1 expression in the liver of mice lacking hepatic Irs1 and Irs2 (DKO-mice). DKO-mice were small and developed diabetes; analysis of the DKO-liver transcriptome identified perturbed expression of growth and metabolic genes, including increased Ppargc1a and Igfbp1, and decreased glucokinase, Srebp1c, Ghr and Igf1. Liver-specific deletion of Foxo1 in DKO-mice resulted in significant normalization of the DKO-liver transcriptome and partial restoration of the response to fasting and feeding, near normal blood glucose and insulin concentrations, and normalization of body size. These results demonstrate that constitutively active Foxo1 significantly contributes to hyperglycemia during severe hepatic insulin resistance, and that the Irs1/2→PI-3K→Akt→Foxo1 branch of insulin signaling is largely responsible for hepatic insulin-regulated glucose homeostasis and somatic growth.
Background & Aims Pharmacological approaches can potentially improve fatty liver condition in alcoholic and non-alcoholic fatty liver diseases. The salutary effects of reducing lipid synthesis or promoting lipid oxidation have been well reported, but the benefits of increasing lipid degradation have yet to be well explored. Macroautophagy is a cellular degradation process that can remove subcellular organelles including lipid droplets. We thus investigated whether pharmacological modulation of macroautophagy could be an effective approach to alleviate fatty liver condition and liver injury. Methods C57BL/6 mice were given ethanol via intraperitoneal injection (acute) or by a 4-week oral feeding regime (chronic), or given high fat diet for 12 weeks. An autophagy enhancer, carbamazepine or rapamycin, or an autophagy inhibitor, chloroquine, was given before sacrifice. Activation of autophagy, level of hepatic steatosis, and blood levels of triglycerides, liver enzyme, glucose and insulin were measured. Results In both acute and chronic ethanol condition macroautophagy were activated. Carbamazepine, as well as rapamycin, enhanced ethanol-induced macroautophagy in hepatocytes in vitro and in vivo. Hepatic steatosis and liver injury were exacerbated by chloroquine, but alleviated by carbamazepine. The protective effects of carbamazepine and rapamycin in reducing steatosis and in improving insulin sensitivity were also demonstrated in high fat diet-induced non-alcoholic fatty liver condition. Conclusions These findings indicate that pharmacological modulation of macroautophagy in the liver can be an effective strategy for reducing fatty liver condition and liver injury.
The insulin receptor substrate 2 (Irs2) branch of the insulin/insulin-like growth factor-signaling cascade prevents diabetes in mice because it promotes  cell replication, function, and survival, especially during metabolic stress. Because exendin-4 (Ex4), a long acting glucagon-like peptide 1 receptor agonist, has similar effects upon  cells in rodents and humans, we investigated whether Irs2 signaling was required for Ex4 action in isolated  cells and in Irs2 ؊/؊ mice. Ex4 increased cAMP levels in human islets and Min6 cells, which promoted Irs2 expression and stimulated Akt phosphorylation. In wild type mice Ex4 administered continuously for 28 days increased  cell mass 2-fold. By contrast, Ex4 failed to arrest the progressive  cell loss in Irs2 ؊/؊ mice, which culminated in fatal diabetes; however, Ex4 delayed the progression of diabetes by 3 weeks by promoting insulin secretion from the remaining islets. We conclude that some short term therapeutic effects of glucagon-like peptide 1 receptor agonists can be independent of Irs2, but its long term effects upon  cell growth and survival are mediated by the Irs2 branch of the insulin/insulin-like growth factor signaling cascade.Diabetes mellitus is a complex disorder that arises from various causes, including dysregulated glucose sensing and impaired insulin secretion (maturity-onset diabetes of youth, MODY), autoimmune-mediated  cell destruction (type 1), or insufficient compensation for peripheral insulin resistance (type 2) (1). Type 2 diabetes is the most prevalent form. It usually occurs at middle age and afflicts more than 30 million people over the age of 65 but is appearing with greater frequency in children and adolescents (2). Dysregulated insulin signaling exacerbated by chronic hyperglycemia promotes a cohort of systemic disorders, including dyslipidemia, hypertension, cardiovascular disease, and female infertility (3, 4). The search for strategies to promote  cell function and regeneration has lead to the discovery that glucagon-like peptide-1 (GLP1) 2 receptor agonists increase insulin biosynthesis and secretion from  cells, inhibit glucagon secretion from ␣-cells, and promote peripheral insulin sensitivity and satiety in type 2 diabetics (5-9). During a meal, GLP1 is secreted into the circulation from L cells located in the intestine (10); however, GLP1 is quickly inactivated by circulating dipeptidyl-peptidase IV, which diminishing its usefulness as an injectable therapeutic. Compounds that inhibit dipeptidyl-peptidase IV or GLP1 homologs like exendin-4 (Ex4) that are not degraded by dipeptidyl-peptidase IV display improved therapeutic efficacy (11-16). Administration of Ex4 to rodents or humans with type 2 diabetes increases first-phase insulin secretion and increases  cell mass, which can compensate for peripheral insulin resistance (8,9,17,18). Recently, a synthetic Ex4 called Exenatide (Byetta, Amylin/Lily) has gained Food and Drug Administration approval as an injectable treatment for type 2 diabetes (15). Because Exenatide is the...
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