Summary Insulin resistance is a hallmark of diabetes and an unmet clinical need. Insulin inhibits hepatic glucose production and promotes lipogenesis by suppressing FOXO1-dependent activation of G6pase and inhibition of Glucokinase, respectively. The tight coupling of these events poses a dual conundrum: mechanistically, as the FOXO1 corepressor of Glucokinase is unknown; and clinically, as inhibition of glucose production is predicted to increase lipogenesis. Here we report that SIN3A is the insulin-sensitive FOXO1 corepressor of Glucokinase. Genetic ablation of SIN3A abolishes nutrient regulation of Glucokinase, without affecting other FOXO1 target genes, and lowers glycemia without concurrent steatosis. To extend this work, we executed a small molecule screen and discovered selective inhibitors of FOXO-dependent glucose production devoid of lipogenic activity in hepatocytes. In addition to identifying a novel mode of insulin action, these data raise the possibility of developing selective modulators of unliganded transcription factors to dial out adverse effects of insulin sensitizers.

Reduced food intake brings about an adaptive decrease in energy expenditure that contributes to the recidivism of obesity following weight loss. Insulin and leptin inhibit food intake through actions in the central nervous system that are partly mediated by FoxO1. We show that FoxO1 ablation in pro–opiomelanocortin (Pomc) neurons (Pomc–Foxo1−/−) reduces food intake without affecting energy expenditure. Analyses of hypothalamic neuropeptides in Pomc–Foxo1−/− mice reveal selective increases of α–Msh and COOH–cleaved β–endorphin, the products of Carboxypeptidase E (Cpe)–dependent processing of Pomc. We show that Cpe is decreased in diet–induced obesity, and that FoxO1 deletion offsets the decrease, protecting against weight gain. Moreover, moderate Cpe overexpression in the arcuate nucleus phenocopies features of the FoxO1 mutation. The dissociation of food intake from energy expenditure in Pomc–Foxo1−/− mice represents a model for therapeutic intervention in obesity, and raises the possibility of targeting Cpe to develop weight loss medications.

Mikulicz's disease (MD) is a unique IgG4-related systemic disease indicated by enlargement of the lachrymal and salivary glands and which differs substantially from Sjögren's syndrome. A male patient with pleural effusion, swelling of the submandibular glands, and swelling of the paraaortic, mediastinal, and pararenal lymph nodes was diagnosed with MD. Analysis of peripheral CD4+ T cells from the patient revealed deviation of the Th1/Th2 balance to Th2. Prednisolone therapy ameliorated the disease and corrected the Th1/Th2 imbalance.

Mikulicz's disease (MD) is a unique IgG4-related systemic disease indicated by enlargement of the lachrymal and salivary glands and which differs substantially from Sjögren's syndrome. A male patient with pleural effusion, swelling of the submandibular glands, and swelling of the paraaortic, mediastinal, and pararenal lymph nodes was diagnosed with MD. Analysis of peripheral CD4+ T cells from the patient revealed deviation of the Th1/Th2 balance to Th2. Prednisolone therapy ameliorated the disease and corrected the Th1/Th2 imbalance.

Despite the significant impact that shortages have had on the PN use system, no adverse impact on patient safety could be identified from these reported PN errors.