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Elevated Drp1-mediated mitochondrial fission was proposed to promote NAFLD, as inhibition of hepatic Drp1 in early life prevented high-fat diet induced liver steatosis in mice. However, whether Drp1-knockdown (Drp1si) can reverse established NASH in adulthood is unknown. Hepatocyte-restricted delivery of siRNA conjugated to N-acetyl-galactosamine (GalNac) is a safe and FDA-approved approach to selectively manipulate hepatic gene expression and treat human liver disease. Here, we show that hepatic Drp1si in adult healthy mice decreased body weight by 12% and induced liver damage, as shown by the elevation in circulating transaminases, liver inflammation, fibrosis and necrosis (p In conclusion, our study supports that increased Drp1 activity is an adaptative mechanism counteracting NASH that prevents ISR overactivation and mitigates ER stress to limit fibrosis, inflammation, and necrosis. Our study argues against blocking Drp1 in hepatocytes to combat NASH. Disclosure J. Steffen: Employee; Janssen Research & Development, LLC. J. Ngo: None. S. Wang: None. H. F. Kramer: Employee; Janssen Research & Development, LLC. L. D. Norquay: Employee; Janssen Pharmaceuticals, Inc. A. Pocai: Employee; Johnson & Johnson. O. Shirihai: None. M. Liesa: None.

Insulin secretion from β cells of the pancreatic islets of Langerhans controls metabolic homeostasis and is impaired in individuals with type 2 diabetes (T2D). Increases in blood glucose trigger insulin release by closing ATP-sensitive K+ channels, depolarizing β cells, and opening voltage-dependent Ca2+ channels to elicit insulin exocytosis. However, one or more additional pathway(s) amplify the secretory response, likely at the distal exocytotic site. The mitochondrial export of isocitrate and engagement with cytosolic isocitrate dehydrogenase (ICDc) may be one key pathway, but the mechanism linking this to insulin secretion and its role in T2D have not been defined. Here, we show that the ICDc-dependent generation of NADPH and subsequent glutathione (GSH) reduction contribute to the amplification of insulin exocytosis via sentrin/SUMO-specific protease-1 (SENP1). In human T2D and an in vitro model of human islet dysfunction, the glucose-dependent amplification of exocytosis was impaired and could be rescued by introduction of signaling intermediates from this pathway. Moreover, islet-specific Senp1 deletion in mice caused impaired glucose tolerance by reducing the amplification of insulin exocytosis. Together, our results identify a pathway that links glucose metabolism to the amplification of insulin secretion and demonstrate that restoration of this axis rescues β cell function in T2D.

Insulin receptor substrate-2 (Irs2) integrates insulin-like signals with glucose and cAMP agonists to regulate beta-cell growth, function, and survival. This study investigated whether increased Irs2 concentration in beta-cells could reduce beta-cell destruction and the incidence of type 1 diabetes in nonobese diabetic (NOD) mice. NOD mice were intercrossed with C57BL/6 mice overexpressing Irs2 specifically in beta-cells to create NOD(Irs2) mice. After backcrossing NOD(Irs2) mice for 12 generations, glucose homeostasis and diabetes incidence were compared against NOD littermates. Compared with 12-wk-old NOD mice, the progression of severe insulitis was reduced and islet mass was increased in NOD(Irs2) mice. Moreover, the risk of diabetes decreased 50% in NOD(Irs2) mice until the experiment was terminated at 40 wk of age. Nondiabetic NOD(Irs2) mice displayed better glucose tolerance than nondiabetic NOD mice throughout the duration of the study and up to the age of 18 months. The effect of Irs2 to increase islet mass and improve glucose tolerance raised the possibility that NOD(Irs2) mice might have an increased capacity to respond to anti-CD3 antibody, which can induce remission of overt diabetes in some NOD mice. Anti-CD3 antibody injections restored glucose tolerance in newly diabetic NOD and NOD(Irs2) mice; however, anti-CD3-treated NOD(Irs2) mice were less likely than NOD mice to relapse during the experimental period because they displayed 10-fold greater beta-cell mass and mitogenesis. In conclusion, increased Irs2 attenuated the progression of beta-cell destruction, promoted beta-cell mitogenesis, and reduced diabetes incidence in NOD(Irs2) mice.

The prevalence of type 2 diabetes mellitus in the Oji-Cree of northwestern Ontario is the third highest in the world. A private mutation, G319S, in HNF1A , which encodes hepatic nuclear factor-1α (HNF-1α), was associated with Oji-Cree type 2 diabetes and was found in ≈40% of affected subjects. The G319S mutation reduced the in vitro ability of HNF-1α to activate transcription by ≈50%, with no effect on DNA binding or protein stability. There was no evidence of a dominant negative effect of the mutant protein. The impact of the G319S mutation at the population level was assessed by classifying subjects with type 2 diabetes according to HNF1A genotype and plotting the cumulative age of onset of diabetes. Disease onset was modeled satisfactorily by two-parameter sigmoidal functions for all diabetic subjects and all three HNF1A genotypes. Pairwise statistical comparisons showed significant between-genotype differences in t 50 (all P < 0.00001), corresponding to the age at which half the subjects had become diabetic. Each dose of G319S accelerated median disease onset by ≈7 years. Thus, the transactivation-deficient HNF1A G319S mutation affects the dynamics of disease onset. The demonstration of a functional consequence for HNF1A G319S provides a mechanistic basis for its strong association with Oji-Cree type 2 diabetes and its unparalleled specificity for diabetes prediction in these people, in whom diabetes presents a significant public health dilemma. The findings also show that HNF1A mutations can be associated with typical adult-onset insulin-resistant obesity-related diabetes in addition to maturity-onset diabetes of the young.