Schoumacher, M. | Search bioRxiv

bioRxiv2026

β-cell NCK1 is reduced in type 2 diabetes, leading to inefficient β-cell UPR and insulin secretion and revealing sex-specific adaptation during metabolic stress

Type 2 diabetes is characterized by failure of pancreatic {beta} cells to adapt insulin secretion to metabolic demand, due to impaired {beta}-cell function and/or reduced {beta}-cell mass. The unfolded protein response (UPR) is central to this adaptation by maintaining endoplasmic reticulum homeostasis and supporting insulin biosynthesis, secretion, proliferation, and survival. NCK1, is an adaptor protein that regulates diverse cellular processes, including insulin biosynthesis and UPR activation, positioning it at the crossroads of several processes essential for {beta}-cell function. Moreover its silencing is reported to enhance adaptive PERK signaling and {beta}-cell survival in vitro, suggesting that it could represent an important regulator of {beta}-cell adaptation. Here, we explored this potential role for NCK1 using {beta}-cell-specific knockout mice (NCK1{beta}KO) and human islets of both sexes. NCK1 expression was positively regulated by glucose yet reduced in islets from individuals living with type 2 diabetes. Loss of {beta}-cell NCK1 impaired insulin gene expression, insulin content, and glucose-stimulated insulin secretion in vitro, and disrupted UPR activation. In vivo, {beta}-cell NCK1 deletion led to sex-dependent adaptation to maintain glucose homeostasis. Under high-fat/high-sucrose diet, both NCK1{beta}KO male and female mice increased pancreatic insulin content, but only males showed improved insulin secretion associated with islet expansion and {beta}-cell proliferation. Females, in contrast, exhibited impaired insulin secretion despite preserved insulin stores, associated with increased numbers of small islets and altered PERK pathway activation. These findings identify NCK1 as a regulator of {beta}-cell insulin synthesis, secretion, and UPR signaling, and reveal sex-specific adaptive mechanisms to {beta}-cell stress. Reduced NCK1 in islets from people living type 2 diabetes may disrupt {beta}-cell adaptation to metabolic stress and contribute to diabetes.

physiology↗

bioRxiv2025

Glucagon-induced PGC-1α4/PPARγ promotes hepatic lipid storage and macrosteatosis in fasting and MASLD

The liver plays a central role in regulating the transition between fasting and feeding states, coordinating glycogen breakdown, gluconeogenesis, fatty acid catabolism, and lipid storage. Disruptions in this balance contribute to metabolic disorders, including Metabolic dysfunction Associated Steatotic Liver Disease (MASLD). Here, we identify a novel biological pathway downstream of glucagon that promotes the hepatic lipid accumulation associated with fasting. Using gain- and loss-of-function in vivo and in vitro models, we found that glucagon induces sustained expression of PGC-14, promoting lipid uptake and storage in hepatocytes by increasing PPAR{gamma} activity. Increased PPAR{gamma}/PGC-14 promotes hepatic Fsp27/Cidec expression, leading to lipid droplet expansion and triglyceride trapping in liver. Activity of the PPARGC1A alternative promoter and PGC-14 expression were higher in livers of patients with MASLD, and PGC-14 expression correlated with macrosteatosis. Consistently, persistent expression of hepatic PGC-14 in mice fed a western diet promoted macrosteatosis, exacerbated oxidative stress and altered hepatic lipid composition to resemble worsening Metabolic dysfunction Associated Steatohepatitis (MASH) in humans. Our findings demonstrate that glucagon-induced hepatic PGC-14/PPAR{gamma} activity facilitates efficient uptake and storage of lipids during fasting, but over-activation of this coordinated metabolic pathway leads to lipid accumulation and worsening of steatosis in MASLD.

physiology↗