Diet‐induced β‐cell insulin resistance results in reversible loss of functional β‐cell mass

Abstract

Although convincing in genetic models, the relevance of β-cell insulin resistance in diet-induced type 2 diabetes (T2DM) remains unclear. Exemplified by diabetes-prone, male, C57B1/6J mice being fed different combinations of Western-style diet, we show that β-cell insulin resistance occurs early during T2DM progression and is due to a combination of lipotoxicity and increased β-cell workload. Within 8 wk of being fed a high-fat, high-sucrose diet, mice became obese, developed impaired insulin and glucose tolerances, and displayed noncompensatory insulin release, due, at least in part, to reduced expression of syntaxin-1A. Through reporter islets transplanted to the anterior chamber of the eye, we demonstrated a concomitant loss of functional β-cell mass. When mice were changed from diabetogenic diet to normal chow diet, the diabetes phenotype was reversed, suggesting a remarkable plasticity of functional β-cell mass in the early phase of T2DM development. Our data reinforce the relevance of diet composition as an environmental factor determining different routes of diabetes progression in a given genetic background. Employing the in vivo reporter islet-monitoring approach will allow researchers to define key times in the dynamics of reversible loss of functional β-cell mass and, thus, to investigate the underlying, molecular mechanisms involved in the progression toward T2DM manifestation.-Paschen, M., Moede, T., Valladolid-Acebes, I., Leibiger, B., Moruzzi, N., Jacob, S., García-Prieto, C. F., Brismar, K., Leibiger, I. B., Berggren, P.-O. Diet-induced β-cell insulin resistance results in reversible loss of functional β-cell mass.

Pancreatic β cell microRNA-26a alleviates type 2 diabetes by improving peripheral insulin sensitivity and preserving β cell function

“…Indeed, extensive decreases were detected in the islets of RIP TG mice in the second phase of GSIS, although there was no discernible difference in first-phase insulin secretion (<20 min) between genotypes ( Fig 6B). Recent evidence suggest insulin signaling in β cells as an emerging regulator of insulin secretion [34][35][36]. To test whether this pathway participants in the function of miR-26a on insulin secretion, we determined the effect of miR-26a in insulin signaling of β cells and islets.…”

The eye as a novel imaging site in diabetes research

“…These autologous islets survive well without experiencing immune rejection (Diez et al, 2017). Virtually, our group mostly uses syngeneic mouse models in our research (Ilegems et al, 2013; Ilegems et al, 2015; Johansson et al, 2015; Lee et al, 2018; Leibiger et al, 2012; Leibiger & Berggren, 2017; Nyqvist et al, 2011; Paschen et al, 2016; Paschen et al, 2018; Rodriguez-Diaz et al, 2012; Speier, Nyqvist, Cabrera, et al, 2008; Speier, Nyqvist, Kohler, et al, 2008; van Krieken et al, 2017). This transplantation setting allows islet grafts to be satisfactorily viable and to suffer from little immune rejection.…”

“…2) (Speier et al, 2008; Speier et al, 2008). We have succeeded in developing the nearly non-invasive technique for transplanting islets into the ACE and the ACE-based imaging technique for visualizing intraocular islets under healthy and diabetic conditions in a non-invasive, longitudinal and in vivo real-time manner (Abdulreda et al, 2011; Abdulreda & Berggren, 2013; Abdulreda, Caicedo, & Berggren, 2013; Abdulreda, Rodriguez-Diaz, Caicedo, & Berggren, 2016; Ali et al, 2016; Almaca et al, 2014; Avall et al, 2015; Diez et al, 2017; Faleo, Berggren, & Pileggi, 2014; Ilegems et al, 2013; Ilegems et al, 2015; Johansson et al, 2015; Juntti-Berggren, Ali, & Berggren, 2015; Lee et al, 2018; Leibiger et al, 2012; Leibiger & Berggren, 2017; Leibiger, Brismar, & Berggren, 2010; Miska et al, 2014; Nyqvist et al, 2011; Paschen et al, 2016; Paschen et al, 2018; Perez et al, 2011; Rodriguez-Diaz et al, 2012; Rodriguez-Diaz et al, 2018; Schmidt-Christensen et al, 2013; Shalaly et al, 2016; Speier, Nyqvist, Cabrera, et al, 2008; Speier, Nyqvist, Kohler, et al, 2008; van Krieken et al, 2017). We and others have tackled a series of issues in the diabetes arena by employing the ACE technology (Fig.…”

“…We and others have tackled a series of issues in the diabetes arena by employing the ACE technology (Fig. 2) (Abdulreda et al, 2011; Abdulreda et al, 2016; Almaca et al, 2014; Avall et al, 2015; Berclaz et al, 2016; Chen et al, 2016; Chmelova et al, 2015; Faleo et al, 2014; Juntti-Berggren et al, 2015; Lee et al, 2018; Miska et al, 2014; Mojibian et al, 2013; Paschen et al, 2016; Paschen et al, 2018; Perez et al, 2011; Schmidt-Christensen et al, 2013; van Krieken et al, 2017).

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Beta-cell specificInsrdeletion promotes insulin hypersecretion and improves glucose tolerance prior to global insulin resistance

“…Impaired insulin receptor signaling is associated with obesity and often precedes the onset of overt type 2 diabetes, but it has been studied primarily in skeletal muscle, fat, and liver where it manifests differently (Boucher et al, 2014). Recent work in mice has established that β-cell specific insulin resistance can be observed early in the progression towards type 2 diabetes, when hyperinsulinemia is prominent, and independently of insulin resistance in other tissues (Paschen et al, 2019). The physiological consequences of reduced insulin receptor (Insr)-mediated signaling in β-cells remain controversial.…”