In This Issue of Diabetes

Based on data from pancreatic tissue samples collected from nondiabetic patients undergoing pancreatoduodenectomy, a new study in this issue of Diabetes (p. 994) suggests that even in the absence of frank diabetes, insulin resistance has a direct impact on islet cell biology. The article describes pre- and postoperative data from 18 nondiabetic patients (9 men and 9 women) who underwent pancreatoduodenectomy for treatment of tumor of the ampulla of Vater. The new study uses tissue samples taken from the downstream edge of the surgical cut. In this procedure, the volume of removed pancreas is constant at 50% and includes removal of the head of the pancreas, which contains 50% of β-cell mass. Another notable feature of the new study is that no participants were diabetic by established criteria, thereby allowing a critical examination of islet biology prior to disease onset. The investigators divided the patients into two groups—insulin resistant and insulin sensitive—based on preoperative assessments. Among the striking findings was that patients who were insulin sensitive before their pancreatoduodenectomy retained their glucose tolerance, but seven of nine insulin-resistant patients developed diabetes in response to the same procedure. In addition, although the surgery resulted in a reduction in insulin secretion for all patients regardless of their preoperative insulin sensitivity, insulin-resistant patients in the postoperative follow-up period also had decrements in all phases of insulin secretion and increased glucagon secretion in response to a mixed meal. Examination of the tissue samples collected during surgery indicated that insulin-resistant patients had greater average islet cell size, a finding that suggests that these patients’ preoperative insulin resistance impacted islet cell morphology. The use of live donors to study changes in β-cell mass may offer new opportunities to identify strategies to increase the β-cell’s response to insulin resistance. — Helaine E. Resnick, PhD, MPH

Mezza et al. Insulin resistance alters islet morphology in nondiabetic humans. Diabetes 2014;63:994–1007

An article by Shang et al. in this issue of Diabetes (p. 923) highlights the role of endoplasmic reticulum (ER) stress as a contributor to pancreatic β-cell failure in Wolfram syndrome. This syndrome, which can be caused by mutations in the WFS1 gene, is a useful model for understanding how ER stress and the unfolded protein response (UPR)—an adaptive response to ER stress—may influence β-cell failure. The new work suggests that chemical chaperones that regulate UPR may offer a novel approach to resolving β-cell dysfunction. Shang et al. used induced pluripotent stem cell lines generated from patients with Wolfram syndrome to produce β-cells deficient in the WFS1 gene. Compared to controls, the Wolfram cells that were deficient in WFS1, showed a 40–50% reduction in insulin mRNA levels and a 30–40% decrease in secretory granules. Notably, insulin deficiency was reversed by a transgene encoding wild-type WFS1. Activation of all three major UPR pathways (mechanisms that cope with ER stress) were observed in the Wolfram cells suggesting that WFS1 operates upstream of the UPR pathway. Several additional experiments in the article focused on the effects of increasing or decreasing ER stress. These experiments showed that the addition of the chemical chaperone sodium 4PBA, which reduces ER stress by assisting protein folding, reduced UPR responses and nearly doubled insulin mRNA levels in Wolfram cells relative to controls. Conversely, in Wolfram cells, challenge with thapsigargin (TG), which increases ER stress, elevated the UPR response to glucose and impaired C-peptide secretion. In an important proof of concept, artificially induced ER stress with TG treatment was remedied by exposure to 4PBA. The effect of sodium 4PBA on ER stress suggests significant therapeutic potential not only in Wolfram syndrome, but in other settings of glucose dysregulation involving insulin deficiency. — Wendy Chou, PhD

Shang et al. β-Cell dysfunction due to increased ER stress in a stem cell model of Wolfram syndrome. Diabetes 2014;63:923–933

Endoplasmic reticulum (ER) stress is known to be elevated in the adipose tissue of obese humans and results from dysfunctional protein folding. Although little is known about the regulation of the unfolded protein response (UPR)—an adaptation to ER stress—new work by Boden et al. in this issue of Diabetes (p. 912) sheds light on the effect of insulin levels on the UPR to ER stress. Importantly, the new study includes data from in vivo studies in adipose tissue from healthy humans as well as in vitro studies in mouse adipocytes. In the in vivo experiments, physiologic insulin levels ranging from 70 to 1,450 pmol/L were correlated in a dose-dependent manner with UPR mRNA and protein level ratios. Supplementing these findings, tests of acute hypoinsulinemia that dropped basal insulin levels to 35 pmol/L for 8 h in the fat tissue of nondiabetic individuals confirmed the dose-response relationship between insulin and the UPR response over the physiologic range of insulin. Notably, the investigators eliminated glucose uptake and oxidative stress as potential explanations for their observations, and in vitro experiments also excluded other potential causes of the UPR, such as variability in plasma free fatty acid levels. Instead, investigators observed a threefold increase in protein ubiquitination. Taken together, the data suggest that insulin causes ER stress in fat tissue by either increasing protein synthesis or suppressing protein breakdown beyond the system’s folding and organizational capacity, thereby resulting in a large buildup of ubiquitinated proteins. These novel findings may have meaningful implications for understanding the risk posed by ER stress among individuals with longstanding hyperinsulinemia and patients who receive high doses of insulin to treat diabetes and obesity. — Wendy Chou, PhD

Boden et al. Insulin regulates the unfolded protein response in human adipose tissue. Diabetes 2014;63:912–922

As diabetes prevalence continues to rise, so too will the occurrence of chronic wounds, a worrisome trend that reflects the need for improved understanding of the mechanisms underpinning wound healing in diabetes. A new report by Mirza et al. in this issue of Diabetes (p. 1103) presents a mechanistic model that may help explain how macrophage inflammasome activity acts to inhibit wound healing. According to this model, activity of the NLRP-3 (Nod-like receptor protein 3) inflammasome in macrophages creates a feedback loop that can lead to chronic inflammation that prevents wound healing. Improved regulation of this loop could not only help promote healing, but it may also ameliorate other problems associated with chronic wounds, including disability and increased risk of amputation. The investigators found that macrophages isolated from chronic wounds in type 2 diabetic patients expressed inflammasome components NLRP-3 and caspase-1, as well as key inflammasome targets interleukin (IL)-1β and IL-18. Importantly, the same macrophages failed to express the inflammasome inhibitors PI-9 and caspase-12. In other experiments, the investigators triggered in vitro inflammasome activity in macrophages collected from healthy humans by exposing them to chronic wound-conditioned medium from diabetic patients. Although experiments with induced wounds in mice showed significant upregulation of inflammasome inhibitors in controls, these inhibitors were absent in db/db mice. Notably, in wounded mice, topical application of various inhibitors to the NLRP-3 inflammasome led to conditions that promoted wound healing, including faster re-epithelialization, more granulation tissue formation, and collagen deposition. Macrophages cultured from these treated wounds showed lower expression of inflammatory cytokines, suggesting that macrophage phenotype plays a role in the wound environment. When knockout mice deficient in either NLRP-3 or caspase-1 were used as bone marrow donors to healing-impaired db/db mice, the impaired mice regained prohealing characteristics including decreased levels of IL-1β and IL-18. These novel observations have important therapeutic implications because they suggest that new approaches to wound healing in diabetic individuals might be linked to improved regulation of the inflammasome activation loop. — Wendy Chou, PhD

Mirza et al. Sustained inflammasome activity in macrophages impairs wound healing in type 2 diabetic humans and mice. Diabetes 2014;63:1103–1114