FEBRUARY 2015

In This Issue of Diabetes Edited by Helaine E. Resnick, PhD, MPH

Kuhre et al. Molecular mechanisms of glucose-stimulated GLP-1 secretion from perfused rat small intestine. Diabetes 2015;64:370–382

Li et al. PD-L1–driven tolerance protects neurogenin3-induced islet neogenesis to reverse established type 1 diabetes in NOD mice. Diabetes 2015;64:529–540

Progress in Tracking Mechanisms of Glucose-Stimulated GLP-1 SecretionAlthough cell culture models inform a large part of the current understanding of how glucose mediates incretin release, this approach fails to capture the complexity of physiological systems. In this issue of Diabetes, work by Kuhre et al. (p. 370) brings new insight into the molecular mechanisms underpinning glucose-stimulated secretion of glucagon-like peptide 1 (GLP-1), and the results suggest that glucose intake affects GLP-1 secretion in the gut before glucose reaches the general circulation. One of the challenges for modeling glucose-mediated GLP-1 release is that cultured intestinal cells have lost their polarity as well as their paracrine and neural features. Important contributions of the new work on male Wistar rats concern the preservation of cell polarity and neural connections, which allow a more detailed look at two competing mechanisms by which glucose uptake can trigger GLP-1 secretion. The fi rst candidate mechanism is glucose transporter 2 (GLUT2) (located basolaterally in enterocytes), and the second is sodium-glucose transporter 1 (SGLT1) (an apically activated mechanism). The investigators measured GLP-1 concentrations when SGLT1 or GLUT2 were enhanced or inhibited, and they also took advantage of the differences in electrochemistry (SGLT1 causes cell depolarization while GLUT2 is electroneutral). Among the study’s central fi ndings was that glucose stimulates GLP-1 secretion in the gut in a manner that is both dose and absorption dependent. Results also showed that SGLT1 is the dominant activator for luminal glucose–stimulated secretion of GLP-1. Kuhre et al. suggest that when glucose concentrations are high, an additional pathway can operate in which glucose transport is followed by intracellular metabolism to ATP and the closure of ATP-sensitive potassium channels. In both of these pathways, calcium mobilization appears to be the fi nal step in GLP-1 secretion. Taken together, these new data provide a more physiologically sound understanding of the molecular mechanisms driving GLP-1 secretion following glucose stimulation. — Wendy Chou, PhD

PD-L1–Mediated Islet Neogenesis Reverses Diabetes in NOD MiceA report by Li et al. (p. 529) in this issue of Diabetes describes a promising gene therapy strategy for the treatment of established type 1 diabetes. Although many studies have used the NOD mouse to explore mechanisms underpinning the onset of diabetes, few have used this model to demonstrate the reversal of diabetes once it has taken hold. The newly published results suggest that novel approaches to reversing type 1 diabetes may be on the horizon. Over a period of 14 weeks, the investigators transferred neurogenin3 (Ngn3), an islet lineage determination gene, and betacellulin (Btc), an islet growth factor gene, into NOD mice. Although these treatments did not promote islet recovery in the pancreas, new islet tissue was generated in periportal regions of the liver. Neo-islets were short-lived and destroyed quickly by immune cells unless the Ngn3-Btc treatment was accompanied by a vector carrying programmed death 1 ligand (PD-L1), which is involved in immunosuppresion. With Ngn3-Btc+PD-L1 combination therapy, liver neo-islets persisted over 14 weeks and mimicked typical islet functions including proinsulin production. Glucose tolerance tests revealed restoration of euglycemia in the NOD mice within 1–2 weeks of Ngn3-Btc+PD-L1 treatment, whereas mice that received either Ngn3-Btc or PD-L1 alone remained hyperglycemic. Furthermore, whole-liver cytokine profi ling in mice receiving the combination treatment showed downregulation of several cytokines (e.g., interleukin [IL]-1β, tumor necrosis factor-α, IL-10, and IL-17) that are typically increased in the pancreas of diabetic mice with β-cell destruction. The tolerance that was induced by PD-L1 was explained by a local reduction in CD4+ T cells in areas surrounding the neo-islets. Outside these areas, CD4+ T-cell numbers remained constant, suggesting that PD-L1 resulted in local, rather than generalized immunosuppression. Additional experiments showed that the transfer of diabetogenic splenocytes from NOD mice to euglycemic Ngn3+Btc+PD-L1–treated mice did not inhibit the reversal of diabetes in the treated mice. Together, these results suggest that targeted PD-L1 expression alters the neo-islet environment independently of the broader immune system. The successful reversal of diabetes in overtly diabetic mice offers an encouraging step forward toward the goal of β-cell replacement therapy to combat type 1 diabetes. — Wendy Chou, PhD

A suggested model for glucose-stimulated GLP-1 release.

Representative sections in the liver of control and Ngn3-Btc+PD-L1–treated NOD mice costained for TUNEL and CD3. Scale bar, 50 µm. PV, portal vein.

Diabetes Volume 64, February 2015 315

Stanford et al. Exercise before and during pregnancy prevents the deleterious effects of maternal high-fat feeding on metabolic health of male offspring. Diabetes 2015;64:427–433

The Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications Research Group. Effect of intensive diabetes therapy on the progression of diabetic retinopathy in patients with type 1 diabetes: 18 years of follow-up in the DCCT/EDIC. Diabetes 2015;64:631–642

Favorable Impact on Offspring of Preconception and Gestational ExerciseData in this issue of Diabetes by Stanford et al. (p. 427) support a strong role for maternal exercise in reducing the risk of obesity and diabetes in offspring. Although the value of exercise in promoting overall health is undisputed, the impact of prepregnancy and gestational exercise on the metabolic characteristics of offspring is unclear. In the new report by Stanford et al., female mice that were fed a chow or high-fat diet were split into four exercise groups. One group was housed with a running wheel before and during pregnancy, a second had the running wheel before pregnancy, the third had the wheel only during pregnancy, and the fourth group was sedentary and did not have a running wheel. This design permitted the investigators to understand how the timing of maternal exercise infl uenced the metabolic characteristics of the offspring, and whether these relationships differed by maternal diet. Among the offspring of sedentary dams, glucose tolerance became less favorable as age increased. In contrast, age-related glucose tolerance was absent through the fi rst year of life among the offspring of dams that exercised before and during pregnancy. Although there was some preservation of glucose tolerance among the offspring of dams that exercised only during pregnancy, this effect was not sustained, and there was no favorable impact on glucose tolerance among the offspring of dams that exercised only before conception. Interestingly, among the offspring of dams that exercised before and during pregnancy, percent body fat and body weight were not reduced until 52 weeks, suggesting that the favorable impact of exercise on the offspring was not due to early changes in body composition. Notably, among the offspring of dams that were fed a high-fat diet, those whose dams exercised before and during pregnancy were protected from the unfavorable metabolic impact of the high-fat diet, whereas the offspring of sedentary dams were glucose intolerant. These fi ndings suggest that maternal exercise before and during pregnancy may reduce the risk that offspring will experience obesity and glucose dysregulation even when mothers have poor nutrition habits. — Helaine E. Resnick, PhD, MPH

The DCCT’s Retinopathy Risk Gap Is NarrowingEighteen years of observational follow-up after the closeout of the Diabetes Control and Complications Trial (DCCT) shows that the gap in the risk of diabetic retinopathy is narrowing between the group formerly randomized to intensive therapy (INT) and the one randomized to conventional care (CONV). Initial DCCT fi ndings showed that the risk of several complications was greatly reduced among patients with type 1 diabetes who were allocated to the INT group, with a 76% risk reduction for retinopathy over the 6.5 years of the trial. The results from the observational follow-up of the cohort demonstrated that the reduced risk of retinopathy among people formerly allocated to INT was present 4 years after the DCCT ended, and 10 years after the trial, the favorable impact of their “metabolic” memory on retinopathy risk still persisted in adults. The new report (p. 631), which provides another 8 years of observational follow-up, shows that although the cumulative risk of retinopathy was still signifi cantly lower in the INT group 18 years after the DCCT ended, the gap is narrowing. At 4, 10, and 18 years after the DCCT, membership in the INT arm of the study was associated with 71, 51, and 46% reductions in the risk of retinopathy progression relative to CONV. At each of these points in time, the signifi cant reductions in risk in the INT group were attributable to differences in HbA1c between the two groups. However, since year 10 after the DCCT ended, the year-to-year incidence of retinopathy has been similar between the two groups, an observation that is accounted for primarily by declining retinopathy incidence in the CONV group. Despite an apparent narrowing of the gap in the risk of retinopathy progression between INT and CONV, risk is still signifi cantly lower in INT, an observation that is linked to the persistent impact of metabolic memory. — Helaine E. Resnick, PhD, MPH

DOI: 10.2337/db15-ti02

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profi t, and the work is not altered.

FEBRUARY 2015

316 Diabetes Volume 64, February 2015