In This Issue of Diabetes

Oral fenofibrate can improve ocular integrity and stimulate corneal nerve regeneration in patients with type 2 diabetes and diabetic corneal neuropathy, according to Teo et al. (p. 932). Fenofibrate also significantly altered neuroprotection, anti-inflammation, and anticoagulation pathways. Given the outcomes of their study, the authors suggest there is now a basis to evaluate whether the drug is a potential treatment option for diabetic corneal neuropathy. The findings come from a single-arm, open-label, interventional study in which 30 individuals with type 2 diabetes received fenofibrate for 30 days. Twenty healthy individuals were also included as control participants, although they did not receive the intervention. To investigate potential mechanisms of action, individuals were assessed for a series of metrics related to cornea health and characteristics via in vivo confocal microscopy, proteomics, and other approaches. After participants received 30 days of fenofibrate treatment, the authors found that there was significant improvement in corneal nerve fiber density and width, indicating corneal nerve regeneration and reduction in nerve edema. They also found that fenofibrate increased tear breakup time and reduced punctate keratopathy (i.e., corneal surface damage, as shown in the figure). The finding that individuals had increased levels of tear substance P following treatment also suggested reduced ocular surface inflammation, which was associated with improved corneal nerve fiber density. Proteomics analyses also revealed modulation of the neurotrophic signaling pathway and fat metabolism, while neutrophil reactions and platelet activation were reduced following treatment. While they acknowledged that the study has some limitations, the authors conclude that, collectively, there is support for further investigations into fenofibrate as a potential treatment for diabetic corneal neuropathy. Currently, there are few therapies for the condition beyond treating symptoms rather than the underlying cause(s). Commenting further, author Yu-Chi Liu said, “We are excited to report the ability of fenofibrate to regenerate damaged corneal nerves. Few treatments reverse the natural history of this diabetes-related complication, but we believe that fenofibrate can be developed as a clinically effective and affordable treatment for diabetic corneal neuropathy.”

Radiolabeled exendin imaging can be used to monitor and quantify islets after intrahepatic transplantation into people with type 1 diabetes, according to Jansen et al. (p. 898). Using a combination of positron emission tomography (PET) and computed tomography (CT) scanning, they found that individuals who received islet transplantation had significantly higher levels of detectable ⁶⁸Ga-exendin hotspots than control individuals. Circulating C-peptide was also higher in individuals who received a transplantation, indicating they had functioning islet grafts, and in one individual with a transplant the authors demonstrated glucagon-like peptide 1 (GLP-1) receptor expression (the target of exendin, a GLP-1 analog) in islet grafts in liver tissue via immunohistochemistry. The findings come from a pilot study involving 13 individuals with type 1 diabetes, 9 of whom had received an islet transplantation and 4 of whom were waiting for the procedure and acted as control participants. The authors then used a combination of mixed-meal tolerance tests to determine β-cell function and PET/CT scanning to examine ⁶⁸Ga-exendin tracer hotspots in liver. Using a measure derived from the scanning, they found that individuals with the grafting had significantly higher uptake of ⁶⁸Ga-exendin (median score 0.55) than control individuals (0.43). Concerns about local fat deposition due to the transplanted islets also prompted the authors to determine intrahepatic fat with a combination of MRI and spectroscopy, but they found little evidence for a relationship between hotspots and fat depositions in most individuals in the study. Issues with intrahepatic islet transplantations include the loss of islets during the procedure and the deterioration of graft function over time, which is compounded by a general inability to monitor their fate, particularly noninvasively. Commenting more widely, author Marti Boss said, “We believe that the ability to noninvasively monitor the fate of transplanted islets with ⁶⁸Ga-exendin PET can be of great value for the improvement of islet transplant strategies. This will allow us to measure the impact of novel strategies like encapsulation or the effects of medical interventions on islet survival rather than only monitoring islet function.”

Insulin sensitivity in mice is improved by exercise, but the magnitude of effect depends on diet, age, and the interaction of diet and age, according to Vieira-Lara et al. (p. 872). For example, exercise in mice improved peripheral insulin sensitivity only at younger age, while exercise fully prevented age-dependent decline in sensitivity in the liver. Exercise also improved sensitivity more in mice fed a low-fat diet than in mice fed a high-fat diet. The findings come from an investigation centered around the use of oral glucose tolerance tests that included a glucose tracer in mice aged between 4 and 21 months. Mice were then assigned to groups to receive a low- or high-fat diet and either a sedentary state or lifelong access to voluntary running. The authors also applied computational modeling to separate effects of exercise on different compartments of peripheral tissue and liver. They found that indices of insulin sensitivity of peripheral tissues and liver decreased with aging and high-fat diet. There was also a decline with age in mitochondrial capacity to oxidize lipids. Mice on a low-fat diet, on the other hand, had enhanced peripheral tissue insulin sensitivity with exercise, which also completely prevented an expected age-dependent decline in insulin sensitivity in liver. This only occurred in mice on a low-fat diet and had a minimal effect on insulin sensitivity in muscle. Numerous previous studies have looked at the effects of exercise on insulin sensitivity and glucose metabolism, with many looking at the effects of age and diet. However, none have systematically addressed how the three factors interact in the development of insulin resistance, prompting the study. Commenting more widely, author Marcel A. Vieira- Lara said, “Our study demonstrates that physical activity benefits glucose homeostasis most under healthy nutritional conditions. Thus, the prevailing idea that a physically active lifestyle might fully compensate for eating unhealthily is probably incorrect.”

A phosphorylation site on a protein called TBC1D4 regulates muscle insulin sensitization in response to exercise and muscle contractions, according to Kjøbsted et al. (p. 857). Specifically, mice lacking phosphorylated TBC1D4-S711 appear to retain whole-body and muscle insulin sensitivity when resting but do not exhibit enhanced muscle insulin sensitivity following a single bout of exercise. Previous studies have suggested that TBC1D4 is a point of convergence for exercise and insulin-induced signals that regulate the glucose transport process. To test the hypothesis that TBC1D4-S711 specifically was key to this interplay, the authors used a knock-in mouse model that has a point mutation that replaces serine with alanine at residue 711 in the long version of Tbc1d4—effectively silencing the phosphorylation at that residue. The authors then used a series of experiments to explore the effects of the change by comparing the knock-in mouse model to wild-type mice. They found that the mouse model had normal growth, eating behavior, and whole-body glycemic control on both standard and high-fat diets. In both the knock-in mouse model and wild-type mice, muscle contraction increased glucose uptake and AMP-activated protein kinase activity. However, following exercise, improvements in whole-body and muscle insulin sensitivity were evident only in the wild-type mice and occurred at the same time as enhanced phosphorylation of TBC1D4-S711. Based on the findings, the authors conclude that TBC1D4-S711 appears to be central to the signaling that mediates the insulin-sensitizing effects of exercise on skeletal muscle glucose uptake, at least in mice. They add that further studies will be needed to understand exactly how TBC1D4-S711 enhances insulin-stimulated muscle glucose uptake after exercise and whether it acts in the same way in humans. Commenting further, author Rasmus Kjøbsted said, “We have taken initial steps to translate and explore these ideas in humans by studying a cohort of Greenlandic Inuit individuals who carry a point mutation in the TBC1D4 gene, leading to loss of TBC1D4 protein in muscle.”