In This Issue of Diabetes

The hunt for a drug that can mimic the effectiveness of bariatric surgery in type 2 diabetes and obesity, but without the surgery, continues with the key possibly lying with G-protein–coupled receptors (GPCRs) in enteroendocrine cells in the gastrointestinal tract. Mouse models have led to some progress in studying the cells, but the question remains as to how similar the cells are in terms of function in humans and mice. The study by Roberts et al. (p. 1062) sets out to answer this question, with the authors concluding that at least on the levels of the transcriptome and peptidome, there are strong correlations between human and murine enteroendocrine cells. The significance, they suggest, is that the mouse models are valid for exploring signaling pathways and that GPCRs in the cells are a potential source of drug targets for type 2 diabetes and obesity. Using enteroendocrine cells from intestinal segments of humans and mice, the authors used RNA sequencing that was deep enough to identify low-abundance GPCRs and other hormone-related transcripts. While they note some differences, they report a strong correlation between the species in terms of genes expressed. They also found numerous peptides and proteins that matched in both species. Roberts et al. suggest the profiles and methods will be useful in drug discovery programs, although they caution that at the individual gene level, there are still differences between humans and mice and that these may have profound implications when using the models to target specific pathways or targets. Authors Fiona M. Gribble and Frank Reimann commented: “This is the first time that the human enteroendocrine cell transcriptome has been studied in detail—the data can be mined for new targets to stimulate gut hormone secretion, and the strong correlation between the human and mouse transcriptome justifies the use of murine models for preclinical target verification.”

Roberts et al. Comparison of human and murine enteroendocrine cells by transcriptomic and peptidomic profiling. Diabetes 2019;68:1062–1072

Glucagon receptor antagonists (GRAs) hold some promise as a treatment for diabetes as they can, in theory, control glucagon-stimulated increases in glucose. Even so, there are concerns, based mainly on evidence from experiments with young mice, that their use might cause uncontrolled α-cell growth. However, according to Lam et al. (p. 963), this concern may not be fully warranted, as it appears that α-cell proliferation is severely restricted in older mice following administration of a GRA called JNJ-46207382. As a result, they suggest this should provide some reassurance on the use of GRAs in middle-aged or elderly patients. The conclusions come from a series of experiments with mice designed to assess adaptive α-cell turnover and proliferation following the administration of JNJ-46207382. Crucially, however, the experiments were performed with both young and aged mice and appropriate controls. The authors found that in controls, basal α-cell proliferation dropped rapidly after birth and continued falling to very low levels as the mice aged. After administering JNJ-46207382, they found that the antagonist drove a 2.4-fold increase in α-cell proliferation in young mice and a 3.2-fold increase in aged mice. However, overall levels of proliferation in the aged mice were severely reduced because of the very low basal rates. They also found that α-cells only appear to divide once in both basal and stimulated conditions and that there is unlikely to be any assistance from other cell types—indicating that α-cells expand by self-renewal. Author Jake A. Kushner told Diabetes: “Although α-cells play key roles in mammalian physiology, the life cycle of mature α-cells remains a bit of a mystery. Our studies seem to indicate that like β-cells, mouse α-cells arise from self-renewal and lose their capacity to divide as the organism ages. We expect that future studies will begin to focus on the developmental biology of human α-cells in healthy and disease states.”

Lam et al. Glucagon receptor antagonist–stimulated α-cell proliferation is severely restricted with advanced age. Diabetes 2019;68:963–974

The role of monosodium urate in the induction of diabetic retinopathy is explored by Thounaojam et al. (p. 1014), with the authors concluding that it likely does contribute to progression via retinal inflammation. As a result, they suggest that monitoring monosodium urate levels might have prognostic value for retinopathy and that clinical studies are now warranted to confirm whether uricemia is a new risk factor for the complication. They also suggest that hypouricemic drugs should be validated in trials to confirm whether they would work as an adjunctive therapy. The findings are the result of a series of experiments involving human eye samples and also a rat model rendered diabetic with streptozotocin (STZ). Initially focusing on postmortem donor retinas and vitreous from patients with diabetic retinopathy (and control subjects), they found elevated levels of uric acid in vitreous of both postmortem donors and patients with diabetic retinopathy. They also found the same elevated levels in serum, vitreous, and retina of rats rendered diabetic for 8 weeks. To further establish a role for uric acid, the authors turn to the hypouricemic drugs allopurinol and benzbromarone, which target different aspects of uric acid disposal. They found that as well as lowering uric acid to levels, in some cases, of those of controls, there were also reductions of retinal and plasma levels of inflammatory cytokines and adhesion factors. There was also a reduction of leukostasis and restoration of the retinal blood barrier. Turning to mechanisms, they found that the drugs were downregulating oxidative stress markers and also components of the NLRP3 inflammasome. While noting that their studies should be considered preliminary, Thounaojam et al. indicate that along with other evidence, there is a need for further studies, as uric acid or its crystal form monosodium urate might represent a new risk factor for retinopathy. They also suggest further studies with the drugs they used, as they could potentially work as a treatment.

Thounaojam et al. Monosodium urate contributes to retinal inflammation and progression of diabetic retinopathy. Diabetes 2019;68:1014–1025

A small study of four individuals with complete melatonin deficiency suggests that melatonin supplementation can increase brown adipose tissue (BAT) volume, which according to Halpern et al. (p. 947) means that melatonin is a possible BAT activator and thus a theoretical tool for the treatment of type 2 diabetes and obesity. The study involved individuals who had undergone surgical removal of the pineal gland or radiotherapy targeting the pineal region due to pineal cancer (a rare form of cancer). The pineal gland is the primary source of melatonin. To estimate active BAT volume, the individuals underwent cold exposure and a combination of MRI, positron emission tomography, and infusion with 2-deoxy-2-[fluorine-18] fluoro-d-glucose. Following that procedure, the individuals then took daily melatonin for 3 months and then returned for a further session of PET-MRI. The authors found that in all individuals, BAT volume increased following the melatonin supplementation. There were also improvements in total cholesterol and triglyceride levels in blood but no effects on weight, liver fat, or HDL or LDL cholesterol levels over the same period. Insulin levels and insulin resistance also decreased in the four individuals. While cautious about the wider implications of the study (mainly because of the very small sample size), the authors explain that they do not believe melatonin will be used as an independent antiobesity or diabetes drug. Author Bruno Halpern commented: “I do not think that melatonin will have any direct indication for obesity or diabetes, but maybe its supplementation in individuals with melatonin deficit (for example, excessive light at night exposure) could improve comorbidities in the long term, or even prevent weight gain or metabolic disturbances. Melatonin is a hormone and should be seen as one; it should be recommended for those who do not produce it and not as a general prescription.”

Halpern et al. Melatonin increases brown adipose tissue volume and activity in patients with melatonin deficiency: a proof-of-concept study. Diabetes 2019;68:947–952