In This Issue of Diabetes

Early intrauterine exposure to gestational diabetes appears to be associated with a radiologically obtained biomarker for mediobasal hypothalamus (MBH) gliosis in offspring children aged 7–11 years, according to Chandrasekaran et al. (p. 2552). Previous studies have linked such gliosis to insulin resistance, visceral adiposity, risk of obesity, and risk for subsequent metabolic disease. “These initial data suggesting offspring metabolic impacts from intrauterine exposure to gestational diabetes lay the foundation and necessity for future studies,” said lead author Suchitra Chandrasekaran. “This is to understand mechanisms at the maternal–fetal–placental interface impacting fetal brain development and subsequent long-term metabolic effects.” Involving 122 children aged ∼9 years, the study used MRI to identify brain regions of interest relating to the MBH, amygdala (i.e., gray matter), and white matter. T2 signal ratios were then calculated to identify any potential MBH gliosis. Participants were grouped according to gestational diabetes exposure (yes/no) and further grouped according to exposure at <26 weeks or >26 weeks of gestation. Overall, there were no significant differences in T2 signal ratios between the exposed and unexposed groups. However, when the exposed group was split according to early or late exposure, there were significant differences in the MBH–to–white matter ratio and a strong trend in the MBH-to-amygdala ratio signal, indicating likely gliosis in the MBH. “Findings from this study suggest that exposure to gestational diabetes during early fetal development is linked to alterations in the hypothalamus, a key brain area for body weight regulation,” said senior author Kathleen Page. “These preliminary findings in humans are consistent with animal studies that showed exposure to diabetes in utero promotes changes in the hypothalamus that predispose to obesity and diabetes later in life.” The authors note that further factors could still contribute to the findings, including the role of diet (both maternal and child), genetics, lifestyle, insulin signaling, and even the gut microbiome, all factors that can be addressed with further studies.

South Asian women with previous gestational diabetes appear to have lower β-cell function, lower hepatic insulin clearance, and lower insulin sensitivity than Nordic women, according to Sharma et al. (p. 2530). Based on the findings they suggest that South Asian women are on a faster course toward developing type 2 diabetes than the comparison group. The findings come from the Diabetes in South Asians 1 (DIASA 1) study that looked at various metabolic indexes related to insulin and β-cell function using a combination of oral glucose tolerance tests and a technique called C-peptide deconvolution. A total of 179 South Asian and 108 Nordic women who had gestational diabetes approximately 17 months previously were enrolled in the study. “An important finding was that insulin secretion estimated with C-peptide deconvolution indicated a markedly lower β-cell function in South Asian women, even women with normal glucose tolerance,” said lead author Archana Sharma. “It also indicates that analyzing only peripheral insulin levels may mask an early β-cell dysfunction.” Around one-third of South Asian women and just over half of Nordic women had normal glucose tolerance at the time of the testing. Further, compared to Nordic women, both normoglycemic and hyperglycemic South Asian women had lower fasting hepatic insulin clearance. “We speculate that this reduced hepatic insulin clearance may be an early and important adaption to the increased insulin resistance in South Asians known to be present decades before developing diabetes,” Dr. Sharma added. Based on mediation analyses the authors also report that waist-to-height ratio explained ∼25–40% of the ethnic differences in insulin sensitivities in participants with normal glucose tolerance. The authors suggest that the ethnic differences in body composition and central fat accumulation lend support to initiatives that recommend strong preventive measures against overweight and obesity, particularly in South Asian women with high risk of diabetes. Dr. Sharma said, “Focusing on prehepatic insulin secretion and hepatic insulin clearance adds to our understanding of the pathophysiology of type 2 diabetes in South Asian populations.”

Calcium dynamics appear to be altered in pancreatic islets and β-cells of individuals with type 2 diabetes, according to Gosak et al. (p. 2584). Given the likely central role of calcium in the signaling networks between β-cells, the authors suggest there are additional targets for improving insulin secretion in diabetes. The findings come from calcium imaging studies of isolated human pancreatic islets that were exposed to glucose under a standardized protocol. Islets came from donors with type 2 diabetes or no diabetes and were analyzed with a combination of imaging and advanced computational techniques. In islets from individuals without diabetes, they found that activity happened in the form of calcium oscillations. The activity was also glucose dependent, with higher concentrations resulting in generally enhanced activity, greater global calcium waves, and denser networks. (A video of the calcium waves and oscillations is available in the article’s supplementary material [doi.org/10.2337/figshare.20775532].) Compared to islets from individuals without diabetes, waves from individuals with diabetes were weaker but retained glucose dependence. They were also more locally restricted in space/time, and networks were more segregated. “Our findings that islets from donors with type 2 diabetes are still responsive to glucose and that some islets are much more severely affected than others support the view emerging from clinical studies that diabetes is not necessarily an irreversible disease,” said senior author Andraž Stožer. Notably, the authors also found that they could change the levels of calcium wave activities with the application of various factors. Glucagon-like peptide 1 receptor stimulation in particular increased activity time and resulted in much denser networks of activity—an effect consistent with the known therapeutic effects of glucagon-like peptide 1 receptor agonists. Commenting further, lead author Marko Gosak added, “In the foreseeable future, we would like to find out more precisely how calcium dynamics change during progression of diabetes and how this correlates with other pathophysiological hallmarks of β-cell dysfunction.”

Retinal oxygen extraction appears to be reduced in individuals with type 2 diabetes and various levels of severity of diabetic retinopathy, according to Hommer et al. (p. 2677). Specifically, it also appears that the impairment in oxygen metabolism is dependent on the severity of retinopathy. This suggests that tissue hypoxia caused by reduced oxygen delivery to retinal tissue is central to the mechanisms behind retinopathy. The findings come from a cross-sectional study that involved 67 individuals with type 2 diabetes and 20 healthy individuals acting as controls. Of those with diabetes, 34 had no retinopathy, while 15 and 18 had mild or moderate to severe retinopathy, respectively. All participants underwent various assessments of retinal oxygen metabolism, including total retinal blood flow and retinal oxygen saturation. Retinal oxygen extraction was calculated from these final two parameters. According to the authors, oxygen saturation was highest in healthy control individuals and lowest in individuals with mild retinopathy. Meanwhile, patients with no or mild retinopathy tended to have higher total retinal blood flow than those with moderate to severe retinopathy or healthy individuals. Based on that data, the authors then calculated retinal oxygen saturation, finding that it was highest in healthy individuals followed by diabetes patients with no retinopathy, mild retinopathy, and finally moderate to severe retinopathy. The authors point out that interpreting the findings is challenging because measuring oxygen saturation in retinal arteries will only give a partial picture of the metabolic changes in retinopathy. Nevertheless, they point towards the observations being in line with other evidence supporting a role for hypoxia in retinopathy. “In summary, our data indicate that oxygen extraction is reduced in patients with type 2 diabetes and moderate to severe diabetic retinopathy,” they write. “Further longitudinal studies are needed to assess whether oxygen saturation may serve as a biomarker in the future to identify high-risk patients.”