In This Issue of Diabetes Free

DNA methylation may have a regulatory role in determining β-cell heterogeneity, according to Parveen et al. (p. 575). Specifically, they look at a subset of β-cells that express tyrosine hydroxylase (TH), an enzyme that is involved in the synthesis of catecholamines. According to the authors, there is very little understanding of the molecular mechanisms underlying β-cell heterogeneity, prompting them to use TH⁺ β-cells as a model system to carry out investigations. Initially focusing on islet cells from wild-type mice, they found that TH⁺ β-cells were readily detectable and that a majority coexpressed insulin. The cells were also replication competent and had distinct molecular and metabolic characteristics that showed differences between mice and humans. Most notably, they describe a near-total lack of such cells in human adult pancreas samples but the existence of TH⁺ β-cell clusters in fetal and neonatal pancreases. They also show that DNA methylation restricts TH expression during the transition from β-cell progenitors to fully differentiated β-cells and maintains the restriction after that. Specifically, ablation of a specific DNA methyltransferase, Dnmt3a, in embryonic progenitors resulted in significant increases in the proportion of TH⁺ β-cells, while β-cell–specific ablation (i.e., after differentiation) of Dnmt3a did not result in any increase. Further experiments then established that loss of Th promoter methylation following overnutrition (a high-fat diet) resulted in increases in the number of TH⁺ β-cells that corresponded to impaired β-cell function. Given the findings, they suggest that embryonic DNA methylation patterns affect postnatal β-cell identity and heterogeneity, which they say is noteworthy given the increased risk of β-cell failure due to overnutrition or undernutrition during development. Commenting further, author Sangeeta Dhawan said, “These studies have prompted us to start delineating the specific contributions of DNA methylation patterns established at different stages of early pancreas development to various aspects of adult β-cell homeostasis. This will allow us to identify the potential developmental events that may predispose to adult β-cell failure.”

Up to 112 proteins may be associated with incident type 2 diabetes and longitudinal changes in blood glucose, according to Cronjé et al. (p. 666). Significantly, 90% of these proteins shared associations with at least one of the measures of glucose homeostasis in an independent, younger, and healthier cohort. The findings come from high-throughput proteomics association studies of type 2 diabetes risk and physiological responses to intravenous glucose tolerance testing. A total of 4,776 proteins were measured and associated with 18-year incident diabetes risk in over 2,500 participants from the Cardiovascular Health Study. They then used various measures of glucose homeostasis from 752 individuals who participated in the Health, Risk Factors, Exercise Training and Genetics Family Study to identify overlapping protein associations and extend the longitudinal findings. They found that 51 proteins were associated with incident type 2 diabetes in their main modeling, with a further 59 associations apparent in base modeling. Of these, 29 were novel and 81 were supported by prior proteomic investigations. The associations largely overlapped those observed in further analyses of longitudinal glucose profiles. The authors then carried forward 112 proteins to look for associations with various measures of blood glucose homeostasis. They highlight β-glucuronidase, which was associated with increased diabetes risk, lower glucose effectiveness, and lower insulin sensitivity, which they suggest indicate its involvement in a pathway alternative to that of insulin for glucose disposal. They also discuss proteomic association patterns related to insulin resistance, pancreatic function, and wider glucometabolic pathways that are independent of insulin. Commenting further, author Héléne T. Cronjé said, “Our study provides insight into the proteins that reflect future type 2 diabetes risk and its various metabolic derangements. We hope that the results may eventually be used to help identify individuals at risk of type 2 diabetes, so that interventions may be initiated earlier. Our findings should also be used to clarify the various mechanisms that lead to type 2 diabetes, thus facilitating the discovery of novel therapeutic opportunities.”

A novel mechanism underlying glucagon receptor antagonism is proposed by Wei et al. (p. 599). They suggest that activation of glucagon-like peptide 1 receptor (GLP-1R) by glucagon leads to β-cell regeneration that can be induced with glucagon receptor antagonism, at least in mice with diabetes. Understanding such mechanisms is seen as important because the glucagon receptor is considered a treatment target in diabetes, with numerous potential treatment routes showing promise in both types of diabetes and in animals and humans. Using a series of (diabetic) mouse models, they found that a monoclonal antibody that targets the glucagon receptor improved glucose control, upregulated plasma insulin level, and expanded β-cell area. Blockage of systemic and pancreatic GLP-1R signaling with either exendin 9-39 or pancreatic Glp1r knockout then substantially reduced the effects of the monoclonal antibody. A glucagon-specific neutralizing antibody could then prevent glucagon from activating GLP-1R and also attenuate any increases in insulin release and β-cell regeneration that would be expected of the glucagon receptor–targeted monoclonal antibody. In examinations of cultured primary mouse islets from normal and diabetic mice, they found that the monoclonal antibody also increased insulin release and upregulated β-cell–specific marker expression. They also could recapitulate the blocking effects of the glucagon–neutralizing antibody, the GLP-1R antagonist exendin 9-39, and Glp1r knockout, effectively confirming the effects seen in the mouse models. Commenting further, author Rui Wei said, “Our study demonstrates that the upregulated glucagon and GLP-1 secretion from a-cells contributes to glucagon receptor antagonism–induced β-cell regeneration. This is a neglected communication between a-cells and β-cells, which represents a shift from the side effect of glucagon receptor antagonism toward its beneficial effects on β-cells. Since glucagon receptor antagonism shows effective glucose control in patients with diabetes, we are eager to know whether our findings can be translated into humans.”

HbA_1c appears to increase marginally following a positive COVID-19 test, according to Sharma et al. (p. 627). While the increase was statistically significant, it was most probably clinically insignificant. The increase was 0.1% or less depending on the presence or absence of diabetes. However, patients who were positive for COVID-19 were much more likely to be diagnosed with type 2 diabetes than those who were negative for COVID-19, and it seems likely the effect can be assigned to patients receiving more intensive levels of care when positive for COVID-19. The findings come from a large real-world clinical cohort that included just under 9,000 COVID-19–positive patients and just under 12,000 patients who were negative for COVID-19. Previous studies have discussed the prospects of COVID-19 potentially raising type 2 diabetes and diabetic ketoacidosis risks. However, the real-world impact of COVID-19 on such risks remains unknown according to the authors, which prompted the study. They found only marginal effects on HbA_1c that could be attributed to a COVID-19 infection, yet COVID-19 patients were 40% more likely to be diagnosed with type 2 diabetes than negative patients. COVID-19 patients were also 274% more likely to receive a type 2 diabetes diagnosis when they had the same HbA_1c level as those without a positive COVID-19 test. They were also 28% more likely than negative patients to be diagnosed with diabetes when comparable increases in HbA_1c were observed after a COVID-19 test. This was most likely underlying diabetes being recognized as part of COVID-19 treatment, according to the authors. In terms of diabetic ketoacidosis risk, there were no differences in risk in individuals with type 1 or 2 diabetes whether they were COVID-19 positive or not. However, Black patients with type 2 diabetes who were positive for COVID-19 were twice as likely to be diagnosed with diabetic ketoacidosis as equivalent White patients.