In This Issue of Diabetes

The genetic basis of type 1 diabetes is fairly well established, although it is clear that beyond the main genetic marker, the HLA complex, there are many other factors involved and probably many more to discover. A report by Hippich et al. (p. 847) provides a good example of this in that the authors uncover a novel risk gene, BTNL2, that encodes butyrophilin-like protein 2. They also provide evidence that in families with a history of type 1 diabetes, there is still excess risk that is unaccounted for, meaning that further relevant variants are undiscovered. The conclusions are the result of a further analysis of the longitudinal The Environmental Determinants of Diabetes in the Young (TEDDY) birth cohort and involved thousands of children with high-risk HLA genotypes undergoing further genotyping. They found that multiple known genes associated with type 1 diabetes risk were enriched in the children with a family history in comparison to children from the general population. They also identify a series of potential genetic risk factors that might be linked to diabetes risk. However, only BTNL2 survived adjustment in hazards models. To then estimate any excess genetic risk in high-risk children with a family history of type 1 diabetes, the authors matched the groups for HLA DR-DQ genotypes. They found that the matching was enough to reduce the risk to below threefold, indicating that some risk was unaccounted for in their analysis. However, when they stratified the children by their genetic risk, they found a gradient of excess risk that became negligible in the family history group in children with a full complement of genetic susceptibility. Author Anette-G. Ziegler told Diabetes: “The surprise to us was that the excess risk in relatives increased as the overall genetic risk decreased. This means that there are other risk factors that are enriched in the relatives and exert their effects more prominently in children who do not have a full set of genetic susceptibility.”

Hippich et al. Genetic contribution to the divergence in type 1 diabetes risk between children from the general population and children from affected families. Diabetes 2019;68:847–857

The quality control mechanism that deals with misfolded or unfolded proteins in the endoplasmic reticulum may have a critical role in supporting insulin secretion in pancreatic β-cells. However, according to Hu et al. (p. 733), deficiencies in the process, known as endoplasmic reticulum–associated degradation (ERAD), may contribute to the development of diabetes by affecting how proinsulin is processed and how insulin granules are released. As a result, they suggest that defective ERAD in diabetes might be a target for therapeutic intervention. The authors used a series of cell and animal experiments involving the rat insulinoma cell line INS-1, mouse models, and isolated islets from those models. They also used a chemical method and CRISPR/Cas9 gene editing to try to unravel the mechanistic basis of how ERAD might be involved in insulin secretion. They found that both chemical and genetic disruption of the ERAD system led to impaired glucose-stimulated insulin secretion, at least in the cell culture experiments. In the animal experiments, they found that mice lacking the core SEL1L protein of ERAD survived but suffered persistent hyperglycemia and glucose intolerance, implicating ERAD in the process. With regard to mechanisms, they found that the ERAD deficiency resulted in three negative effects: low mitochondrial membrane potential, reduced Ca²⁺ levels, and defective proinsulin processing at the early stages of the pathway. They also reveal details of potential overproduction of reactive oxygen species and potential alterations in mitochondrial function, which, with the other results, points toward familiar mechanistic pathways involved in diabetes progression. Taken together, the authors suggest that ERAD has a “pivotal role” in inducing insulin secretion in pancreatic β-cells and, hence, any inhibition might be a lead case for the treatment of diabetes. They also highlight that their experiments are probably the first to link ERAD deficiency to defective insulin generation and release.

Hu et al. Endoplasmic reticulum–associated degradation (ERAD) has a critical role in supporting glucose-stimulated insulin secretion in pancreatic β-cells. Diabetes 2019;68:733–746

A genome-wide association study by Syreeni et al. (p. 858) has uncovered another series of genetic loci that appear to be associated with glycated hemoglobin (HbA_1c) levels in individuals with type 1 diabetes. Specifically, the authors found three single nucleotide polymorphisms (SNPs) on chromosome 13 close to relaxin family peptide receptor 2 (RXFP2) that were significantly associated with HbA_1c. The study is based on the wider Finnish Diabetic Nephropathy (FinnDiane) Study cohort that was established in 1997 to investigate complications in diabetes and involved ∼4,600 individuals with type 1 diabetes. HbA_1c levels were then established on a roughly annual basis up to the beginning of 2016. Following SNP genotyping, any lead/top SNPs that showed a strong association with HbA_1c were then compared and replicated with data from a series of previous studies, both singly and via a meta-analysis approach. Additionally, the authors attempt to further validate their observations by comparing them with publicly available data from another genome-wide association study involving individuals without diabetes and by also constructing genetic risk scores. In addition to identifying three SNPs that associated with HbA_1c, they also found that two of them, rs2085277 and rs1360072, were associated with increased HbA_1c after a meta-analysis with one other study. They also found that the relationship held in the cohort involving individuals without diabetes. After combining their top SNPs with a series of SNPs that had previously associated with HbA_1c as a genetic risk score, they found that the relationship with HbA_1c held but that it only explained around 2.5% of the variation seen in the cohort. Syreeni et al. go on to explain the result in mechanistic and biological terms, concluding that further studies are needed to establish the role of the relaxin hormone and any potential effects it may have on HbA_1c.

Syreeni et al. Genetic determinants of glycated hemoglobin in type 1 diabetes. Diabetes 2019;68:858–867

Insulin treatment for gestational diabetes mellitus (GDM) can protect offspring from much of the detrimental effects of glycemia during pregnancy. However, evidence from Zhu et al. (p. 696) suggests that such protection might not be complete. Rather, the authors show that adult offspring exposed in utero to insulin-treated maternal glycemia can still develop a range of metabolic issues later in life, particularly if exposed to a high-fat diet. The experiments they report involve pregnant female mice randomly assigned to one of three groups: control, untreated GDM, or insulin-treated GDM. Offspring from these groups were raised for 8 weeks and then exposed to a normal chow diet or a high-fat diet. A range of measurements was used to assess metabolic outcomes of the diets. Additional experiments on isolated islets and also methylated DNA sequencing are also reported. In addition to the detrimental effects of the high-fat diet on offspring in later life, the authors also describe the effects of maternal glycemia on pancreatic islets and β-cell function in offspring. Exploring mechanisms, they focus on epigenetic modifications, particularly DNA methylation and gene expression, and identify a series of hypermethylated regions in genes that regulate insulin secretion or encode the related K_ATP and Ca²⁺ channels. Together, they suggest, such alterations might account for the intergenerational glucose intolerance they observed. Author He-Feng Huang commented: “To date, results from randomized treatment trials are still inconsistent on whether therapy for GDM confers long-term benefit to offspring. Our study provides significant experimental evidence that insulin therapy for GDM is insufficient to fully protect adult offspring from diet-induced metabolic disorders, at least partly due to the unfavorable restoration of DNA methylation. These findings are intriguing and may serve as a springboard for future research. Importantly, we hope that our study may contribute to a modification of the current screening and diagnosis of GDM and provide novel therapeutic targets for the GDM offspring in the future.”

Zhu et al. Insulin therapy for gestational diabetes mellitus does not fully protect offspring from diet-induced metabolic disorders. Diabetes 2019;68:696–708