By Max Bingham, PhD

Metabolic profiles in the period prior to seroconversion to either insulin or GAD autoantibodies (IAA and GADA, respectively) are different according to an analysis by Li et al. (p. 465). Specifically, the authors suggest that the findings imply there might be distinct causes of each type of autoimmunity that can ultimately lead to the onset of type 1 diabetes. The findings come from an analysis of The Environmental Determinants of Diabetes in the Young (TEDDY) study and involved a nested case-control cohort of approximately 2,000 young individuals. Blood samples were collected prospectively every 3 months after birth until the appearance of the first islet autoantibody. Only individuals who were positive for IAA or GADA were included and were matched 1:3 with control subjects according to clinical site, type 1 diabetes family history, and sex. Metabolomics approaches (based on mass spectrometry) were then used to generate metabolic profiles. They found that numerous features were associated with conversion to the two different autoantibodies and that these appeared at different time points following birth. In particular, the authors highlight dehydroascorbic acid, γ-aminobutyric acid, the amino acids proline, alanine, and methionine, various branched-chain amino acids, fatty acids, and triglycerides as features in the profiles. The authors go on to explain some of the possible biological phenomena leading up to seroconversion to either IAA or GADA, although it is clear that numerous differences between the profiles may be relevant to the outcomes. In terms of limitations, they point toward the 3-month sampling cycle, which could mean they may have missed certain profiles. Despite this, they highlight that the distinct metabolic profiles prior to seroconversion point toward the possibility of different causes and that ultimately means type 1 diabetes might have multiple causes. Commenting further, author Qian Li told Diabetes: “This work, which focused on metabolome-wide features in early childhood, validated and extended previous findings on islet autoimmunity, identifying different metabolic markers for distinct islet autoantibodies.”

Li et al. Longitudinal metabolome-wide signals prior to the appearance of a first islet autoantibody in children participating in the TEDDY study. Diabetes 2020;69:465–476

A key issue in obesity is the failure of glucose homeostasis, as it can lead to type 2 diabetes. This occurs when pancreatic β-cells fail to meet insulin requirements in the face of insulin resistance. Under normal circumstances, β-cells increase insulin secretion capacity and mass to deal with increases in glucose, but only up to a point. What is less clear, according to Maachi et al. (p. 369), are the precise mechanisms underlying this β-cell proliferation. Based on a series of experiments, they now propose the key to β-cell proliferation seems to rest with a signaling axis centered around glucose, heparin-binding EGF-like growth factor (HB-EGF), and the corresponding epidermal growth factor receptor (EGFR). Using a series of molecular techniques, they report that isolated islets from both rats and humans showed β-cell proliferation when exposed to HB-EGF. Conversely, in rat islets, inhibition of either EGFR or HB-EGF (and hence HB-EGF signaling) resulted in prevention of the proliferative response. To confirm the effects, they also used a genetic knockdown of HG-EGF in rat islets and found that β-cell proliferation was blocked in response to glucose in rats. Moving to mechanisms, they found that HB-EGF mRNA levels increased in β-cells following glucose exposure and that this depended on levels of carbohydrate-response element–binding protein (ChREBP). They also found evidence of binding sites for ChREBP close to the gene for HB-EGF and that inhibition of Src family kinases also reduced β-cell proliferation following exposure to glucose. Commenting further, author Vincent Poitout told us: “Our findings identify an interesting link between glucose, a major substrate for metabolic signaling within the β-cell, and an extracellular signaling pathway involving HB-EGF and its receptor. They suggest that complex functional interactions between different signals regulate β-cell replication, which may well act as safeguards against uncontrolled cell proliferation. Of course, the key question we now have to address is whether this system is operational in human β-cells and whether it can be harnessed for therapeutic purposes.”

HB-EGF is required for glucose (Glu)-induced β-cell proliferation in vivo. Representative images of Ins (green), Ki67 (red), and nuclei (blue) staining in transplanted rat islets.

HB-EGF is required for glucose (Glu)-induced β-cell proliferation in vivo. Representative images of Ins (green), Ki67 (red), and nuclei (blue) staining in transplanted rat islets.

Maachi et al. HB-EGF signaling is required for glucose-induced pancreatic β-cell proliferation in rats. Diabetes 2020;69:369–380

Whether or not the regular decrease in insulin sensitivity seen during pregnancy is due to the “maternal-fetal conflict” is tackled by Hivert et al. (p. 484), with the authors suggesting that placental DNA methylation is linked to maternal insulin sensitivity in pregnancy. Using a cohort of 430 mother-offspring pairs, they looked at the oral glucose tolerance tests of the mothers-to-be at 26 weeks to estimate glucose and insulin levels. Then at delivery, they collected placenta samples (among others) to measure DNA methylation levels. After adjusting for a series of factors, they identified 188 CpG sites from placenta samples that might be related to insulin sensitivity in mothers. Among the sites they identified, they found enrichment for microRNAs, histone modification, and various placental imprinted genes, many with a paternal origin. To then untangle the direction of effect, they used a Mendelian randomization approach to reveal five potential DNA methylation loci that appeared to be causally implicated in maternal insulin sensitivity. Based on this analysis, they suggest that placental methylation is more likely to affect maternal insulin sensitivity rather than the other way around. Despite strengths in the study, they do mention one notable limitation: that the second part of the Mendelian randomization was likely limited in terms of statistical power, meaning that it is not possible to exclude the chance that insulin sensitivity affects methylation levels. Commenting more widely, author Marie-France Hivert told Diabetes: “Our findings offer new understanding of the placenta’s role in maternal glycemic regulation. Future functional studies will hopefully help reveal exact roles of genes at identified loci. In particular, the highlighted microRNAs may have autocrine and paracrine actions on the placenta, or endocrine roles in other insulin sensitive tissues. Understanding the role of these microRNA and other identified genes may lead to identification of treatment targets to improve insulin sensitivity inside and outside of pregnancy.”

Hivert et al. Interplay of placental DNA methylation and maternal insulin sensitivity in pregnancy. Diabetes 2020;69:484–492

The adipokine Gremlin 1 is a key mediator of insulin resistance in obesity and type 2 diabetes, according to Hedjazifar et al. (p. 331). Based on this and their previous findings that Gremlin 1 prevents the browning of adipose tissue and thus energy expenditure, the authors suggest that Gremlin 1 should be considered as a target for treatment for obesity, type 2 diabetes, and even nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH). The claims are based on an analysis of six small cohorts of individuals that variously had genetic risk for diabetes or not, severe obesity with or without diabetes, moderate obesity, NAFLD or NASH, or normal weight and health. In total, 495 individuals were involved in the study. They found that Gremlin 1 expression was high in subcutaneous adipose tissue and further increased in visceral fat and that overall levels were higher in obesity and even higher in type 2 diabetes. They also found that expression was elevated in liver biopsies but not in skeletal muscle. Additionally, they report that transcriptional activation in adipose tissue and liver and serum levels of the protein were strongly associated with degree of insulin resistance and the presence of NAFLD and NASH. To support the evidence from the cohort studies, they also carried out a series of experiments with cells, finding that Gremlin 1 is an antagonist of insulin signaling in adipocytes, skeletal muscle, and liver cells. Author Ulf Smith commented: “We show that Gremlin 1 is an antagonist of insulin signaling in key human metabolic target tissues and is highly upregulated in the adipose tissue and liver in obesity and type 2 diabetes and increased in serum. Importantly, we also show that Gremlin 1 mRNA levels are further increased in liver biopsies from individuals with NAFLD/NASH. Together, these data make Gremlin 1 an interesting target in the treatment of insulin resistance, type 2 diabetes, and NAFLD/NASH.”

Insulin signaling is inhibited by secreted Gremlin 1 and not a truncated nonsecreted form of Gremlin 1. Cellular localization of WT.GREM1.myc and mut.GREM1.myc in HepG2 hepatocytes stained by Myc antibody (green) and DAPI (blue) and imaged with a confocal microscope.

Insulin signaling is inhibited by secreted Gremlin 1 and not a truncated nonsecreted form of Gremlin 1. Cellular localization of WT.GREM1.myc and mut.GREM1.myc in HepG2 hepatocytes stained by Myc antibody (green) and DAPI (blue) and imaged with a confocal microscope.

Hedjazifar et al. The novel adipokine Gremlin 1 antagonizes insulin action and is increased in type 2 diabetes and NAFLD/NASH. Diabetes 2020;69:331–341

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