By Max Bingham, PhD
Prepregnancy High-Fat Feeding Reduces Offspring Blood Glucose Levels via Increased β-Cell Development
The effects of maternal obesity on the development of offspring are explored by Qiao et al. (p. ) revealing that, at least in mouse models, a prolonged high-fat diet prior to pregnancy reduces blood glucose concentrations in both newborn offspring and fetuses in late pregnancy. Significantly, however, the authors also explore the potential underlying mechanisms that might be involved. The relationship between maternal obesity and neonatal hypoglycemia is well established, with concern pointing toward developmental issues, but why the phenomenon occurs is relatively unexplored. The authors explain that identifying the mechanisms underlying the relationship could unlock diagnostic and therapeutic options that might improve pregnancy outcomes. Using a series of mouse models, they report that feeding prepregnant and pregnant mice a high-fat diet did result in reduced blood glucose in both neonates and fetuses in late pregnancy and also resulted in increased blood insulin concentrations and pancreatic β-cell mass. They also found hyperactivation in a series of metabolically active tissues, which they suggest explains the reduction in offspring blood glucose concentrations. While they did not find an increase in placenta cross-sectional area or GLUT1 expression, there was a significantly enhanced expression of genes that control placental fatty acid supply. Turning to a mouse model with placenta-specific knockout of adipose triglyceride lipase, they found it had a reduced fetal β-cell area and blood insulin concentrations and also attenuated the reductions in offspring blood glucose concentrations due to maternal high-fat feeding and obesity. Author Jianhua Shao told Diabetes: “This is the first animal study that reveals the significance of prepregnant maternal obesity, but not dietary fat during pregnancy, in offspring islet development and glucose metabolism. This study also demonstrates that fetal glucose metabolism is not simply and passively controlled by placental glucose supply but is also regulated by insulin in late pregnancy. The reduction of fetal blood glucose concentrations is a novel phenotype, and its impact on development and later health should be investigated.”
Prepregnant high-fat feeding increased fetal and neonatal blood insulin concentrations and pancreatic β-islet area. Pancreatic β-islet areas (green arrowheads) were probed by immunohistochemistry using an antibody against insulin.
Prepregnant high-fat feeding increased fetal and neonatal blood insulin concentrations and pancreatic β-islet area. Pancreatic β-islet areas (green arrowheads) were probed by immunohistochemistry using an antibody against insulin.
Next-Generation Sequencing Identifies Further “Causal Residues” Responsible for Risk of T1D
A series of amino acid residues has been identified by Zhao et al. (p. ) as potentially “causal” in the risk of childhood type 1 diabetes. Using next-generation targeted sequencing (NGTS) of HLA-DRB1, 3, 4, and 5, the authors identify numerous structural features that maintain significant associations with type 1 diabetes risk. They suggest the list of amino acid residues they have identified might contain targets for intervention in the pre- or new-onset phase of type 1 diabetes. The case-control study involved ∼1,000 patients with type 1 diabetes from a Swedish cohort and ∼650 geographically matched control subjects and involved next-generation sequencing of whole-blood samples. Using a complex series of statistical and structural analyses, including a novel “recursive organizer” process, they identify 11 residues of DRB1 that all had structural features that suggested functional mechanisms through peptide binding. They also identify 15 further residues in the other DRB proteins (i.e., 3, 4, and 5) that suggest interactions and binding with accessory molecule CD4 and retain significant disease association. Further analyses then suggested residues in DRB1 that were significantly associated with autoantibodies against ZnT8 (ZnT8A) and residues in the other DRB proteins associated with autoantibodies against GAD65 (GADA). The authors identify four residues with a particularly strong association with autoantibodies against IA-2 (IA-2A), identifying a sequence termed ERKA that confers a strong risk association and ERKG that confers a strong protective association. On that basis, they suggest that the list of targets should be studied further, possibly expanding the analyses to neighboring DQ genes. Author Åke Lernmark commented: “The HLA NGTS has uncovered unexpected relationships and a promise to better understand possible mechanisms and generate novel hypotheses through the molecular simulation analyses. Indeed, dissecting HLA through NGTS suggests to us that there is much to learn about HLA and the etiopathogenesis of type 1 diabetes.”
Results from analyzing T1D association with HLA-DRB345. The crystal structure of the heterodimer HLA-DRA/HLA-DRB3:03:01 (3c5j.pdb) shown in a manner presumed to participate in the formation of a homodimer of two HLA-DRαβ heterodimers.
Results from analyzing T1D association with HLA-DRB345. The crystal structure of the heterodimer HLA-DRA/HLA-DRB3:03:01 (3c5j.pdb) shown in a manner presumed to participate in the formation of a homodimer of two HLA-DRαβ heterodimers.
Genome-Wide Association Study Identifies Locus That Predicts Risk for Diabetic Peripheral Neuropathy
A genome-wide association (GWAS) study by Tang et al. (p. ) has identified a potential genetic locus on chromosome 2q24 that is predictive for diabetic peripheral neuropathy (DPN) risk in type 2 diabetes. Specifically, the study focuses on the ACCORD trial cohort and, crucially, the authors have managed to validate the findings by replicating the main outcome in a separate population in the BARI 2D trial. The ACCORD study participants involved 4,384 case subjects with type 2 diabetes and prevalent or incident DPN and a further 784 control subjects with type 2 diabetes but no DPN at baseline or during follow-up. Meanwhile, validation was carried out with 791 DPN-positive case and 158 DPN-negative control subjects involved in the BARI 2D trial. Approximately 6.8 million single nucleotide polymorphisms (SNPs) were tested in the wider GWAS. The authors found that a cluster of 28 highly correlated SNPs on chromosome 2q24 reached genome-wide significance, with the minor allele of the lead SNP (rs13417783) decreasing DPN odds by 36%. All the associations were only modestly affected after adjusting for a number of factors such as age and BMI or treatment assignment in ACCORD. Moving to validation with the BARI 2D participants, they found that the effect of the top genome locus 2q24 could successfully be replicated with an odds ratio of 0.57, suggesting an even stronger effect in the cohort. In an additional analysis, mainly using the Genotype-Tissue Expression database, they found that the lead SNP was associated with higher tibial nerve expression on an adjacent gene that codes for human voltage-gated sodium channel NaV1.2, suggesting that there is a functional basis for the genetic effects observed. Author Alessandro Doria commented: “This is the first GWAS of DPN yielding a genome-wide significant signal with independent replication and biological plausibility. If we can confirm NaV1.2 upregulation as the mechanism underlying the protective effect of this genetic locus, we might have a new target for drugs aimed at preventing this serious complication of diabetes.”
Hyperinsulinemia, but Not Hyperglycemia, Drives Insulin Resistance in Type 1 Diabetes
Iatrogenic hyperinsulinemia, rather than hyperglycemia, appears to drive insulin resistance in type 1 diabetes, according to a study by Gregory et al. (p. ). Specifically, the authors compare the contribution of the two factors to insulin resistance in individuals with type 1 diabetes as well as those with glucokinase–maturity-onset diabetes of the young (GCK-MODY) and control subjects, concluding that peripheral hyperinsulinemia is the major contributor to insulin resistance in type 1 diabetes. Given that insulin resistance is closely linked to macrovascular disease risk in type 1 diabetes, they propose, based on the results, that therapies targeting hyperinsulinemia could mitigate macrovascular disease in type 1 diabetes. Specifically, they propose therapies designed to restore the distribution of insulin between the liver and periphery, giving examples such as hepatopreferential insulin analogs and intraperitoneal insulin delivery. The conclusions are the result of a study that used hyperinsulinemic-euglycemic clamps in the three groups (n = 10/group). They explain that the control subjects had euinsulinemia and euglycemia, the GCK-MODY group had euinsulinemia and hyperglycemia, and the group with type 1 diabetes had both hyperinsulinemia and hyperglycemia. Based on that differentiation, the authors could test the hypothesis that hyperinsulinemia had a greater influence on insulin resistance by comparing outcomes of the clamps in each group. They found that HbA1c was normal in control subjects but elevated in the type 1 diabetes and the GCK-MODY groups, while basal insulin levels were about equal in control subjects and the GCK-MODY group but 2.5 times higher in the type 1 diabetes group. Low-dose insulin infusion resulted in endogenous glucose production being suppressed in all groups, while suppression of nonesterified fatty acids happened to a lesser extent in the type 1 diabetes group. High doses of insulin, meanwhile, stimulated glucose disposal in control subjects and the GCK-MODY group but was 22-29% less effective in the type 1 diabetes group. Using a linear multiple regression approach, the authors then conclude it is insulinemia and not hyperglycemia that drives insulin sensitivity and resistance.
