By Max Bingham, PhD

According to Satake et al. (p. 1013), a series of plasma microRNAs (miRNAs) may be associated with variations in HbA1c and their dysregulation might contribute to complications in type 1 diabetes. However, the conclusions come with a caveat: there are likely numerous possible mechanisms and pathways through which disruption of miRNAs might impact risk of complications in the disease. Using two panels of patients with type 1 diabetes, the authors report an initial investigation with sequencing technology into 2,083 miRNAs present in plasma samples. Reportedly, the patients had a median HbA1c level of 8.3% (interquartile range 7.9–9.2), allowing the authors to look for correlations between the measure and miRNA levels. After filtering and normalization, they identified 54 candidate miRNAs that had statistically significant correlation with HbA1c levels. Moving onto a second panel of patients with type 1 diabetes, they then attempted to replicate the findings with quantitative RT-PCR. The authors managed to assay 48 of the candidates and found that 26 were detectable in more than half of the patients. Of these, 10 correlated with HbA1c at P < 0.05, with 5 positively correlating and 5 negatively correlating with HbA1c. Four candidates reportedly correlated very strongly with HbA1c. The authors then turned to KEGG pathway analysis to try to uncover putative pathways that might be involved—and this is where it gets complicated—reportedly finding as many as 50 unique pathways that might be involved. The authors go on to explore a number of the pathways and the different ways they may be involved in various diabetes complications. Author Andrzej S. Krolewski told Diabetes: “Researchers should be aware that hyperglycemia may have pleiotropic effects on many pathways through new mechanisms such as dysregulation of circulating candidate miRNAs. A novel finding of our research is that one of these pathways is the axon guidance pathway. This pathway may play a role in the development of microvascular complications.”

Venn diagram of pathways enriched with genes targeted by the four candidate miRNAs with P < 0.01. Nineteen pathways related to cancer were eliminated. In the middle of the diagram, there is the axon guidance signaling pathway, which was enriched by genes targeted by all four miRNAs.

Venn diagram of pathways enriched with genes targeted by the four candidate miRNAs with P < 0.01. Nineteen pathways related to cancer were eliminated. In the middle of the diagram, there is the axon guidance signaling pathway, which was enriched by genes targeted by all four miRNAs.

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Satake et al. Circulating miRNA profiles associated with hyperglycemia in patients with type 1 diabetes. Diabetes 2018;67:1013–1023

Catestatin, a peptide, may be able to control hepatic glucose production and improve sensitivity to insulin in obese mice, according Ying et al. (p. 841). Specifically, it seems that the peptide can directly suppress glucose production in hepatocytes and indirectly suppress lipid accumulation in the liver. In addition, catestatin may also have direct anti-inflammatory effects as well as a role in the recruitment and function of macrophages. The net result, the authors say, is that the peptide may be able to improve glucose homeostasis in obesity, with the suggestion that it might have potential as a treatment for type 2 diabetes. The conclusions come from a series of experiments that initially focused on the effects of catestatin treatment in mice with diet-induced obesity. Reportedly, the treatment resulted in inhibition of macrophages to the liver and a consequent decrease in inflammation. There were also reduced hepatic fatty acid levels and normalization of glucose and insulin levels. In addition to uncovering alterations to the structure of macrophages following treatment, the authors report significant alterations in the expression of both pro- and anti-inflammatory genes, suggesting that overall the effects of the treatment were anti-inflammatory. Administering catestatin to healthy lean mice had no effect on glucose or insulin levels, indicating that the effect was limited to obesity. Further work then revealed that catestatin levels in obese mice were reduced. The authors then turned to mice with catestatin knocked out, finding that such mice ate more and were heavier but lost weight when treated with catestatin. Author Sushil K. Mahata said: “Given that our previous work established catestatin as an antihypertensive peptide, current results suggested that catestatin could be a dual-acting therapeutic agent that could normalize both blood pressure and hyperglycemia. Going forward, the key issue will be, does it bring benefits to patients with diabetes with or without hypertension?”

Ying et al. Catestatin inhibits obesity-induced macrophage infiltration and inflammation in the liver and suppresses hepatic glucose production, leading to improved insulin sensitivity. Diabetes 2018;67:841–848

Fetal genetics, on top of maternal glycemia, is likely to have a significant impact on fetal growth, according to Hughes et al. (p. 1024), potentially better explaining why some babies are born large for gestational age (LGA). According to the authors, maternal glycemia is a major determinant of fetal growth but, as they point out, only explains a small percentage of birth weight variance. They say that genetics, meanwhile, may help account for further variation in fetal growth. Using a genetic scoring approach based on 60 single nucleotide polymorphisms previously linked to birth weight, the authors examined its effects on birth weight alongside that of maternal fasting plasma glucose (FPG). Reportedly, the fetal genetic score did influence birth weight independently of maternal FPG and additionally influenced growth at all levels of glycemia. In terms of frequency of LGA births, when maternal FPG was in the highest tertile, 31.1% of births were LGA when the fetal score was also in the highest tertile. However, the rate dropped to 14% when the score was in the lowest tertile. Similar patterns were evident in a group of women with gestational diabetes mellitus (FPG ≥5.1 mmol/L), where the frequency of LGA was 42.6% in the highest genetic score tertile compared with 21.3% in the lowest score tertile. Finally, the genetic score was not associated with cord insulin levels or C-peptide levels. This was in contrast with maternal glucose level, which was strongly associated with cord insulin and C-peptide levels. Author Rachel M. Freathy commented: “Our results raise the possibility that genetics may one day be added to other risk factors to predict LGA births. However, further studies are needed to optimize clinical prediction of birth weight and to assess the clinical utility of this approach.”

Hughes et al. Fetal genotype and maternal glucose have independent and additive effects on birth weight. Diabetes 2018;67:1024–1029

Two potential biomarkers found in urine, IgG4 and Smad1, might have prognostic value for spotting the early stages of diabetic nephropathy, according to Doi et al. (p. 986). Reportedly, the authors have managed to link up levels of the compounds to specific pathological changes and found that raised urinary levels of the compounds were associated with greater risk of albuminuria and reductions in estimated glomerular filtration rates (eGFR) over 5 years. The conclusions come from a study of just over 500 individuals with type 2 diabetes and no macroalbuminuria at baseline who were then followed for 5 years. A small number of additional patients were recruited to also undergo a renal biopsy. Urinary levels of IgG4 and Smad1 were then determined via validated ELISA with specific antibodies. Reportedly, increased baseline levels of IgG4 and Smad1 correlated with increased urinary albumin and reductions in eGFR. Levels of urinary IgG4 reportedly also significantly correlated with surface density of peripheral glomerular basement membrane, while Smad1 levels correlated with mesangial expansion. Both measures are classic pathologies of diabetic nephropathy, according to the authors. Looking at outcomes over 5 years, they go on to show that increased baseline levels of the two compounds predicted later declines in eGFR. Specifically reporting odds ratios, they found that urinary Smad1 alone, urinary Smad1 and IgG4 together, and microalbuminuria were all significant predictors of eGFR loss at 5 years. Actual percent declines of eGFR over 5 years ranged from just over 5% when neither compound was elevated at baseline to just over 10% when both compounds were raised. Author Toshio Doi said: “Diabetic nephropathy (DN) is the major cause of chronic and end-stage kidney disease in the world. Therapy at earlier stages might prevent DN development and progression, but early biomarkers of DN risk are limited. Herein we first uncover that urinary IgG4 and Smad1 are novel specific biomarkers for the early stage of DN and the later development of DN.”

Doi et al. Urinary IgG4 and Smad1 are specific biomarkers for renal structural and functional changes in early stages of diabetic nephropathy. Diabetes 2018;67:986–993

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