By Max Bingham, PhD

A preclinical study by Iyer et al. (p. 3453) investigating renal denervation in obese dogs suggests that the procedure can totally reverse high-fat diet–induced hepatic insulin resistance and that it does so by primarily decreasing hepatic-specific gluconeogenic gene expression. The study used a nonhypertensive obese canine model to assess insulin sensitivity before and after 6 weeks of high-fat diet and then again after a surgical renal denervation procedure or a sham operation. The 6-week high-fat diet induced insulin resistance in both groups, and in the sham group, insulin resistance continued despite the operation. In the renal denervation group, however, hepatic insulin sensitivity was completely restored following the operation. According to the authors, they felt it was reasonable to assume that the insulin suppression of normal glucose production was due to the suppression of gluconeogenesis and, on that basis, went on to assess whether gene expression associated with that process was also suppressed. Accordingly, they report that the procedure did result in the suppression of certain hepatic gluconeogenic genes, with a concurrent upregulation of the liver X receptor α. In short, they say that the procedure restored the impaired ability of insulin to suppress hepatic glucose production—an outcome that will likely have ramifications for diabetes treatment directly. Previously, renal denervation has mainly been viewed as a potential intervention for hypertension. One further observation that they say may be important is that the dogs that received the renal denervation operation were also resistant to hypoglycemia, suggesting yet another potential application in diabetes. They conclude that “the translational potential of this work to the clinical setting will be fascinating to investigate.” Commenting more widely, author Malini S. Iyer told Diabetes: “Elevated fasting glucose is a biomarker of diabetes. Our results suggest that the kidneys play a role in controlling liver glucose output via the sympathetic nervous system. Exploring this mechanism can lead to new therapeutic targets in the treatment of prediabetes.”

Iyer et al. Renal denervation reverses hepatic insulin resistance induced by high-fat diet. Diabetes 2016;65:3453–3463

Liver glucose output can be regulated indirectly by afferent and efferent renal nerves by either central integration of afferent renal nerve signals, central insulin signaling, adrenergic control of adipose tissue lipolysis, or neurogenic control of the renin-angiotensin-aldosterone system (RAAS). FFA, free fatty acid; SNA, sympathetic nerve activity.

Liver glucose output can be regulated indirectly by afferent and efferent renal nerves by either central integration of afferent renal nerve signals, central insulin signaling, adrenergic control of adipose tissue lipolysis, or neurogenic control of the renin-angiotensin-aldosterone system (RAAS). FFA, free fatty acid; SNA, sympathetic nerve activity.

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A standardized manufacturing process for human pancreatic islet production is reported in this issue by Ricordi et al. (p. 3418), with the suggestion that the authors may have finally solved a number of intractable issues that have led to a wide variability in outcomes in previous multicenter studies into the efficacy of islet transplantation in patients with type 1 diabetes. They report the key to success was standardization of manufacturing protocols, rigid donor selection criteria, and the addition of a short culturing step to test the safety of the product and the capacity of the isolated islet cells to actually produce insulin. Taken together, the refinements of the process seem to have worked, with the majority of patients who received the transplants at the eight centers achieving and maintaining glycemic control after 1 year. Achieving greater success rates with islet transplantations is seen as essential because the approach can yield dramatic results for patients with type 1 diabetes. However the limited supply of suitable donor islet cells means the treatment has to be restricted to patients who have glycemic control that is most out of control and particularly to cases with hypoglycemia unawareness. Commenting more widely on the study, author Julia S. Goldstein said: “The CIT [Clinical Islet Transplantation] Consortium conducted a phase 3 clinical trial to evaluate the safety and efficacy of purified human pancreatic islet product to provide sufficient evidence of effectiveness. To support the pivotal trial, manufacture of the cellular product was harmonized across participating centers by meticulously describing each process step and assay method and by defining raw materials and product quality specifications. This important effort resulted in a successful demonstration that allogeneic islet transplantation may be a feasible novel therapeutic alternative for subjects with type 1 diabetes and hypoglycemia unawareness. The strategy adopted for the conduct of the CIT trials serves as a novel pathway toward regulatory approval and as an example for future cell therapy developments. The data will support licensure of the product for marketing in the U.S. and will foster the technological development of further islet products.”

Ricordi et al. National Institutes of Health–sponsored Clinical Islet Transplantation Consortium phase 3 trial: manufacture of a complex cellular product at eight processing facilities. Diabetes 2016;65:3418–3428

The relationship between salivary α-amylase levels and obesity risk is fairly well established, with the suggestion that lower levels of the enzyme increase risk. However, quite why this is the case remains open to question. Copy numbers of the AMY1 gene that encodes salivary amylase do generally correlate with low salivary amylase levels, but whether copy numbers of AMY1 correlate with obesity risk remains a source of debate, with some studies suggesting it does whereas others do not. To understand this more fully, Arredouani et al. (p. 3362) used metabolomics to compare a carefully selected group of healthy women that differed only in terms of whether they had a low or high copy number of AMY1. By using metabolomics, they could then compare metabolic differences between the two groups. Furthermore they directly measured serum α-amylase levels, confirming that the groups actually had significantly different levels of the enzyme. The subsequent modeling suggested metabolites involved in lipid metabolism best explained the clear profile differences between the groups and that low α-amylase levels likely result in reduced cellular glucose uptake and a shift toward lipid usage to derive energy. According to author Mario Falchi, the outcome could be significant: “Our study suggests that subjects with low salivary amylase levels, as highlighted by their low AMY1 copy number and correspondingly low serum amylase levels, may potentially have difficulty in utilizing glucose derived from starch for energy production. Less salivary amylase means that the amount of simple sugars released in the mouth during a starchy meal may not be proportional to the actual amount of starch ingested, and this may mislead the signaling pathways that stimulate the release of insulin.” Abdelilah Arredouani, another author, added: “If confirmed, the outcome may conceivably have clinical importance. Thus, low salivary amylase individuals who ingest starch chronically should eventually be considered at-risk of developing metabolic disorders, and therefore preventive nutritional and behavioral counseling should be provided to them.”

Arredouani et al. Metabolomic profile of low–copy number carriers at the salivary α-amylase gene suggests a metabolic shift toward lipid-based energy production. Diabetes 2016;65:3362–3368

A longitudinal case-control study into the role of the insulin-like growth factor (IGF) axis in gestational diabetes mellitus (GDM) suggests that a specific IGF binding protein (IGFBP-2) may be associated with the pathogenesis of the disease and may even have predictive value as early as 10–14 weeks’ gestation. If confirmed in further study populations, this would suggest IGFBP-2 represents a potential biomarker for GDM that can be used a full 10–18 weeks prior to the current GDM screening (normally at weeks 24–28). The study by Zhu et al. (p. 3495) prospectively investigated three IGF biomarkers in 107 subjects with GDM and 214 subjects who had pregnancies not complicated by GDM through the collection of blood samples at regular intervals during pregnancy. The authors characterized the longitudinal profile of each IGF axis biomarker throughout pregnancy and observed an increasing trend of IGF-I and IGFBP-3 (and the ratio between the two biomarkers) in both groups, whereas a decreasing trend of IGFBP-2 was found throughout pregnancy. Significantly, GDM risk, after controlling for other major risk factors of GDM, was positively associated with IGF-I and the ratio of IGF-I/IGFBP-3, whereas IGFBP-2 was associated with decreased risk. In particular, they found that when IGFBP-2 was added to the traditional risk factors for GDM and other biomarkers, there was significantly improved incremental predictive value, especially when measured at very early stages of pregnancy (10–14 weeks). Commenting more widely on the study, author Cuilin Zhang told Diabetes: “Although our findings are subject to replication in future studies, they may stimulate further discussion and investigation of prediagnostic markers in early pregnancy for the early prediction and possibly prevention of gestational diabetes. This is even more relevant when considering the potential adverse impacts of maternal hyperglycemia on fetal development given that the fetus is exposed to maternal glycemia starting from early pregnancy.”

Zhu et al. Insulin-like growth factor axis and gestational diabetes mellitus: a longitudinal study in a multiracial cohort. Diabetes 2016;65:3495–3504

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