In This Issue of Diabetes

Oral L-serine may offer a new strategy for the treatment of diabetic neuropathy (DN), according to a report in this issue of Diabetes. The new study by Othman et al. (p. 1035) builds on the group’s earlier work that focused on hereditary sensory and autonomic neuropathy type 1 (HSAN1). HSAN1 is a rare neuropathy that is caused by 1-deoxysphingolipids (1-deoxySLs), which are neurotoxic. Oral L-serine supplementation reduced the concentration of 1-deoxySLs in HSAN1 patients and in mouse models of HSAN1. The treatment also protected mice from developing neuropathy. Using a rodent model of diabetes, the new report explored the impact of L-serine supplementation in the setting of hyperglycemia. The experimental animals were given a standard diet or one enriched with L-serine. To assess various aspects of DN, thermal and mechanical tests of DN were conducted, measures of nerve conduction velocity were collected, and epidermal nerve fiber density was measured. In addition, the sphingoid base composition of extracted lipids was also examined. The results of these experiments showed that diabetic rats that received the serine-enriched diet had lower plasma 1-deoxySLs relative to those that received the standard diet. Rats on the enriched diet also showed more favorable DN phenotypes. They had more favorable sensory nerve function and nerve conduction measures, and they exhibited improvements in the percentage of large-diameter fibers/axons. The authors also observed a very strong negative correlation between plasma 1-deoxySLs and nerve conduction velocity. The results of this new report suggest that further research on the effects of L-serine supplementation on DN is warranted. Future work in this area may be particularly important given the lack of adequate treatments that are currently available for this condition. — Helaine E. Resnick, PhD, MPH

Othman et al. Lowering plasma 1-deoxysphingolipids improves neuropathy in diabetic rats. Diabetes 2015;64:1035–1045

In obesity, when rapid expansion of adipose tissue outpaces vascular response, the resulting hypoxia can lead to localized inflammation, fibrosis, metabolic syndrome, insulin resistance, and other unfavorable conditions. While it is believed that activation of hypoxia-inducible factor (HIF)-1α signaling could help mitigate these responses, targeting of HIF has proven elusive. In this issue of Diabetes, work by Michailidou et al. (p. 733) shows that inhibition of prolyl hydroxylase enzymes (PHDs), which sense oxygen upstream of HIF, may help adipose tissue expand with fewer adverse consequences. The investigators rendered adipose tissue pseudohypoxic by overriding the oxygen-sensing enzyme that is regulated by PHDs. This inhibition prevented HIF-1α degradation, thereby stabilizing HIF-1α levels even in a normoxic state. The new study employed two approaches to induce pseudohypoxia—genetic deletion and pharmacological inhibition. Investigators first performed a knockdown of the Phd2 gene in C57BL/6J transgenic mouse adipose tissue. Additional experiments used a selective small-molecule PHD2 pharmacological inhibitor to induce pseudohypoxia in both human and murine adipocytes. Data from the 30-week in vivo portion of the new report indicated that although Phd2 knockdown mice gained more weight and accumulated more adipose mass from 9–30 weeks relative to controls, they also exhibited increased adipose vascularization. Despite increased adiposity, the knockdown mice maintained normal glucose tolerance, and they also had lower circulating levels of nonesterified fatty acids (NEFAs) compared with controls. The in vitro experiments revealed lower levels of two key lipolytic proteins—HSL and perilipin—indicating attenuation of lipolytic signaling. The new work suggests that inhibition of the PHD2 pathway and the resulting suppression of adipocyte lipolysis may lead to conditions in which fat can accumulate in a less metabolically injurious manner. The potential therapeutic implications of these findings will certainly require additional investigation. — Wendy Chou, PhD

Michailidou et al. Adipocyte pseudohypoxia suppresses lipolysis and facilitates benign adipose tissue expansion. Diabetes 2015;64:733–745

Data by Dash et al. in this issue of Diabetes (p. 766) demonstrate that intranasal insulin (INI) lowers endogenous glucose production (EGP), an observation that raises the possibility that INI could be used to treat excess hepatic glucose production in diabetes. The findings are based on data from eight healthy men who were examined in two study visits in which they were randomly given either 40 IU of INI or intranasal placebo (INP). Euglycemia was maintained with a 20% dextrose solution, and multiple blood samples were collected over a period of 360 min. A critical feature of the new study was that EGP was assessed under arterial pancreatic clamp conditions. In this approach, venous insulin and glucagon concentrations were kept at basal concentrations to prevent changes that could influence the interpretation of experimental data. Because venous insulin concentrations were similar between INI and INP, this strategy helped isolate the impact of INI on EGP. The data showed that between 180 and 360 min after INI administration, EGP was suppressed by more than 35% in the INI group. Although it is not known whether INI would lower EGP in a more physiological setting, these results provide strong support for further exploration of this pathway as a potential therapeutic strategy for addressing excess glucose production in diabetes. — Helaine E. Resnick, PhD, MPH

Dash et al. Intranasal insulin suppresses endogenous glucose production in humans compared with placebo in the presence of similar venous insulin concentrations. Diabetes 2015;64:766–774

A new report in this issue of Diabetes (p. 960) suggests that changes to human serum albumin (HSA)—especially its binding capacity—caused by a glucose-rich environment may help explain the association between type 2 diabetes (T2D) and platelet hyperactivity. This observation may underpin long-held observations concerning the elevated cardiovascular morbidity and mortality among people with T2D. In the clinical portion of the new study by Blache et al., fasting blood samples were collected from 20 T2D patients and 20 healthy control subjects. Plasma was analyzed for albumin concentration and other parameters including triglycerides, nonesterified fatty acids, glycated HSA, and albumin-associated thiols. As an antioxidant, albumin utilizes its single free thiol for redox reactions and to scavenge free radicals. The results of the new experiments showed significantly lower albumin concentrations and dramatically higher glycated albumin among the T2D subjects. Another distinguishing feature of the T2D group was the impaired antioxidant capacity of their serum albumin, which was reflected by decreased albumin-associated free thiols. Albumin from the T2D patients also showed diminished fatty acid binding capacity. To better understand the mechanisms underpinning the observed alterations in albumin in the T2D patients, in vitro experiments were used to modify native HSA and BSA with 25 mmol/L glucose (G25) or 2 mmol/L methylgloxal. The modified HSA and BSA mimicked how albumin function might be impaired in a diabetic milieu. As expected, binding properties of modified HSA and BSA were diminished after glycoxidation. In addition, ¹⁴C-labeled rat platelets allowed investigators to monitor the rates of thrombin-induced platelet aggregation in the presence of native, versus glycated, albumin. Relative to native albumin, the glycated HSA and BSA showed much less capacity to inhibit platelet aggregation. These novel findings suggest that glycation of albumin in T2D patients reduces albumin’s capacity to bind to fatty acids. This diminished binding capacity may lead to more abundant oxidized compounds that can then promote prothrombotic conditions. The end result of this chain of events is increased platelet hyperactivity that may lead to greater risk of thrombosis. Additional work will be necessary to confirm this proposed pathway and to determine if targeting these mechanisms is likely to be promising for future drug development. — Wendy Chou, PhD

Blache et al. Glycated albumin with loss of fatty acid binding capacity contributes to enhanced arachidonate oxygenation and platelet hyperactivity: relevance in patients with type 2 diabetes. Diabetes 2015;64:960–972