In This Issue of Diabetes

Impaired myocardial perfusion is a forerunner of cardiovascular events and is therefore an appealing therapeutic target. A study in this issue of Diabetes (p. 1381) provides novel evidence that reduced flow-mediated dilation (FMD)—the degree of vasodilation in response to increasing wall shear stress—in the coronary arterioles of diabetic patients results from peroxynitrite (ONOO^-) targeting of endothelial caveolae, a type of lipid raft whose primary functional protein is caveolin. Nitric oxide (NO), a critical regulator of vasodilation, is produced by nitric oxide synthase (NOS). When NO synthesis is derailed by ONOO^-, a process called NOS uncoupling, the result is impeded resistance arterial flow. To better characterize the mechanism of endothelial NOS uncoupling in diabetes, Cassuto et al. examined FMD in coronary arterioles of 41 diabetic and 37 nondiabetic patients at the time of heart surgery. Their results show that coronary arteries of diabetic patients exhibited reduced FMD and enhanced ONOO^- levels. Further, the investigators demonstrated that the location of ONOO^- production in the diabetic endothelium overlapped with membrane regions that contained caveolin-1, an observation suggesting that ONOO^- targets the caveolae. In a series of intriguing experiments, the investigators varied levels of ONOO^- and BH₄ (tetrahydrobiopterin, an NOS cofactor) and assessed coronary FMD in response to these changes. Exogenous ONOO^- significantly reduced the number of endothelial caveolae in diabetic patients in a dose-dependent manner and also decreased FMD in nondiabetic patients. To solidify their findings, the investigators showed that sequestering excess ONOO^- in diabetic patients restored FMD. In diabetic arteries, incubation with sepiapterin, a BH₄ precursor, improved FMD, whereas no effect was observed in the nondiabetic patients. Notably, FMD loss following administration of methyl-β-cyclodextrin (mβCD)—which is known to disrupt caveolae—was reversed and FMD was partly restored after the addition of sepiapterin. The new study proposes a mechanism by which disruption of caveolae predisposes BH₄ to oxidation by ONOO^-, ultimately resulting in diminished NO-mediated coronary dilation in diabetic patients. The investigators tested this model using knockout mice with disrupted endothelial caveolae. As expected, the mice exhibited impaired FMD, but sepiapterin administration restored FMD to a level similar to the wild-type response. The new findings suggest that rehabilitation of endothelial caveolae, either by ONOO^- sequestration or treatment with a BH₄ precursor, could be a potential new therapeutic target with favorable impacts on cardiovascular health. — Wendy Chou, PhD

Cassuto et al. Peroxynitrite disrupts endothelial caveolae, leading to eNOS uncoupling and diminished flow-mediated dilation in coronary arterioles of diabetic patients. Diabetes 2014;63:1381–1393

Among people with diabetes, use of endothelial progenitor cell (EPC) populations for cell-based therapies is challenging because of the reduced function and numbers of circulating EPCs. Strategies that improve the yield, survival, and function of these cells could lead the way toward improved performance of cell-based therapies in patients with diabetes. Glycogen synthase kinase-3β (GSK3β) activity is increased in diabetes and may contribute to the diminished success of EPCs. Intriguing new work by Hibbert et al. in this issue of Diabetes (p. 1410) investigated the impact of pharmacological inhibition of GSK3β in patients with diabetes. Human EPCs were grown in culture with and without supplementing the culture media with GSK3β inhibitors (GSKis). The results showed that GSKi dramatically increased EPC yield in samples from healthy control subjects as well as from patients with diabetes. Stress caused by serum starvation increased apoptosis in both cell populations, but this effect was greatly reduced by treatment with GSKi. Another important finding from the new report was that the activity of cathepsin B (cathB) was 40% lower in EPCs from patients with diabetes compared with control cells, and treatment with GSKi increased cathB activity. To explore the impact of this observation in a mouse model of vascular repair, cells from patients with diabetes and from control subjects were administered in a xenotransplant femoral artery wire injury experiment. The EPCs from patients with diabetes exhibited reduced therapeutic effect. While pretreatment of cells with GSKi increased the therapeutic benefit, this effect disappeared when cells were pretreated with both GSKi and a cathB inhibitor. These observations suggest that at least part of the benefit of GSKi results from upregulation of cathB. Taken as a whole, the new data indicate that inhibition of GSK3β in EPCs from patients with diabetes increases cathB activity, which in turn improves the effectiveness of cell-based therapy in vascular repair. Small molecule antagonism of GSK3β may therefore offer a new therapeutic option for arterial repair in patients with diabetes. — Laura Gehl, PhD

Hibbert et al. Glycogen synthase kinase-3β inhibition augments diabetic endothelial progenitor cell abundance and functionality via cathepsin B: A novel therapeutic opportunity for arterial repair. Diabetes 2014;63:1410–1421

Responding to the dearth of information related to brain fatty acid (FA) levels during fasting and feeding, a new report from Le Foll et al. (p. 1259) describes the development of a microdialysis technique to assess FA level changes in the ventromedial hypothalamus (VMH) concurrently with changes in serum FA levels and food intake. Published in this issue of Diabetes, the new study describes experiments in which both serum and ventromedial hypothalamic free fatty acids (FFAs) were measured in rats that were fasted for 18 h and then fed either a low-fat diet (LFD) or a high-fat diet (HFD). In the rats that were given an LFD, serum FFAs were initially elevated after fasting, then they fell during the first 30 min of meal initiation and remained low for the next 6 h. In contrast, rats that were given an HFD maintained high serum FFA over the full 6-h period. Surprisingly, VMH FFA levels were lower in HFD rats than in their LFD counterparts for much of the first 3 h after feeding. Further, both HFD and LFD rats had similar intake during the first 3 h of feeding, but HFD rats had lower intake during the subsequent 3 h. The lack of correlation between VMH FFA levels and food intake led investigators to hypothesize that ketone production by astrocytes after an HFD might act to regulate intake. In fact, HFD rats had a higher VMH-to-serum ketone ratio after food exposure, an observation suggesting local production of ketones by astrocytes. When hymeglusin—an inhibitor of ketone production in astrocytes—was reverse-dialyzed into the VMH of rats, it completely inhibited the rise in VMH ketones relative to serum ketones in HFD rats for the first 2 h after HFD presentation. Food intake also increased in the second 3-h period, suggesting that in animals fed an HFD, VMH ketone production by astrocytes was responsible for the decrease in food intake observed during the second 3-h interval. To understand the mechanism of the ketone effect on food intake, the investigators looked at ketone-, glucose-, and FA-sensing in VMN neurons and found that ketones overrode normal glucose- and FA-sensing in VMN neurons. These intriguing results suggest that neuronal sensing of FAs is modulated by astrocytes and closely associated with dietary composition. — Laura Gehl, PhD

Le Foll et al. Regulation of hypothalamic neuronal sensing and food intake by ketone bodies and fatty acids. Diabetes 2014;63:1259–1269

While the remission of type 2 diabetes following Roux-en-Y gastric bypass (RYGBP) is well documented, the mechanisms behind the effects remain poorly understood. Although weight loss and caloric restriction are two pieces of the puzzle, increased attention is being paid to changes in gut physiology, particularly in relation to observed improvements in β-cell function after RYGBP. This issue of Diabetes features work by Dutia et al. (p. 1214) that investigates the gut’s role in postsurgical recovery of β-cell function. The study included 16 severely obese subjects with type 2 diabetes, 11 obese patients with normal glucose tolerance, and 7 lean control patients with normal glucose tolerance. The surgical groups were studied before RYGBP as well as at 1 month and at 1, 2, and 3 years after surgery. Results of oral glucose tolerance testing after RYGBP showed significant improvement in β-cell function at 1 month, an effect that was sustained up to 3 years after surgery. In contrast, challenges with intravenous glucose revealed that β-cell function and insulin secretion improved little during the 3-year postsurgical follow-up period, even in subjects with sustained weight loss and in whom diabetes was “in remission.” RYGBP therefore resulted in improved measures of insulin secretion only when the gut was directly engaged. Although the new data support an important role for the gut in improved β-cell function after RYGBP, the authors stress that weight loss remained the strongest predictor of improved function after surgery, along with presurgical measures of β-cell function and glucagon-like peptide 1. The new data indicate that while β-cell dysfunction can be observed long after RYGBP, even among patients in whom clinical diabetes has reverted, gastrointestinal factors help explain the significant improvements in glucose regulation after gastric bypass surgery. — Laura Gehl, PhD

Dutia et al. Limited recovery of β-cell function after gastric bypass despite clinical diabetes remission. Diabetes 2014;63:1214–1223