NOVEMBER 2015

In This Issue of Diabetes By Max Bingham, PhD

Yoshida et al. Leptin suppresses mouse taste cell responses to sweet compounds. Diabetes 2015;64:3751–3762

Sharma et al. Direct endothelial nitric oxide synthase activation provides atheroprotection in diabetes-accelerated atherosclerosis. Diabetes 2015;64:3937–3950

Mechanisms Involved in Sweetness Suppression by Leptin Uncovered, and It May Be Relevant to DiabetesLeptin, a key hormone involved in energy balance regulation, may directly suppress sensitivity to sweet tastes. This has been known for a while, but the molecular mechanisms have remained elusive. Writing in this issue of Diabetes (p. 3751), Yoshida et al. report on a series of experiments in mice that suggest leptin suppresses sweetness via a single leptin receptor isoform called Ob-Rb and subsequently through the activation of KATP channels in specifi cally sweet-sensitive taste cells. Physiologically relevant administration of leptin suppressed cell responses to sweet compounds but not bitter or sour compounds in the mice. To prove the case, the effect was blocked upon administration of a leptin antagonist in leptin receptor–defi cient db/db mice and in mice with diet-induced obesity (where leptin resistance is a common occurrence). While explaining much about the role of leptin in energy regulation and sweet taste sensitivity, the authors suggest that this fi nding might present an opportunity to target the regulation of sweetness sensitivity and therefore, possibly, food intake and glucose homeostasis in cases where the leptin system is impaired—which is highly relevant for metabolic syndrome and diabetes. The authors suggest in particular that targeting the activation of KATP channels in taste cells to restore sweetness sensitivity could present an opportunity for restoring glucose homeostasis in cases of diabetes. Commenting on the study more widely, author Ryusuke Yoshida said, “Our fi ndings indicate a strong linkage between metabolism and sweet taste. Through the development of leptin resistance in the taste system, the sweet suppressive effect of leptin is impaired, which may result in extra sweet food consumption and extra weight gain. Such a negative cycle may be cut off by activation of KATP channels in sweet taste cells. We presume that further understanding of this regulatory system for sweet taste, including a mechanism for the development of leptin resistance, may help to improve obesity and diabetes.”

CavNOxin Study Suggests Direct eNOS Activation Protects Against Atherosclerosis in DiabetesA highly specifi c peptide called CavNOxin can increase bioavailability of endothelial synthase nitric oxide (eNOS)–derived nitric oxide and as a result may attenuate atherosclerotic plaque formation by up to 84% in mice models of both type 1 and type 2 diabetes. That is according to the research by Sharma et al. who report the investigation in this issue of Diabetes (p. 3937). In a series of experiments, the authors show signifi cant effects on atherosclerotic plaque formation and that mice lacking eNOS are resistant to the effects of CavNOxin, indicating specifi city for the target. Turning to mechanisms, the authors show a range of relevant effects of CavNOxin, including reductions in oxidative stress markers, inhibition of proatherogenic mediators, and blocked leukocyte-endothelial interactions. Taken together, the data suggest direct eNOS activation could provide protection against the development of atherosclerosis in diabetes with CavNOxin possibly representing the basis for the development of therapies designed around novel agonist peptides or small molecules from candidate fragment libraries. Previously only in vitro evidence was available relating to the actions of CavNOxin, and there was no evidence available on whether targeting the peptide directly at eNOS could have effects on diabetes-associated atherosclerosis. Indeed, the potential protective effects of stimulating eNOS have remained controversial since they have the double capacity of producing nitric oxide and/or oxygen radicals depending on the disease setting, and they can be proatherogenic or alternatively antiatherogenic. Commenting on the implications of the work, authors Judy B. de Haan and Pascal Bernatchez stated, “To date, strategies to limit or reduce diabetes-associated atherosclerosis have remained elusive, and diabetic patient morbidity and mortality from cardiovascular disease remain high despite the availability of intensive blood glucose and lipid-lowering therapeutics. Our targeted strategy of disrupting the binding of an inhibitory protein to eNOS, which results in improved endogenous nitric oxide bioavailability, offers a unique strategy to lessen diabetes-associated plaque burden with implications for lowering not only oxidative stress but also infl ammation. Our results pave the way for the development of further agonists around this paradigm to lessen diabetes-driven atherosclerosis.”

Triple staining in fungiform papillae (top panel) and circumvallate papillae (bottom panel) of C57BL/6J mice. The dotted lines outline the taste buds.

Images of aortas stained with 4-HNE from streptozotocin-induced diabetic mice.

Diabetes Volume 64, November 2015 3629

Grillo et al. Hippocampal insulin resistance impairs spatial learning and synaptic plasticity. Diabetes 2015;64:3927–3936

Coen et al. Exercise and weight loss improve muscle mitochondrial respiration, lipid partitioning, and insulin sensitivity after gastric bypass surgery. Diabetes 2015;64:3737–3750

Insulin Resistance in the Hippocampus Might Explain Memory and Learning Loss in Diabetes Insulin resistance in the hippocampus may be a key mediator in the cognitive and learning defi cits often associated with diabetes and such resistance may be independent of glycemic control. That is according to the conclusions of a study of rats by Grillo et al. reported in this issue of Diabetes (p. 3927). Using a lentiviral vector, the authors managed to downregulate insulin receptor expression in the hippocampus of rats without affecting body weight, adiposity, or peripheral glucose homeostasis. That meant it was possible to specifi cally test a whole range of variables associated with insulin resistance in the hippocampus. Overall, they noted that the downregulation of hippocampal insulin receptors resulted in the impairment of neuroplasticity and specifi cally long-term potentiation of synapses, which is thought to be one of the major cellular mechanisms underlying learning and memory. The same effects were not observed in the control rats. A number of other changes in neurons at the molecular level were also reported. Perhaps the most striking change was when the researchers used the behavioral task called the Morris water maze to demonstrate that downregulation of hippocampal insulin receptors results in clear impairment of hippocampal-dependent learning. After sending the rats swimming to fi nd the platform in the test, it became clear that the rats with impaired hippocampal insulin receptor regulation took longer to fi nd the platform overall and forgot the location of the platform in repeated tests in comparison to controls. The authors suggest that short-term memory may be unaffected but that long-term memory seems to be impaired in the rats with hippocampal insulin resistance. Translating all of this to diabetes in humans will still require more work but as the authors point out, there are striking similarities to the impairments typically observed in patients with diabetes when it comes to complex tasks. According to Claudia Grillo, “The neuroplasticity defi cits observed in our model of hippocampal insulin resistance emphasize the importance of the central actions of insulin since these defi cits were independent of peripheral metabolic imbalance. The hippocampal insulin resistance that leads to cognitive defi cits may represent the link between metabolic diseases, such as diabetes, and neurodegenerative diseases, such as Alzheimer’s. These fi ndings also emphasize the need to identify new therapies to restore central insulin activity to treat diseases associated with cognitive impairment.”

Exercise Following Gastric Bypass Surgery: Trial Data Suggest Improvements in Insulin and Fitness Outcomes for People With Diabetes Implementation of an exercise regime on top of weight loss following gastric bypass surgery is likely to provide additional health benefi ts in terms of improved insulin sensitivity, cardiorespiratory fi tness, and mitochondrial respiration in muscle. That is according to the conclusions of a study by Coen et al. that appears in this issue of Diabetes (p. 3737). The results suggest that bariatric surgery alone does not necessarily rectify a number of facets of cellular energetics that may be important in obesity and diabetes. Indeed, additional benefi ts could be expected if surgery-induced weight loss and exercise were coupled in the midterm period following the operation. Using a randomized exercise intervention study, the authors examined the effects of a 6-month moderate exercise program versus a control health education program in patients following surgery. Parameters measured included insulin sensitivity, mitochondrial respiration, and the intramyocellular triglycerides, sphingolipids and diacylglycerols. Additional improvements in insulin sensitivity were associated with exercise, and only exercise resulted in a variety of improvements associated with cardiovascular fi tness and specifi cally mitochondrial respiration. As well as highlighting the potential extra benefi ts of exercise on top of weight loss following bariatric surgery, the authors suggest that the data provide valuable mechanistic insights into improving metabolic profi les in severe obesity and presumably patients with diabetes. Commenting on the wider implications of the study, author Bret H. Goodpaster said, “These data clearly highlight that bariatric surgery patients should engage in at least a modest amount of physical activity or exercise to improve their health that otherwise may not occur from weight loss alone.”

DOI: 10.2337/db15-ti11

© 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profi t, and the work is not altered.

NOVEMBER 2015

Green fl uorescent protein is expressed in Ammon’s horn and the dentate gyrus of rats infused with lentivirus.

Representative image of immunofi ber typing and oil red O staining generated from a muscle biopsy specimen.

Diabetes Volume 64, November 20153630