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Chee M.J.,University of Alberta | Price C.J.,University of Alberta | Statnick M.A.,Diabetes Research | Colmers W.F.,University of Alberta
Journal of Physiology | Year: 2011

Nociceptin or orphanin FQ (N/OFQ) stimulates food intake when injected into the ventromedial nucleus of the hypothalamus (VMN). The VMN negatively regulates energy balance in part by tonically activating proopiomelanocortin arcuate neurons, thereby suppressing food intake. However, it is not clear how orexigenic neurotransmission within the VMN can stimulate food intake. We tested the hypothesis that the orexigenic action of N/OFQ results from its inhibition of anorexigenic VMN neurons. We studied the effects of N/OFQ on the electrical properties of anorexigenic VMN neurons in acute brain slices. Ionic mechanisms underlying the actions of N/OFQ were studied using whole cell patch-clamp recordings from VMN neurons expressing the anorexigenic leptin receptor (LepRb). Bath application of N/OFQ to LepRb-expressing VMN neurons elicited a robust, reversible membrane hyperpolarization that suppressed neuronal excitability by raising the action potential firing threshold and cell rheobase. N/OFQ activated a postsynaptic, G-protein coupled, inwardly rectifying potassium (GIRK) current that was sensitive to G-protein inactivation, blocked by the GIRK blocker SCH23390, and occluded by the GABA B agonist and potent GIRK activator, baclofen. Application of the selective N/OFQ receptor antagonist SB-612111 blocked the inhibitory effects of N/OFQ. We concluded that N/OFQ directly inhibited VMN neurons by activating a GIRK. These results implicate the site-specific contributions of orexigenic neuropeptides at VMN neurons to suppress anorexigenic output. This study thus advances our understanding regarding the contributions of the VMN to hypothalamic regulation of energy balance. © 2011 The Authors. Journal compilation © 2011 The Physiological Society. Source


Liu S.Q.,Northwestern University | Roberts D.,Northwestern University | Kharitonenkov A.,Diabetes Research | Zhang B.,Northwestern University | And 4 more authors.
Scientific Reports | Year: 2013

Myocardial ischemia, while causing cardiomyocyte injury, can activate innate protective processes, enhancing myocardial tolerance to ischemia. Such processes are present in not only the heart, but also remote organs. In this investigation, we demonstrated a cardioprotective process involving FGF21 from the liver and adipose tissue. In response to myocardial ischemia/reperfusion injury in the mouse, FGF21 was upregulated and released from the hepatic cells and adipocytes into the circulation and interacted with FGFR1 in cardiomyocytes under the mediation of the cell membrane protein β-Klotho, inducing FGFR1 phosphorylation. This action caused phosphorylation of the signaling molecules PI3K p85, Akt1, and BAD, thereby reducing caspase 3 activity, cell death, and myocardial infarction in association with improvement of myocardial function. These observations suggest that FGF21 is upregulated and released from the liver and adipose tissue in myocardial injury, contributing to myocardial protection by the mediation of the FGFR1/β-Klotho-PI3K-Akt1-BAD signaling network. Source


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Johnson & Johnson, continuing its long quest for a Type 1 diabetes cure, is joining forces with biotech company ViaCyte to speed development of the first stem cell treatment that could fix the life-threatening hormonal disorder. They've already begun testing it in a small number of diabetic patients. If it works as well in patients as it has in animals, it would amount to a cure, ending the need for frequent insulin injections and blood sugar testing. ViaCyte and Johnson & Johnson's Janssen BetaLogics group said Thursday they've agreed to combine their knowledge and hundreds of patents on their research under ViaCyte, a longtime J&J partner focused on regenerative medicine. The therapy involves inducing embryonic stem cells in a lab dish to turn into insulin-producing cells, then putting them inside a small capsule that is implanted under the skin. The capsule protects the cells from the immune system, which otherwise would attack them as invaders - a roadblock that has stymied other research projects. Researchers at universities and other drug companies also are working toward a diabetes cure, using various strategies. But according to ViaCyte and others, this treatment is the first tested in patients. If the project succeeds, the product could be available in several years for Type 1 diabetes patients and down the road could also treat insulin-using Type 2 diabetics. "This one is potentially the real deal," said Dr. Tom Donner, director of the diabetes center at Johns Hopkins University School of Medicine. "It's like making a new pancreas that makes all the hormones" needed to control blood sugar. Donner, who is not involved in the research, said if the device gives patients normal insulin levels, "it's going to prevent millions of diabetics from getting dangerous complications." People with Type 1 diabetes no longer produce insulin, the hormone that converts sugar in the blood into energy, because their immune system has killed off the beta cells in the pancreas. Those cells make insulin in response to rising blood sugar levels after a meal. Over years, excess sugar in the bloodstream damages blood vessels and organs. Without effective treatment, diabetics suffer severe complications: blindness, kidney failure, heart disease, amputations, even premature death. On the other hand, too much insulin can cause very low blood sugar, which can kill patients, particularly young children. According to the American Diabetes Association, about 29.1 million Americans have diabetes, including 1.25 million with type 1 diabetes. The number with Type 1, or insulin-dependent, diabetes is growing steadily. Meanwhile, the number with Type 2 diabetes, whose bodies make some insulin but don't use it efficiently, is increasing exponentially due to the global epidemic of obesity and sedentary lifestyles. Many patients can't control it well because treatment is exhausting, requiring a strict diet, frequent exercise, multiple daily insulin injections or other medicines and several finger pricks a day to test blood sugar. Also, some patients can't afford the expensive medicines. ViaCyte Inc., based in San Diego, has been researching its treatment for a decade, partly with funding from the Juvenile Diabetes Research Fund and the California Institute for Regenerative Medicine. Johnson & Johnson, based in New Brunswick, New Jersey, is a major ViaCyte investor and has been conducting parallel research for about 13 years, said Diego Miralles, J&J's head of global innovation. "We wanted to hedge our bets to make sure we would win in this space ... that is so transformational," Miralles said. He wouldn't disclose financial terms of the deal with ViaCyte. The privately held company began the first round of patient testing a year ago, implanting its product, dubbed VC-01, in a dozen people with Type 1 diabetes, said Paul Laikind, ViaCyte's CEO and president. They received a small dose of insulin-producing cells inside their devices and are being closely monitored for two years to see insulin production and other effects. After 12 weeks, the device had properly attached to nearby blood vessels, their new insulin-producing cells were still multiplying and no side effects were seen. Another dozen planned patients will soon get the same cell dose in capsules to be implanted in them. If that goes well, in the next round of testing a few dozen patients will get devices holding a full dose of the cells implanted, likely in the second half of this year. Further testing may be needed before the product can be approved by regulators. "We do believe that it will need to be replaced periodically," Laikind said. Earlier testing in thousands of mice over years showed the lab-created insulin-producing cells matured and produced the needed hormone inside the mice for as long as they lived, about a year, noted Laikind. Because of the protective capsule, which is flattish and smaller than a business card, if something goes awry, the capsule can be removed immediately to prevent patient harm. Dr. Betul Hatipoglu, an endocrinologist at Cleveland Clinic, wrote in an email that preliminary results on the device are promising. "More research is needed to continue to understand its impact," she wrote, adding that researchers must fine tune the device and determine whether there are any unforeseen safety issues.


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Adding 2 oz. of walnuts daily could improve diets, blood vessel cell wall function and LDL (‘bad’) cholesterol in people at risk for diabetes, new research shows. The findings, published in the online journal BMJ Open Diabetes Research & Care, show diets, along with other certain risk factors, improved in participants who added a daily intake of 56 g of walnuts for a six-month period. Adding walnuts did not have any impact on blood pressure or blood glucose levels. For the study, 112 participants were randomly assigned to one of two groups – one received dietary counseling to reduce calorie intake and the other did not.  Within the two groups, participants were randomly assigned to either add walnuts to their daily diet or avoid walnuts for six months. Participants included 81 women and 31 men, between the ages of 25 and 75, and all at high risk of developing diabetes. According to a press release, diet quality was assessed using the Healthy eating Index 2010 (HEI-2010), and improved diet was associated with a better cardiovascular risk profile and lowered risk of long term conditions. At the beginning of the study, participants were assessed across a number of health variants, including height, weight, BMI, cholesterol, fasting blood glucose, and blood pressure.  These numbers, along with dietary intake were assessed again after 3, 6, 12 and 15 months. Eating walnuts on a daily basis was associated with improved diet quality, after factors such as exercise, age, and calorie and fatty acid intakes, where accounted for. Both those who received caloric-intake dietary counseling and those who did not, saw improvement in endothelial cell function associated with a walnut-rich diet. “Our data suggest that inclusion of walnuts in the diet, with or without dietary counseling to adjust caloric intake, improved diet quality and may also improve [endothelial function], and reduce total and LDL cholesterol in this sample of adults at risk for diabetes,” the researchers concluded in a prepared statement. Walnuts, which contain essential fatty acids and vitamin E, have been associated with various health benefits, such as heart health and brain health. The researchers said further studies in more diverse groups of people are needed.


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A new Northwestern Medicine study has pinpointed thousands of genetic pathways an internal body clock takes to dictate how and when our pancreas must produce insulin and control blood sugar, findings that could eventually lead to new therapies for children and adults with diabetes. The body’s circadian clocks coordinate behaviors like eating and sleeping, as well as physiological activity like metabolism, with the Earth’s 24-hour light-dark cycle. There’s a master clock in the brain, as well as peripheral clocks located in individual organs. When genetics, environment or behavior disrupt the synchrony of these clocks, metabolic disorders can develop. In a previous publication in Nature, Northwestern Medicine investigators showed that a circadian clock in the pancreas is essential for regulating insulin secretion and balancing blood sugar levels in mice. The scientists demonstrated that knocking out clock genes led to obesity and type 2 diabetes, but they still had much to learn if they wanted to manipulate clock action to treat the conditions. “We knew that the pancreas didn’t work if we removed these clock genes, but we didn’t know how the genes were affecting the normal function of the pancreas,” said principal investigator Dr. Joe Bass, chief of endocrinology at Northwestern University Feinberg School of Medicine and a Northwestern Medicine physician. Clock genes are responsible for producing transcription factors, special proteins that help tell a cell how to function. In the new study, published Nov. 6 in Science, Bass’s laboratory revealed thousands of genes in the pancreas that the clock’s transcription factors control in rhythm with the planet’s daily rotation from light to dark. “We established a new gene map that shows how the entire repertoire of factors produced in the pancreas maintain and anticipate daily changes in the external environment,” Bass said. “These factors are all tied to the rotation of the Earth -- to the timekeeping mechanism that has evolved to control when we sleep, wake up, eat and store nutrients each day.” Bass’s team focused on cells in the pancreas called beta cells, which secrete insulin into the blood stream to help the body absorb glucose -- sugar -- to use for energy. Using genome-wide sequencing technology on beta cells with both intact and disrupted clock gene function, the scientists were able to lay out the map of transcription factors and genes. In ongoing research, Bass’s group continues to study how the body’s circadian clocks interact and how their rhythm is thrown off -- not just in diabetes, but also during the normal aging process and from day-to-day conditions like jetlag, stress or dietary changes. “This study reinforces the idea that clocks operating in cells are fundamental to health,” Bass said. “They represent an important untapped target for improving the functions of cells in the pancreas.” Bass is also the Charles F. Kettering Professorship of Medicine at Feinberg. Other Northwestern authors include Dr. Grant Barish, Mark Perelis, Biliana Marcheva, Kathryn Ramsey, Clara Bien Peek, Hee-kyung Hong, Matthew Schipma, Dr. Akihiko Taguchi, Dr. Wenyu Huang, Chiaki Omura and Amanda Allred. This study was supported by National Institutes of Health (NIH) National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), NIH National Institute on Aging , the Chicago Biomedical Consortium , Juvenile Diabetes Research Foundation , University of Chicago Diabetes Research and Training Center 5; NIDDK T32 ; National Heart, Lung, and Blood Institute T32and Defense Advanced Research Projects Agency.

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