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Can treating the brain help in the fight against diabetes?

Melissa Healy

In research that may point the way to new treatments for Type 2diabetes, obese and diabetic mice who got a single shot of a growth-promoting peptide directly into their brains experienced lasting remission from the metabolic disorder without any sustained changes to their diet or their weight.
A week after researchers injected a low dose of synthesized mouse Fibroblast Growth Factor 1 — FGF1 — directly into the ventricles of diabetic mouse brains, the mice’s erratic blood glucose levels stabilized at normal levels. Then they stayed normal for 17 weeks — effectively curing the mice of their diabetes.
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It was a level of remission until now seen only in the wake of bariatric surgery, the authors reported Monday in the journal Nature Medicine. The study was led by endocrinologist Michael W. Schwartz, gastroenterologist Jarrad M. Scarlett and molecular physiologist Jennifer M. Rojas. Schwartz directs the University of Washington’s Diabetes and Obesity Center of Excellence and Scarlett and Rojas conduct research there.
The success of a direct-to-the-brain treatment for diabetes in mice is unlikely to prompt such radical treatments for humans — not anytime soon, at least. But it does highlight a little-appreciated surmise about Type 2 diabetes: that it may be, to some extent at least, a brain disease, and that treatments that go to the source of the metabolic dysfunction may lead to “cures” that have not been achieved by treating its downstream effects in the pancreas, blood, liver, muscles and fat.
"That's a novel perspective," Schwartz said. The ways in which the brain influences diabetes are not understood, he added. But "there's enough data to take a good look at" the relationship.
The introduction of FGF1 into the brain’s fluid-filled caverns appeared to unleash a sequence of changes in the mice. Production of a powerful neuroprotective protein surged in the brain. That, in turn, fostered the robust growth of brain connections in the hypothalamus — the source of many hormones that play a role on appetite and metabolism. Outside the brain, the skeletal muscles and livers of the diabetic mice quickly improved their uptake of post-meal glucose. As glucose clearance improved, the high blood-sugar levels that are a hallmark of Type 2 diabetes quickly normalized.
Researchers saw no evidence that the treated mice were plagued by hypoglycemia — a problem of over-correction that many on Type 2 diabetes treatments experience. Nor, they concluded, were the metabolic improvements the result of weight loss: while treated mice briefly dialed back their intake and lost some weight, their appetites and their weight quickly returned.
But their Type 2 diabetes was gone.
To ensure that the effect they were seeing was real, the authors of the new research repeated the experiment on rats, as well as on mice that were bred to develop Type 2 diabetes by a different means than did the first set of mice. In both cases, a single infusion of FGF1 had the same anti-diabetic effect.
“Except for certain bariatric surgical procedures, we are unaware of any intervention capable of inducing sustained remission of Type 2 diabetes in humans or rodents,” the authors wrote. The administration of FGF1 directly into the brain, the authors wrote, “unmasks the brain’s inherent capacity to induce sustained diabetes remission.” And all, they added, “without the need for surgical revision of the gastrointestinal tract.”
While pumping growth factor directly into human brains may seem unwieldy, diabetes treatment that focuses on the brain is not out of reach, the authors wrote. Working with mice and rats, scientists have demonstrated that the intranasal delivery of FGF1 to the brain is feasible.
"We are entering an era where, really, when it comes to treating diabetes using insulin or insulin-related treatments — which they all are — we've gotten as far as we're going to get," Schwartz said. Increasingly, drug developers "understand there probably are not going to be breakthroughs by hammering away at the same drug targets," he added.
"So if there's going to be a paradigm shift in finding treatments that might complement or make other drugs more effective, then targeting the brain might be the way to do this," he said.
Close to 30 million Americans — more than 9% of the U.S. adult population — suffer from Type 2 diabetes, and new diagnoses are surging as obesity soars and the U.S. population ages.
A wide range of medications are available, and under development, but remission most often requires substantial weight loss. In recent years, bariatric surgery has been recognized as highly effective in allowing diabetic patients to reduce or discontinue medication, but its high cost has limited access to such treatment.

Diabetes drug found no better than placebo at treating nonalcoholic fatty liver disease

Diabetes drug found no better than placebo at treating nonalcoholic fatty liver disease
But randomized, double-blind clinical trial suggests better way to conduct future trials
May 12, 2016
University of California - San Diego
A diabetes medication described in some studies as an effective treatment for nonalcoholic fatty liver disease (NAFLD) works no better than a placebo, report researchers after conducting the first randomized, double-blind, controlled clinical trial of sitagliptin, an oral antihyperglycemic marketed under the name Januvia.
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A diabetes medication described in some studies as an effective treatment for nonalcoholic fatty liver disease (NAFLD) works no better than a placebo, report researchers at University of California San Diego School of Medicine, after conducting the first randomized, double-blind, controlled clinical trial of sitagliptin, an oral antihyperglycemic marketed by Merck & Co. under the name Januvia.
Writing in the Journal of Hepatology, a multidisciplinary team headed by study senior author Rohit Loomba, MD, professor of medicine in the Division of Gastroenterology and director of the NAFLD Translational Research Unit at UC San Diego School of Medicine, found that sitagliptin was not significantly better than a placebo in reducing liver fat, as measured by magnetic resonance imaging-proton density fat fraction (MRI-PDFF) and other technologies.
The team included Claude Sirlin, MD, professor and vice chair (translational research) of radiology at UC San Diego School of Medicine, and Richard Ehman, MD, professor of radiology at Mayo Clinic. The labs, led by Sirlin and Ehman, invented and validated the advanced noninvasive imaging techniques applied in this study.
NAFLD is the accumulation of fat in the livers of people who drink little or no alcohol. It is the leading cause of chronic liver disease in the United States. Roughly one-quarter of Americans -- an estimated 100 million adults and children -- have NAFLD, which can progress to a more serious form called nonalcoholic steatohepatitis, which in turn can develop into cirrhosis, liver cancer and liver failure.
Currently, there are no approved, specific therapies for NAFLD. However, it is commonly associated with diabetes, which has prompted researchers to test diabetes medications, such as metformin, rosiglitazone and liraglutide, as potential treatments.
Sitagliptin is another possibility. In clinical trials conducted in patients with type 2 diabetes, sitagliptin has been shown to be effective in improving glycemic (blood sugar) control, cholesterol, lipoproteins and other health measures compared to placebo.
"But human trials of sitagliptin have been limited to date because they have lacked important tools like a placebo arm and allocation concealment (in which researchers do not know what the next treatment allocation will be, further preventing selection bias in testing)," said Loomba.
In the new study, 50 NAFLD patients with pre-diabetes or early diabetes were randomized into two groups: one received a 100 milligram oral dose of sitagliptin daily for 24 weeks, the other received a placebo. Primary outcome was assessed by changes to liver fat measured by MRI-PDFF, conducted by the Liver Imaging Group in the Department of Radiology at UC San Diego Health.
At end-of-treatment, Loomba and colleagues found no significant differences between sitagliptin and placebo across a range of measures. Neither study group experienced any adverse effects.
While the study did not support earlier findings that sitagliptin was an effective treatment for NAFLD, Loomba said it provided new evidence that clinical trials with patients at higher risk of diabetes do not necessarily need a liver biopsy to be efficiently screened for potential therapeutic agents.
"Biopsies present their own complications, such as possible pain and infection," said Loomba. "MRI-PDFF, and magnetic resonance elastography (a non-invasive imaging technique that measures the stiffness of soft tissues) proved to be accurate, quantitative, and useful over the study duration in measuring the state and progression of disease. These technologies should be further investigated in clinical trials, especially those of longer duration."
Added Sirlin: "These advanced magnetic resonance imaging techniques continue to be refined. Although they remain mainly in the research domain now, we anticipate they will become part of standard clinical care within a few years."
Story Source:
The above post is reprinted from materials provided byUniversity of California - San Diego. The original item was written by Scott LaFee. Note: Materials may be edited for content and length.
Journal Reference:
1.         Jeffrey Cui, Len Philo, Phirum Nguyen, Heather Hofflich, Carolyn Hernandez, Ricki Bettencourt, Lisa Richards, Joanie Salotti, Archana Bhatt, Jonathan Hooker, William Haufe, Catherine Hooker, David A. Brenner, Claude B. Sirlin, Rohit Loomba. Sitagliptin versus placebo in the treatment of nonalcoholic fatty liver disease: A randomized controlled trial. Journal of Hepatology, 2016; DOI: 10.1016/j.jhep.2016.04.021
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University of California - San Diego. "Diabetes drug found no better than placebo at treating nonalcoholic fatty liver disease: But randomized, double-blind clinical trial suggests better way to conduct future trials." ScienceDaily. ScienceDaily, 12 May 2016. <