TAG: "Diabetes"

Protein essential for maintaining beta cell function ID’d


Finding underlies concept that loss of beta cell-specific traits contributes to diabetes.

Maike Sander, UC San Diego

Maike Sander, UC San Diego

Researchers at the Pediatric Diabetes Research Center (PDRC) at the UC San Diego School of Medicine have shown that the pancreatic protein Nkx6.1 – a beta-cell enriched transcription factor – is essential to maintaining the functional state of beta cells.

Type 2 diabetes is characterized by impaired insulin secretion by pancreatic beta cells in response to a rise in blood glucose levels. The study, published in the Sept. 26 edition of Cell Reports, shows that loss of NKx6.1 in mice caused rapid onset diabetes.

UC San Diego scientists – led by PDRC director Maike Sander, M.D., professor in the UCSD departments of pediatrics and cellular and molecular medicine – studied the molecular mechanisms that underlie loss of beta cell functional properties, such as regulated insulin secretion, during the progression of type 2 diabetes. They concluded that – by impairing beta cell function – reduced Nkx6.1 levels, as seen in type 2 diabetes, could contribute to its pathogenesis.

Inactivating the Nkx6.1 transcription factor in adult mice, then conducting a genome-wide analysis of Nkx6.1-regulated genes and functional assays, the scientists revealed the critical role of this protein in the control of insulin biosynthesis, insulin secretion and beta cell proliferation.  Their findings demonstrate an intricate link between the beta cell’s ability to import glucose, supporting an emerging concept that glucose metabolism plays a critical role in beta cell proliferation.

“We found the loss of Nkx6.1 activity had an immediate and dramatic impact on the expression of genes that give beta cells their ability to synthesize and release insulin in a regulated fashion,” said Sander. They discovered that genes involved in insulin biosynthesis, glucose import and glucose metabolism are direct transcriptional target genes of Nkx6.1. Its ablation also indirectly impacted the expression of numerous genes important for the function and proliferation of beta cells.

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Autoimmune disease strategy emerges from immune cell discovery


UCSF experiments halt pancreas destruction in mouse model of diabetes.

Mark Anderson led a team that identified an immune cell, called eTAC cells (shown in green), that may help prevent autoimmune diseases. ETAC cells, which contain a protein in their nucleus called AIRE (shown in red) are relatively rare, and found in lymph nodes and the spleen.

Mark Anderson led a team that identified an immune cell, called eTAC cells (shown in green), that may help prevent autoimmune diseases. ETAC cells, which contain a protein in their nucleus called AIRE (shown in red) are relatively rare, and found in lymph nodes and the spleen.

Scientists from UC San Francisco have identified a new way to manipulate the immune system that may keep it from attacking the body’s own molecules in autoimmune diseases such as type 1 diabetes, rheumatoid arthritis and multiple sclerosis.

The researchers, led by immunologist Mark Anderson, M.D., Ph.D., a professor with the UCSF Diabetes Center, have discovered a distinctive type of immune cell called an eTAC, which puts a damper on immune responses.

Anderson’s research team found that eTACs reside in lymph nodes and spleen in both humans and mice, and determined that they could be manipulated to stop the destruction of the pancreas in a mouse model of diabetes. The study appears in the September issue of the journal Immunity.

Using green fluorescent protein (GFP) to highlight a key regulatory protein called AIRE, Anderson’s research team tracked down the rare eTACs and their role in a phenomenon known as peripheral tolerance, which helps prevent autoimmune disease throughout the body.

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Portable device invented for common kidney tests


UCLA researchers develop device that attaches to smartphones and provides instant results.

Albumin tester

Albumin tester

A lightweight and field-portable device invented at UCLA that conducts kidney tests and transmits data through a smartphone attachment may significantly reduce the need for frequent office visits by people with diabetes and others with chronic kidney ailments.

The smartphone-based device was developed in the research lab of Aydogan Ozcan, a professor of electrical engineering and bioengineering at the UCLA Henry Samueli School of Engineering and Applied Science, and associate director of the California NanoSystems Institute. Weighing about one-third of a pound, the gadget can determine levels of albumin in the patient’s urine and transmit the results within seconds. Albumin is a protein in blood that is a sign of danger when found in urine.

Ozcan’s lab also developed the opto-mechanical phone attachment, disposable test tubes, Android app and software to transmit the data. The research was published this month by the peer-reviewed journal Lab on a Chip.

“Albumin testing is frequently done to assess kidney damage, especially for diabetes patients,” Ozcan said. “This device provides an extremely convenient platform for chronic patients at home or in remote locations where cell phones work.”

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Type 1 diabetes drug proves effective in clinical trial


Drug developed by UCSF researcher shows promise in blocking advance of disease.

Child with diabetesAn experimental drug designed to block the advance of type 1 diabetes in its earliest stages has proven strikingly effective over two years in about half of the patients who participated in the phase 2 clinical trial.

Patients who benefited most were those who still had relatively good control of their blood sugar levels and only a moderate need for insulin injections when the trial began. With the experimental drug, teplizumab, they were able to maintain their level of insulin production for the full two years – longer than with most other drugs tested against the disease.

Results are published online in the journal Diabetes, and will appear in the November issue of the print edition.

The treatment did not benefit all patients. Some lost half or more of their ability to produce insulin – a drop similar to many of the controls not receiving the drug. Reasons for the different responses are unclear, but likely involve differences in the metabolic condition of the patients and in the severity of their disease at the trial’s start, the researchers said.

Jeffrey Bluestone, UC San Francisco

Jeffrey Bluestone, UC San Francisco

“The benefits of treatment among the patients who still had moderately healthy insulin production suggests that the sooner we can detect the pre-diabetes condition and get this kind of drug onboard, the more people we can protect from the progressive damage caused by an autoimmune attack,” said Jeffrey Bluestone, Ph.D., co-leader of the research and A.W. and Mary Clausen Distinguished Professor at UC San Francisco, who collaborated in developing the drug.

The clinical trial was led by Kevan Herold, M.D., Ph.D., a professor of immunobiology and deputy director for translational science at Yale University. He and Bluestone have collaborated on four previous clinical trials of the experimental drug.

“We are very excited by the efficacy of the drug,” Herold said. “Some of our patients and families have described a real impact on their diabetes.”

Bluestone, an immunologist who is now executive vice chancellor and provost at UCSF, developed teplizumab in collaboration with Ortho Pharmaceuticals in 1987. He is a leader in research that aims to understand how and why the immune system attacks the body’s own tissues and organs, and to develop drug strategies to eliminate the autoimmune response without producing severe side effects.

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A second amyloid may play a role in Alzheimer’s disease


UC Davis study is first to identify deposits of amylin in brains of people with Alzheimer’s.

Amylin molecule

A protein secreted with insulin travels through the bloodstream and accumulates in the brains of individuals with type 2 diabetes and dementia, in the same manner as the amyloid beta (Αβ) plaques that are associated with Alzheimer’s disease, a study by researchers with the UC Davis Alzheimer’s Disease Center has found.

The study is the first to identify deposits of the protein, called amylin, in the brains of people with Alzheimer’s disease, as well as combined deposits of amylin and Aβ plaques, suggesting that amylin is a second amyloid as well as a new biomarker for age-related dementia and Alzheimer’s.

“We’ve known for a long time that diabetes hurts the brain, and there has been a lot of speculation about why that occurs, but there has been no conclusive evidence until now,” said UC Davis Alzheimer’s Disease Center Director Charles DeCarli.

“This research is the first to provide clear evidence that amylin gets into the brain itself and that it forms plaques that are just like the amyloid beta that has been thought to be the cause of Alzheimer’s disease,” DeCarli said. “In fact, the amylin looks like the amyloid beta protein, and they both interact. That’s why we’re calling it the second amyloid of Alzheimer’s disease.”

“Amylin deposition in the brain: A second amyloid in Alzheimer’s disease?” is published online today (June 27) in the Annals of Neurology.

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UC Irvine researchers awarded $2.3M to create novel diabetes treatments


Grants will support islet cell transplantation and insulin sensor projects.

Elliot Botvinick, UC Irvine

Two UC Irvine research groups have received $2.27 million from the JDRF to develop innovative methods of treating and possibly curing Type 1 diabetes.

The JDRF, formerly the Juvenile Diabetes Research Foundation, awarded one grant to Jonathan Lakey, associate professor of surgery and biomedical engineering, and Elliot Botvinick, assistant professor of surgery and biomedical engineering; and another to Weian Zhao, assistant professor of pharmaceutical sciences and biomedical engineering. Lakey and Zhao are affiliated with the campus’s Sue & Bill Gross Stem Cell Research Center.

With $1.27 million in funding over three years, Lakey and Botvinick will try to find a way to successfully transplant encapsulated, stem cell-created pancreatic islets. In Type 1 diabetes, the pancreas cannot produce insulin – a hormone key to regulating carbohydrate and fat metabolism in the body – making daily insulin treatments necessary.

Jonathan Lakey, UC Irvine

The pancreas, an organ about the size of a hand, is located behind the lower part of the stomach. It makes insulin and enzymes that help the body digest and use food. Throughout the pancreas are clusters of cells called the islets of Langerhans. Islets are composed of several types of cells, including beta cells that make insulin.

In a previous study, Lakey helped show that transplanted encapsulated islets can create and secrete insulin. A major hurdle, though, is overcoming immune-system rejection of these transplanted islets.

The Lakey-Botvinick team – which includes researchers and products from UC Irvine, the University of Oxford, the Netherlands’ University of Groningen, Eastern Virginia Medical School, Islet Sheet Medical in San Francisco, Islet Sciences in New York and Danish pharmaceutical company Novo Nordisk – will explore the use of isolated islets in which the cells are encased in an ultrapure algae membrane.

The encapsulation chemistry allows for selective permeability, meaning that some small molecules, such as glucose and insulin, can pass across the barrier, while large antibodies and immunological molecules are blocked from entering into the space containing the islets.

Weian Zhao, UC Irvine

“Perhaps the greatest challenge in the field of islet transplantation is to make the metabolic benefits available to patients with Type 1 diabetes without the need for chronic immunosuppression,” said Lakey, who’s also director of UC Irvine Health’s Clinical Islet Program. “I believe that this technology has great promise for realizing our goal. And this welcome support from the JDRF should speed our progress.”

With the other grant, Zhao and his colleagues will try to develop an insulin sensor for the JDRF’s Artificial Pancreas Project, which supports the creation of an automated system to dispense insulin based on real-time changes in blood sugar levels. Central to such a device is a mechanism that can accurately determine blood insulin amounts to provide feedback control for the artificial pancreas.

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Alzheimer’s and low blood sugar in diabetes may trigger a vicious cycle


UCSF researcher urges caution on use of certain diabetes drugs in dementia patients.

Kristine Yaffe, UC San Francisco

A new UC San Francisco-led study looks at the close link between diabetes and dementia, which can create a vicious cycle.

Diabetes-associated episodes of low blood sugar may increase the risk of developing dementia, while having dementia or even milder forms of cognitive impairment may increase the risk of experiencing low blood sugar, according to the study published online today (June 10)  in JAMA Internal Medicine.

Researchers analyzed data from 783 diabetic participants and found that hospitalization for severe hypoglycemia among the diabetic, elderly participants in the study was associated with a doubled risk of developing dementia later. Similarly, study participants with dementia were twice as likely to experience a severe hypoglycemic event.

The study results suggest some patients risk entering a downward spiral in which hypoglycemia and cognitive impairment fuel one another, leading to worse health, said Kristine Yaffe, M.D., senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco VA Medical Center.

“Older patients with diabetes may be especially vulnerable to a vicious cycle in which poor diabetes management may lead to cognitive decline and then to even worse diabetes management,” she said.

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Californians with regular doctor more likely to get preventive care


Patients in “medical homes” more likely to get flu shots, receive regular care.

Too many cooks may spoil a recipe, and too many doctors may give you the flu.

That’s the takeaway from a new study by the UCLA Center for Health Policy Research that found that Californians who jump from provider to provider rather than seeing a regular doctor who coordinates their care may be less likely to get the kind of preventive treatment that protects against the flu and flare ups in their chronic conditions.

Specifically, the study used data from the 2009 California Health Interview Survey (CHIS) to estimate whether the approximately 4.76 million California adults with chronic conditions such as diabetes, asthma and heart disease had three key characteristics of “medical home” care. Those three characteristics are:

  • The patient saw a regular doctor over time rather than switching from provider to provider.
  • This regular doctor developed an individual treatment plan for the patient.
  • The doctor coordinated the patient’s care.

The result? Californians who had all three of these characteristics were the most likely to get a regular flu shot, compared with those without a usual source of care. They were also more likely to have seen their doctor five or more times in the past year and to have called their doctor with a question about their care. Additionally, they were the most confident about their ability to manage their health.

“Seeing the same doctor over time builds familiarity, trust and confidence for both provider and patient,” said Nadereh Pourat, the UCLA center’s director of research and lead author of the study. “And if that doctor takes a coordinated approach to their patients’ care, there seems to be a big payoff in terms of better health for their patients.”

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A new protein target for controlling diabetes


Fractalkine circulates in bloodstream and stimulates insulin secretion, researchers find.

Jerrold Olefsky, UC San Diego

Researchers at the UC San Diego School of Medicine have identified a previously unknown biological mechanism involved in the regulation of pancreatic islet beta cells, whose role is to produce and release insulin. The discovery suggests a new therapeutic target for treating dysfunctional beta cells and type 2 diabetes, a disease affecting more than 25 million Americans.

Writing in the April 11 issue of Cell, Jerrold M. Olefsky, M.D., associate dean for scientific affairs and distinguished professor of medicine, and colleagues say a transmembrane binding protein called fractalkine, which typically mediates cell-to-cell adhesion though its receptor, CX3CR1, can also be released from cells to circulate in the blood and stimulate insulin secretion.

“Our discovery of fractalkine’s role in beta cells is novel and has never been talked about in prior literature,” said Olefsky. More importantly, the research highlights fractalkine’s apparently vital role in normal, healthy beta cell function. In mouse models and in cultured human islets, the researchers found administering the protein stimulated insulin secretion and improved glucose tolerance, both key factors in diabetes.  In contrast, fractalkine had no effect in mice or islets when the fractalkine receptor was deleted.

“Whether or not decreased fractalkine or impaired fractalkine signaling are causes of decreased beta cell function in diabetes is unknown,” said Olefsky. “What we do know, without doubt, is that administration of fractalkine improves or restores insulin secretion in all of the mouse models we have examined, as well as in human islet cells.”

Olefsky said fractalkine or a protein analog could prove “a potential treatment to improve insulin secretion in type 2 diabetic patients. It might also improve beta cell function or beta cell health, beyond simply increasing insulin secretion, since fractalkine prevents beta cell apoptosis (cell death) and promotes the beta cell differentiation program.

“If successfully developed, this could be an important new complement to the therapeutic arsenal we use in type 2 diabetes,” Olefsky continued. “It is not likely to ‘cure’ diabetes, but it would certainly do a good job at providing glycemic control.”

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Research suggests popular diabetes drugs can cause abnormal pancreatic growth


The abnormalities may be associated with increased risk of neuroendocrine tumors.

Peter Butler, UCLA

Individuals who had taken a type of drug commonly used to treat Type 2 diabetes showed abnormalities in the pancreas, including cell proliferation, that may be associated with an increased risk of neuroendocrine tumors, according to a new study by researchers from UCLA and the University of Florida. Their findings were published online March 22 in the journal Diabetes.

The researchers, from the Larry L. Hillblom Islet Research Center at UCLA and the Diabetes Center at the University of Florida, found that cell mass was increased approximately 40 percent in the pancreases of deceased organ donors who had Type 2 diabetes and who had been treated with incretin therapy. This widely used type of treatment takes advantage of the action of a gut hormone known as glucagon-like peptide 1 (GLP-1) to lower blood sugar in the body.

Although there have been conflicting reports on the effects of the incretin class of drugs on the pancreas in animal studies, this is the first study to note such changes in the human pancreas. The research was made possible by a unique research consortium called nPOD (Network for Pancreatic Organ Donors with Diabetes), led by Dr. Mark Atkinson, a professor of pathology and pediatrics at the University of Florida. The network, which is funded by the Juvenile Diabetes Research Foundation, obtains pancreases from deceased organ donors, with permission of their next of kin, to better understand diabetes by investigating tissues of those with the disease.

“There is an increasing appreciation that animal studies do not always predict findings in humans,” said Dr. Peter Butler, director of UCLA’s Hillblom Islet Research Center and chief of the endocrinology, diabetes and hypertension unit. “The nPOD program is therefore a very precious resource.”

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Youth with diabetes at greater risk after transitioning to adult care


Study suggests need for additional support when leaving pediatric providers.

Debra Lotstein, UCLA

Debra Lotstein, UCLA

Type 1 diabetes is a condition in which the body does not produce insulin and cannot convert sugar, starches and other food into energy. Generally diagnosed during childhood or adolescence, the disease requires lifelong access to medical care and intensive daily self-management.

As children with Type 1 diabetes grow into young adults, they must leave their pediatric health care providers for adult providers. But the timing of this process and its impact on the young people’s health had not been fully explored.

In a new study published in the April issue of the journal Pediatrics and currently available online, UCLA researchers found that young people with Type 1 diabetes who had transitioned from pediatric to adult care were 2.5 times more likely to have chronically high blood glucose levels, putting them at higher risk for heart attacks, strokes, blindness and kidney failure later in life.

The estimated median age of patients when this transition occurred was 20.1 years, the researchers said, and 77 percent had left pediatric care by age 21.

The findings suggest that young adults need additional support and guidance when leaving their pediatric providers to avoid the risk of poor diabetes control.

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Nurses can play key role in reducing deaths from diseases


UCLA nursing professor co-authors World Health Organization report.

Linda Sarna, UCLA

Nurses and midwives can play a critical role in lessening people’s risk of cardiovascular diseases, cancers, chronic respiratory disease and diabetes, according to a groundbreaking new report issued by the World Health Organization and co-authored by a UCLA nursing professor.

These four non-communicable disease types account for a combined 60 percent of all deaths worldwide.

“The global burden of non-communicable diseases is already high and continues to grow in all regions of the world,” said Linda Sarna, a professor at the UCLA School of Nursing and co-author of the report. “Nurses and midwives have the expertise to help individuals and communities improve health outcomes.”

Sarna points out that since nurses and midwives make up more than 50 percent of all health care providers in most countries, they are the logical candidates to affect lifestyle changes among patients and increase health awareness. Worldwide, there are more than 19 million nurses and midwives, she said.

The 38-page report issued by the WHO highlights evidence-based, value-added nursing interventions that have been shown to reduce such risk factors as tobacco use, alcohol dependence, physical inactivity and unhealthy diets.

“The examples contained in the report are proven activities that nurses can start doing today to make a meaningful impact with their patients and in their community,” Sarna said. “Many of the interventions have been proven to reduce costs and improve the quality of care.”

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