TAG: "Diabetes"

Researchers explain why some wound infections become chronic


Decreasing levels of “reactive oxygen species” can break cycle of unhealing wounds.

Manuela Martins-Green, UC Riverside

Manuela Martins-Green, UC Riverside

Chronic wounds affect an estimated 6.5 million Americans at an annual cost of about $25 billion. Further, foot blisters and other diabetic ulcers or sores account for the vast majority of foot and leg amputations in the United States today.

Why does treating chronic wounds cost so much?  What complicates chronic wound infections, making healing difficult?

Manuela Martins-Green, a professor of cell biology at the University of California, Riverside, reports that two biological activities are out of control in chronic wound infections. These are reactive oxygen species (ROS), which are chemically reactive molecules formed by the partial reduction of oxygen, and biofilms that are formed by selective invading bacteria.

ROS is the natural byproduct of the normal oxygen metabolism and plays a role in cell signaling and homeostasis. However, excessive ROS can induce chronic inflammation, a key characteristic of wounds that do not heal. The biofilms are bacterial defense mechanisms. Together they create a toxic environment that can resist efforts to heal and close a chronic wound.

“By decreasing ROS levels within a chronic wound in a diabetic mouse model, my lab was able to normalize conditions and heal the wound,” Martins-Green said. “Indeed, we saw significant improvement in healing the wound.”

She announced her findings today (Dec. 17) in New Orleans at the 53rd annual meeting of the American Society for Cell Biology.

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Minorities’ health would benefit most from beverage sugar tax


UCSF research team concludes that tax would result in lower rates of diabetes, heart disease.

Kirsten Bibbins-Domingo, UC San Francisco

Kirsten Bibbins-Domingo, UC San Francisco

Taxing sugar-sweetened beverages is likely to decrease consumption, resulting in lower rates of diabetes and heart disease, and these health benefits are expected to be greatest for the low-income, Hispanic and African-American Californians who are at highest risk of diabetes, according to a new analysis led by researchers at UC San Francisco.

Over the course of the next decade, lowered incidence of these diseases would save over half a billion dollars in medical costs, concluded the research team, which includes members from Oregon State University and the Mailman School of Public Health at Columbia University.

The researchers previously modeled the national health effects of a penny-per-ounce tax over the course of 10 years and found that it would reduce consumption among adults by 15 percent, modestly lower the prevalence of diabetes and obesity and prevent tens of thousands of coronary heart events, strokes and premature deaths. The new study considered a range of reductions in sugary beverage consumption among Californians.

In the new study, assuming a decline of 10 to 20 percent in the consumption of soda and other sugary beverages from the tax, researchers concluded that new cases of diabetes and coronary heart disease would drop statewide, and those health benefits would be greatest in poor and minority communities. The analysis, published Dec. 11 in the online journal PLOS ONE, predicted that overall, one in 20,000 Californians would avoid diabetes. This estimate would double for Hispanics and poor Californians and triple for African Americans.

”Poor and minority communities in California and nationally have very high rates of diabetes, a chronic condition with potentially devastating health complications,” said Kirsten Bibbins-Domingo, M.D., Ph.D., UCSF professor of medicine and director of the UCSF Center for Vulnerable Populations at San Francisco General Hospital and Trauma Center. “Although many steps are needed to reverse the rising diabetes trends in the state, our study suggests that efforts to curb sugary beverage consumption can have a significant positive impact, particularly in those most likely to be affected.”

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Islet transplantation gains momentum in type 1 diabetes


UCSF experts improve treatments to prevent rejection.

A close-up of islet cells from a human pancreas. (Image courtesy of Gregory Szot, UC San Francisco)

A close-up of islet cells from a human pancreas.

For the worst cases of type 1 diabetes, islet transplantation already has freed hundreds of people from complete dependence on insulin and from life-threatening consequences of the disease.

However, the procedure still is regarded as experimental by the U.S. Food and Drug Administration (FDA).

Islets are clusters of insulin-making cells in the pancreas that are destroyed in people with type 1 diabetes. After transplanting islet cells from a donor pancreas, the new islet cells can begin to produce insulin.

“Overall the results of islet transplantation are much better than they used to be,” said UC San Francisco transplant surgeon Andrew M. Posselt, M.D., Ph.D.,  “We’re approaching results as good as we see with whole pancreas transplants.”

Posselt, who co-directs the Clinical Islet Transplant Program at UCSF, is part of an international push to bring islet transplantation into the mainstream. As part of that movement, experts gathered in Monterey in September for 14th World Congress of the International Pancreas and Islet Transplant Association (IPITA). World Congress chair, Peter Stock, M.D., Ph.D., is the other co-lead of the UCSF program.

The meeting – sponsored by IPITA, the Transplantation Society and the Department of Surgery at UCSF – included discussions on new ways to foster long-term survival of transplanted islets and to prevent their rejection by the immune system, which is the key to controlling blood sugar without reliance on precisely administered insulin injections.

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Enzyme restores function with diabetic kidney disease


Mouse findings reverse prevailing theory, point to potential treatment options.

Transmission electron micrograph of a cell mitochondrion. (Image courtesy of Thomas Deerinck, National Center for Microscopy and Imaging Research, UC San Diego)

Transmission electron micrograph of a cell mitochondrion.

Researchers at the UC San Diego School of Medicine say that while a prevailing theory suggests elevated cellular levels of glucose ultimately result in diabetic kidney disease, the truth may, in fact, be quite the opposite. The findings could fundamentally change understanding of how diabetes-related diseases develop – and how they might be better treated.

Writing in today’s (Oct. 25) issue of Journal of Clinical Investigation, Kumar Sharma, M.D., professor of medicine and director of the Center for Renal Translational Medicine (CRTM) at UC San Diego; Laura Dugan, M.D., professor of medicine and Larry L. Hillblom Chair in geriatric medicine; Young You, Ph.D., CRTM; Robert Naviaux, M.D., Ph.D., professor of medicine; and colleagues describe first-ever studies of real-time superoxide production in the kidneys of live mice with type 1 diabetes.

Current theory posits that impaired diabetic kidney function in humans as well as in mice is the result of chronically high glucose (sugar) levels which prompt energy-generating mitochondria in cells to produce an overabundance of superoxide anion – a highly reactive, toxic molecule that ultimately leads to downstream cellular damage, organ dysfunction and disease.

But Sharma, who also works for the Veterans Administration San Diego Healthcare System, and colleagues upend this theory. Rather than detecting higher-than-normal levels of superoxide in the damaged kidneys of the diabetic mice, the researchers discovered reduced superoxide production and suppressed mitochondrial activity. When they stimulated the mitochondria by activating a key energy-sensing enzyme called AMPK, superoxide production increased but evidence of diabetic kidney disease markedly declined.

“Mitochondrial superoxide does not seem to be a causative factor of diabetic kidney disease,” said Sharma. “Indeed, when mitochondrial superoxide is increased with AMPK activation, there is reduced kidney disease, suggesting that improving mitochondrial function and superoxide production is actually beneficial for diabetic complications. This idea is a sea change in the field of diabetic complications.”

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Urine biomarkers reveal mitochondrial dysfunction in diabetic kidney disease


Study suggests suppression of mitochondria is a key characteristic of diabetic kidney disease.

X-ray of human kidneys

X-ray of human kidneys

Researchers at the UC San Diego School of Medicine have identified 13 metabolites – small molecules produced by cellular metabolism – that are significantly different in patients with diabetes and chronic kidney disease compared to healthy controls.

Twelve of the 13 metabolites are linked to mitochondrial function, suggesting that suppression of mitochondria – the powerhouses of cells – is a fundamental characteristic of diabetic kidney disease. The findings are published in the November edition of the Journal of the American Society of Nephology.

“This work provides strong evidence that reduced mitochondrial function is a dominant feature of human diabetic kidney disease,” said first author Kumar Sharma, M.D., professor of medicine and director of the Center for Renal Translational Medicine at UC San Diego. “We found that a specific cellular pathway, AMPK-PGC1a, likely plays a key role to reduce mitochondrial function and content, which means that new therapeutic approaches that restore and increase mitochondrial function and content could ameliorate or perhaps even arrest chronic kidney disease.”

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UCLA, Takeda collaborate on diabetes research


They will explore impact of circadian rhythm disruption on type 2 diabetes development.

Aleksey Matveyenko, UCLA

Aleksey Matveyenko, UCLA

Millions of individuals worldwide are exposed to shift work and numerous environmental conditions that disturb circadian clock function and disrupt normal circadian rhythms. Environmental conditions associated with disrupted circadian rhythms greatly increase the risk for development of type 2 diabetes and metabolic syndrome and also hinder the treatment and management of hyperglycemia in existing patients with diabetes.

A new collaboration effort between the New Frontier Science Group at Takeda Pharmaceutical Co. Ltd. and Dr. Aleksey Matveyenko at UCLA will undertake studies to better understand how disruption of circadian rhythms globally and at the level of pancreatic beta-cells promotes development of type 2 diabetes and, specifically, loss of pancreatic beta-cell function and mass.  This research will provide an enhanced molecular understanding of the relationship between circadian clock disruption, beta-cell dysfunction and loss, and type 2 diabetes that may lead to the development of innovative circadian medicines.

Opened in November 2004, the Larry L. Hillblom Islet Research Center at UCLA is the first center dedicated to the study of the islets of Langerhans, which include the insulin-producing cells in the pancreas. An understanding of the causes of islet cell destruction is key to finding a cure for diabetes. The center’s faculty members, recruited from around the world, provide leadership in the worldwide fight against the disease. The center is made possible through a grant from the Larry Hillblom Foundation, established to support medical research in the state of California.

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Researchers discover biological link between diabetes and heart disease


Discovery helps explain why diabetes is significant independent risk factor for heart disease.

(From left) Lianguo Wang, Crystal Ripplinger and Donald Bers, UC Davis

(From left) Lianguo Wang, Crystal Ripplinger and Donald Bers, UC Davis

UC Davis Health System researchers have identified for the first time a biological pathway that is activated when blood sugar levels are abnormally high and causes irregular heartbeats, a condition known as cardiac arrhythmia that is linked with heart failure and sudden cardiac death.

Reported online today (Sept. 29) in the journal Nature, the discovery helps explain why diabetes is a significant independent risk factor for heart disease.

“The novel molecular understanding we have uncovered paves the way for new therapeutic strategies that protect the heart health of patients with diabetes,” said Donald Bers, chair of the UC Davis Department of Pharmacology and senior author of the study.

While heart disease is common in the general population, the risk is up to four times greater for diabetics, according to the National Institutes of Health. The American Heart Association estimates that at least 65 percent of people with diabetes die from heart disease or stroke and has emphasized the need for research focused on understanding this relationship.

Through a series of experiments, Bers, his UC Davis team and their collaborators at the Johns Hopkins University School of Medicine showed that the moderate to high blood glucose levels characteristic of diabetes caused a sugar molecule (O-linked N-acetylglucosamine, or O-GlcNAc) in heart muscle cells to fuse to a specific site on a protein known as calcium/calmodulin-dependent protein kinase II, or CaMKII.

CaMKII has important roles in regulating normal calcium levels, electrical activity and pumping action of the heart, according to Bers. Its fusion with O-GlcNAc, however, led to chronic overactivation of CaMKII and pathological changes in the finely tuned calcium signaling system it controls, triggering full-blown arrhythmias in just a few minutes. The arrhythmias were prevented when CaMKII or its union with O-GlcNAc was inhibited.

“While scientists have known for a while that CaMKII plays a critical role in normal cardiac function, ours is the first study to identify O-GlcNAc as a direct activator of CaMKII with hyperglycemia,” said Bers.

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Madison Clinic helps young diabetes patients manage their own care


UCSF clinicians study impact of health care transition on patients.

Diabetes transitionWhen children are diagnosed with type 1 diabetes­ – one of the most common chronic conditions of childhood – parents typically shoulder the burden of managing their care.

This includes a rigorous daily routine of supervising what the child eats, checking blood sugar levels, administering insulin and keeping regular medical appointments. It’s a big job, and as children become independent adults, it’s one they must gradually take upon themselves.

This process of “transition” is important for maintaining optimal health, and it is highly influenced by socio-economic and cultural factors.

UCSF psychologist Diana Naranjo, Ph.D., an assistant professor of pediatrics, is particularly interested in how the health care transition occurs in ethnic minority families. Her work is part of a broad effort to smooth the transition process for all young adult patients at the Madison Clinic for Pediatric Diabetes at UCSF Benioff Children’s Hospital.

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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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