UCSF study suggests stress-amplifying TXNIP protein may be powerful new drug target.

Feroz Papa, UC San Francisco

At its most fundamental level, diabetes is a disease characterized by stress — microscopic stress that causes inflammation and the loss of insulin production in the pancreas, and system-wide stress due to the loss of that blood-sugar-regulating hormone.

Now, researchers led by scientists at the University of California, San Francisco, have uncovered a new key player in amplifying this stress in the earliest stages of diabetes: a molecule called thioredoxin-interacting protein (TXNIP). The molecule, they’ve discovered, is central to the inflammatory process that leads to the death of the cells in the human pancreas that produce insulin.

“This molecule does something remarkable — it takes stress and makes it worse,” said the senior author of the study, UCSF’s Feroz Papa, M.D., Ph.D., an associate professor of medicine at UCSF and a member of the UCSF Diabetes Center and the California Institute for Quantitative Biosciences (QB3).

The study is published this week in the journal Cell Metabolism, with a parallel study by researchers at Washington University in St. Louis. Both studies were funded by the Juvenile Diabetes Research Foundation (JDRF).

The work provides a roadmap for finding new drugs that could target and shut down the action of TXNIP, thus preventing or stalling the inflammatory processes it amplifies. Researchers in the field believe that this strategy could benefit people in the early days of the disease, when diabetes is first developing or is soon to develop — a time referred to as the “honeymoon” period.

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Study authors recommend adding palliative care to diabetes management.

Rebecca Sudore

Almost half of adults with type 2 diabetes report acute and chronic pain, and close to one quarter report neuropathy, fatigue, depression, sleep disturbance and physical or emotional disability, according to a study of more than 13,000 adults conducted by researchers at the San Francisco VA Medical Center, the University of California, San Francisco, and the Kaiser Permanente Division of Research in Oakland. The researchers also found significant rates of shortness of breath, nausea and constipation.

Patients in the study reported significant pain and non-pain symptoms across the entire course of the disease, among all age groups, with prevalence increasing as people neared the end of their lives.

The findings appear in the Journal of General Internal Medicine and are available online on Aug. 3 at www.SpringerLink.com. According to the authors, it is the largest observational study to assess a full range of pain and non-pain symptoms among patients with type 2 diabetes, and the first to characterize the kinds of symptoms that patients experience.

“Adults living with type 2 diabetes are suffering from incredibly high rates of pain and non-pain symptoms, at levels similar to patients with living with cancer,” said lead author Rebecca Sudore, a staff physician at SFVAMC and associate professor of medicine at UCSF.

She noted that tens of millions of Americans have type 2 diabetes.

“The field of diabetes has focused, and rightfully so, on decreasing patients’ blood sugar, blood pressure and cholesterol levels in attempt to prevent complications such as cardiovascular disease, kidney failure, amputations and blindness,” said Andrew J. Karter, Ph.D., a principal investigator of the DISTANCE and Diabetes & Aging Studies, and senior research scientist at Kaiser. “However, our observations provide an important wake-up call for clinicians to not wait until the latest stages of diabetes to focus on these patient-reported outcomes, but rather to consider early palliative care as part of usual chronic disease management.”

Palliative care is specialized medical care for people with serious illness that provides an added layer of support in addition to regular disease management, with the goal of relieving symptoms and improving quality of life, explained Sudore. She noted that other studies suggest that seriously ill patients who receive palliative care live longer with a better quality of life.

“Palliative care has already begun to be woven into the care provided to patients with cancer, heart failure and kidney failure,” she said. “Our results highlight the need to expand diabetes management to also include the palliative care model.”

The research team surveyed 13,171 adults with diabetes, aged 30 to 75 years, who were enrolled in Kaiser Permanente Northern California and participated in the NIH-funded Diabetes Study of Northern California (DISTANCE) and its ancillary Diabetes & Aging Study.

Adults over the age of 60 reported more physical symptoms such as pain, whereas adults younger than 60 reported more psychosocial symptoms such as fatigue and depression. Symptom burden remained high even after the researchers accounted for other medical illnesses and duration of diabetes. Results were based on self-reported symptoms and chart review.

In type 2 diabetes, the most common form of the disease, patients’ blood sugars become chronically elevated, which in turn damages blood vessels and nerves leading to and from the heart, brain, kidneys, gastrointestinal tract, eyes, ears, legs and feet. This damage can lead to serious illness and death.

Dean Schillinger, M.D., of the UCSF Center for Vulnerable Populations and UCSF Division of General Internal Medicine at San Francisco General Hospital, is senior co-author of the study. He also is director of the California Diabetes Program, a federally-funded program that is administered by UCSF for the California Department of Public Health.  Elbert S. Huang, M.D., of the University of Chicago, is the co-principal investigator for the Diabetes & Aging Study and co-director for the Chicago Center for Diabetes Translation Research.

Co-authors include Andrew J. Karter, Ph.D., Howard H. Moffet, M.P.H., Jennifer Liu, M.P.H., Alyce Adams, Ph.D., and Rachael Whitmer, Ph.D., from the Division of Research, Kaiser Permanente Northern California; Elbert S. Huang, M.D., M.P.H., Neda Laiteerapong, M.D., and Priya John, M.P.H., from the University of Chicago; Yael Schenker, M.D., from the University of Pittsburgh; and Yinghui Miao, M.P.H. from UCSF.

Funds were provided by the National Institute of Diabetes, Digestive and Kidney Diseases, the National Institute of Child Health and Human Development and the National Center for Research Resources. Sudore is supported by funds from the Department of Veterans Affairs. Schillinger is supported by a grant from Agency for Healthcare Research and Quality and a NIH Clinical and Translational Science Award.

About the San Francisco VA Medical Center

SFVAMC has the largest medical research program in the national VA system, with more than 200 research scientists, all of whom are faculty members at UCSF.

About UCSF

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit www.ucsf.edu.

About the Kaiser Permanente Division of Research

The Kaiser Permanente Division of Research conducts, publishes and disseminates epidemiologic and health services research to improve the health and medical care of Kaiser Permanente members and the society at large. It seeks to understand the determinants of illness and well-being and to improve the quality and cost-effectiveness of health care. Currently, DOR’s 500-plus staff is working on more than 250 epidemiological and health services research projects.

Neutrophils’ role is a surprise — and a potential new target for treating diabetes.

A false-colored, scanning electron micrograph of a neutrophil

Researchers at the UC San Diego School of Medicine say neutrophils, an abundant type of white blood cell typically tasked with attacking bacteria and other foreign invaders, also plays an unexpected role in mediating insulin resistance — the central characteristic of type 2 diabetes, which afflicts an estimated 26 million Americans.

The findings are published in Sunday’s (Aug. 5) Advance Online Publication of Nature Medicine.

Neutrophils are the first immune cells to respond to tissue inflammation, and can promote chronic inflammation by summoning other white blood cells called macrophages. Chronic low-grade inflammation — common in adipose or fat tissue — is an important cause of systemic insulin resistance.

Using liver and fat cells from mice and humans and live mouse models, a team led by Jerrold M. Olefsky, M.D., associate dean for scientific affairs at UC San Diego Health Sciences and professor of medicine, discovered that an enzyme secreted by neutrophils called neutrophil elastase (NE) impairs insulin signaling and boosts resistance. Conversely, deletion of NE in obese mice fed a high-fat diet improved insulin sensitivity.

“These results are largely unexpected,” said Da Young Oh, an assistant project scientist in Olefsky’s lab and study co-author. “Although several immune cells have been established in the etiology of insulin resistance, the role of neutrophils in this process has remained unclear until now.”

Oh said neutrophils were considered to be “transient infiltrates,” temporary cells (average lifespan: 5 days) that were incapable of sustaining chronic, low-grade inflammation. “Our studies now suggest neutrophils possess powerful immune modulatory effects,” Oh said.

Specifically, neutrophils use NE to activate a signaling pathway which triggers pathogen-eating macrophages to secrete proinflammatory molecules called cytokines. NE degrades IRS1, a key protein in the insulin signaling pathway in both liver and fat cells. Although NE has been shown to degrade this protein in lung cancer cells, the scientists said, the effect on insulin target tissues such as liver and adipose is striking.

The insulin-mediating role of neutrophils makes them a new target for developing treatments of insulin resistance in particular and diabetes in general. “Given that NE mediates insulin resistance, one could, in theory, take an NE activity inhibitory approach to reverse or improve insulin resistance,” Oh said, noting that NE inhibitors are already used for treatment of emphysema in Japan and are being tested in the United States, both for emphysema and type 1 diabetes.

Co-authors are Saswata Talukdar, Gautan Bandyopadhyay, Jianfeng Xu, Joanne McNelis, Min Lu, Pingping Li, Jachelle Ofrecio and Michael Lin, Department of Medicine, UCSD; Dongmei Li, Qingyun Yan, Yimin Zhu and Martin B. Brenner, Pfizer.

Funding for this research came, in part, from the National Institutes of Health (grants DK033651, DK074868, T32 DK007494, DK090962, and DK063491) and the Eunice Kennedy Shriver NICHD/NIH agreement (U54 HD 012303-25), part of the specialized Cooperative Centers Program in Reproduction and Infertility Research.

Biologists’ finding points in new direction for developing drugs to treat metabolic disorders.

Biologists at UC San Diego have discovered a chemical that offers a completely new and promising direction for the development of drugs to treat metabolic disorders such as type 2 diabetes — a major public health concern in the United States due to the current obesity epidemic.

Their discovery, detailed in a paper published July 13 in an advance online issue of the journal Science, initially came as a surprise because the chemical they isolated does not directly control glucose production in the liver, but instead affects the activity of a key protein that regulates the internal mechanisms of our daily night and day activities, which scientists call our circadian rhythm or biological clock.

Scientists had long suspected that diabetes and obesity could be linked to problems in the biological clock. Laboratory mice with altered biological clocks, for example, often become obese and develop diabetes. Two years ago, a team headed by Steve Kay, dean of the Division of Biological Sciences at UC San Diego, discovered the first biochemical link between the biological clock and diabetes. It found that a key protein, cryptochrome, that regulates the biological clocks of plants, insects and mammals also regulates glucose production in the liver and that altering the levels of this protein could improve the health of diabetic mice.

Now Kay and his team have discovered a small molecule — one that can be easily developed into a drug — that controls the intricate molecular cogs or timekeeping mechanisms of cryptochrome in such a manner that it can repress the production of glucose by the liver. Like mice and other animals, humans have evolved biochemical mechanisms to keep a steady supply of glucose flowing to the brain at night, when we’re not eating or otherwise active.

“At the end of the night, our hormones signal that we’re in a fasting state,” said Kay. “And during the day, when we’re active, our biological clock shuts down those fasting signals that tell our liver to make more glucose because that’s when we’re eating.”

Diabetes is caused by an accumulation of glucose in the blood, which can lead to heart disease, strokes, kidney failure and blindness. In type 1 diabetes, destruction of insulin producing cells in the pancreas results in the high blood sugar. In type 2 diabetes, which makes up 90 percent of the cases, gradual resistance to insulin because of obesity or other problems, leads to high blood sugar.

Kay and his collaborators discovered in 2010 that cryptochrome plays a critical role in regulating the internal timing of our cyclical eating patterns, timing our fasting at night with our eating during the day to maintain a steady supply of glucose in our bloodstream. Other researchers have recently discovered that cryptochrome also has the potential to reduce high blood sugar from asthma medication by adjusting the time of day a patient takes their medication. “We found that if we increased cryptochrome levels genetically in the liver we could inhibit the production of glucose by the liver,” said Kay.

What he and his team found in their most recent discovery was that a much smaller molecule, dubbed “KL001” (for the first such compound from the Kay Lab), can regulate that activity as well. It slowed down the biological clock by stabilizing the cryptochrome protein — that is, it essentially prevented crypotochrome from being sent to the cellular garbage can, the proteasomes.

The discovery of KL001 was serendipitous, a complete surprise to the scientists that came about from a parallel effort in Kay’s laboratory to identify molecules that lengthen the biological clock. Two years ago, Tsuyoshi Hirota, a postdoctoral fellow in Kay’s laboratory found a compound that had the greatest effect ever seen on circadian rhythm, a chemical the biologists dubbed “longdaysin” because it lengthened the daily biological clocks of human cells by more than 10 hours.

Continuing his search, Hirota resumed his efforts to find more chemicals that lengthened or slowed down circadian rhythms, enabling the scientists to understand more about the intricate chemical and genetic machinery of the biological clock. He and his colleagues in Kay’s lab did this by screening thousands of compounds from a chemical library with human cells in individual micro-titer wells in which a luciferase gene from fireflies is attached to the biological clock machinery, enabling the scientists to detect a glow whenever the biological clock is activated. Their molecular fishing expedition came up with a number of other compounds, one of which was KL001.

“We found other compounds that like longdaysin slowed down the biological clock,” said Kay. “But unlike longdaysin, these compounds did not inhibit the protein kinases that longdaysin inhibits so we knew this compound must be working differently. What we needed to know was what is this compound interacting with? And we were absolutely stunned when we discovered that what was binding most specifically to our compound, KL001, was the clock protein cryptochrome that our lab has worked on in plants, flies and mammals for the last 20 years.”

Kay’s team turned to biological chemists in Peter Schultz’s laboratory at The Scripps Research Institute to characterize the compound and understand better chemically how it affected cryptochrome to lengthen the biological clock.

“Those biochemical studies showed us that KL001 prevents cryptochrome from being degraded by the proteasome system, which was another big surprise,” said Kay. “It essentially interferes with the signal to send cryptochrome to the garbage can.”

To understand how KL001 worked mechanistically with cryptochrome to control the biological clock, the team initiated a collaboration with Frank Doyle and his group at UC Santa Barbara. “They constructed a beautiful mathematical model of cryptochrome’s role in the clock,” said Kay. “That model was essential in allowing us to understand the action of the compound because the biological clock is very complicated. It’s like opening the back of a Rolex and seeing the hundreds of tiny little cogs that are tightly integrated.”

Based on that mathematical model, the scientists predicted that adding KL001 to mouse liver cells should stabilize cryptochrome and that the increased level of cryptochrome would inhibit the production of enzymes in the liver that stimulate the process of gluconeogenesis—the generation of glucose during fasting. Experiments done together with the laboratory of David Brenner, dean of the UC San Diego School of Medicine and vice chancellor for health sciences, confirmed that prediction to be true.

“In mouse liver cells,” said Kay, “we showed that KL001 inhibited gene expression for gluconeogenesis that is induced when exposed to the hormone glucagon, which promotes glucose production by the liver. It’s a hormone we all produce in fasting states. And our compound, in a dose dependent way, inhibits hepatic gluconeogenesis, the actual production of glucose by those liver cells.”

Kay said the next step for the research group is to understand how KL001 and similar molecules that affect cryptochrome function in living systems, such has laboratory mice. The scientists also plan to probe how such compounds affect other processes besides the liver that may tie the biological clock to metabolic diseases. “As with any surprise discovery,” he notes, “this opens the door to more opportunities for novel therapeutics than we can currently imagine.”

Besides Kay, Hirota, Schultz, Doyle and Brenner, other scientists involved in the discovery were Mariko Sawa, Pagkapol Y. Pongsawakul and Tim Sonntag of UC San Diego’s Division of Biological Sciences; Jae Wook Lee of TSRI; Peter St. John of UC Santa Barbara; Keiko Iwaisako, Takako Noguchi and David Welsh of UC San Diego’s School of Medicine.

The study was supported by grants from the National Institutes of Health (GM074868, H051573 GM085764, GM096873, MH082945).

UC San Diego clinical trial will study how online social network may enhance patient care.

Jason Bronner, UC San Diego

Researchers at the UC San Diego School of Medicine are evaluating a new social media tool called Wellaho to treat patients with type I and II diabetes. The clinical trial will study whether the use of social networking can improve patient-physician interactions and the patient’s overall health and wellbeing.

“This trial will study how an online social network may better enable patient care,” said Jason Bronner, M.D., associate clinical professor, UC San Diego School of Medicine and internist at UC San Diego Health System. “With a controlled group of the patient’s clinicians, friends, family and fellow patients, we will measure any changes in knowledge, attitudes and self care towards diabetes.”

Wellaho, developed by Sanitas Inc. in La Jolla, is an interactive online system designed to help patients manage their care outside the hospital. The system is HIPAA compliant, compatible with provider networks, and includes telemedicine capabilities.

“Social networking provides a common way for patients with chronic disease to learn about their condition while interacting with others in similar situations,” said Bronner. “As opposed to open networks, the use of this tool allows us to ensure that the medical information they receive and share is accurate, safe and absent of advertising.”

The online site provides self-monitoring tools as well as evidenced-based education customized for the patient’s specific condition. Subjects will be monitored for the number of times they access the site, length of use and number of invited participants. The site will also track measures of weight, blood pressure and glycostated hemoglobin.

“Long term, we hope that patients will learn behaviors that impact blood sugar, control blood pressure, improve satisfaction and potentially decrease cost of care,” said Bronner.

According to the American Diabetes Association, diabetes now affects 25.8 million children and adults in the United States. An additional 79 million Americans are considered pre-diabetic.

To learn more about this clinical trial, please call (858) 657-8000.

First study to link risk of cognitive decline to severity of diabetes.

Kristine Yaffe

Preventing diabetes or delaying its onset has been thought to stave off cognitive decline — a connection strongly supported by the results of a 9-year study led by researchers at the University of California, San Francisco, and the San Francisco VA Medical Center.

Earlier studies have looked at cognitive decline in people who already had diabetes. The new study is the first to demonstrate that the greater risk of cognitive decline is also present among people who develop diabetes later in life. It is also the first study to link the risk of cognitive decline to the severity of diabetes.

The result is the latest finding to emerge from the Health, Aging, and Body Composition (Health ABC) Study, which enrolled 3,069 adults over 70 at two community clinics in Memphis, Tenn., and Pittsburgh beginning in 1997. All the patients provided periodic blood samples and took regular cognitive tests over time.

When the study began, hundreds of those patients already had diabetes. A decade later, many more of them had developed diabetes, and many also suffered cognitive decline. As described this week in Archives of Neurology, those two health outcomes were closely linked.

People who had diabetes at the beginning of the study showed a faster cognitive decline than people who developed it during the course of the study — and these people, in turn, tended to be worse off than people who never developed diabetes at all. The study also showed that patients with more severe diabetes who did not control their blood sugar levels as well suffered faster cognitive declines.

“Both the duration and the severity of diabetes are very important factors,” said Kristine Yaffe, M.D., the lead author of the study. “It’s another piece of the puzzle in terms of linking diabetes to accelerated cognitive aging.”

An important question for future studies, she added, would be to ask if interventions that would effectively prevent, delay or better control diabetes would also lower people’s risk of cognitive impairment later in life.

Yaffe is the Roy and Marie Scola Endowed Chair of Psychiatry; professor in the UCSF departments of psychiatry, neurology and epidemiology and biostatistics; and chief of geriatric psychiatry and director of the Memory Disorders Clinic at the San Francisco VA Medical Center.

Diabetes and cognitive decline

Diabetes is a chronic and complex disease marked by high levels of sugar in the blood that arise due to problems with the hormone insulin, which regulates blood sugar levels. It is caused by an inability to produce insulin (type 1) or an inability to respond correctly to insulin (type 2).

A major health concern in the United States, diabetes of all types affects an estimated 8.3 percent of the U.S. population — some 25.8 million Americans — and costs U.S. taxpayers more than $200 billion annually. In California alone, an estimated 4 million people (one out of every seven adults) has type 2 diabetes and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent the disease.

Over the last several decades, scientists have come to appreciate that diabetes affects many tissues and organs of the body, including the brain and central nervous system — particularly because diabetes places people at risk of cognitive decline later in life.

In their study the scientists looked at a blood marker known as “glycosylated hemoglobin,” a standard measure of the severity of diabetes and the ability to control it over time. The marker shows evidence of high blood sugar because these sugar molecules become permanently attached to hemoglobin proteins in the blood. Yaffe and her colleagues found that greater levels of this biomarker were associated with more severe cognitive dysfunction.

While the underlying mechanism that accounts for the link between diabetes and risk of cognitive decline is not completely understood, Yaffe said, it may be related to a human protein known as insulin degrading enzyme, which plays an important role in regulating insulin, the key hormone linked to diabetes. This same enzyme also degrades a protein in the brain known as beta-amyloid, a brain protein linked to Alzheimer’s disease.

The article, “Diabetes, Glucose Control, and 9-Year Cognitive Decline Among Non-Demented Older Adults Without Dementia” by Kristine Yaffe, Cherie Falvey, Nathan Hamilton, Ann V. Schwartz, Eleanor M. Simonsick, Suzanne Satterfield, Jane A. Cauley, Caterina Rosano, Lenore J. Launer, Elsa S. Strotmeyer and Tamara B. Harris, is published online by the Archives of Neurology on June 18.

In addition to UCSF, authors on this study were affiliated with University of Tennessee, the National Institute on Aging and the University of Pittsburgh.

This work was funded by the National Institutes of Health (NIH) through its National Institute of Aging and National Institute of Nursing Research. Specific contract and grant numbers were: N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050, R01-NR012459 and K24AG031155. This research was also supported by the Intramural Research Program of the NIH and by the American Health Assistance Foundation.

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit www.ucsf.edu.

Monthly phone calls can help encourage lifestyle changes, UCSF study finds.

Alka Kanaya, UC San Francisco

A simple, inexpensive method for preventing type 2 diabetes that relies on calling people and educating them on the sort of lifestyle changes they could make to avoid developing the disease has proven effective in a study conducted by researchers at the University of California, San Francisco, and the city of Berkeley Department of Public Health.

The study involved 230 people in poor, urban neighborhoods in the San Francisco Bay Area cities of Richmond, Oakland and Berkeley. Contacted by phone about once a month, half of them received specific dietary guidance and other lifestyle counseling. After six months, those who had received the counseling had on average lost more weight, were consuming less fat, were eating more fruits and vegetables and showed more improvements in lowering in their blood triglycerides, a key risk measure for type 2 diabetes.

Described this week in the American Journal of Public Health, the new intervention is specifically designed for urban, poor and predominantly minority communities. It addresses the need for diabetes prevention interventions in these communities and highlights a simple fact that doctors at UCSF and elsewhere have been repeating for years — that type 2 diabetes is preventable in the first place.

“Diabetes is not something you are necessarily going to get just because it runs in your family,” said Alka Kanaya, M.D., an associate professor of medicine at UCSF and one of two senior authors on the study. “It is very preventable, and lifestyle changes can really impact the onset of diabetes.”

Anita Stewart, UC San Francisco

“You can do something about it,” said Anita Stewart, Ph.D., a professor at the UCSF Institute for Health & Aging and the Center for Aging in Diverse Communities who is the other senior author on the paper.

How lifestyle changes can prevent diabetes

Diabetes is a chronic and complex disease marked by high levels of sugar in the blood that arise due to problems with the hormone insulin, which regulates blood sugar levels. It is usually caused by an inability to produce insulin (type 1) or an inability to respond correctly to insulin (type 2).

A major health concern in the United States, diabetes of all types affect an estimated 8.3 percent of the U.S. population — some 25.8 million Americans — and cost U.S. taxpayers more than $200 billion annually.

In California alone, an estimated 4 million people (one out of every seven adults) have type 2 diabetes and millions more are at risk of developing it. These numbers are poised to explode in the next half century if more is not done to prevent diabetes.

Previous studies have shown that counseling and other lifestyle interventions are effective at preventing type 2 diabetes, but those interventions have generally been designed for clinical settings and include separate sessions with numerous health professionals. This makes them expensive and difficult to scale to large urban populations where diabetes interventions are needed the most.

Many of this country’s urban poor face thin health insurance coverage, low literacy and low income and a higher risk of developing type 2 diabetes. These disparities were apparent in the UCSF study. About half of the study population was composed of immigrants, and nearly a quarter had no health insurance. Almost a third said they faced financial hardship, and 22 percent had less than a high-school education.

By focusing on a phone-based solution delivered by the public health department staff, the UCSF researchers designed their new intervention specifically as a low-cost community-based approach that would be relevant to poor, minority and low-literacy populations. Similar telephone interventions have been used to reach out broadly to populations in San Francisco and in other cities to spread lifestyle messages related to hypertension, smoking, high cholesterol and other issues.

“This adds to our public health toolkit of ways to do outreach and prevent diabetes,” said Kanaya.

The article, “The Live Well, Be Well Study: A Community-Based, Translational Lifestyle Program to Lower Diabetes Risk Factors in Ethnic Minority and Lower–Socioeconomic Status Adults” by Alka M. Kanaya, Jasmine Santoyo-Olsson, Steven Gregorich, Melanie Grossman, Tanya Moore and Anita L. Stewart, appears in the June 14 issue of the American Journal of Public Health.

This work was funded by the National Institutes of Health through a translational research grant from the National Institute of Diabetes and Digestive and Kidney Diseases (DK067896-01A2) and by the Resource Centers for Minority Aging Research program of the National Institute on Aging (P30-AG15272).

UCSF is a leading university dedicated to promoting health worldwide through advanced biomedical research, graduate-level education in the life sciences and health professions, and excellence in patient care. For further information, please visit www.ucsf.edu.

Studies suggest greater danger, but risk appears to vary by definition.

Bruce Ovbiagele, UC San Diego

Millions of pre-diabetic Americans may be at increased risk of future stroke, say researchers at the UC San Diego School of Medicine in a new meta-analysis of epidemiological studies, but the precise degree of that threat is confounded by differing medical definitions and factors that remain unknown or unmeasured.

“The immediate implication of our findings is that people with pre-diabetes should be aware they are at increased risk of stroke, and that this condition is frequently associated with one or more major risk factors for cardiovascular disease,” said Bruce Ovbiagele, M.D., a professor of neurosciences at UC San Diego School of Medicine and the study’s senior author. “Beyond that, there’s a great need to further refine our understanding of that risk and how it’s measured.”

Writing in the June 8 online edition of the British Medical Journal, Ovbiagele and an international team of colleagues reviewed 15 qualifying prospective cohort studies that looked at the association between pre-diabetes and stroke risk. The studies, published between 2004 and 2011, involved 760,925 participants.

Pre-diabetes occurs when blood glucose levels are consistently higher than normal, but not yet high enough to be diagnosed as diabetes. The condition is widespread in the United States: An estimated 35 percent of American adults – approximately 79 million people – are believed to be pre-diabetic, and thus at greater risk of developing full-blown type-2 diabetes, which afflicts roughly 26 million Americans. Diabetes is the seventh leading cause of death in the U.S., and a major risk factor for heart disease and stroke, the first and fourth leading causes of death.

People with pre-diabetes typically have the same risk factors for cardiovascular disease as people with type 2 diabetes – specifically, high blood pressure, high cholesterol levels and obesity – but the condition’s effect on future stroke risk has not been established.

Ovbiagele and colleagues found that an association between future stroke risk and pre-diabetes depended upon the definition of the latter. To determine whether someone has pre-diabetes, blood glucose levels are typically measured after a 12-hour fast. According to the 1997 American Diabetes Association (ADA), a normal fasting glucose measurement ranges between 70.2 to 100 milligrams per deciliter (mg/dL). A level between 100 and 126 mg/dL is considered pre-diabetic. A level of 126 mg/dL or above is diabetic.

By the 1997 standard, the researchers found that pre-diabetics in the studies with a fasting glucose measurement of 110 to 125 mg/dL carried a 21 percent higher chance of suffering a future stroke. Heart disease and stroke account for roughly two-thirds of all deaths among people with diabetes.

In 2003, however, the ADA redefined the fasting glucose level for pre-diabetes to 100 to 125 mg/dL. Using this less stringent definition, the researchers found no increased stroke risk for pre-diabetics.  Indeed, when they analyzed three studies that provided information on participants with fasting glucose levels of 100 to 109 mg/dL they found no increased risk of stroke.

Ovbiagele said the difference in the findings suggests there may be a “threshold effect” in the relationship between fasting glucose levels and future stroke risk. “Elevated risk may only begin at or above a fasting glucose level of 110 mg/dL,” he said.

Additional research is needed to determine the best definition predicting stroke risk among diabetics, Ovbiagele noted. It should include an assessment of more recent glycemic biomarkers, such as glycosylated hemoglobin, and be followed by randomized, controlled trials involving drugs and/or lifestyle modification to evaluate the effect of treatments on reducing the risk of future strokes.

“In the meantime, to avoid progression to diabetes or occurrence of strokes, clinicians should strongly consider recommending therapeutic lifestyle changes and maximizing the control of established stroke risk factors in their patients with pre-diabetes,” Ovbiagele said.

Co-authors of the study are Meng Lee, Chang Gung University College of Medicine, Chiayi, Taiwan; Jeffrey L. Saver and Sarah Song, University of California, Los Angeles; Heun-Sik Hong, Inje University, South Korea and Kuo-Hsuan Chang, Chang Gung University College of Medicine, Linkuo, Taiwan.

Funding, in part, came from Chang Gung Memorial Hospital and the National Institutes of Health (grants P50 NS044378 and U01 NS079179).

Findings have important implications for public as well as health care providers.

Christopher Saigal, UCLA

The number of Americans suffering from kidney stones between 2007 and 2010 nearly doubled from 1994, according to a new study by researchers at UCLA and the RAND Corp.

“While we expected the prevalence of kidney stones to increase, the size of the increase was surprising,” said Dr. Charles D. Scales Jr., a Robert Wood Johnson Foundation/U.S. Department of Veterans Affairs Clinical Scholar in the departments of urology and medicine at the David Geffen School of Medicine at UCLA. “Our findings also suggested that the increase is due, in large part, to the increase in obesity and diabetes among Americans.”

The study, “The Prevalence of Kidney Stones in the United States” is being presented today (May 23) at the 2012 meeting of the American Urological Association in Atlanta and will appear in the July print edition of the peer-reviewed journal European Urology.

This is one of the first studies to examine new data from the National Health and Nutrition Examination Survey (NHANES) that was collected from 2007 to 2010. NHANES is a program of studies within the Centers for Disease Control and Prevention to assess the health and nutritional status of adults and children in the U.S.

Scales and his colleagues reviewed responses from 12,110 individuals and found that between 2007 and 2010, 8.8 percent of the U.S. population had a kidney stone — one out of every 11 people. In 1994, the rate was one in 20. (No data about the national prevalence of kidney stones in the U.S. were collected between 1994 and 2007.)

Because NHANES also asks about other health conditions and includes measurements of height and weight, the researchers were able to identify associations between kidney stones and other health conditions. The results suggest that obesity, diabetes and gout all increase the risk of kidney stones.

While the national obesity rate was 23 percent in 1994, more than a third of all American adults are obese today, according to the Centers for Disease Control and Prevention.

The authors assert that these findings have important implications for the public, as well as health care providers.

“People should consider the increased risk of kidney stones as another reason to maintain a healthy lifestyle and body weight,” said the study’s senior author, Dr. Christopher S. Saigal, principal investigator within RAND Health for the Urologic Diseases in America project and associate professor of urology at the David Geffen School of Medicine at UCLA. “But physicians need to rethink how to treat and, more importantly, prevent kidney stones.”

Currently, the primary approach to treating patients is to focus on those who already are suffering from kidney stones. Yet helping patients maintain a healthy diet and body weight can reduce the number of patients with kidney stones.

“Imagine that we only treated people with heart disease when they had chest pain or heart attacks and did not help manage risk factors like smoking, high cholesterol or high blood pressure,” Scales said. “This is how we currently treat people with kidney stones. We know the risk factors for kidney stones, but treatment is directed towards patients with stones that cause pain, infection or blockage of a kidney rather than helping patients to prevent kidney stones in the first place.”

In an accompanying editorial that will also appear in the journal, Dr. Brian Matlaga, associate professor of urology at Johns Hopkins University School of Medicine, writes that the cost of care for this disease is enormous, and there is no indication that the coming years will see any improvement in this trend. He also warns that, since approximately 10 percent of the population has kidney stones, a greater emphasis on prevention is imperative.

The study was funded by the National Institute of Diabetes and Digestive and Kidney Diseases (N01-DK70003), as part of the Urologic Diseases in America project based at UCLA and RAND.

The Robert Wood Johnson Foundation Clinical Scholars program has fostered the development of physicians who are leading the transformation of health care in the United States through positions in academic medicine, public health and other leadership roles. Through the program, future leaders learn to conduct innovative research and work with communities, organizations, practitioners and policymakers on issues important to the health and well-being of all Americans. This program is supported, in part, through collaboration with the U.S. Department of Veterans Affairs.

UC San Diego nutrition experts launch yearlong study of participants with Type 2 diabetes.

Cheryl Rock, UC San Diego

Diabetes affects nearly 24 million people in the United States, most with Type 2 diabetes, a disease which is often coupled with obesity. Concerned by the increasing number of overweight Americans, nutrition experts with the UC San Diego School of Medicine are launching Take Charge, a research study analyzing the effectiveness of a commercial weight-loss program on participants with Type 2 diabetes who have a BMI of 25 – 45.

“We know that commercial weight loss programs can contribute to weight loss. Now we ask if they can have an impact on diabetes,” said Cheryl Rock, Ph.D., R.D., professor in the Department of Family and Preventive Medicine at the UC San Diego School of Medicine. “We want to find out if participants using a weight loss program do better than those who receive individualized dietary counseling with a registered dietitian.”

Rock and her team will work with primary care physicians throughout the San Diego community to enlist potential participants. “This is about the health of our entire community,” said Rock. “The problem of obesity is so great in that we need help on all fronts: medical, surgical and pharmaceutical. And we want to know if science-based commercial weight loss programs can contribute to solving this national problem as well.”

Take Charge participants must:

• Be 18 years old or older
• Be overweight
• Have Type 2 diabetes
• Be willing to participate for one year
• Otherwise be in generally good physical and mental health
• Agree to take part in the diet, exercise and lifestyle counseling program

Participants will be randomly assigned to one of three groups:

• Group one will receive dietary counseling, including menu planning and exercise advice from a registered dietitian.
• The other two groups will receive dietary counseling at a commercial facility and receive prepackaged meals coinciding with the assigned diet.
• All study participants will receive follow-up phone calls and/or emails from the study coordinator every few weeks throughout the course of the study.
• In addition, the investigators want to look at the effects of treatment on:
  • Feelings and quality of life
  • Waist circumference
  • Cardiovascular fitness

The costs of all study procedures, examinations, and medical care that may be delivered as part of this study will be provided at no cost. Participants will be compensated for travel-related costs.  This study is funded by Jenny Craig Inc. For more information on participation, please contact study coordinator, Angela Leone, M.S., R.D., UC San Diego Moores Cancer Center, (858) 822-4792 or AFLeone@ucsd.edu.

UC San Diego explores complex interactions of lipids, inflammation in insulin resistance.

Christopher Glass, UC San Diego

In the online May 2 issue of the journal Cell Metabolism, researchers at the UC San Diego School of Medicine publish three distinct articles exploring:

• the complex interactions of lipids and inflammation in insulin resistance
• the roles of omega 3 fatty acids and a particular gene in fighting inflammation
• how elevated levels of a particular protein might delay the muscle-destroying effects of amyotrophic lateral sclerosis.

Type 2 diabetes has reached epidemic proportions around the world, fueled in large part by the equally alarming expansion of obesity as a global health problem. But while it’s well-known that obesity is the most common cause of insulin resistance – the primary metabolic abnormality in type 2 diabetes – researchers have only recently begun to effectively parse the underlying, complicated relationships between lipids (fats and related molecules essential to cell structure and function) and chronic tissue inflammation (a key cause of obesity-induced insulin resistance).

In a wide-ranging perspective article published in Cell Metabolism, Christopher K. Glass, M.D., Ph.D., a professor in the departments of cellular and molecular medicine, and medicine at the UC San Diego, and Jerrold M. Olefsky, M.D., associate dean for scientific affairs and distinguished professor of medicine at UC San Diego, survey where the science stands, describing, for example, the pro-inflammatory effects of saturated fatty acids and the anti-inflammatory benefits of omega 3 fatty acids. They also discuss how inflammation impacts lipid metabolism at the cellular, tissue, organ and whole-body levels.

In a second, related article, Olefsky and colleague Da Young Oh, an assistant project scientist, discuss the critical role of a gene called GPR120 in inhibiting pro-inflammatory macrophages while simultaneously boosting the anti-inflammatory benefits of omega 3 fatty acids. They argue that new research highlights the importance of GPR120 as an attractive target for new drugs that could increase insulin sensitivity and, perhaps, have anti-obesity effects as well.

Finally, Don W. Cleveland, Ph.D., professor and chair of the Department of Cellular and Molecular Medicine and head of the Laboratory of Cell Biology at the Ludwig Institute for Cancer Research at UC San Diego and colleagues report the effects of elevated levels of a gene- regulating protein in mouse cells afflicted by a form of amyotrophic lateral sclerosis or ALS.

In humans, ALS is a progressive, adult-onset neurodegenerative disorder characterized by selective motor neuron and muscle loss that ultimately results in fatal paralysis. Among the key players in muscle function is a transcriptional activator protein called PGC-1alpha, which helps enhance various aspects of muscle cell function, including metabolism and mitochondrial biogenesis.

Cleveland and colleagues report that elevated levels of PGC-1alpha in the muscles of a mouse model of inherited ALS helps maintain health and function, though it does not extend survival time. The researchers suggest that increasing PCG-1alpha activity in muscle could be a new and attractive therapeutic target for maintaining, improving and extending physical abilities in ALS patients.

UCLA researcher: Dietary intervention during early life can have long lasting effects.

Sherin Devaskar, UCLA

Babies who are born small have a tendency to put on weight during childhood and adolescence if allowed free access to calories. However, a new animal model study at UCLA found when small babies were placed on a diet of moderately regulated calories during infancy, the propensity of becoming obese decreased.

Because this is an early study, UCLA researchers do not recommend that mothers of low-birth weight infants start restricting their child’s nutrition and suggest they consult with their child’s pediatrician regarding any feeding questions.

Previous studies have shown that growth restriction before birth may cause lasting changes of genes in certain insulin-sensitive organs like the pancreas, liver and skeletal muscle. Before birth, these changes may help the malnourished fetus use all available nutrients. However, after birth these changes may contribute to health problems such as obesity and diabetes.

“This study shows that if we match the level of caloric consumption after birth to the same level that the growth-restricted baby received in the womb, it results in a lean body type. However, if there is a mismatch where the baby is growth-restricted at birth but exposed to plenty of calories after birth, then that leads to obesity,” said the lead author, Dr. Sherin Devaskar, professor of pediatrics and executive chair of the department of pediatrics at Mattel Children’s Hospital UCLA. ”While many trials that include exercise and various drug therapies have tried to reverse the tendency of low birth weight babies becoming obese, we have shown that a dietary intervention during early life can have long lasting effects into childhood, adolescence and adult life.”

The study appears in the June issue of the journal Diabetes and is currently available online.

About 10 percent of babies in the United States are born small, defined as less than the 10th percentile by weight for a given gestation period, said the study’s first author, Dr. Meena Garg, professor of pediatrics and a neonatologist and medical director of the neonatal intensive care unit at Mattel Children’s Hospital UCLA. She added that some organizations define low birth weight as less than 2,500 grams or 5 pounds, 5 ounces at term.

Low birth weight can be caused by malnutrition due to a mother’s homelessness or hunger or her desire not to gain too much weight during pregnancy. Additional causes include illness or infection, a reduction in placental blood, smoking or use of alcohol or drugs during pregnancy.

To conduct the study, researchers used rodent animal models and simulated a reduced calorie scenario during pregnancy. The results showed that low-birth weight offspring exposed to moderately tempered caloric intake during infancy and childhood resulted in lean and physically active adults related to high energy expenditure, as opposed to unrestricted intake of calories, which resulted in inactive and obese adults due to reduced energy expenditure. The authors concluded that early life dietary interventions have far reaching effects on the adult state.

Future studies will follow this study over the stages of aging to see if early regulation of calorie intake reverses diabetes and obesity while aging.

“This is an early pre-clinical trial that first needs to be tested in clinical trials before any form of guidelines can be developed,” Devaskar said. “More importantly, we must make sure that control of caloric intake during infancy and childhood does not have any unintended side effects before taking on clinical trials. More research is required to ensure that these metabolic advantages will persist later in life.”

The study was funded by the National Institute of Child Health and Human Development.

In addition to Devaskar and Garg, the study was conducted by a team of UCLA researchers including Manikkavasagar Thamotharan, Yun Dai, Shanthie Thamotharan, Bo Chul Shin and David Stout.

The authors have no financial ties to disclose.