Diabetes Gene Common In Latinos Has Ancient Roots

When it comes to the rising prevalence of Type 2 diabetes, there are many factors to blame.

Diet and exercise sit somewhere at the top of the list. But the genes that some of us inherit from Mom and Dad also help determine whether we develop the disease, and how early it crops up.

Now an international team of scientists have identified mutations in a gene that suggests an explanation for why Latinos are almost twice as likely to develop Type 2 diabetes as Caucasians and African-Americans.

But here’s the kicker: You have to go further back on the family tree than your parents to find who’s to blame for this genetic link to diabetes. Think thousands of generations ago.

Harvard geneticist and his colleagues uncovered hints that humans picked up the diabetes mutations from Neanderthals, our ancient cousins who went extinct about 30,000 years ago.

"As far as I know, this is the first time a version of a gene from Neanderthal has been connected to a modern-day disease," Altshuler tells Shots. He and his colleagues the findings Wednesday in the journal Nature.

A few years ago, geneticists at the in Germany sent shock waves through the scientific community when they the genome of a Neanderthal from a fossil. Hidden in the genetic code were patterns that matched those in human DNA. And the data strongly suggested that humans were more than just friendly neighbors with Neanderthal.

"Now it’s well accepted that humans interbred with Neanderthals," Altshuler says. On average most of us carry about 2 percent of Neanderthal DNA in our genome. So it’s not surprising, he says, that 2 percent of our traits would be inherited from the ancient primates.

The new data don’t mean that Neanderthals had diabetes, Altshuler is quick to point out. “It just happens that this disease sequence came from them,” he says.

To identify genes that contribute to Latinos’ high rate of Type 2 diabetes, Altshuler and his team analyzed DNA from over 8,000 Mexicans and other Latinos.

The team found many genes already known to be involved with diabetes, such as one related to insulin production. But a new one also popped up in the analysis: a gene that’s likely involved in fat metabolism.

Mutations in this gene increase a person’s risk of getting Type 2 diabetes by about a 20 percent, Altshuler and the team found. If the person has two copies of the mutations, one from each parent, the risk rises by about 40 percent.

So for Mexican Americans, their for Type 2 diabetes goes from about 13 percent to 19 percent if they inherit two copies of the mutations. For other Americans, the risk gets boosted to about 11 percent from 8 percent.

"This is a genetic factor that has a modest affect on the risk of getting the disease. Not everybody that has it will have the disease," Altshuler says. "But the genes are very common in Latinos and Asians."

About half of Latinos carry the disease mutations, while 20 percent of Asians have it. On the other hand, only 2 percent of European Americans carry the mutations.

So the new genetic data help to explain a big chunk — perhaps almost a quarter — of the difference in Type 2 diabetes prevalence in Latinos versus European Americans.

"The findings are important because they give us a new biological clue about a gene involved in diabetes, which could lead to more treatments," Altshuler says. "The Neanderthal connection is interesting, but it’s not the essence of the work."

Sleep-Deprived Mice Show Connections Among Lack of Shut-eye, Diabetes, Age

Sleep, or the lack of it, seems to affect just about every aspect of human physiology. Yet, the molecular pathways through which sleep deprivation wreaks its detrimental effects on the body remain poorly understood. Although numerous studies have looked at the consequences of sleep deprivation on the brain, comparatively few have directly tested its effects on peripheral organs.

During sleep deprivation cells upregulate the UPR – the unfolded protein response – a process where misfolded proteins get refolded or degraded.

Five years ago, researchers at the Perelman School of Medicine, University of Pennsylvania, showed that the UPR is an adaptive response to stress induced by sleep deprivation and is impaired in the brains of old mice. Those findings suggested that inadequate sleep in the elderly, who normally experience sleep disturbances, could exacerbate an already-impaired protective response to protein misfolding that happens in aging cells. Protein misfolding and clumping is associated with many diseases such as Alzheimer’s and Parkinson’s, noted Nirinjini Naidoo, Ph.D., research associate professor in the Division of Sleep Medicine in that study.

Naidoo is also senior author of a follow-up study in Aging Cell this month that shows, for the first time, an effect of sleep deprivation on the UPR in peripheral tissue, in this case, the pancreas. They showed that stress in pancreatic cells due to sleep deprivation may contribute to the loss or dysfunction of these cells important to maintaining proper blood sugar levels, and that these functions may be exacerbated by normal aging.

“The combined effect of aging and sleep deprivation resulted in a loss of control of blood sugar reminiscent of pre-diabetes in mice,” says Naidoo. “We hypothesize that older humans might be especially susceptible to the effects of sleep deprivation on the disruption of glucose homeostasis via cell stress.”

Working with Penn colleague Joe Baur, Ph.D., assistant professor of Physiology, Naidoo started a collaboration to look at the relationship of sleep deprivation, the UPR, and metabolic response with age. Other researchers had suggested that the death of beta cells associated with type 2 diabetes may be due to stress in a cell compartment called the endoplasmic reticulum (ER). The UPR is one part of the quality control system in the ER, where some proteins are made.

Knowing this, Naidoo and Baur asked if sleep deprivation (SD) causes ER stress in the pancreas, via an increase in protein misfolding, and in turn, how this relates to aging.

The team examined tissues in mice for cellular stress following acute SD, and they also looked for cellular stress in aging mice. Their results show that both age and SD combine to induce cellular stress in the pancreas.

Older mice fared markedly worse when subjected to sleep deprivation. Pancreas tissue from older mice or from young animals subjected to sleep deprivation exhibited signs of protein misfolding, yet both were able to maintain insulin secretion and control blood sugar levels. Pancreas tissue from acutely sleep-deprived aged animals exhibited a marked increase in CHOP, a protein associated with cell death, suggesting a maladaptive response to cellular stress with age that was amplified by sleep deprivation.

Acute sleep deprivation caused increased plasma glucose levels in both young and old animals. However, this change was not overtly related to stress in beta cells, since plasma insulin levels were not lower following acute lack of sleep.

Accordingly, young animals subjected to acute sleep deprivation remained tolerant to a glucose challenge. In a chronic sleep deprivation experiment, young mice were sensitized to insulin and had improved control of their blood sugar, whereas aged animals became hyperglycemic and failed to maintain appropriate plasma insulin concentrations.

While changes in insulin secretion are unlikely to play a major role in the acute effects of SD, cellular stress in pancreatic tissue suggests that chronic SD may contribute to the loss or dysfunction of endocrine cells, and that these effects may be exacerbated by normal aging, say the researchers.

High Blood Sugar Linked to Dementia

People with diabetes face an increased risk of Alzheimer’s disease and other forms of dementia, a connection scientists and physicians have worried about for years. They still can’t explain it.

Now comes a novel observational study of patients at a large health care system in Washington State showing that higher blood glucose levels are associated with a greater risk of dementia — even among people who don’t have diabetes. The results, published Thursday in The New England Journal of Medicine, “may have influence on the way we think about blood sugar and the brain,” said Dr. Paul Crane, the lead author and associate professor of medicine at the University of Washington.

The researchers tracked the blood glucose levels of 2,067 members of Group Health, a nonprofit HMO, for nearly seven years on average. Some patients had Type 2 diabetes when the study began, but most didn’t. None had dementia.

Over the years, as they saw doctors at Group Health, the participants received blood glucose tests. “It’s a common test in routine clinical practice,” Dr. Crane said. “We had an amazing opportunity with all this data. All the lab results since 1988 were available to us.”

The participants (average age at the start: 76) also reported to Group Health every other year for cognitive screening and, if their results were below normal, further testing and evaluation. Over the course of the study, about a quarter developed dementia of some kind, primarily Alzheimer’s disease or vascular dementia.

To measure blood sugar levels, the researchers combined glucose measurements, both fasting and nonfasting, with the HbA1c glycated hemoglobin assay, which provides a more accurate long-term picture. They also adjusted the data for other cardiovascular factors already linked to dementia, like high blood pressure and smoking.

“We found a steadily increasing risk associated with ever-higher blood glucose levels, even in people who didn’t have diabetes,” Dr. Crane said. Of particular interest: “There’s no threshold, no place where the risk doesn’t go up any further or down any further.” The association with dementia kept climbing with higher blood sugar levels and, at the other end of the spectrum, continued to decrease with lower levels.

This held true even at glucose levels considered normal. Among those whose blood sugar averaged 115 milligrams per deciliter, the risk of dementia was 18 percent higher than among those at 100 mg/dL, just slightly lower. The effects were also pronounced among those with diabetes: patients with average glucose levels of 190 mg/dL had a 40 percent higher risk of dementia than those whose levels averaged 160 mg/dL.

Though a longitudinal study like this one provides insight into the differences between people, it can’t explain why higher blood glucose might be connected to dementia, or tell individuals whether lower blood glucose is protective.

“People shouldn’t run for the hills or try crazy diets,” Dr. Crane cautioned. While an epidemiological study like this one can guide further exploration, he said, “This doesn’t show that changes in behavior that lower your individual blood sugar would decrease your individual risk of dementia.”

As for the blood glucose levels the study recorded, “clinically, they’re not big differences,” said Dr. Medha Munshi, a geriatrician and endocrinologist who directs the geriatric diabetes program at the Joslin Diabetes Center in Boston, who was not involved in the study. “I wouldn’t change my goals for diabetes management based on this study.” Nor would she warn someone whose blood glucose hits 115 mg/dL that he or she faces a greater risk of dementia.

But because diabetes itself can pose such a threat to health and quality of life, she still urges patients to adopt healthy practices like exercising regularly and maintaining a normal weight to try to avoid the disease. If by doing so they also lower their dementia risk — and knowing that would require a different study, focused on interventions — that would be a bonus.

This research “offers more evidence that the brain is a target organ for damage by high blood sugar,” said Dr. Munshi. “And everyone is still working on the ‘why’.

High Sugar Intake Linked to Low Dopamine Release in Insulin Resistant Patients

PET study led by Stony Brook Professor indicates that overeating and weight gain contributing to onset of diabetes could be related to a deficit in reward circuits in the brain

Using positron emission tomography (PET) imaging of the brain, researchers have identified a sweet spot that operates in a disorderly way when simple sugars are introduced to people with insulin resistance, a precursor to type 2 diabetes. For those who have the metabolic syndrome, a sugar drink resulted in a lower-than-normal release of the chemical dopamine in a major pleasure center of the brain. This chemical response may be indicative of a deficient reward system, which could potentially be setting the stage for insulin resistance. This research could revolutionize the medical community’s understanding of how food-reward signaling contributes to obesity, according to a study presented at the Society of Nuclear Medicine and Molecular Imaging’s 2013 Annual Meeting.

"Insulin resistance is a significant contributor to obesity and diabetes," said Gene-Jack Wang, MD, lead author of the study and Professor of Radiology at Stony Brook University and researcher at the U.S. Department of Energy’s Brookhaven National Laboratory in Upton, N.Y. "A better understanding of the cerebral mechanisms underlying abnormal eating behaviors with insulin resistance would help in the development of interventions to counteract the deterioration caused by overeating and subsequent obesity. We suggest that insulin resistance and its association with less dopamine release in a central brain reward region might promote overeating to compensate for this deficit."

An estimated one-third of Americans are obese, according to the U.S. Centers for Disease Control and Prevention. The American Diabetes Association estimates that about 26 million Americans are living with diabetes and another 79 million are thought to be prediabetic, including those with insulin resistance.

The tendency to overeat may be caused by a complex biochemical relationship, as evidenced by preliminary research with rodents. Dr. Wang’s research marks the first clinical study of its kind with human subjects.

"Animal studies indicated that increased insulin resistance precedes the lack of control associated with pathological overeating," said Wang. "They also showed that sugar ingestion releases dopamine in brain regions associated with reward. However, the central mechanism that contributes to insulin resistance, pathological eating and weight gain is unknown."

He continued, “In this study we were able to confirm an abnormal dopamine response to glucose ingestion in the nucleus accumbens, where much of the brain’s reward circuitry is located. This may be the link we have been looking for between insulin resistance and obesity. To test this, we gave a glucose drink to an insulin-sensitive control group and an insulin-resistant group of individuals and we compared the release of dopamine in the brain reward center using PET.”

In this study, a total of 19 participants-including 11 healthy controls and eight insulin-resistant subjects-consumed a glucose drink and, on a separate day, an artificially sweetened drink containing sucralose. After each drink, PET imaging with C-11 raclopride-which binds to dopamine receptors-was performed. Researchers mapped lit-up areas of the brain and then gauged striatal dopamine receptor availability (which is inversely related to the amount of natural dopamine present in the brain). These results were matched with an evaluation in which patients were asked to document their eating behavior to assess any abnormal patterns in their day-to-day lives. Results showed agreement in receptor availability between insulin-resistant and healthy controls after ingestion of sucralose. However, after patients drank the sugary glucose, those who were insulin-resistant and had signs of disorderly eating were found to have remarkably lower natural dopamine release in response to glucose ingestion when compared with the insulin-sensitive control subjects.

"This study could help develop interventions, i.e., medication and lifestyle modification, for early-stage insulin-resistant subjects to counteract the deterioration that leads to obesity and/or diabetes," said Wang. "The findings set a path for future clinical studies using molecular imaging methods to assess the link of peripheral hormones with brain neurotransmitter systems and their association with eating behaviors."

Alzheimer’s and Low Blood Sugar in Diabetes May Trigger a Vicious Cycle

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 Monday 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, MD, senior author and principal investigator for the study, and a UCSF professor of psychiatry, neurology and epidemiology based at the San Francisco Veterans Affair 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.

Cognitive Function a Factor in Managing Diabetes

The researchers analyzed hospital records of patients from Memphis and Pittsburgh, ages 70 to 79 at the time of enrollment, who participated in the federally funded Health, Aging and Body Composition (Health ABC) study, begun in 1997. The UCSF results are based on an average of 12 years of follow-up study. Participants in the Health ABC study periodically underwent tests to measure cognitive function.

Nearly half of participants included in the newly published analysis were black, and the rest were white. None had dementia at the start of the study, and all either had diabetes at the beginning of the study or were diagnosed during the course of the study.

“Individuals with dementia or even those with milder forms of cognitive impairment may be less able to effectively manage complex treatment regimens for diabetes and less able to recognize the symptoms of hypoglycemia and to respond appropriately, increasing their risk of severe hypoglycemia,” Yaffe said. “Physicians should take cognitive function into account in managing diabetes in elderly individuals.”

Certain medications known to carry a higher risk for hypoglycemia — such as insulin secretagogues and certain sulfonylureas — may be inappropriate for older adults with dementia or who are at risk for cognitive impairment, according to Yaffe.

Previous studies in which researchers investigated hypoglycemia and cognitive function have had inconsistent findings. A strength of the current study is that individuals were tracked from baseline over a relatively long time, and the older age of participants may also have been a factor in the highly statistically significant outcome, Yaffe said.

Heart Health Matters to Your Brain

People suffering from type 2 diabetes and cardiovascular disease (CVD) are at an increased risk of cognitive decline, according to a new study from Wake Forest Baptist Medical Center.

Lead author Christina E. Hugenschmidt, Ph.D., an instructor of gerontology and geriatric medicine at Wake Forest Baptist, said the results from the Diabetes Heart Study-Mind (DHS-Mind) suggest that CVD is playing a role in cognition problems before it is clinically apparent in patients. The research appears online ahead of print in the Journal of Diabetes and Its Complications.

 ”There has been a lot of research looking at the links between type 2 diabetes and increased risk for dementia, but this is the first study to look specifically at subclinical CVD and the role it plays,” Hugenschmidt said. “Our research shows that CVD risk caused by diabetes even before it’s at a clinically treatable level might be bad for your brain.

"The results imply that additional CVD factors, especially calcified plaque and vascular status, and not diabetes status alone, are major contributors to type 2 diabetes related cognitive decline."

Hugenschmidt said DHS-Mind is a follow-up study to the Diabetes Heart Study (DHS), which examined relationships between cognitive function, vascular calcified plaque and other major diabetes risk factors associated with cognition. The DHS investigated CVD in siblings with a high incidence and prevalence of type 2 diabetes, where extensive measurements of CVD risk factors were obtained during exams that occurred from 1998 to 2006.

The study was supported by the National Institutes of Health through NINDS R01NS058700-02S109 and NIDDK 1F32DK083214-01.

The DHS-Mind study added cognitive testing to existing measures with the express purpose of exploring the relationships between measures of atherosclerosis and cognition in a population heavily affected by diabetes, a novel approach given that previous studies have focused on diabetes and cognition in the context of clinically evident CVD, Hugenschmidt said. The researchers followed up with as many of the original 1,443 DHS study participants as possible who had cardiovascular measures. Of that 516 total, 422 were affected with type 2 diabetes and 94 were unaffected.

Hugenschmidt said the researchers ran a battery of cognitive testing that looked at different kinds of thinking like memory and processing speed, as well as executive function, which is a set of mental skills coordinated in the brain’s frontal lobe that includes stop and think processes like managing time and attention, planning and organizing. She said that being able to look at data where the comparison group was  siblings, some of whom had a high level of CVD themselves, made the results more clinically relevant because the participants shared the same environmental and genetic background.

"We still saw a difference between these two groups. Even compared to their own siblings who were not disease free, those with diabetes and subclinical cardiovascular disease had a higher risk of cognitive dysfunction," Hugenschmidt said.

CVD explains a lot of the cognitive problems that people with diabetes experience, Hugenschmidt said. “One possibility is that your brain requires a really steady blood flow and it’s possible that the cardiovascular disease that accompanies diabetes might be the main driver behind the cognitive deficits that we see.”

Hugenschmidt said the takeaway for clinicians is to take CVD risk factors into consideration when they’re treating patients with type 2 diabetes patients because even at borderline clinical levels, it might have long-term implications for peoples’ mental, cognitive health.

Research Suggests Link Between Elevated Blood Sugar, Alzheimer’s Risk

A new University of Arizona study, published in the journal Neurology, suggests a possible link between elevated blood sugar levels and risk for developing Alzheimer’s disease.

About 5 percent of men and women, ages 65 to 74, have Alzheimer’s disease, and it is estimated that nearly half of those age 85 and older may have the disease, according to the U.S. Centers for Disease Control and Prevention. Among the known factors that contribute to the disease are age and genetics. Scientists also think that high blood pressure, high cholesterol and diabetes may increase risk.

Although the link between diabetes and Alzheimer’s has been studied, UA researchers wondered if elevated blood sugar levels in non-diabetic individuals also might indicate a higher risk for developing Alzheimer’s disease.

"There have been studies that have linked diabetes to Alzheimer’s disease as a risk factor," said Alfred Kaszniak, UA professor of psychology and a co-author on the study. "What was not known when we began this work is whether that risk was only at levels of blood sugar that qualify for diagnoses of diabetes, or in the borderline or pre-diabetic range, or would we also see a relationship across the so-called normal range of blood glucose?"

The researchers used fluorodeoxyglucose (18F) positron electron tomography, or FDG PET, a medical imaging technique that produces three-dimensional images of metabolic activity in the brain. Fasting serum glucose levels – blood sugar levels following several hours of not eating – are routinely acquired as part of the FDG PET protocol.

"When compared to those without the disease, Alzheimer’s disease patients demonstrate a pattern of reduced brain metabolism in particular brain regions," explained Christine Burns, lead author on the study and a UA pre-doctoral student in psychology. "What we show is an association between elevated fasting serum glucose levels and a similar pattern of reduced metabolism in these same AD-related brain regions in cognitively healthy adults."

The researchers studied data on 124 cognitively normal, non-diabetic adults with a family history of Alzheimer’s disease. The individuals, who ranged in age from 47 to 68, were among participants in a larger study, led by Dr. Eric Reiman, executive director of the Banner Alzheimer’s Institute in Phoenix, looking at a variety of Alzheimer’s risk factors, including genetic risk. 

The link between high blood sugar and reduced brain metabolism existed regardless of whether individuals carried the Apolipoprotein E4 gene variant, an established risk factor for the development of Alzheimer’s disease.   

In addition to suggesting a link between elevated blood sugar levels and Alzheimer’s risk in non-diabetic individuals, the study also shows promise for the use of brain imaging techniques like PET in identifying Alzheimer’s risk and developing early preventative interventions, researchers say.

"Right now, if you want to develop a drug or evaluate some other kind of a preventive measure for Alzheimer’s disease, the labor and expense is prohibitive," Kaszniak said. "If you recruit people who may be at some risk, but are 20 years away from developing signs of the illness, what drug company or governmental agency is going to fund research that follows people for 20 years to see whether something is effective in prevention?

"However, if you have a biologic marker, it suggests what areas you should really focus on in those very expensive longitudinal studies," he said.

Burns said she hopes the findings will inform ongoing work designed to help develop early Alzheimer’s interventions.

"A lot of valuable research is focused on treatment and slowing decline in Alzheimer’s patients," she said. "I’m interested in complementing this work with interventions that can be implemented earlier on, perhaps at middle age."

Our internal clocks can become ticking time bombs for diabetes and obesity

New research in The FASEB Journal using mice suggests that disrupting our internal clocks can lead to a complete absence of 24-hour bodily rhythms and an immediate gain in body weight

If you’re pulling and all-nighter to finish a term paper, a new parent up all night with a fussy baby, or simply can’t sleep like you once could, then you may be snoozing on good health. That’s because new research published in The FASEB Journal used mice to show that proper sleep patterns are critical for healthy metabolic function, and even mild impairment in our circadian rhythms can lead to serious health consequences, including diabetes and obesity.

"We should acknowledge the unforeseen importance of our 24-hour rhythms for health," said Claudia Coomans, Ph.D., a researcher involved in the work from the Department of Molecular Cell Biology in the Laboratory of Neurophysiology at Leiden University Medical Center in Leiden, Netherlands. "To quote Seneca ‘We should live according to nature (secundum naturam vivere).’"

To make this discovery, Coomans and colleagues exposed mice to constant light, which disturbed their normal internal clock function, and observed a gradual degradation of their bodies’ internal clocks until it reached a level that normally occurs when aging. Eventually the mice lost their 24-hour rhythm in energy metabolism and insulin sensitivity, indicating that relatively mild impairment of clock function had severe metabolic consequences.

"The good news is that some of us can ‘sleep it off’ to avoid obesity and diabetes," said Gerald Weissmann, M.D., Editor-in-Chief of The FASEB Journal. "The bad news is that we can all get the metabolic doldrums when our normal day/night cycle is disrupted."