Interrupting sitting time improves blood sugar control in people with type 2 diabetes

A new study published in Diabetologia (the journal of the European Association for the Study of Diabetes [EASD]) suggests that a 'Sit Less' intervention ? breaking sitting with standing and light-intensity walking ? may be an alternative to structured exercise to promote blood sugar control in patients with type 2 diabetes, giving improved 24-hour glucose levels and improved insulin sensitivity.

The use of moderate to vigorous exercise is one of the cornerstones of prevention and treatment of type 2 diabetes, with current physical activity guidelines recommending a performance of at least 150 min per week of exercise at these intensities. Despite the proven effectiveness of such a regime, however, over 90% of the healthy population does not adhere to the guidelines. Non-compliance is likely to be even higher in those with type 2 diabetes, in which related comorbidities such as muscle weakness and peripheral neuropathy can be a barrier to physical exercise. An alternative approach is needed.

This study considered the possible benefits of a 'Sit Less' programme, replacing sitting time with standing and light-intensity walking, in comparison to the use of a conventional structured exercise regimen of the same energy expenditure. It was conducted by Bernard Duvivier, Department of Human Biology and Movement Science, NUTRIM School for Nutrition and Translational Research in Metabolism, Maastricht University Medical Centre+, Netherlands, and colleagues.

The study involved 19 adults (13 men and 6 women) with type 2 diabetes, with a mean disease duration of 6 years, a mean HbA1c of 6.7% and a mean fasting plasma glucose of 7.88 mmol/l during screening. Their mean age was 63 years and the mean BMI was 30.5 kg/m2 (just within the definition of obese). A total of 14 participants were using glucose-lowering diabetes drugs and 13 were using lipid-lowering drugs (most often statins).

The participants followed three activity regimens - 'Sitting', 'Exercise' and 'Sit Less' - each lasting 4 days. During the sitting regimen participants were restricted to 1 hour/day of walking and 1 hour/day standing, with the remaining 14 hours spent sitting. During the exercise regimen approximately 1 hour/day of sitting time was replaced by supervised cycling on an ergometer at the research centre, in 20 minute bouts separated by 5 minutes rest. In the sit less regimen, 5 hours/day sitting were replaced by 2 hours walking and 3 hours standing, with participants encouraged to break up their sitting time every 30 minutes with small bouts of walking and standing throughout the day. The exercise and sit less regimens were designed to have comparable energy expenditure for each participant. The order of the regimens was randomised, and 10 days of usual lifestyle was maintained as a 'wash-out' period before and between regimens.

Diet was controlled with use of the participants' normal diet, supplemented during the last 36 hours of each regimen by the provision of pre-packed meals based on their energy requirements for each regimen. Glucose levels were measured continuously using a subcutaneous glucose monitor and also via the collection of blood glucose samples four times daily. The use of light-intensity walking was diarised and verified using advanced accelerometry (which monitors motion via multiple parameters). 24-hour glucose levels were analysed during the last 24 hours of each four-day regimen. On the day after each regimen, between 08.30 and 09.30 hours, after an overnight fast, blood was collected for glucose, insulin and lipid measurements.

The data were analysed to provide: 24 hour glucose concentration; incremental AUC for glucose (incremental area under the curve - a summary measure of glucose usage - the increase above fasting level over 24 hours); duration of hyperglycaemia; an average glucose concentration for each 30 minutes to indicate any bouts of hypoglycaemia; an estimate of insulin sensitivity; fasting triacylglycerol levels and non-esterified fatty acid (NEFA) levels.

The study found that the use of the sit less regimen led to significant improvements in insulin sensitivity, mean 24-hour glucose levels, 24-hour glucose excursions, durations of hyperglycaemia and fasting triacylglycerol levels, compared with sitting. Whilst positive effects for most variables (other than 24-hour glucose) were also found in the traditional exercise regimen, these were generally less potent than the improvements found for the sit less group. In addition, glucose level reductions, which can lead to hypoglycaemia and render some diabetic patients reluctant to perform structured exercise, were found to be less for the sit less regimen.

Previously it has been noted that a sedentary (inactive) lifestyle is associated with an increased risk of type 2 diabetes, and that regular interruption of sitting using small bouts of walking may be beneficial to insulin action and glucose control. This study, however, is the first to consider the effects of a sit less regimen for people with type 2 diabetes in free-living conditions. The outcome of the study fits the emerging picture that breaking up sedentary behaviour by light-intensity activities may be a potent way to help improve blood glucose control.

The authors suggest that sustained compliance with exercise programmes, especially by individuals with type 2 diabetes, is at best mediocre. Strategies to reduce sitting time are generally considered to be less demanding than structured exercise programmes and hence are more likely to have long-term compliance. The authors say that their findings "provide indications favouring the implementation of interventions targeting the breaking-up of sitting time over interventions involving structured exercise". As the volume of activities in this proof-of-concept study was high (an additional 2 hours walking and 3 hours standing during the sit less regimen in comparison to the other regimens), the authors suggest "that future long-term studies are needed to determine the volume of light-intensity activity that is feasible in daily life".

Diabetes drug, metformin, lowers risk of heart disease deaths better than sulfonylureas

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A new analysis of 204 studies involving more than 1.4 million people suggests that metformin, the most frequently prescribed stand-alone drug for type 2 diabetes, reduces the relative risk of a patient dying from heart disease by about 30 to 40 percent compared to its closest competitor drug, sulfonylurea.

The study, designed to assess the comparative -- not absolute or individual -- benefits and risks of more than a dozen FDA-approved drugs for lowering blood sugar in type 2 diabetes, is described in the April 19, 2016 issue of the Annals of Internal Medicine. Diabetes now affects almost 10 percent of the U.S. population and poses a growing public health threat, and most people will eventually need drug treatment, the researchers say.

"Metformin looks like a clear winner," says Nisa Maruthur, M.D., M.H.S., assistant professor of medicine at the Johns Hopkins University School of Medicine. "This is likely the biggest bit of evidence to guide treatment of type 2 diabetes for the next two to three years." 

Maruthur, the lead author on the meta-analysis, notes that cardiovascular fatalities -- heart attacks and strokes -- are major risks for people with uncontrolled blood sugar, but it has never been clear if one diabetes drug is better than another at lowering these fatalities. Other diabetes-related complications include blindness, kidney failure and limb amputations.

This review, Maruthur says, provides a much-needed update to two previous analyses, the last one published in 2011. Since then, researchers have published more than 100 new studies comparing the effectiveness of various blood sugar-lowering drugs, and several new drugs have also come on the market since the last report.

Of the total 204 studies analyzed, 50 spanned several continents, while others were conducted across Europe, Asia and the United States. Most of the studies were short term, with only 22 mostly observational studies lasting more than two years. Participants in the studies were generally overweight with uncontrolled blood sugar levels. Many studies excluded the elderly and those with significant health problems. Just shy of half of the studies made no mention of race or ethnicity. When researchers did report that information, only 10 to 30 percent of participants were nonwhite. 

Maruthur says the new analysis not only looked at cardiovascular disease but also other drug effects, including glucose control, and common side effects, such as weight gain, hypoglycemia and gastrointestinal problems. Because the majority of patients with type 2 diabetes end up using multiple blood sugar-lowering drugs, Maruthur and her team also evaluated how the drugs performed when used alone or in combination. While some of the various studies' participants were on insulin, this injectable drug was only evaluated when used in combination with other drugs. 

Among other findings, the new review revealed that DPP-4 inhibitors, a class of anti-diabetic drugs that were very new at the time of the 2011 review, were clearly less effective at lowering blood sugar levels compared to metformin and sulfonylureas.

In terms of side effects, a new class of drugs known as SGLT-2 inhibitors, which work by shuttling excess glucose out of the body through urine, caused yeast infections in 10 percent of users, a side effect unique to this drug, Maruthur says. However, SGLT-2 inhibitors, along with another drug class known as GLP-1 receptor agonists, helped patients lose weight. Sulfonylureas, on the other hand, caused weight gain and resulted in the highest rates of hypoglycemia, or too-low blood sugar, among the oral medications.

Cautioning that such meta-analyses can be limited because of differences in research protocols and measurements across studies, Maruthur and her colleagues took steps to ensure that only studies using similar methods were combined. Also, they excluded from their analysis any studies that included patients taking additional, nonstudy diabetes drugs. 

Overall, Maruthur says, the results indicate that metformin, which has been around since the late 1990s, works just as well, if not better, than sulfonylureas, which have been on the market since the late 1950s/1960s, and diabetes drugs that have appeared on the market more recently. She says the new findings are in line with the current recommendation that metformin be used as a first-line therapy. The real question arises, Maruthur says, when patients and doctors must choose a second drug to be used in combination with the metformin. 

"The medications all have different benefits and side effects, so the choice of second-line medications must be based on an individual patient's preferences," Maruthur says. 

Maruthur and her team's work will be published alongside the report they wrote for the Agency for Healthcare Research and Quality, the funding agency for the study, detailing the hundreds of studies included in Maruthur's analysis and an exhaustive summary. Both the American College of Physicians and the Veterans Association plan to use these publications to update their guidelines. 

The cost of diabetes drugs is a major consideration when prescribing. While metformin is available as a relatively cheap generic, many newer drugs carry a hefty price tag. In 2014, per-person spending was higher for diabetes drugs for any other class of traditional drugs, in part because over half the prescriptions filled for diabetes were for nongenerics.

Additional benefits of type 2 diabetes treatment found for non-alcoholic fatty liver disease patients

A type 2 diabetes treatment has been found to also have 'off-label' benefits for glucose control in the liver and in fatty cells known as adipose.1 Presented at The International Liver CongressTM 2016 in Barcelona, Spain, today, the study shows that exenatide, a treatment that targets the pancreas to improve glucose absorption, enhances glucose uptake and reduces insulin resistance in the liver and in adipose tissue.

Non-alcoholic fatty liver disease (NAFLD) is a condition in which fat builds up in the liver. In some cases this accumulation of fat can cause inflammation of the liver and eventually lead to permanent scarring (cirrhosis), which can seriously impair the liver's ability to function. NAFLD is closely associated with obesity and diabetes and the consequences of the condition can be grave, representing a major global public health problem.2 Two large European studies reported NAFLD prevalence rates of between approximately 43% and 70% in adults with type 2 diabetes.3

"There has been much discussion around the benefit of using injectable diabetes treatments, such as exenatide, on other tissues than the pancreas to improve glucose control," said Dr Amailia Gastaldelli, Institute of Clinical Physiology, CNR, Pisa, Italy, University of Texas Health Science Center, San Antonio, USA, and lead author of the study. "This is why we set out to evaluate the effects of exenatide on the liver and adipose tissue; to better understand the benefits this treatment could offer to a wider group of patients."

Male participants (n=15) with a fatty liver index score of >30 (a classification system that ranges from 0 to 100)4 were tested on two occasions. Those with a score <30 are deemed to have a negative likelihood of having fatty liver. Exenatide or placebo was injected 30 minutes before an oral glucose test in the double blinded study. The test measured glucose uptake in liver tissue and abdominal adipose tissue glucose uptake. 

The results showed that acute exenatide administration (5mcg) decreased glucose production and insulin resistance (p=0.02) in the liver tissue when blood sugars were low. The treatment also improved liver tissue uptake of glucose when it is eaten (p=0.039). Furthermore, exenatide decreased insulin resistance in fatty adipose tissue (p=0.009).

"This interesting study shows promising findings for the many people around the world who suffer from non-alcoholic fatty liver disease," says Professor Tom Hemming Karlsen, EASL Vice-Secretary. "The authors have succeeded in identifying an existing treatment that can improve liver metabolism, which is an important step forward for the hepatology community."

Controlling blood pressure, sugar, cholesterol linked to lower cardiovascular disease

While controlling blood pressure, blood sugar and LDL-cholesterol levels reduces the risk of cardiovascular disease in people with diabetes, only 7 percent of diabetic participants in three major heart studies had recommended levels of these three factors, according to research from the Heart Disease Prevention Program at the University of California, Irvine School of Medicine.

The findings illustrate the need for persons with diabetes to better manage their blood pressure, blood sugar and LDL-cholesterol levels, which are prime indicators of future cardiovascular disease. The diabetic participants surveyed in the UCI review were enrolled in the three heart studies between the late '80s and early 2000s, when treatment was not as good as it is now. Still, more recent data show that only 25 percent of Americans with diabetes achieve all three of these targets.

The good news is that those in the heart studies who did control all three factors had a 62 percent lower risk of developing cardiovascular disease, according to Nathan D. Wong, lead author of the UCI report, which appears online in Diabetes Care.

"But we have done a dismal job nationally at getting most of our patients with diabetes controlled for even just these three measures," said Wong, director of the Heart Disease Prevention Program and a cardiology professor at UCI.

"Since cardiovascular diseases - including coronary heart disease, stroke and heart failure - are leading causes of death for people with diabetes, these findings underscore the value of achieving target or lower levels of these modifiable risk factors," he added.

Wong and colleagues studied 2,018 adults (57 percent female) with diabetes mellitus but without known cardiovascular diseases who participated in the Atherosclerosis Risk in Communities Study, the Multi-Ethnic Study of Atherosclerosis or the Jackson Heart Study. Fifty-five percent were African American, 30 percent white, 11 percent Hispanic and 4 percent Asian/Pacific Islander.

The researchers compared measurements of the three key factors to American Diabetes Association guidelines that were in effect at the time - blood pressure under 130/80 mmHg, LDL (or bad) cholesterol less than 100 mg/dL and blood HbA1c (glycated hemoglobin) under 7 percent. Forty-one percent of the study group were on target in one of the three categories; 27 percent had achieved two of the benchmarks; but only 7 percent met the recommended scores in all three.

Study participants' control of individual and composite factors was also examined in relation to the occurrence of new cardiovascular events (including heart attacks, coronary deaths, strokes, heart failure, percutaneous interventions and bypass surgeries) over an average follow-up of 11 years.

Wong said that proper management of any one factor translated to a 36 percent lower risk, proper management of any two factors was linked to a 52 percent lower risk, and proper management of all three factors correlated to a 62 percent lower risk of cardiovascular events compared to those without any factors controlled.

Blood pressure management appeared to benefit African Americans and women more than other ethnic groups or men; however, the converse was true for LDL control.

"Our analysis of three large U.S. cohorts including persons in whom diabetes has been diagnosed shows those who were at target levels for HbA1c, blood pressure and LDL to have substantially lower risks for cardiovascular disease than persons with diabetes who were not at target levels for such factors," Wong said. "These findings emphasize the importance of composite control of these modifiable risk factors to better address the cardiovascular disease risks seen in persons with diabetes, the need for the development of healthcare strategies to better ensure such management, and the need for studies to evaluate and eliminate barriers to risk factor control in persons with diabetes."

New proteins discovered that link obesity-driven diabetes to cancer

For the first time, researchers have determined how bromodomain (BRD) proteins work in type 2 diabetes, which may lead to a better understanding of the link between adult-onset diabetes and certain cancers. 

The findings, which appear in PLOS ONE, show that reducing levels in pancreatic beta cells of individual BRDs, called BET proteins, previously shown to play a role in cancer, may also help patients who are obese and diabetic.

The research was led by Gerald V. Denis, PhD, associate professor of pharmacology and medicine at Boston University School of Medicine, who was the first to show that BET protein functions are important in cancer development. 

Adult-onset diabetes has been known for decades to increase the risk for specific cancers. The three main members of the BET protein family, BRD2, BRD3 and BRD4, are closely related to each other and often cooperate. However at times, they work independently and sometimes against each other. 

According to the researchers new small molecule BET inhibitors have been developed that block all three BET proteins in cancer cells, but they interfere with too many functions. 

"The BET proteins provide a new pathway to connect adult-onset diabetes with cancer, so properly targeting BET proteins may be helpful for both," explained Denis, who is the corresponding author of the study. 

He believes this discovery shows the need for deeper analysis of individual BET proteins in all human cell types, starting with boosting insulin and improving metabolism in the pancreas of adults who are obese. 

"Without better targeted drugs, some ongoing cancer clinical trials for BET inhibitors are premature. These new results offer useful insight into drug treatments that have failed so far to appreciate the complexities in the BET family."

CPAP may not improve glycemic control in people with diabetes

People with type 2 diabetes and obstructive sleep apnea (OSA) may not experience improved glycemic control by using continuous positive airway pressure, or CPAP, as some studies have suggested, according to the results of a randomized, controlled trial published online ahead of print in the American Thoracic Society's American Journal of Respiratory and Critical Care Medicine.

"Many studies have indicated that OSA may contribute towards the development and progression of type 2 diabetes," said lead study author Jonathan Shaw, MD, associate professor and head of population health at Melbourne's Baker IDI Heart and Diabetes Institute "However, proving that link, and determining if treating OSA could have benefits for glucose control, requires intervention studies. Some uncontrolled studies had reported improved glucose control after starting CPAP, but some small controlled trials did not support this." 

In "The Effect of Treatment of Obstructive Sleep Apnea on Glycemic Control in Type 2 Diabetes," researchers in Australia and the U.S. randomly assigned 298 patients with "relatively well-controlled" type 2 diabetes and newly diagnosed OSA to either treat their sleep apnea with CPAP or receive usual care. 

In addition to measuring the change in glycemic control, researchers studied changes in blood pressure, daytime sleepiness and quality of life over six months. Researchers found:

• No difference between those receiving CPAP and the control group in change in glycated hemoglobin (HbA1c) at three and six months. 
• Greater fall in diastolic blood pressure over six months in the CPAP group compared to controls -- a finding that was statistically significant only among those who used CPAP for at least four hours a night.
• Daytime sleepiness improved significantly among those using CPAP as measured by the Epworth Sleepiness Index.
• Quality of life between the two groups was not statistically significant overall as measured by the RAND 36-Item Short Form Health Survey. Among those using CPAP for at least four hours a night, there was a significant difference with controls on vitality and mental health subscores.

Authors offered several possible explanations for why participants using CPAP did not experience better glycemic control. OSA may play a bigger role in the development of diabetes than in the control of established diabetes. The bar for adherence to CPAP -- set at four hours a night -- may have been set too low. And, lastly, CPAP may only benefit those with severe OSA and/or poor glycemic control. Participants with those characteristics were not well represented in the study, the authors noted.

"OSA is common in people with type 2 diabetes, and although we did not find a glycemic benefit for its treatment, clinicians should have a high index of suspicion for its presence when patients experience daytime sleepiness, snoring and resistant hypertension," Dr. Shaw said. "Identification and treatment of OSA in these patients may lead to clinically meaningful benefits."

Anthocyanins in Strawberries Improve Insulin Resistance

A new study in Molecular Nutrition & Food Research found that anthocyanin-rich strawberries may improve insulin sensitivity.

Insulin resistance (IR) is a hallmark of metabolic syndrome and a risk factor for heart disease and type 2 diabetes. Typically, after a meal, the pancreas produces an appropriate amount of insulin to usher glucose from the bloodstream into the cells. People with IR have built up a tolerance to insulin, so the pancreas must churn out extra insulin to coax blood sugar into the cells. Over time, this process can lead to type 2 diabetes.

Researchers observed the effect of anthocyanins on the postprandial insulin response of 21 obese adults with insulin resistance. Subjects were served a typical ‘Western-style’ meal high in carbohydrates and fat plus a beverage that contained freeze-dried whole strawberry powder. The beverages were controlled for fiber, and the amount of strawberry powder ranged from 0 grams to 40 grams (equivalent to 3 cups of fresh strawberries). When subjects drank the most concentrated beverage, they didn’t produce as much insulin as when they drank the least concentrated versions. In other words, they didn’t need as much insulin to metabolize their meal after drinking the anthocyanin-rich strawberry shake.

While the exact mechanisms are unclear, strawberry anthocyanins may alter insulin signaling at a cellular level.

These results add to the collective evidence that consuming strawberries may help improve insulin action, says study author Britt Burton-Freeman, Ph.D.

Eunyoung Park, et al. A dose-response evaluation of freeze-dried strawberries independent of fiber content on metabolic indices in abdominally obese individuals with insulin-resistance in a randomized, single-blinded, diet-controlled crossover trial. Molecular Nutrition & Food Research, February 2016.

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