Welcome back to our monthly digest of recent diabetes research.

In this editio, research uncovers new uses for a drug originally designed to treat people with type 2 diabetes that may bring us one step closer to reducing the number of people suffering from transplant rejection.

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Researchers uncovered a gene variant associated with slower aging and which protects from diabetes. This variant causes people to produce unusually low levels of a protein which may serve as a new biomarker in the control of insulin resistance and the prevention of obesity.

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A new study compared a low carb diet with a low fat diet for reducing liver fat and fat depots elsewhere in the body. It has found that the low carb diet elicits greater reductions in liver and pancreas fat than the low fat diet did. The researchers fill us in on why low carb diets offer a distinct advantage for fat loss.

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Recent evidence suggests that lifestyle interventions for diabetes prevention have lasting effects, compared to medication. A review identifies the best lifestyle programs for cutting the risk of developing type 2 diabetes and provides some estimates of risk reduction achieved through committing to a healthy lifestyle.

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There is growing interest in activating brown fat thermogenesis with drugs in order to treat obesity, diabetes and other associated conditions such as heart disease. This is because it enables the disposal of excess fat in a relatively safe manner. A new review of evidence includes some of the latest thinking about this process.

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Discarded diabetes drug could help prevent organ transplant rejection

(Research link)

A shelved diabetes drug could be repurposed to reduce the risk of transplant rejectio, according to new research from Queen Mary University of London (QMUL) funded by the British Heart Foundation.

The trial drug AZD1656, formerly manufactured by AstraZeneca for people with type 2 diabetes, could be just as effective as current immunosuppressive drugs at preventing rejection with no apparent side effects.

The team has found that the diabetes drug increases the activity of an enzyme called glucokinase (GCK), which instructs white blood cells called T cells to migrate to organs for suppressing inflammation and inhibiting rejection post-transplant.

GCK is best known for its role as a beta cell glucose sensor. A reduction in GCK levels in beta cells was previously shown to increase the glucose threshold for insulin secretio, and genetically altering GCK levels improves glucose metabolism in type 2 diabetes.

In addition to regulating insulin secretion in beta cells, GCK controls a process of glucose breakdown in the liver known as glycolysis.

The QMUL researchers discovered that protective immune responses against transplant rejection require glycolysis to be properly coordinated. Specifically, the movement of T cells into organs is triggered by an increase in glycolysis.

The diabetes trial drug is known to increase the work rate of GCK and, by extensio, glycolysis. In an experiment, the researchers showed that T cells that were treated with the drug moved into the inflamed organ tissue of mice in much greater numbers.

There is evidence that this might hold true for the human immune system. The team’s research, which involved studies on human blood, revealed that the motility of T cells increased in people who have a mutation in a gene inhibiting GCK in the liver that makes it more active.

This means that it may be possible to manipulate the trafficking of immune cells by targeting metabolic enzymes, and that a drug developed for type 2 diabetes which increases the activity of one such enzyme (GCK) could be used to prevent organ rejection after a transplant.


Rare gene variant reduces risk for diabetes and prolongs lifespan

(Study link)

Carriers of one copy of the gene variant live longer and healthier lives

A new genetic study uncovered the actions of a gene variant that offers protection from diabetes and can make people live ten years longer. A possible mechanism, consistent with other research, is lower insulin levels in these individuals.

The gene is called SERPINE1, and encodes a protein that promotes aging. In this study, researchers followed a group of Amish people who are carriers of the gene variant, causing them to produce half as much of the protein.

This protein, known as plasminogen activator inhibitor type 1 (PAI-1), plays an important role in blood clotting. But people with type 2 diabetes and those who are obese have higher-than-normal PAI-1 levels in the blood and arterial wall. And mice that make extra PAI-1 show signs of premature aging.

Researchers from Northwestern University, Chicago, studied the SERPINE1 gene in 177 members of the Old Order Amish community in Berne, Indiana.

The team analysed the DNA of those with one copy of the gene variant and compared the results with others that had two normal versions.

Carrying one copy of the gene variant was associated with longer telomeres (a sign of lower biological age) and 30 per cent lower fasting insulin levels. More importantly, none of the carriers of the variant developed diabetes.

Using additional data on dead relatives who would have carried the gene variant, the researchers were able to work out that people who carried at least one copy lived, on average, ten years longer and died at the median age of 85.

One hypothesis for the prolonged longevity benefits in carriers of the gene variant is that lower PA1-1 levels reduces cellular senescence, a fundamental aging mechanism implicated in many age-related diseases and diabetes complications.

Drugs that target the protein are already being developed. However, the difficulty lies in reducing PAI-1 just enough to gain protection from diabetes and prolong lifespan while retaining enough of it for blood clotting.

A research team in Japan has already isolated a molecule that blocks PAI-1 and begun testing it in people who are at high risk for diabetic kidney disease (DKD). Clinical trials of obesity and insulin resistance are also in the pipeline.


Low carb diet promotes leaner liver and greater fat mobilisation

(Study link)

The low carb diet induced greater losses in intra-hepatic fat

New results of an earlier study add evidence to the theory that a low carb diet is superior to a low fat diet for fat oxidatio, especially surrounding organs.

The recent findings show that a Mediterranean style-low carb diet significantly reduced liver fat, pancreas fat, and fat deposits in the heart after only 18 months.

Earlier research led by the same team at the University of the Negev and Soroka University Medical Centre suggested that low carb was more powerful than low fat in clearing heart fat deposits and improving other cardiovascular risk factors.

This 18-month trial involved 278 participants who had abdominal obesity and a high body mass index (BMI), and were randomised to eat a Mediterranean style low carb diet (MED/LC) or a calorically equal low fat diet with or without increasing physical activity.

The researchers monitored and compared changes in the quantity of fat in the abdominal cavity, liver, heart, muscle and pancreas with each diet using magnetic resonance imaging (MRI).

They have found that although the weight loss was similar between the two groups, those in the MED/LC and who were engaging in physical activity saw a two times greater reduction in waist circumference.

More importantly, independent of weight loss, the MED/LC diet plus physical activity led to significantly greater reductions in liver fat, pancreatic fat and pericardial fat.

Further analyses also revealed that the clearance of fat in the liver was associated with improved lipids, and The MED/LC diet reduced triglycerides more than the low fat diet did.

These results illustrate the superior capacity of MED/LC to reduce fat accumulation in the liver as well as other organs, including the heart and the pancreas.

The findings have implications for dietary strategies aimed at preventing and treating complications associated with a build-up of fat within cells, such as non-alcoholic fatty liver disease (NAFLD).


Lifestyle changes for diabetes prevention maintain benefit seven years later

(Meta-analysis link)

A recent meta-analysis put together the results of 43 trials into the effects of lifestyle interventions and medications on the risk of developing type 2 diabetes.

The study, led by researchers from Emory University in Atlanta, US, includes lifestyle interventions whose lengths ranged from six months to six years.

The objective of this study was twofold: quantifying the impact of lifestyle modification on the risk for type 2 diabetes, and working out whether their effects was sustained over the long haul.

Researchers found that weight loss interventions, and other interventions aimed at restoring insulin sensitivity, can decrease the risk of developing type 2 diabetes by up to 39 per cent in some individuals. In comparison, drugs alone achieved a 36 per cent relative risk reduction.

However, the effects of medication were short lived, whereas those derived from lifestyle modification were sustained for several years before declining. Lifestyle modification carried a 28 per cent sustained risk reduction after 7.2 years.

Combining both diet and physical activity was found to confer the highest degree of protection from diabetes, achieving an estimated relative risk reduction of 41 per cent.

Weight loss appears to be the key factor in curbing the risk of developing type 2 diabetes, as  every kilogram of weight lost was associated with an additional seven per cent decrease in risk.

Although these figures reflect relative risk reductions, lifestyle modification interventions are promising diabetes prevention strategies that have long-lasting benefits and healthcare professionals should more systematically refer high-risk patients to such programs.


The science of fat and drug-activated thermogenesis in diabetes

(Review link)

Targeting thermogenesis can help treat obesity, diabetes and other associated conditions

Scientists at Baton Rouge’s Pennington Biomedical Research Centre recently reviewed evidence regarding brown fat activatio, which is considered a potential treatment for type 2 diabetes, metabolic syndrome and insulin resistance.

The body burns calories to produce heat in response to a process in brown fat activated by cold known as thermogenesis. Increasing the quantity of brown fat and thermogenesis activity is thought to aid weight loss.

Indeed, previous research has found that the amount and activity of brown fat were much higher (about four-fold higher) in lean individuals compared to overweight or obese individuals.

But according to the Baton Rouge researchers, there isn’t enough evidence yet to indicate that mimicking the possible anti-obesity effects of higher brown fat activity and thermogenesis with drugs would be effective.

The researchers said brown fat itself only contributes a small amount to overall energy expenditure (the number of calories burned) in humans, and boosting its activation is unlikely to cause significant weight loss.

However, they state that brown fat is linked to real improvements in glucose metabolism.

White fat is the primary site of storage and of release of hormones and cytokines that promotes insulin resistance, whereas brown fat quickly burn its own fat stores and increases insulin sensitivity within weeks when transplanted into visceral fat in mice.

Similarly, activating brown fat through cold exposure for ten days in obese people with type 2 diabetes was shown to increase whole-body insulin sensitivity by 43 per cent.

Of course, cold stimulation is not a real tool to improve obesity and associated metabolic problems because few people are going to be willing to endure the discomfort of it, so researchers explored advances in brown fat activation with drugs.

Low temperatures increase the activity of an uncoupling protein, known as UCP1, in the mitochondria of brown fat. This is what activates the “thermogenic program” and a lot of research went into finding how to boost UCP1, primarily as an obesity treatment.

One way to do this, which the current review focuses o, is through beta 3-adrenoreceptor agonists – a family of compounds that have been extensively studied as anti-diabetic drugs in humans.

Exercise has also been shown to increase UCP1 activity in brown fat, and mice on a ketogenic diet display higher UCP-1 activity in white fat, making it behave more like brown fat.

A few other molecules have already been identified to increase thermogenesis and/or the number of fat cells capable of thermogenesis, which acts as a signal to decrease fat storage and allow excess energy loss.

Overall, this research suggests that unlocking the thermogenic potential of brown fat could stimulate the development of new insulin sensitising drugs or ones controlling weight loss.

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