Tag Archives: Insulin Sensitivity

Limiting Cholesterol Levels May Minimize Inflammation and Reduce Type 2 Diabetes Risk

Study will make possible new target therapies that help predict susceptibility to the metabolic condition and perhaps prevent diabetes

BY stimulating the enzyme cholesteryl ester hydrolase (CEH) to remove more cholesterol from cells, it may be possible to limit inflammation, improve insulin sensitivity and reduce an individual’s type 2 diabetes risk, claims a group of researchers from Virginia Commonwealth University School of Medicine. The results of the study have been published online in the Journal of Biological Chemistry.

Cholesterol has long been known to increase inflammation levels, and inflammation is well regarded as a risk factor for type 2 diabetes. Yet the researchers noted that few treatments for type 2 diabetes specifically target high cholesterol levels. It is hoped that the study will make possible new target therapies that help predict susceptibility to the metabolic condition, and perhaps prevent diabetes in the future.

“Although diabetes and heart disease often co-exist, current management of diabetes does not necessarily include cholesterol and/or inflammation control,” said lead researcher Shobha Ghosh, PhD. “These studies provide the first evidence that targeting fat tissue inflammation as well as elimination of cholesterol from the body may be emerging new strategies to prevent diabetes.”

For the study, the team analyzed the effect of turning up the expression of a gene that regulates CEH levels in a group of mice. The results showed that even when fed a high-fat diet, these mice had lower levels of inflammation and were more sensitive to the effects of insulin.

The results held true despite the fact that mice still gained significant weight from being fed the high-fat diet. Ghosh explained CEH appeared to cause low-density lipoprotein cholesterol molecules to exit cells, where they could then be neutralized by high-density lipoprotein cholesterol cells and taken to the liver for processing.

Ghosh said that these findings suggest that taking steps to control cholesterol levels in individuals with other risk factors for type 2 diabetes may be an effective treatment strategy. Additionally, they reveal that stimulating the genes that regulate CEH levels in the body may be one of the surest ways to control cellular cholesterol levels and limit fat’s pro-inflammatory effects.

From Endocrine Today

Related story: Arterial Plaques May Be Reduced By Increasing the Amount of a Key Enzyme in Cells Storing Cholesterol

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How Fatty Foods Lead To Diabetes

Findings provide further evidence of importance of choosing foods low in unhealthy saturated fats

FINALLY, new research from the University of North Carolina at Chapel Hill School of Medicine adds clarity to the connection between high saturated fat diet and type 2 diabetes.

Several decades ago scientists noticed that people with type 2 diabetes have overly active immune responses, leaving their bodies rife with inflammatory chemicals. In addition, people who acquire the disease are typically obese and are resistant to insulin, the hormone that removes sugar from the blood and stores it as energy.

But for years no one has known exactly how the connection between high levels of body fat (obesity), inflammation and insulin resistance, three factors that are known to increase type 2 diabetes risk.

The Chapel Hill study has found that saturated fatty acids ‒ but not the unsaturated type ‒ can activate immune cells to produce an inflammatory protein, called interleukin-1beta.

Using mouse cell lines (in vitro) and genetically engineered (defective inflammasome pathway) and wild-type mice (in vivo), the researchers found that intake of the saturated fatty acid palmitate, activates the NLRP3-ASC inflammasome-triggering production of IL-1beta, as well as the additional inflammatory factors caspase-1 and IL-18. The activation of the inflammasome then impairs insulin signaling in several target tissues, such as muscle and adipose fat, thus reducing glucose tolerance and insulin sensitivity. IL-1beta also affects insulin sensitivity through tumor necrosis factor-α-independent and dependent pathways. When fed with a high-fat diet, mice with a defective inflammasome pathway had better maintenance of glucose homeostasis and higher insulin sensitivity.

The Chapel Hill researchers found that induction of the inflammasome by saturated palmitate is distinguished by its use of the AMP-activated protein kinase and unc-51-like kinase-1 autophagy-signaling pathways, and the presence of mitochondrial reactive oxygen species.

“The cellular path that mediates fatty acid metabolism is also the one that causes interleukin-1beta production. Interleukin-1beta then acts on tissues and organs such as the liver, muscle and fat (adipose) to turn off their response to insulin, making them insulin resistant. As a result, activation of this pathway by fatty acid can lead to insulin resistance and type 2 diabetes symptoms,” explains senior study co-author Jenny Y. Ting, PhD, William Kenan Rand Professor in the Department of Microbiology and Immunology

In layman terms, a diet rich in saturated fat, in addition to causing weight gain, activates certain cells of the immune system, instructing them to produce a protein called interleukin-1beta. This molecule is known to cause inflammation throughout the body.

This molecular complex inside cells, called the inflammasome, plays an important role in immunity by triggering inflammation in response to a wide variety of harmful agents ranging from bacteria to asbestos. This inflammation, in turn, affects the tissue of muscles, the liver and other organs, impairing their ability to react to insulin. This characteristic is one of the hallmarks of type 2 diabetes

Ting and colleagues have found that palmitate, a fatty acid common in a high fat diet, triggers activation of the inflammasome. Palmitate-triggered inflammation is also responsible for interfering with the insulin sensitivity of liver cells ― a major feature of type 2 diabetes.

In addition to explaining a poorly understood set of processes that were known to increase type 2 diabetes risk, the findings also provide further evidence of the importance of choosing foods low in unhealthy saturated fats. The researchers found that unsaturated fats, like omega-3s, did not activate this process.

Study To Check If Garlic And Asparagus Can Fight Diabetes

Researchers are investigating whether foods including garlic and asparagus could help weight loss and diabetes. In news that could make ardent vegans and vegetarians feel a little smug, the charity Diabetes UK is examining whether foods rich in fibre could supress people’s appetites and reduce their blood sugar levels.

Fermentable carbohydrates, a kind of fibre, are found in foods such as asparagus, garlic, chicory and Jerusalem artichokes. If the foods are found to have this effect it could revolutionise treatments to tackle obesity and type 2 diabetes. Recent research has suggested that foods high in fermentable carbohydrates are particularly good at stabilising blood sugar levels.

The three-year study by the Nutrition and Research Group at Imperial College London, aims to establish whether these carbohydrates cause the release of gut hormones that could reduce appetite and enhance insulin sensitivity, which could reduce blood sugar levels and help control weight. The carbohydrates will be given to participants in the study as a daily supplement.

Dietitian Nicola Guess, who is leading the study, said: “By investigating how appetite and blood glucose levels are regulated in people at high risk of type 2 diabetes, it is hoped that we can find a way to prevent its onset. Type 2 diabetes accounts for 90% of diabetes cases and, if left untreated, can lead to serious health complications including heart disease, stroke, blindness, kidney failure and amputation, according to Diabetes UK.

Dr Iain Frame, the charity’s director of research, said: “It is unlikely that any single measure used on its own will bring about improved prevention of type 2 diabetes. But it’s hoped that the research being funded at Imperial College will help by aiming to develop an easy and affordable way to help people to reduce their risk of developing type 2 diabetes and managing their blood glucose levels.”

Thank you David Batty/Guardian

Scientists Uncover Novel Anti-Diabetes Mechanism

In a joint study, scientists from The Scripps Research Institute and the Dana-Farber Cancer Institute at Harvard University have uncovered a novel mechanism that dramatically increases insulin sensitivity and reduces the risk of developing type 2 diabetes and cardiovascular disease.

These findings offer a potent new target in the continuing search for new and improved anti-diabetic treatments.

The new study, which focuses on controlling a fat-regulating protein known as PPARy, was published July 22, 2010, in the journal Nature (Volume 466, Issue 7304).

“The field has become interested in finding drugs that can promote increased insulin sensitization but not activate the classical fat cell generating pathway of PPARγ,” said Patrick R. Griffin, chairman of the Department of Molecular Therapeutics at Scripps Florida who headed up the Scripps Research part of the study.

“We examined the mechanism of action of compounds that bind to PPARγ that improve insulin sensitivity but have minimal induction of fat. It was clear from the studies that these compounds have a unique but overlapping mechanism with the class of drugs used clinically that target PPARγ.”

Adipose or fat tissue lies at the center of the metabolic syndrome, a cluster of risk factors that increases the possibility of type 2 diabetes, as well as stroke, coronary artery disease, even certain cancers. Of those risk factors, excessive body fat is considered the most problematic.

PPARγ can be considered the master gene of fat cell biology because it drives the conversion of cellular precursors into fat cells.

The collaborative studies showed obesity causes a modification on PPARγ that leads to alterations in the expression of a number of genes, including a reduction in the production of an insulin-sensitizing protein (adiponectin). This leads to an increase in insulin resistance.

The reprogramming of genes controlled by PPARγ occurs when it undergoes phosphorylation (a phosphate group is added to a protein) by the cdk5 kinase, an enzyme that is involved in a number of important sensory pathways and that can be activated by pro-inflammatory proteins.

The scientists were able to use both full and partial agonists (compounds that activate a cellular response) to reverse these phosphorylation effects and improve the production of adiponectin.

These results strongly suggest that cdk5-mediated phosphorylation is involved in the development of insulin-resistance and open the door to a novel opportunity for creating an improved generation of anti-diabetic drugs.

In 2007, Griffin and his colleagues published a study in the journal Structure (October 16, 2007, Volume 15, Number 10, pp.1258-1271) that explained the difference between how full and partial agonists interacted with PPARγ. Full agonists interacted strongly with a region of the receptor known to be important for the classical fat generation program.

On the other hand, partial agonists, which are poor agonists of the receptor, did not interact with this region at all but interacted more strongly with a potentially critical region of the receptor. From a drug development point of view, these results offered a new area of the protein to focus on to optimize therapeutic molecules that would be potent insulin sensitizers without driving fat generation.

“Bruce Spiegelman at Dana-Farber was starting to uncover the fact that the phosphorylation of PPARγ takes place in the very region where MRL-24, one of the partial agonists interacted,” Griffin said. “I suggested that compounds like MRL24 might be better at antagonizing the cdk5 site given their strong interaction in this region of the receptor. For the new study, we provided significant amounts of compound to support the animal studies and provided an plausible mechanism for how partial agonists might recruit co-activator proteins to the cdk5 surface of PPARg.”

While the team found that PPARγ phosphorylation effects were reversed by both full and partial agonists, partial agonists indeed accomplished this as well or better than the full agonists. Mimicking the effects of just blocking the phosphorylation event by mutation of the site on the receptor showed improvements in the production of adiponectin.

The new study also suggests a unified framework for understanding the relationship between fat cell dysfunction in obesity and anti-diabetic therapies based on PPARγ. In animal studies, high fat diets activate the cdk5 kinase, initiating phosphorylation, disrupting a number of key metabolic regulators including adiponectin and adipsin, a fat cell-selective gene whose expression is altered in obesity.

“The great paradox of this whole effort is we’re targeting a receptor critical for fat production to offset the problem of fat overproduction,” Griffin said. “Unfortunately, current drugs that target PPARg increase fat as one of their unwanted long-term side effects.”

While the study is a big step forward, important questions still remain such as does a high fat diet and obesity lead to activation of cdk5 in non-fat tissues, Griffin said, since the negative effects of obesity extend far beyond metabolic syndrome to diseases like cancer and neurodegeneration.

More information: “Anti-diabetic drugs inhibit obesity-linked phosphorylation of PPARγ by Cdk5,” Jang Hyun Choi, et al. Nature Volume 466, Issue 7304

Courtesy: The Scripps Research Institute

Coffee Ameliorates Effects Of Hyperglycemia, Say Researchers

Drinking coffee may help prevent diabetes, according to a new study published in the Journal of Agricultural and Food Chemistry (2010;58(9):5597-603).

Researchers fed either water or coffee to a group of laboratory mice commonly used to study diabetes. Coffee consumption prevented the development of high-blood sugar and also improved insulin sensitivity in the mice, thereby reducing the risk of diabetes.

Coffee also caused a cascade of other beneficial changes in the fatty liver and inflammatory adipocytokines related to a reduced diabetes risk. Additional lab studies showed that caffeine may be “one of the most effective anti-diabetic compounds in coffee,” the scientists said.

Researchers at Nagoya University have reported evidence that drinking coffee may help prevent diabetes, and that coffee can ameliorate the effects of fatty liver, hyperglycemia and improve insulin sensitivity.

The research, published in the Journal of Agricultural and Food Chemistry, fed diabetes-prone mice either water or diluted coffee for five weeks. The coffee-drinking mice showed improved insulin sensitivity, reduced fatty liver and lower levels of inflammatory adipocytokines – all factors known to reduce the risk of type 2 diabetes.

Previous research has also linked coffee drinking to lowered risk of diabetes. A meta-analysis of research, conducted last year at the George Institute for International Health at the University of Sydney, found that each cup of coffee was associated with a 7% reduction in the excess risk of diabetes, and those drinking 3-4 cups a day had a 25% lower risk between those drinking 0-2 cups.

Even decaffeinated coffee had an effect, with those drinking 3-4 cups of decaf a day clocking a 33% lower risk than non-drinkers. Tea had less of an effect, with 3-4 cups a day translating to one-fifth lower risk than those who drank none.

These protective effects appeared to be independent of other potentially confounding variables. The link between decaf coffee and lowered risk suggests that the active component is more than just caffeine, although the Nagoya research suggests it may be one of the most effective components.

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