Archive for the ‘Diabetes’ Category

Low vitamin D level is linked to greater chance of risk factors for Type 2 diabetes

Sunday, July 15th, 2012

We are getting more data on the effects of deficient vitamin D published in mainstream peer-reviewed journals. Bioactive vitamin D or calcitriol is a steroid hormone that has long been known for its important role in regulating body levels of calcium and phosphorus, and in mineralization of bone. More recently, it has become clear that receptors for vitamin D are present in a wide variety of cells, and that this hormone has biologic effects which extend far beyond control of mineral metabolism. {{{0}}}

The active form of vitamin D binds to intracellular receptors that then function as transcription factors to modulate gene expression. Like the receptors for other steroid hormones and thyroid hormones, the vitamin D receptor has hormone-binding and DNA-binding domains. The vitamin D receptor forms a complex with another intracellular receptor, the retinoid-X receptor, and that heterodimer is what binds to DNA. In most cases studied, the effect is to activate transcription, but situations are also known in which vitamin D suppresses transcription.

The vitamin D receptor binds several forms of cholecalciferol. Its affinity for 1,25-dihydroxycholecalciferol is roughly 1000 times that for 25-hydroxycholecalciferol, which explains their relative biological potencies

A new study presents more evidence of a possible link between low vitamin D levels and a higher risk of Type 2 diabetes and heart disease. The results will be presented Saturday at The Endocrine Society’s 94th Annual Meeting in Houston (see also Type 2 Diabetes).

The study found an inverse relationship between the level of vitamin D in the blood and the presence of the metabolic syndrome, which is a group of risk factors that increases the risk of heart disease and Type 2 diabetes. People with the highest blood levels of vitamin D had a 48 percent lower risk of having the metabolic syndrome than did those with the lowest vitamin D levels, the authors reported.

“This association has been documented before, but our study expands the association to people of diverse racial and ethnic backgrounds,” said the lead author, Joanna Mitri, MD, a research fellow at Tufts Medical Center in Boston. “These include minority groups that are already at higher risk of diabetes.”

Furthermore, all study participants were at risk of developing diabetes because they had prediabetes, abnormally high blood sugar levels that are not yet high enough to be classified as diabetes. Prediabetes affects an estimated 79 million Americans ages 20 or older, according to 2010 statistics from the Centers for Disease Control and Prevention.

Mitri and her co-investigators conducted the study using data from participants of the Diabetes Prevention Program, a large, now-completed study funded by the National Institutes of Health. They divided study subjects into three groups based on plasma 25-hydroxyvitamin D level, which is the most common way used to measure vitamin D status in the body, according to Mitri. The Institute of Medicine recommends a 25-hydroxyvitamin D level of 20 to 30 ng/mL as adequate for healthy people.

In the new study, the group with the highest levels of vitamin D had a median vitamin D concentration of 30.6 nanograms per milliliter, or ng/mL, and those in the lowest group had a median vitamin D concentration of 12.1 ng/mL. The risk of having the metabolic syndrome with a high vitamin D level was about one half the risk with a low vitamin D level, Mitri said.

The researchers also found an association between vitamin D status and some of the individual components of the metabolic syndrome, which includes a large waist size, low HDL (“good”) cholesterol, high triglycerides (fats in the blood), high blood pressure and high blood glucose (sugar). Study participants with the best vitamin D status had a smaller waist circumference, higher HDL cholesterol and lower blood sugar.

Mitri cautioned that their research does not prove that vitamin D deficiency causes Type 2 diabetes, or even that there is a link between the two conditions

Aspirin and Metformin share common mechanism

Thursday, July 5th, 2012

I have personally benefited from the use of Metformin as a pre-diabetic with a strong family history of type II diabetes mellitus. Recent American Diabetes Association (ADA) consensus panel recommends the use of Metformin to prevent or delay the development of diabetes. In a study published by Rhee MK et al  in Diabetes Care, 2010 Jan; 33(1):49-54. Epub 2009 Oct 6, more than 96% of individuals with both impaired fasting glucose and impaired glucose tolerance test are likely to meet ADA consensus criteria for consideration of metformin

A report by scientists from McMaster University, the University of Dundee and the University of Melbourne, published online on April 19, 2012 in the journal Science, suggests a common mechanism for salicylate—aspirin’s active compound—and the drug metformin in decreasing the risk of several diseases.

“Salicylate, a plant product, has been in medicinal use since ancient times,” Simon A. Hawley and colleagues write in their introduction to the article. “More recently, it has been replaced by synthetic derivatives such as aspirin and salsalate, both rapidly broken down to salicylate in vivo.”

The authors explain that salsalate or aspirin administered in high doses result in the activation by salicylate of adenosine monophosphate-activated protein kinase (AMPK), a regulator of cell growth and metabolism. AMPK is known to be activated by exercise as well as the antidiabetic drug metformin. “We’re finding this old dog of aspirin already knows new tricks,” commented co-principle investigator Dr Greg Steinberg, who is an associate professor of medicine in the Michael G. DeGroote School of Medicine at McMaster University and the Canada Research Chair in Metabolism and Obesity. “In the current paper we show that, in contrast to exercise or metformin which increase AMPK activity by altering the cells’ energy balance, the effects of salicylate are totally reliant on a single Ser108 amino acid of the beta 1 subunit.

“We show that salicylate increases fat burning and reduces liver fat in obese mice and that this does not occur in genetically modified mice lacking the beta1 subunit of AMPK,” he noted.

The fact that both metformin and aspirin activate AMPK suggests that their recently publicized benefits in reducing the risk of cancer could be d5e to a shared mechanism. However, only further studies can confirm the validity of this interesting hypothesis.

Further elucidation of the action of metformin:

Metformin is a widely used drug for treatment of type 2 diabetes with no defined cellular mechanism of action. Its glucose-lowering effect results from decreased hepatic glucose production and increased glucose utilization. Metformin’s beneficial effects on circulating lipids have been linked to reduced fatty liver. AMP-activated protein kinase (AMPK) is a major cellular regulator of lipid and glucose metabolism. Metformin activates AMPK in hepatocytes; as a result,

  1. Acetyl-CoA carboxylase (ACC) activity is reduced, fatty acid oxidation is induced, and expression of lipogenic enzymes is suppressed – Phosphorylation and inactivation of ACC, as a result of AMPK activation,kserves to inhibit the proximal and rate-limiting step of lipogenesis. Reduced synthesis of the ACC product, malonyl-CoA, is also predicted to relieve inhibition of CPT-1, resulting in increased fatty acid oxidation. These effects are likely to contribute to metformin’s in vivo ability to lower triglycerides and VLDL.
  2. Suppresses expression of SREBP-1, a key lipogenic transcription factor. In metformin-treated rats, hepatic expression of SREBP-1 (and other lipogenic) mRNAs and protein is reduced; Known target genes for SREBP-1, which include FAS and S14, are also downregulated in liver, further contributing to metformin’s effects to modulate circulating lipids and to reduce hepatic lipid synthesis and fatty liver. It should be noted that increased SREBP-1 is postulated as a central mediator of insulin resistance in DM2 and related metabolic disorders and that increased liver lipid content is implicated in hepatic insulin resistance
  3. In isolated rat skeletal muscles, metformin stimulates glucose uptake coincident with AMPK activation. this effect is also additive with insulin (12). Thus, the observed association of increased glucose uptake and AMPK activation in isolated skeletal muscles suggests that metformin’s effect to augment muscle insulin action in vivo may be attributed to AMPK as well.
  4. Metformin-mediated effects on hepatic glucose production contribute to its glucose-lowering efficacy. AMPK activation is required for inhibition of hepatocyte glucose production by metformin. Additional studies will be required to further elucidate precise mechanism(s) by which metformin-stimulated AMPK activation could result in inhibition of hepatic glucose production.