MD-Writer Blog

When young, I was told by my mom (a dietician) and my teachers that vitamin D was necessary for strong healthy bones. If you didn’t get enough, you might get rickets, a softening of bones that leads to fractures. That was pretty much the story about it until recently. I wouldn’t have guessed that Vitamin D might turn out to be one of the most important vitamins for many bodily functions.

Last March, I wrote in a post that British medical researchers had found that people with higher vitamin D levels had lower rates of cardiovascular disease and diabetes. Danish and Canadian researchers found that vitamin D is necessary for the proper functioning of both innate and adaptive immune systems. And Dutch researchers found that the vitamin may counter mental depression in regions with where winters are long and dark, like the Netherlands.

But vitamin D may have more benefits still. An article yesterday in USA Today described a study by British scientists on cognitive impairment, which they presented at the Alzheimer’s Association international conference now underway in Honolulu. Using data on cognitive functioning and vitamin D levels from 3000 Americans aged 65 and older, who had participated in a U.S. national health survey, the researchers found that rates of cognitive impairment were more than 40% higher in people with deficiency of the vitamin and nearly 400% higher in those with severe deficiency.

Also, medical scientists at the University of Rochester and University of Chicago investigated the roles of the vitamin D receptor, the site where the vitamin binds to the cell and exerts its effect, in the health and disease of the intestines. The results of their work appeared in the American Journal of Pathology online last month and were reported in ScienceDaily on Thursday.

The researchers studied mice that had been engineered to lack the vitamin D receptor (VDR knockout mice) and compared them with normal mice. They found that Salmonella bacteria were much more virulent when infecting the intestines of the knockout mice than the normal ones. The knockout mice would lose weight more quickly and succumb to infection more often. But even when the knockout mice were free of germs, they had higher levels of inflammatory molecules in their intestines than the normal mice.

The findings indicated that the activity of the vitamin D receptor, which is stimulated by vitamin D, plays a major role in protecting the animals from intestinal infection and maintaining their intestines in a normal state free from inflammation. The findings suggest also that besides helping to limit infections, the activity of vitamin D and its receptor may play an important role in preventing inflammatory bowel disease and cancer.

Addendum: While I was composing this post, I received an email from Scientific American reporting two more studies on the benefits of vitamin D. So I’m updating the post now, several hours later.

A study of Parkinson’s disease incidence among 3000 Finnish men and women aged 50-79 determined the subjects’ blood levels of vitamin D and followed them for 29 years. All participants were free of the disease at the start of the study. Those the highest levels of vitamin D (above 50 nmol/L) had a 65% lower rate of developing Parkinson’s disease than those with the lowest levels (below 25 nmol/L). That country’s National Institute for Health and Welfare conducted the investigation, which was reported this week in the Archives of Neurology.

Another study by the University of Exeter in the U.K. determined the vitamin D levels of more than 800 Italian men and women. More than half the subjects who had dementia were deficient in the vitamin, with levels below 50 nmol/L. Moreover, those with levels below 25 nmol/L were 60% more likely to experience cognitive impairment during a 6-year follow-up period. The study was reported this week in the Archives of Internal Medicine.

The SciAm article also notes that three-quarters of American adults and teenagers are believed to be vitamin D deficient. According to the U.S. Institute of Medicine, daily vitamin intake should range between 200-600 IU per day. The article noted that the optimal blood level of the vitamin is above 75 nmole/L.

Statin drugs, which decrease levels of LDL cholesterol (the harmful kind) and reduce inflammation, are the most widely prescribed drugs in the U.S., as the NY Times reported on Tuesday. But the use of these medications is about to become a lot greater, if a drug company and a doctor achieve their goal.

Elevated blood levels of lipids (the biochemical name of a group of fatty compounds including cholesterols) increase the risks of heart attack and stroke. Statin use lowers lipid levels and is presumed to have prevented many tens of thousands of heart and brain blockages and saved thousands lives. But until this year, doctors prescribed statins only for patients with high lipid levels.

That is about to change. In February, the FDA approved new directions for use of Crestor, the statin marketed by AstraZeneca, the huge pharmaceutical company. The agency allows the prescription of the drug for men 50 and over and women 60 and over who have no heart or stroke disease, if they have one risk factor, like high blood pressure, and a high level of hsCRP, an indicator of inflammation. The hsCRP test provides royalties to a doctor, Paul Ridker, who invented the test and has worked with AstraZenica on Crestor.

The FDA based its action on the results of the JUPITER trial , in which 18,000 men over 50 and women over 60 participated. 1.6% of subjects taking Crestor had a cardiovascular event, in comparison to 2.6% taking a placebo. The results were reported in 2008 by the New England Journal of Medicine, which noted that the pharmaceutical company sponsored the JUPITER trial and Dr. Ridker led it.

But one aspect of the issue is whether there might be a downside to so many people taking statins. Such a possibility has come up in a study reported last month in The Lancet, a British medical journal. Reviewing 13 clinical trials of statin drugs, including Crestor, involving 91,000 patients, the authors found a 9% increase in onset of diabetes in the statin patients as compared to those on control treatments. They reported that the small increase in diabetes risk would produce an extra case of diabetes for each 255 patients treated for four years.

The extra risk of diabetes seems small until one takes into account the benefit of treatment with statins. That benefit is also small, about 1% in the JUPITER trial. The Times reports that “500 people would need to be treated with Crestor for a year to avoid one usually survivable heart attack. Stroke numbers were similar.”

There’s a fundamental (even philosophical) question in considering whether healthy people should be treated for the possibility of getting a disease. The physician’s oath, which requires “first do no harm,” attaches greater importance to the possibility of causing harm than preventing disease.

The issue is in no way simple. To stay healthy, I take vitamins, even though I have no deficiencies. I take baby aspirin even though I have no heart disease or other major risk factor at the present time. Is my consumption of these chemicals fundamentally different from taking a statin to prevent heart disease and stroke?

I think it is different. The problem is the profit involved. As a physician who has observed and worked in the field of pharmacotherapy, I am inherently skeptical about the idea of drugs being used on an extremely wide scale, as will very likely happen with Crestor and other statins.

In this case, the company and the lead physician both stand to gain hugely from the new FDA-approved guidelines. Such financial conflicts have too often undermined science and swayed science toward premature and faulty conclusions.

If I were trying to decide whether to prescribe Crestor or some other statin for my healthy patients, I would wait a few years … wait a few years … and see what happens.

Heart disease, stroke, diabetes—in recent decades the most widespread of Americans’ chronic diseases—appear to be linked to inflammation and the accumulation of body fat. Several news articles this month reinforce this conclusion by pointing to a common physiologic mechanism connecting these conditions.

Eating too much food, especially the high-fat-high-carb kind, overwhelms the body’s ability to store fat, which spills over into other types of cells and brings on the metabolic syndrome of obesity, elevated blood sugar and LDL cholesterol, hypertension, and high risk of cardiovascular disease. The inactivity of modern life makes things worse by making it easier to consume more calories than necessary.

Doctors at UT Southwestern Medical Center have proposed this unified theory of the most prevalent modern diseases. Quoted in ScienceDaily, one of the doctors, Roger Unger, commented:

If one imagines the USA population to be unwitting volunteers in the largest (300 million subjects) and longest (50 years) clinical research project in history, the specific aim of which was to determine if the deleterious effects of sustained caloric surplus in rodents also can occur in humans, the outcome of the project becomes clear — after 50 years of exposure to an inexpensive calorie-dense diet high in fat and carbohydrates, 200 million subjects are overweight and >50 million have metabolic syndrome.

The metabolic syndrome develops because the cells that take up the excess fat—muscle, liver and macrophages, a type of immune cell—aren’t adapted to storing it and in reaction secrete inflammatory chemicals into the blood. The fat cells, in contrast, serve the storage function well, at least until they reach overcapacity. Thus, the accumulation of body fat actually protects against the metabolic syndrome and the chronic diseases.

A recent article in USA Today reports other research that supports the theory. Medical scientists at UCSF found that macrophages exposed to a lot of saturated fat become inflamed, but if the cells are genetically modified to hold more fat, this doesn’t happen. Another scientist at Columbia University found that macrophages make up only 5% of the cells in the body fat of lean people, but they may comprise 50% of these cells in the fat of obese people.

Another article by the AP reported that a doctor at Albert Einstein College of Medicine gave healthy but overweight volunteers intravenous fatty acids, as might happen when excess fat spills out from fat cells. She found that the subjects became resistant to the action of insulin, the characteristic of the metabolic syndrome that causes elevated blood sugar.

If the theory is correct, the best treatment for diabetes and cardiovascular disease may be to reduce daily calorie intake to match daily calorie need, and to do so by eating less high-fat-high-carb food. That, of course, would be no surprise. But Americans are having a hard time changing their food preferences and adjusting their energy requirements. So if all those excess calories are causing inflammation, which in turn is causing the diseases, why not test the effect of an anti-inflammatory drug?

Researchers at NIH are doing just that, according to the AP report. They will try the anti-inflammatory drug salsalate in several hundred people with type 2 diabetes, as an addition to their usual medication. The drug is related to aspirin but is less harmful to the GI system. Earlier research suggested that salsalate helped lower blood sugar.

Inflammation appears increasingly to play a central role in all the chronic diseases of modern life. It now appears that overeating may be one of the reasons for it.

Diabetic mice lacking pancreatic ß-cells that make insulin have been successfully treated with the hormone leptin alone. The leptin treatment, administered by implanted infusion pumps, normalized mice’s blood glucose levels and and other diabetic abnormalities. In addition, leptin lowered fatty acid blood levels, and it corrected abnormalities of lipid levels induced by insulin treatment that promote insulin resistance and atherosclerosis.

Leptin is the hormone secreted by fat cells that has stirred widespread interest because of its effect on the appetite centers of the brain to reduce appetite and regulate weight.

The report of the new research appeared yesterday in PNAS, the journal of the National Academy of Sciences. Medical scientists at the University of Texas, Duke, Albert Einstein College of Medicine, and the VA North Texas Health Care System demonstrated these remarkable effects of leptin using mice whose insulin-secreting cells had been chemically destroyed. They are now planning a clinical trial of combination insulin/leptin therapy in diabetic people. (Because insulin is a mandatory life-sustaining treatment for type I diabetes, clinical trials of leptin alone would not be permitted, at least initially.)

The new hormonal treatment appears to work because of the action of leptin to suppress glucagon, another metabolic hormone secreted by the pancreas. Insulin and glucagon have opposing effects on blood glucose. Insulin stimulates the cells of the body to take in the sugar from the blood as the main source of energy. This reduces glucose levels in the blood.

In contrast, glucagon increases blood glucose by promoting synthesis of the sugar in the liver and stimulating the breakdown into glucose of glycogen, the starch stored in the body’s cells. Thus, blood glucose levels are raised in the blood either by insufficient insulin or glucagon secretion. The researchers showed that that effect of leptin in controlling blood glucose could be mediated by its effect on glucagon, because they found that glucagon levels were suppressed 80% in leptin-treated animals in comparison to those treated with insulin and saline-treated controls.

Insulin also increases blood fatty acid levels, fat storage and abnormalities of fat metabolism that promote atherosclerotic disease of the cardiovascular system. In contrast, leptin treatment normalized these lipid abnormalities. The scientists determined that these effects of insulin did not happen in the absence of glucagon secretion, and leptin treatment may have prevented them from occurring due to its suppression of glucagon.

Glucose levels were controlled at least as well by leptin as by insulin in the diabetic mice. Glucose levels in the leptin mice averaged 88 mg/dl (a normal level in humans); iin the insulin mice glucose averaged 160 mg/dl (a somewhat elevated level in humans). The variability of blood glucose on leptin was less than on insulin, perhaps showing that glucose control was superior in the leptin group. Both leptin and insulin prevented the most severe effects of type I diabetes: ketoacidosis, wasting and death. And both normalized glycocylated hemoglobin A1c levels, a clinical marker of glucose control.

Leptin also substantially decreased the food intake of the mice. Leptin-treated mice ate 72% less than untreated diabetic mice and 15% less than insulin-treated mice. But the scientists showed that weight loss in the leptin mice resulted from loss of body fat, but lean tissue was spared.

These findings raise great hope that a superior treatment of insulin-dependent diabetes may be developed. Nevertheless, demonstrating the effectiveness of a new therapy in animals is always far from proving it in humans.

The potential of this new hormonal treatment is that it could revolutionize and improve the therapy of the most severe form of diabetes. We should keep our fingers crossed.