The Doctor Weighs In

By Pat Salber, MD

We have known about the association between snoring and obesity for a long time. But we now know that sleep-disordered breathing (SBD) -- a sleep disturbance characterized by snoring and episodes of apnea or not breathing for periods of time -- is linked, independent of obesity, to insulin resistance, abnormal glucose metabolism, and Type 2 diabetes.

Sinziana Seicean, MD, MPH and colleagues published results of the Sleep Heart Health Study in the May 2008 issue of Diabetes Care. They studied 209 normal weight and 1,036 overweight/obese individuals who had a diagnosis of SDB, but did not have a diagnosis of diabetes. They found that SDB was associated with all of the manifestations of impaired glucose metabolism, including impaired fasting glucose, impaired glucose tolerance, and occult diabetes. The magnitude of the association between SDB and abnormal glucose metabolism was the same regardless of whether the individual was normal or overweight/obese.

This suggests that obesity is not the common cause of both insulin resistance and sleep-disordered breathing. Rather there appears to be an independent association between SDB and impaired glucose metabolism that is not explained by adiposity.

The authors suggest that the association of SDB with glucometabolic disturbances may relate to the “often-profound physiological stresses that occur overnight with sleep apnea.” They suggest that these stresses may transiently increase autonomic sympathetic activity, increase outpouring of the stress hormone, cortisol, and a decrease insulin sensitivity. Indeed, they point out that a human study of people with sleep apnea demonstrated improved insulin sensitivity after treatment of the SDB with continuous positive airway pressure (CPAP)

Why is this study important? Because it means that individuals with SDB who are normal weight may be at risk of impaired glucose metabolism. It also suggests that therapy aimed specifically at SDB and not just at obesity may be indicated to reverse that risk.

To learn if you are at risk of having SDB, answer the following questions based on the Berlin Questionnaire:

By Dov Michaeli MD, Ph.D

Have you ever looked at the list of ingredients on the foods you buy? I can guarantee that you’ll be hard put to find even one item that does not contain fructose in one form or another: it could be straight fructose, or masquerading as corn syrup, or sucrose (table sugar) whose content is 50% fructose. I recently checked 10 items in my foray to the local Safeway store; of the packaged foods, all ten contained fructose in one form or another. It's found in ketchup, fruits, jellies, pastries, and many processed foods. Even sugar substitutes can have high fructose corn syrup in them.

So what of it? Plenty.

Fructose and metabolic syndrome

One of the hallmarks of metabolic syndrome diagnosis is insulin resistance. What it basically means is the following: When glucose level in the blood gets to a certain level, glucose sensors in the beta cells of the pancreas initiate a commensurate release of insulin. The insulin binds to its receptors in the various tissues, and that results in uptake of the glucose by the cells and its utilization for energy and storage.

But something funny happens on the way to the insulin receptor when fructose undergoes metabolism: one of the end products is uric acid. Yes, the same compound that ends up in the urine, and that can cause such unpleasant things like kidney stones and gout. But uric acid turns out to do even more harm—it causes the cell to become insensitive to the message that insulin is trying to convey: take up more glucose from the blood. End result: increasing blood glucose levels, or hyperglycemia. And this, in turn leads to obesity and diabetes type 2.

The new food indexes

Beginning next year (and that’s in about 2 weeks) you will start seeing on the packaging of the foods you buy a new “index”: the nutritional value scale. One of these scales will use a numerical value, on a scale of one to one hundred, with 100 being the most nutritious. Others will use a star system, with 3 stars being the “best for you”. This is a laudable effort, initiate by academics specializing in nutrition science. But the subject of nutrition is so complex that I am sure each one of these scales will be subject to withering criticism. One of the reasons is that if real foods, no substance acts in isolation; grapes contain glucose, but dark-skin grapes also contain a high concentration of antioxidants. How do you balance the two? Or more relevant to the point of this article: apples, for instance, are high in fructose but also contain many other substances that far outweigh the latter’s deleterious effects. Will the new scales be able to account for that?

Caveat emptor

Be vigilant: check the label and look for fructose in all its disguises: corn syrup, corn fructose, or just fructose hiding in plain view. Sounds a bit paranoid? Next time when you in are the supermarket, do the experiment; check out the labels and you’d be amazed.

Interestingly, most food companies blamed the rising costs of corn (which nowadays is diverted to another political boondoggle—corn-based ethanol) for their poor financial results and the need to raise prices in the last two quarters. Corn, you might ask, in oat or wheat cereals? Yes, check the label: it is laced with corn syrup, which is nothing but a high-concentration solution of fructose.

Another interesting thought: could it be that our obesity/ diabetes epidemic is not entirely due to excess calories per se, but partly due to the ubiquitous fructose in our foods? This is quite conceivable; fructose is a food of extremely high glycemic value (namely, causes a rise in blood sugar) because of its high caloric content and because of its glucose resistance action.

So in this Christmas shopping season, here is one two-for-the-price-of-one bargain you should definitely pass up.

By Dov Michaeli MD, Ph.D

Every Sunday morning we have a family ritual: 8-9 in the morning it’s “Meet the Press”, 9-9:30—the Chris Matthews Show. And while the TV is blaring and we OD on politics, we walk on the treadmill or step on the elliptical, do abdominals and pushups, do Yoga and lift weights—in short: we indulge our political and fitness addictions simultaneously, and feel self-righteous and quite superior to the flabby unwashed masses.

I love to watch Chris at his best: benignly opinionated, urging his guests to express their opinion on a political subject before pronouncing the Matthews ‘truth’ (“Tell me something I don’t know… here is what I think”), full of lively energy; the man is manifestly enjoying exposing hypocrisy, mendacity, stupidity and other ills of our political leading lights.

So guess how surprised I was when I found out that Chris Matthews makes stupid mistakes, like any one of us. As I sorted through today’s mail my eyes fell on the cover of the latest issue of Diabetes Forecast. There he is on the cover, smiling his heart-melting Irish smile, over the title: “Chris Matthews: the Hardball host goes head-to-head with type 2”. I guess for the readership of this magazine there is only one sort of “type 2”— diabetes. Chris was interviewed by Dan Gilgoff, the politics editor of Beliefnet.com and author of The Jesus Machine: How James Dobson, Focus on the Family, and Evangelical America are Winning the Culture War. (I can’t resist a digression here. Dan, don’t fret: Dobson, Focus on the Family, and Evangelical America are losing the cultural war!).

The interview was an eye-opener for me. I have to admit, I used to attribute much of the American people’s lack of sophistication in health matters to poor education. No more; here is a highly educated individual, possessing an uncanny capacity to ferret out ignorance, stupidity, and dishonesty who betrays an incredible degree of ignorance when it comes to his own health.

Here are some excerpts from the interview, along with some gratutitous comments.

Q. You knew for years that you had diabetes but did very little about it.

A. … I had malaria after coming back from a trip to South Africa in 2001, but what I kept [hearing about] from my doctor was my high blood sugar levels. And I said, “What does that have to do with anything?”

Comment: Chris, with your sharp ear to nuance and encrypted messages—what did you think your doctor was trying to tell you? And you, doctor, were you too pressed for time to press your point home? By the way, going to South Africa without taking the Malaria pills? Did you think you were beyond the reach of lowly creatures such as mosquitoes?

Q. But you more or less ignored your diabetes until even more recently, right?

A… I also wasn’t doing any kind of dieting. I was aware of a general need to skip some things. The toughest habit is going to an airport in the morning when you haven’t had breakfast and seeing the pastries there. Hunger is the best chef—you see a couple pastries and have that and a cup of coffee for breakfast. There was a time when I’d have a hamburger and French fries for lunch with a beer or white wine, and I’d have cheesecake for dessert. It was pretty outrageous.

Comment: I agree. Many a time did I find myself struggling to walk past the Peet’s and Starbuck’s Coffee stands at the SF airport, without succumbing to the temptation of the pastries. But where was your doctor? How come you weren’t warned about pastries, hamburgers, French fries, beer or white wine for lunch? This is inexcusable.

Q. Did you consider reforming your diet after learning about your high blood sugar levels?

A…. I didn’t say, “Wait a minute, this is something I can reasonably deal with.” I didn’t understand the importance of it or the doability of it—that I could solve this problem, that it would be over, and I would be just like everybody else….

Comment: That he didn’t understand the importance of it is in part his doctor’s fault, and in part Matthews’ own dismissive attitude when confronted with inconvenient facts.

Q. You stayed in the hospital a few days. How scary was it?

A. When you have three doses of morphine and it still hurts, you begin to worry.

Comment: And I am sure you went back to your TV show, blasting any and all comers for their lack of clear solutions to our health care problem. Chris, it is people like you who are part of the problem.

Q. You’ve certainly lost a good bit of weight in the past year.

A. On my scale at home I’ve gone from around 235 to about 205, and I think I can lose some more if I do a little more exercise. I really haven’t done any exercise to lose all this weight, just changing what I eat.

Comment: Chris, I watch you every Sunday on TV. You need to lose a minimum of 20 more lbs. You may rid yourself of the daily insulin injections, and as a bonus, you’ll wow the beautiful female political commentators on your show if you lost 40 lbs, and exercised!

Q. Why your aversion to exercise?

A. Don’t have any time. When am I going to do it?

Comment: What a lame excuse. There are people who run multi-billion dollar enterprises who find time to exercise. You make time, Chris. Get up one hour before you normally do, and just do it. It is going to grow on you, it will energize you to go after the bad guys, and you’ll feel sick on days that you skip—I guarantee it.

Q. As a public figure, do you feel obligated to send a message about diabetes?

A. What people ought to be told about diabetes is that if they have it in the family or sense that they’re on the road to it, they should go to their doctor and ask him what he thinks and actually listen to the doctor like they would use [their] financial advisor.

Maybe it’s an Irish thing—we like to think we can talk our way out of things or that we can avoid them. But I’ve come to respect doctors a whole lot through this whole thing because they know what they’re talking about and they’re telling you to do something for your own good.

Comment: You are right, Chris; people ought to listen, even more than to their financial advisor. It is a matter of their health and life—pretty existential stuff.

But you are wrong about it being an “Irish thing”. I have had Russian patients come in with a list of medications and treatments they had decided they needed, and all attempts at telling them otherwise were a waste of time. My own father would go to the doctor only to tear up the prescriptions he was given and treat himself with his grandmother’s nostrums. And my Rabbi told me that when your Celtic forefathers had no idea that the emerald island even existed, the Jews of Ireland already suffered from diabetes. And why did they have diabetes? Because they didn’t listen to their (Jewish) doctors.

See you next Sunday on TV.

Dov Michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

“Go to the ant, my son

Observe her ways

And wisen”

King Solomon, Proverbs (free translation).

Undoubtedly you have seen pictures of those emaciated characters who practice calorie restriction in the name of living a long, long life. The normal daily diet of an adult male contains about 2000-2400 calories. The ‘calorie restriction’ people limit their diet to about half of that. They may live longer, but are they happier? Hard to tell; they are going to die hungry but maybe also happy, for the ordeal is finally over.

One of the organisms that provided the ‘intellectual’ basis for this cruel and unusual experiment in long living is called C. elegans.

Where in the world is C. elegans?

Caenorhabditis elegans (Caeno, recent; rhabditis, rod; elegans, nice), is a free-living, non-parasitic soil nematode that can be safely used in the laboratory and is common around the world. It is small (about 1 mm in length) and has a short life cycle. From egg to egg takes about 3 days, and its life span is around 2 to 3 weeks under suitable living condition. What is unique to this organism is that wild-type (normal, non-mutated) individuals contain a constant 959 cells. The position of cells is constant as is the cell number. Moreover, it is transparent. It is easy to track cells and follow cell lineages. This provides a great tool for research on how genes influence cell fate. These traits enable the study of the biology of a single cell in an intact, living organism.

The genome size of C. elegans is about a hundred million base pairs. This is approximately 20X bigger than that of E. coli and about 1/30 of that of human. But, as its genome is surprisingly similar to that of humans (40% homologous), C. elegans became an attractive organism in the study of human biology and diseases.

The insulin-like pathway of C. elegans

Among those remarkably human-like genes are the ones that control energy metabolism, and specifically those coding for an insulin-like pathway. Genetic analysis now conclusively demonstrated that several of those genes, when mutated, extended life through reducing the activity of this insulin signaling pathway; in other words, life was extended by reducing the metabolic rate. Conversely, there is now considerable evidence showing that senescence (aging) is associated with increased metabolic rate.

Therefore, a logical conclusion would be that an insulin-like pathway drives senescence in C. elegans by enhancing metabolic activity. Right? Not quite…Genetic manipulation has now demonstrated that it is the insulin-like pathway specifically in neurons, not muscle or other highly metabolically active tissues, that regulate life span in C. elegans. And consider this: in humans the neurons most sensitive to insulin are probably the hypothalamic neurons that regulate metabolism and body weight, destruction of which leads to profound metabolic impairment.

Biology never ceases to confound our most ‘obvious’ theories. Although many hypotheses were offered to explain this unexpected discovery, in truth scientists were stymied.

 A tantalizing clue

In a paper published this week in Nature, scientists from the University of Washington in Seattle reported on an intriguing discovery. They screened 88,000 chemicals for the ability to extend the lifespan of adult C. elegans. They found that a drug that was once used as an antidepressant in humans, increased lifespan by 30%. The drug, a tricyclic, is called mianserin and was marketed as Tolvol, before being largely phased out of the market.

Its mode of action is interesting; it blocks two serotonin receptors, SER4 which signals the presence of food, and SER3, which signals starvation, in C. elegans. But the blocking action of the drug is not equal—it blocks SER 4 (food available) ten fold more than SER3 (starvation). The authors state: “In this way, mianserin might potentially create a ‘perceived’ state of starvation that, despite adequate food intake, would activate mechanisms of lifespan extension downstream of dietary restriction”.

Or in other words: it is not the actual caloric restriction and starvation that is responsible for lifespan extension. It is rather the perception of starvation that causes the brain to activate the mechanisms that lead to life extension. Which may explain the original observation that disruption of the insulin pathway in neurons, and not in muscles or other ‘obvious’ tissues, that leads to prolongation of lifespan.

Another example of mind over body. Or is it perception trumps reality?

Whatever the philosophical musings this experiment evokes, the practical implication is awesome: we won't have to spend a lifetime in starvation in order to live an extra few years. Drugs will be available that would allow us to literally have the cake, eat it and live long enough to tell the tale to our great-great-great grandchildren.

Dov Michaeli MD, Ph.D is in the biotech industry

by Pat Salber

Today is the first ever UN-observed World Diabetes Day led by the International Diabetes Federation. It was established as a result of a resolution passed last December by the General Assembly of the UN. The idea behind the Day is to increase visibility of diabetes world-wide.  Hopefully this will lead to better funding, more research, public education, and other resources being applied to the condition.

The focus of this year’s World Diabetes Day campaign is diabetes in children and adolescents. Diabetes is one of the most common chronic disease of childhood. Children and teens can develop Type 1 diabetes – an autoimmune disorder in which the insulin producing cells in the pancreas are destroyed – or they can develop Type 2 diabetes – a condition caused by the development of resistance to the hormone, insulin.

Type 2 diabetes used to be rare in kids, but with the advent of the childhood obesity epidemic, Type 2 diabetes is now seen in even very young children. Both Type 1 and Type 2 diabetes are associated with serious complications, such as kidney, nerve and eye damage, as well as atherosclerotic vascular diseases, such as coronary artery disease.

Type 1 diabetes is rapidly fatal if not treated with insulin. Type 2 diabetes has a longer course, but if untreated or inadequately treated, lifespan is usually shortened significantly. In developing countries, access to early diagnosis and appropriate treatment of diabetes may be limited resulting in many children dying from a treatable disease. In countries with good access to health care, failure of family members, teachers, and others who care for children to recognize symptoms of diabetes can lead to delays in diagnosis that can occasionally be fatal.

The World Diabetes Day 2007 and 2008 campaigns are focused on changing the status quo with the stated goal that “no child should die of diabetes.”

Here are some statistics that highlight the magnitude of the problem:

• Type 1 diabetes is increasing by 3% per year in children and adolescents and by 5% in pre-school children - that translates into almost 200 children per day developing the disease.
• Of the approximately 440,000 cases of Type 1 diabetes in children worldwide, more than a quarter live in South East Asia and more than a fifth in Europe.
• Type 2 diabetes, previously rare in children, now constitutes between 8 to 45% of new childhood cases depending on geographic location.
• Over the past 20 years, type 2 diabetes has doubled in Japanese children. It is now more common than Type 1 diabetes.
• In native and aboriginal children in North America and Australia, type 2 diabetes range from 1.3% to 5.3%

Diabetes can be very difficult for adults to manage. It involves checking blood glucose levels, taking multiple medications, and in the case of Type 1 diabetes, multiple daily doses of insulin by injection. Imagine how hard it is for children who are also trying to do well at school, make and keep friends, and deal with the emotional issues related to growing up – particularly during adolescence. Families with diabetic children often find themselves overwhelmed by all there is to know and do. Add to that the socioeconomic challenges that people with limited resources face on a daily basis, for example, those living in poverty and the ability to manage diabetes must seem insurmountable. These families and other caregivers need help – to access needed health care and health education and support.

World Diabetes Day highlights these formidible challenges, but we must all respond by supporting this campaign with our time…and yes, with our money. To learn more, go to the World Diabetes Day website, http://www.worlddiabetesday.org.

By Dov Michaeli MD, Ph.D

Just returned from a dinner gala put on by the American Diabetes Association, to honor people and organizations who passionately work day in and day out in the cause of diabetes prevention and cure. I must say, this was truly an eye-opening experience.

But first, some statistics on the extent of the problem we are having, and the disastrous trajectory in which the disease is progressing:

• 21 million Americans have diabetes, and 54 million have pre-diabetes, or metabolic syndrome. Add the two figures, and we have 75 million Americans, or about 25% of the population suffering from the disease or its precursor.
• 1 in 3 children born this year will suffer from diabetes during their lifetime. Think of it, in a few short years one third of the population will have diabetes. I recall reading somewhere that physicians and advocates are overstating the problem; that  the appellation of “epidemic” is alarmist. I must say, to me a jump from a relativly minor disease about 30 years ago to 25% today, to 33% in a few short years meets all the criteria of an epidemic. And if you consider the spread of diabetes in Europe , China , India , and even Africa —this is a true pandemic.
• Diabetes is not an equal opportunity disease: 1 in 2 Latino, African American, and Asian American children will develop the disease.
• African Americans are 1.5 times more likely to develop diabetes than their Caucasian counterparts. Hispanic/Latino Americans have 1.8 times the risk. Asian Americans/Pacific Islanders have 2.0 times the risk. Native Americans have 2.2 times the risk. And these are the populations that suffer the most from our broken health care system.
• For the fiscally-inclined among us: the annual cost of diabetes in the U.S. is $132 billion. Consider that a proposed budget of $35 billion to cover all poor children (1 in 2 of them will develop diabetes), was just vetoed because it was “too expensive”. Were our ‘decider’ and his cohorts left behind when they taught arithmetic at school?
• 1 in 10 health care dollars spent in the U.S. are for diabetes and its complications.
• 1 in 6 Americans between the ages of 12-19 have pre-diabetes. So brace yourselves: a wave of young adults is threatening to “mature” into full fledged diabetics. If this is not an epidemic, I don’t know what is.

A ray of light

It was truly heartwarming to realize that there are heroes who are fighting the bleak reality. They don’t whine, complain or just disengage in disgust: they fight. They are there in the proverbial trenches, day in and day out, at great financial and personal sacrifice. Am I talking about doctors, or nurses? No, although I am sure there are plenty of them who deserve accolades. Believe it or not, I am talking about lawyers. Yes, lawyers! The ADA gala was to honor six lawyers of the Reed Smith law firm, who worked thousands of hours pro bono to mitigate the harsh reality our diabetics have to face.

 Here are but two examples of their work. They forced the city of Philadelphia to reverse their hiring ban on police officers with diabetes. Young children with diabetes in public schools in California had to call 911 if they needed insulin. Nobody was authorized to administer it to them. Can you imagine a 5 year old afraid that she might need insulin at school and would have to wait for an ambulance to come to her aid? And what if the ambulance arrives a few minutes late? The lawyers of Reed Smith, working on behalf of the ADA and parents of children with diabetes, won the arduous legal fight for the children; School personnel will be trained to administer insulin to the children if the school nurse is unavailable. To the Nurses Association’s shame, it is now suing the ADA to reverse the settlement. I used to believe their pious propaganda about their concerns for patients, first and foremost.

I never thought that I’d find myself praising lawyers when it comes to Medicine. But my hat is off to these lawyers—they are true heroes .

Dov Michaeli MD, Ph.D is in the biotech industry

By Dov Michaeli MD, Ph.D

Here are three headlines from today’s paper:

1. Front page: “GOP Losing Grip On Core Business Vote”. For obvious reasons.
2. Opinion page: “Immigration Losers” by Richard Nadler, President of Americas Majority Foundation, a Midwest public policy think tank (and I might add, a Republican organization in the mold of the Taft dynasty): “ …Republicans need to repudiate… the immoral, uneconomical goal of mass deportation”.
3. Opinion page: “The Future of Bioenergy”, by Juan Enriquez, managing director of Excel Medical Ventures, cofounder of Synthetic Genomics, and founding director of Harvard Business School Life science Project.

The first article Chronicles the takeover of the Republican party by the social conservatives, and the virtual disappearance of the fiscal conservatives/social moderates from the party. The second decries the xenophobic and punitive stance of the Republican party with regard to immigration issues. The last one calls for innovative approaches, using biology to solve the energy and global warming dilemmas we are confronted with.

Quiz: which newspaper was I reading?

1. The New York Times.
2. The Washington Post.
3. The Los Angeles Times.

Answer: none of the above. It was the Wall Street Journal, the bastion and mouthpiece of conservative (read: regressive) ideology, and a fierce opponent of anything liberal, such as fiscal responsibility and global warming. The editorial page had labeled the global warming issue as a liberal hoax, a figment of liberal scientists’ imagination, invented out of whole cloth and computer models.

But the purpose of this posting is not to harangue one particular political view. I want to highlight the salient points made in Enriquez’s article as to what Biology can bring to the table in solving our energy and climate problems. I had intended to write about this issue for a long time and this article was the catalyst.

A paradigm shift

One of the deepest thinkers of the history of science was Thomas Kuhn who, in 1962, published his seminal book “The Structure of Scientific Revolutions”. In it he argued that we all share a certain view of the world (paradigm) at a given time, on which the science of the time is based. But then and insight occurs, which shakes the foundation of our old world view and on which a new paradigm is founded. For example, until the 17^th century Anatomy and Medicine were based on the writings of Galen, a Greek physician from the 2^nd century. For 15 centuries scientists and physicians did not bother to dissect an animal in order to observe and verify the Galenic dogmas handed down to them since antiquity. But then William Harvey, a British physician, had an insight: why not observe how blood flows-- which led to the discovery of the circulation. But more happened: the demonstration that Galen’s writings about blood flow were wrong led other scientists to question his other assertions, test them through direct observations- which led to the modern sciences of Anatomy and Physiology. In fact, the revolution did not stop there; people learned to view with suspicion “received wisdom” handed down by higher authorities. These momentous changes in world view were a “paradigm shift”.

We are changing our world view,again

When our agricultural practices, inherited from the time we began to cultivate crop plants about 10,000 years ago, no longer sufficed to feed an exploding population we invented better ploughs, bigger machines, synthetic fertilizers, powerful insecticides. But this solution finally reached its inherent limitations. In the 20^th century the world could not feed the hungry multitudes of China, India and Africa. Malthus was triumphant. But then another revolution took place.

‘We began to apply more Gregor Mendel and less Henry Ford. Plant geneticists like Nobel Prize winner Norman Borlaug found that altering plants biologically was even more powerful and efficient than brute-force mechanical solutions. By altering seeds, harvest cycles and climate range, Mr. Borlaug and his colleagues launched the green revolution. Poor farmers in China and India, who could never afford a mechanical solution, became net exporters using a biological solution.’

The new world view is that the cleanest and most efficient solutions to our environmental and energy problems will be provided by Biology.

Consider coal, the most abundant and most polluting source of energy we have. Hydrocarbons are, in essence, sunlight concentrated in plant, animal or bacterial matter. Be it coal, gas or oil, what we are extracting and burning is bioenergy concentrated in carbon. Molecular Biology, the science that launched a thousand medical advances, is now enabling us to convert coal into ethanol in the ground; no more mining, no more environmental degradation, no more millions of tons of carbon emission, no more global warming.

And how is this miracle going to be accomplished? By genetically engineering bacteria that will break down the hydrocarbons of coal (or oil, for that matter) and convert it into ethanol. This is eminently doable, the technology is already here—all we need to do is change our thinking from big engineering solutions to clean and elegant biological ones.

You ain’t seen nothing yet

In the August 3 2007 issue of Science, an article titled “ Genome Transplantation in Bacteria: Changing One Species to Another” was published by scientists from the Craig Ventner Institute in Bethesda Maryland . (In its previous incarnation as the Celera Corporation, it was one of the two teams that deciphered the human genome). The article begins thus: “ As a step toward propagation of synthetic genomes, we completely replaced the genome of a bacterial cell with one from another species by transplanting a whole genome as naked DNA” (italics mine).

The significance of this simple statement is hard for the layman to fathom. In fact, it is almost impossible to grasp the enormity of the consequences of such a statement. What it means is that it will be possible in the not too distant future to synthesize new organisms. Not preexisting ones—completely synthetic new species! Now think of it:

· Synthetic bacteria whose whole mission in life is to convert coal and oil into ethanol at a rate faster than we could extract the hydrocarbons from the ground. And much cleaner and enormously cheaper, to boot.

· Synthetic bacteria that will consume any pollutant or toxic material we manage to create.

· Synthetic bacteria that will consume prodigious amount of carbon dioxide from the atmosphere, and convert it into ethanol—a two’fer.

· Synthetic bacteria that will course our blood vessels and convert LDL into HDL particles, and consume triglycerides while they are at it.

· Synthetic bacteria that will be able to sense glucose levels in the blood and release the appropriate amount of synthetic insulin in response.

Need I go on? The possibilities of this scientific revolution are mind boggling. Our world view will become totally biological. Sounds like science fiction or at least a distant dream: not at all. In an interview Craig Ventner stated that his team will have the first synthetic bacterial “species” in 5-10 years!

There is an ancient Chinese curse “may you live in interesting times”. Science will convert the curse into a blessing.

Dov Michaeli MD, Ph.D is in the Biotech industry.

By William H. Bestermann Jr. MD

Type 2 diabetes is a condition that costs Americans terribly in terms of death, disability, and health care expenditures. This chronic condition is a vicious cycle type of illness. Glucose control tends to deteriorate over time. Most of these patients also have problems with blood pressure and cholesterol. Only about a third of type 2 diabetics have their pressure, sugar, or cholesterol under control as individual risk factors. Only 7% have all three risk factors controlled simultaneously to conservative goals. This sad fact has dramatic consequences. The lifetime risk of a diabetic having a heart attack or a stroke is 80%. For each risk factor that is controlled to goal using the right medication, the risk is reduced by roughly half—so when we control pressure, sugar, and cholesterol the risk is reduced from 80% to 40% to 20% to 10%. Now maybe the risk is not really 10%, but it is very dramatically reduced and in 10 years of experience with 450 diabetics, I believe that I have seen a very important reduction in vascular events that has been achieved by aggressively controlling these risk factors..

Everything bad that happens to a diabetic is fundamentally arterial or vascular. Obviously the heart attacks, strokes and amputations are vascular, but even the kidney, nerve and eye damage relate to arterial damage as well. So the target here is not just the sugar or the cholesterol. The fundamental question is “how do we lower the sugar, cholesterol and pressure with the maximum benefit on the artery?” Furthermore, how do we accomplish this in such a way that the patient’s life is minimally altered and this is sustainable.

In this post, I will focus on sugar control. Everyone agrees that type 2 diabetes is at its core a life-style illness. As one of my colleagues in South Carolina said: “There is nothing that we can do for diabetes that you cannot outrun with a spoon.” In other words, if the patient does not make some effort with diet and exercise, it is difficult and perhaps impossible to get risk factors to goal. I have controlled the sugar in disabled patients, but it is more difficult. Type 2 diabetes is a disease of elevated blood sugar. It is self-evident that sugar consumption must be limited. Less widely appreciated is the impact of starch or carbohydrate consumption. Processed starch becomes sugar in 2 minutes once it is consumed. When a person eats 100 calories of white rice, in 2 minutes it is just as if he took a spoon and ate 100 calories of sugar out of the sugar bowl. The less processed a carbohydrate, the more slowly it is consumed.

Some understanding of nutrition is vital. Formal dietary instruction by a certified diabetic instructor is helpful but I see substantial variation in what patients are told. As a practical matter I have found the South Beach diet to be very useful and just bought the book for a friend at Walmart for $12.00. I have recommended that diet for patients and found it very effective with sustainable effects on weight and sugar control. Dr Agatson, the author, is a cardiologist famous for developing the cat scan calcium score we use to determine cardiac risk. He teaches two very important concepts. First, we have to learn to limit starch and to eat our starch in the form of whole foods. Second, we need to limit fats, especially animal fats and trans fat. This program is attractive because it is effective, widely available, and supported by recipe books and pre-packaged items.

Next we come to drug therapy. Doctors are trained in the treatment of diabetes with medication by learning about all of the medications that are available, and then they are left to decide which of these many medications they will use and in what order. There are several different classes of oral drugs with multiple drugs in each class. There are multiple types of insulin with differing durations of action. There is no real protocol that is universally agreed upon as best practice.

Type 2 diabetes is the later stage of the metabolic syndrome. Most type 2 diabetics have been metabolically abnormal for decades. They have been resistant to the effects of insulin for years and just before they become diabetic they have been maintaining their normal sugar by producing levels of insulin in the blood that are three times normal. As time goes on they are unable to sustain that level of insulin production and when insulin levels fall the sugar begins to rise. At the time of diagnosis, insulin production has fallen by 50% and the loss of the ability to produce insulin is aggravated by poor sugar control—a built-in vicious cycle. When it comes to diabetes, we just do too little too late.

In recognition of this fact, there was a recent consensus algorithm published in Diabetes Care. This is a joint statement from the American Diabetes Association and the European Association for the Study of Diabetes. They emphasized the importance of diet and exercise as first therapy. Most notably in my view the authors went on to say, “The authors recognize that for most individuals with type 2 diabetes, lifestyle interventions fail to achieve or maintain metabolic goals, either because of failure to lose weight, weight regain, progressive disease, or a combination of factors. Therefore, our consensus is that metformin therapy should be initiated concurrent with lifestyle intervention at diagnosis.” Most medications for diabetes cause weight gain. Metformin has modest effects in assisting with weight reduction and it is the only medical treatment for diabetes that is proven to lower the incidence of heart attack and stroke by 40%. That effect is on a par with the best cholesterol and pressure treatments.

If treatment with metformin fails, it is generally because insulin production is at least relatively inadequate. The most effective and rational next step is to instruct the patient in a self-adjusted insulin shot using Lantus or Levemir. In the protocol I use, the patient is able to rapidly bring the sugar safely down and most patients are at goal with this reasonably simple approach. It seems to me that the proven vascular benefits of metformin would be preserved in these patients since all we are doing is replacing insulin that they cannot make themselves. Most patients are really surprised at how easy this is to work with and how much better they feel when their sugar is controlled.

by Bill Besterman

The underpinning for much of the death and disability from arterial vascular disease in this country is the metabolic syndrome. One of the real authorities on the metabolic syndrome is a Dr. Ralph DeFronzo.  I particularly like his description of this collection of disorders as a “complex metabolic web.” 

The patients who have this diagnosis are burdened with multiple chronic conditions: hypertension, high LDL or bad cholesterol, high triglycerides, low HDL or good cholesterol, and high blood sugar ultimately resulting in type 2 diabetes. These patients routinely have vascular systems where the vessels are inflamed and the blood more likely to clot.

Early in the condition the arteries are thicker and less distensible than in people without the syndrome; progression of the arterial disease is the norm. Many of affected individuals also have gout. More recently, the metabolic syndrome has been called the cardiometabolic syndrome because this name underscores the impact of these conditions on the heart and the rest of the vascular system. Metabolic syndrome patients have an increased risk of coronary artery disease, cardiac enlargement and congestive heart failure.  Type 2 diabetes is the late stage of the syndrome

Dr. DeFronzo highlights a very important clinical reality in describing the cardiometabolic syndrome as a complex metabolic web. "Job one" of the clinicians who treat these patients is to unravel that complex web using every medical and lifestyle tool in the medical toolbox.

Only 7% of these patients have all of their risk factors (hypertension, blood sugar, and cholesterol) simultaneously controlled to the most conservative goals. For each risk factor that is controlled, using the proper interventions, the risk of all adverse outcomes is reduced by roughly 50%. So, the task of the clinician is not just to control hypertension or diabetes, but rather to control all risk factors to goal at the same time.

That is where the focus, skill and training of your provider come into play. The particular medical choices that are made are critical for success. For three decades now I have heard physicians blame patients for not being “compliant:”

 “Mrs. Brown is diabetic and she does not listen to a thing I tell her. She just stuffs herself with anything she wants and she continues to gain weight.”

Here is the reality. Every medication commonly used for the treatment of type 2 diabetes causes weight gain with the exception of metformin (Glucophage) and the Byetta-type medications. The new drug Januvia is weight neutral. Most patients do not have their sugar controlled to goal using a single medication. Most patients require multiple drugs and even then progressive loss of glucose control is the norm. Weight gain not only makes control of the sugar more difficult—the metabolic syndrome is itself worsened by increased abdominal weight—weight gain also makes controlling pressure, cholesterol, triglycerides and gout more difficult.

The patient that receives a prescription for two shots of NPH insulin a day will gain 10 pounds in a year. The patient that uses glyburide plus a single shot of NPH gains 9 pounds. The regimen combining  glyburide, metformin and a single shot of NPH, produces a similar weight gain. Metformin added to a single injection of NPH at bedtime produces no weight gain, the best control of the blood sugar and the least number of hypoglycemic attacks. The doctor with the prescription pad is producing this result—not the patient. These are impressive weight changes and they make a big difference over time. I have treated 450 type 2 diabetics for nearly 10 years with a regimen based on metformin and a long-acting insulin injection with durable control in most patients.

The treatment of high blood pressure hides the same kind of traps. Until very recently beta blockers like propranolol (Inderal), metoprolol (Toprol) and atenolol (Tenormin) were recommended as first line therapies for the treatment of hypertension.  Many patients continue to be on these medications for the one purpose of treating high blood pressure. These medications have important metabolic effects:

• Propranolol increases triglycerides by 25%, decreases HDL by 10%, increases total cholesterol by 9% and increases insulin resistance by 33%
• Metoprolol increases triglycerides by 30%, decreases HDL by 7%, decreases total cholesterol by 1%, and increases insulin resistance by 21%

Tricor (fenofibrate) is prescribed to treat the lipid or cholesterol abnormalities that go with the metabolic syndrome decreases triglycerides by 29%, increases HDL by 11%, and decreases total cholesterol by 18%.  When we prescribe propranolol and fenofibrate simultaneously, we have simply cancelled the lipid effect of two drugs.

The prescription of propranolol makes it 28% more likely that the patient will develop diabetes. Choosing an ACE inhibitor makes it 33% less likely that a patient will develop diabetes. These are critical metabolic issues. There is a newer beta blocker carvedilol, with dramatically improved metabolic effects relative to the older drugs.

The point of all this is that treatment of these patients is very complex if it is done properly. 95% of type 2 diabetes care is provided by primary care doctors who are under tremendous pressure to see patients at the rate of 5-6 per hour. They are required to be experts in the whole massive knowledge base of medical practice We need focused clinics of the type described by the Institute of Medicine to treat metabolic syndrome patients. The providers in these clinics will need to be very expert in the coordinated, integrated management of metabolic syndrome patients and the resulting complications. Until that happens, we will continue to produce the same poor levels of risk factor control and pay a terrible price in lives, disability and treasure.

I recently came across an article in the April 23 issue of the Archives of Internal Medicine (vol. 167, pp. 802-807; 2007) describing a newly-discovered connection between depression and diabetes type 2 in older adults. The study enrolled 4,681 non-diabetic men and women over age 65, and followed them for 10 years. The participants filled out every year a questionnaire to measure their depressive symptoms, and every 2-4 years had their blood pressure measured. After removing confounding factors that are well known to increase the incidence of diabetes, like increased body mass index, alcohol consumption, and smoking, they discovered that even a single report of high depressive symptoms is highly associated with increased risk of diabetes type 2. In fact, there was a 60% increased chance of developing diabetes after reporting one incidence of high depression; this is significant by any measure.

Is it a good study?

I think it is an excellent study. The study group was ‘clean’, namely all diabetics and pre-diabetics were excluded from participation in the study. It was longitudinal, following the 4,581 participants for 10 years. The numbers were large enough and the observation period long. Furthermore, the authors accounted for all the obvious confounding factors, like obesity, smoking status, alcohol consumption, and anti depressant use. What is most convincing is that there was a relationship between the score of depression and the likelihood of developing diabetes, what we call in experimental medicine a ‘dose/ response’ relationship. The highest score had the highest increase in risk (60%).

How could depression cause diabetes?

There could be several explanations for this observation, and the answer is not really known. But if we look at the hormonal changes that accompany depression, we may find a possible link to diabetes. Cortisol is a stress hormone that is elevated in depressive states. Cortisol also happens to inhibit the secretion of insulin from the beta cells in the pancreas. Lower blood insulin would in turn lead to higher blood sugar, a hallmark of diabetes.

Caveat emptor

As always, when I speculate I feel obliged to caution that what ‘makes sense’, in biology it ain’t necessarily so. Biology is so complex, and largely still unknown, that any attempt to ‘dry lab’ it is an exercise in futility. Still, using speculation to form a testable hypothesis is how science works. For instance, we could test the cortisol hypothesis by measuring its blood levels in patients reporting an episode of depression and see if there is a correlation between it and the onset of diabetes. Or an experiment could be devised in which any participant reporting a depressive episode would be immediately treated with anti depressive drugs. Would that reduce the risk of developing diabetes?

I am sure many of you have other suggestions to study the depression/diabetes relationship. Send in your suggestions; we promise to publish and critique them.

Dov Michaeli, MD, Ph.D.

Good news!  The SF Chronicle reports that charges against Mr. Universe related to a hypoglycemic episode have been dropped.

According to the story, "prosecutors initially insisted Burns needed to provide more medical evidence that he was a Type I diabetic suffering from insulin shock at the time. "  Come on!  A history of Type 1 diabetes, taking insulin, and ER documentation of a glucose of 29...I'd say that pretty much cinches the diagnosis. 

I hope the end result of this fiasco is that the San Mateo police get  a lesson from the local American Diabetes Association Leadership Council on manifestations of low blood sugar.  How about it guys?

Pat Salber, MD

Mr. Universe, Doug Burns got arrested and has to go to trial. Why? Because he was acting drunk and, supposedly, resisted arrest. Why? Because his blood sugar was 29! Why? Because he is a Type 1 diabetic and he was experiencing a “low” related to a mismatch between his insulin dose and his insulin need.  This happens sometimes.

Low blood sugar can have many different manifestations. Sometimes people pass out. Some people just get jittery and nervous. And, it is not uncommon for people to become confused and seem like they are drunk when their blood sugar gets too low. That is what happened to Doug. Unfortunately, Doug’s low occurred in a public place – a movie house – and police thought they had a public drunk on their hands. They arrested him and placed him in handcuffs despite the fact that a bystander suggested it could be low blood sugar that was causing the problem.

Despite having his low blood sugar confirmed in the emergency room and having had numerous physicians and other diabetes experts provide testimonials, the Redwood City District Attorney has insisted on taking this case to trial. That’s right. He is trying to criminalize low-blood sugar-related confusion. They are calling it “criminal assault and resisting arrest” even though only Doug initially reported any injury during the scuffle. (According to journalist Amy Tenderich, a week and a half later, a policeman involved in the episode reported a “strained arm and shoulders.”

Come on, guys. Is this a case of “I have my story and I am sticking to it – reason (and science) be damned?

Doug’s pre-trial conference is today. I suggest we follow Amy’s advice (from an email sent by Amy Tenderich 5/29/07:

“For all of you who are as incensed as I am over the Mr. Universe Going to Trial issue, I now have the information* on how you can speak up today:

Please place phone calls with your objections/support to

- Chief Deputy District Attorney Steve Wagstaffe
(650) 363-4752

and

- Assistant District Attorney Morley Pitt
(650) 363-4785

Please leave angry messages! The idea is to rattle their chain here, and put some pressure on the DA's office to drop the charges, as well they should.

*These contacts come directly from Doug Burns' lawyer, Micah Jacobs, of Jacobs & Ferraro, LLP, in San Francisco, which has donated its services free-of-charge to show its support for the diabetes community.

Mr. Jacobs filled me in on a few other key details you might like to know:

- The police report documents Doug's blood sugar at 26, at the time it was checked in ER following the incident.

- The initial police report also makes no mention of any violence -- solid evidence that Doug did not fight with the officers or attack them in any way.

- The theater security guard apparently escorted Doug outside the theater, and then called the cops when he stood there looking dazed, rather than leaving.

"It's one thing if he would have harmed someone, and could later prove that it was a medical issue," Jacobs says. "But nothing even happened, AND he can prove it was a medical issue. It's absurd to press ahead with these charges. Their personnel need to be better trained to distinguish a medical emergency from a real threat of harm."

Amen, Mr. Attorney, Sir. Now let's go make some noise about this!!”

- Amy Tenderich
Diabetes Mine blog www.diabetesmine.com
Know Your Numbers, Outlive Your Diabetes book http://amytenderich.vox.com/

2006 Winner, LillyforLife Achievement Award for Diabetes Journalism

We have known for a long time that the distribution of fat in the body is important in determining important health risks, such as type 2 diabetes and cardiovascular disease. “Apples” (or the abdominally obese) are at much greater risk than pear-shaped people who tend to deposit their fat in the hips, thighs and butts.

More recently, researchers have determined that one type of belly fat, called visceral fat, is worse than belly fat just below skin.  Visceral fat is deposited the omentum, the tissue that drapes around the intestines and other abdominal cavity organs (or viscera). You don’t have to be obese to have visceral fat. One the other hand, not all people who are obese develop significant amounts of this “bad fat.”

An article in the San Francisco Chronicle reports that recent research suggests that abdominal fat is related to the release of the stress hormone, cortisol. According to UCSF’s assistant professor of psychiatry, Elissa Epel, an expert on the physiological effects of stress, cortisol which is released when people are under stress, seems to interact with the pancreatic hormone, insulin, to create visceral fat. At the same time, cortisol stimulates a craving for “comfort foods” – the sweet stuff and the stuff high in fat. This is a double whammy – you desire and, as a result, often consume high calorie foods and you deposit those excess calories as bad fat in your belly.

To test the hypothesis that stress is related the deposition of visceral fat, researchers at the University of California San Francisco are recruiting 50 overweight women to participate in a study on the impact of stress relief techniques on body fat, particularly visceral fat. The study is not designed to help the participants lose weight per se, rather it is designed to reduce stress and stress-related eating.

The 50 women will be divided into two groups. One group will start stress reduction classes right away, the other won’t start these classes until after 6 months have passed. The classes will teach women stress reduction techniques and will also teach them how to recognize triggers that prompt stress-related eating. They will also be taught “mindful eating.”

I described mindful eating in my recent post “Getting in touch with your feelings…about raisins.” In that post, I describe a “raisin exercise” developed by the author of Soul-Full Eating, Maureen Whitehouse. This approach to eating involves really engaging with the foods you eat. As opposed to gulping them down as many of us do in the course of our hectic lives, you are taught to visually examine the food and then explore it with your fingers and hands. When you put it in your mouth, you explore it with your tongue and chew it, ever so slowly, letting the flavors linger in your mouth and in your mind.

According to a co-researcher on the UCSF study, Jennifer Daubenmier, a postdoctoral fellow with the UCSF Center for Obesity Assesment, Study and Treatment, mindful eating helps participants to think about how and why they eat. The goal of the UCSF program is to ultimately help the participants make better, smarter food choices. Although weight loss is not the goal, it is hoped that the program will result in a reduction of bad belly fat.

To qualify for the study, women must weigh less than 300 pounds and have apple-shaped figures. They must be between 21 and 50 years old. They must not be recently pregnant, diabetic or have heart disease. If you fit these criteria and are interesting in participating in the study, send an email to ucsfcalmmstudy@yahoo.com. If you want to learn more about what it means to participate in a clinical trial, click here.

In the old days….

When I trained in endocrinology many moons ago, we used to categorize diabetes as either “juvenile-onset” or “adult-onset.” We knew it wasn’t a perfect classification scheme  since a small number of older individuals contracted juvenile diabetes  -- a disorder characterized by immune destruction of the pancreatic islet cells (in particular, the Beta cells that produce insulin). People with this type of diabetes cannot make insulin and, therefore, require exogenous insulin, such as insulin injections, for long term survival.

Then, we really didn’t think the adult-type diabetes occurred in kids…but now it is found in children of all ages, even toddlers. What we called adult-onset diabetes, at that time, is actually a form of diabetes commonly found in overweight or obese individuals. At least initially, people with this type of diabetes have higher than normal levels of insulin.  It just doesn't work as well because these individuals are insulin resistant.

Insulin dependent vs insulin taking

Because individuals with the juvenile form of diabetes can’t make insulin, and therefore have to take insulin shots to survive, we started calling this form “insulin-dependent diabetes mellitus” or IDDM. Since people with the adult form of diabetes did not die quickly without administered insulin, we started calling it “non-insulin dependent diabetes mellitus” or NIDDM. (The mellitus part of the name refers to the fact that both forms of diabetes are characterized by having glucose in the urine….mellitus means honey.)

We changed the names of these conditions again because many people with NIDDM were found to eventually require insulin for good glucose control. Some people got confused by this and incorrectly labeled insulin-taking NIDDM patients as insulin-dependent. Are you following all of this?

Changing names again: Type 1 and Type 2

As a result of the confusion about dependence vs. use, it was decided to change the names again. IDDM became Type 1 diabetes. And NIDDM became Type 2 diabetes.

The problem is, however, that some individuals whom appear clinically to have Type 1 diabetes, do not have the immune markers associated with pancreatic islet cell destruction – a feature that is considered characteristic of that disorder. The American Diabetes Association has proposed calling this type of diabetes, Type 1b with “true” autoimmune diabetes mellitus being called Type 1a.  

In addition, some people who initially look like Type 1 diabetics – because they have diabetic ketoacidosis (DKA) [*]  and serologic markers of islet cell autoimmunity at the time they are initially diagnosed -- eventually go on to resolve their insulin deficiency.  Unlike "true Type 1 diabetes, the insulin insufficiency in these individuals appears to be reversible.

Yet another classification:  The AB classification of ketosis-prone diabetics

Now, it is proposed that we adopt yet another classification scheme. And this one makes a lot of sense on  paper. In the December 2006 issue of Diabetes Care, Ashok Balasubramanyam, MD and colleagues make the case for placing certain types of diabetics -- those who have ketosis at the time of their initial diagnosis -- in new categories depending on their immunologic status and beta cell function.

They propose an “AB” classification scheme comprised of four categories. The categories are based on whether or not the individual has immune markers related to destruction of their beta cells (that's the “A” component”) and whether or not their beta cells are able to produce the hormone insulin (that's the “B” component).

Here are the categories:

KPD type 1A (for ketosis-prone diabetes). These individuals would be labeled A+B-. The A+ means they have immune markers, evidence of immunity to their own pancreatic islet cells (aka, “autoimmunity”). The B- means they have complete and permanent loss of beta cell function. KPD type 1A diabetics must take insulin treatments for life.

KPD type 1B individuals are A-B-. Like people with type 1A, these folks cannot make, and therefore must take, insulin for life. Unlike 1As, they do not have serologic evidence of autoimmunity to their islet cells.

KPD type 2A individuals are A+B+. They have preserved beta cell function at the time of diagnosis, but they also have evidence of autoimmunity. Their prognosis varies. Some appear to have a reversible form of beta cell dysfunction and are able to eventually discontinue insulin shots. Others progress to full beta cell failure, and like Type 1 individuals will then require insulin treatments for the rest of their life.

KPD type 2Bs are A-B+ patients. They have preserved beta cell function and also lack any markers of islet cell autoimmunity. Although they initially had ketosis when diagnosed, they ultimately do not behave like people with true Type 1 diabetes. Most will be able to discontinue exogenous insulin therapy. In this respect, they are similar to “pure” Type 2 diabetics who do not require insulin for long-term survival.

Although this new classification system is not perfect, at first glance it seems better than the current Type 1, Type 2 dichotomy even with the addition of the catch-all, Type 1B:

• It is easy to understand.
• It provides information related to prognosis (although you have to wait a while to confirm exactly which category someone finally falls into).

But is it practical?

An editorial accompanying the article, written by Guillermo Umpierrez, MD, points out that this new classification scheme may be hard to operationalize in clinical practice. It is not easy to measure insulin secretion outside of research settings and it can be costly. Dr. Umpierrez points out that more than half of blacks and Hispanics with Type 2 diabetes present with ketosis. He suggests instead of the AB classification, simply modifying the current ADA classification so that Type 1b patients are called “ketosis-prone Type 2 diabetes.”   Perhaps, he should also suggest that they be called Type 2 b instead?

Regardless of what the final outcome of this debate is, the paper by Balasubramanyam and the accompanying editorial helps to remind us that the clinical condition we call diabetes mellitus, in fact is much more complicated that it seemed 30 years ago.

[*] (DKA is a life-threatening condition characterized by having a build-up of “ketone bodies” in the blood stream. It occurs when there is not enough insulin to process glucose normally. The body begins to use fatty acids (FA) as an energy source instead. When FAs are metabolized, the end result is the production of ketone bodies. Thus, the term ketosis.)