In my last post I discussed the anatomy of the eye. Keep this in mind as we begin to consider what diabetes does to this anatomy. Remember that the most important aspect of diabetes is high blood sugar. This is the source of all complications that will make life so miserable down the line. The two major issues with glucose, as I have written before, are that it is reactive outside the cell and that it can get converted to sorbitol inside the cell.

The tissue at risk here are the capillaries and other small blood vessels in the choroid. These are the sources of nutrients for the retina which is the most metabolically active tissue in the body. We have a great deal of information about how diabetes changes these vessels at very early times in the disease. The early heroes who made this possible are the people who have specified that their bodies can be used for research after they die. Sadly, there are too many of them. Car accidents probably account for the vast majority along with heart attacks and cancer. People studying diabetic retinopathy put together a proposal to obtain eyes from these people after they die. Once the proposal is reviewed and accepted, specific hospitals would be set up as sources for the material and everything would be scrutinized carefully by ethics committees before the work began. Once the eyes were in hand, these researchers carefully examined the vascular structure of the choroid and compare it to the status of diabetes in the person before they died. In the present day, we have very powerful imaging tools that can examine many aspects of the retinal vasculature in the living patient – more on this later.

Those first researchers found interesting abnormalities in the vascular structure that supplies the retina and have associated this with very early times during the development of diabetes. First of all, they found that the walls of certain capillaries thicken. What do I mean by walls? Capillaries are, of course, made up of cells that create these tiny tubes through which the blood flows. However, what I am talking about is the stuff that is secreted just outside of these cells. We call this stuff “basement membrane”. Think of basement membrane kind of like a lattice of fibers. It is made up of collagen – you know…that stuff that some people inject to make their lips look fuller. Its real function is to create these lattice structures that surround tissues. All of the tissues of our body have basement membrane surrounding it. The lattice contains many important molecules that help information pass from tissue to tissue. This lattice is what gets thickened in places as diabetes progresses. Since nutrients need to pass from the capillaries to the RPE layer (see the previous post for the definition) to get to the photoreceptors it is probably no surprise that a thickening of the basement membrane will decrease the flow rate for these nutrients. This sets up a problem. Nutrients are no longer getting to the photoreceptors in that area fast enough. What happens is that the tissue begins to build up an oxygen debt – a state called ischemia. Let’s hold onto that thought for a while since we have to talk about some other changes to the vasculature.

In other capillaries researchers have found tiny ruptures (called microaneurysms). The presence of microaneurysms is considered the first sign of diabetic retinopathy in medical textbooks. We do not really know how this fits in with the pathology. Imaging can detect these microaneurysms so we can now see them in live patients and try to correlate them with the onset of diabetes and with diabetic retinopathy. The problem is that they don’t seem to correlate with any of the standard pathologies apart from the fact that we see them at the beginning of the disease.

In yet other capillaries we see something called pericyte ghosts. Pericytes are going to end up playing a big role in diabetic retinopathy so let’s spend a minute on them. Blood vessels tighten and relax. This is how blood pressure is regulated. It can let one organ get lots of blood while decreasing blood flow to another organ. In order for a blood vessel to tighten it needs a band of muscle to surround the vessel. This vascular smooth muscle is what does the job of squeezing and releasing. Really small blood vessels like arterioles, veinules, and the capillaries in between are too small. Instead they use pericytes. The pericyte surrounds the tiny tube at strategic spots and squeezes to create pressure. When they are missing we can tell. We see an outline of where they were positioned and we call this a pericyte ghost.

In still other capillaries we see a different kind of ghost. In imaging studies of patients it is possible to actually see blood flow through the capillaries. Actually, in pictures what we really see are the red blood cells in a line (the capillary is so small that red blood cells go through one at a time). In patients who are developing diabetic retinopathy we see whole capillary branches that appear empty.

So to sum up, we see lots of changes in the vascular bed of the retina long before the patient has any kind of problem with their vision. These changes are visible with current imaging techniques and unequivocally herald the onset of diabetic retinopathy. How long it takes to develop depends on how well the patient controls their glucose. Good glucose control can keep things under control for many years.

Note to self: when someone asks you to write a book chapter…run. I do not think I have absorbed so much new information in such a short time since my neurophysiology class back in grad school (or pulled so many late night writing sessions).

The chapter has the tremendously exciting title: “Druggable Targets and Therapeutics for Diseases of the Back of the Eye”. I do not think it will hit the NYT best seller list but it will be of use to clinicians interested in the latest therapeutics and current clinical trials for the next generation therapeutics. It is now in the hands of the editor and so I am free Free FREE. Sorry.

At any rate, one of the sections in my chapter concerns the varied forms of diabetic retinopathy so I thought I would share a bit of it here (rewritten for the non-clinician).

Diabetes is one of the major causes of blindness in the industrialized world. We call the condition “retinopathy” because it is the retina that is affected. Vision loss is linked to glucose control. Keep your A1C levels below 6.5 and you are not at risk. This, of course, is pretty hard to do unless you are a very disciplined individual who exercises relentlessly. Generally, what clinicians see is that the average patient with type 2 diabetes has some degree of retinopathy upon diagnosis. It is subclinical at that point and will remain subclinical for quite a few years. Vision loss is gradual. Early stages are reversible but late stages are irreversible.

In order to understand what is going on during diabetes we need to understand how the eye is structured. The eye is unique in a number of ways. It is one of the most metabolically active tissues in the body. While most of our body is shielded from solar radiation, the eye focuses it and must constantly replace the damaged bits. The visible wave lengths of this radiation are, of course, the signal that the eye was designed to “see”. Given this one would expect that the detectors (rods and cones) would be placed right at the focal point where the light is concentrated – sort of like how your satellite TV dish is set up. Instead, things are quite a bit more complicated. The problem that causes this complexity is all of that metabolic activity. Photoreceptors do a LOT of work to process those photons and need access to glucose. In fact our photoreceptors have so much to do that they need assistants. Those assistants are called Retinal Pigment Epithelial cells and we will abbreviate this tissue RPE. One of the things that the RPE does is to recycle the compounds that are used up during the process of detecting photons. Photoreceptors are constantly shedding their detectors and growing new ones (remember, solar radiation causes damage and they need to constantly renew the damaged bits) and the RPE gobble up these shed pieces and reprocess them as well. Now the blood supply is at the very back of the eye. We call this tissue that contains the blood vessels the Choroid. The RPE sit right next to the Choroid and take up all the nutrients. They pass these nutrients on to the photoreceptors. This arrangement makes the most sense since if the blood vessels and the RPE were in front of the photoreceptors they would really screw up the light path. Unfortunately, we still have a ton of neural circuitry that needs to get placed somewhere. It sits in front of the photoreceptors (there is no more room behind). Apparently, during evolution, creatures that processed the visual signal immediately (before it was transported back to the brain) had a survival advantage since they could avoid predators and strike prey more quickly. Presumably it is for this reason that we have several layers of neurons between the photoreceptors and the light.

It always seemed to me to be a weird arrangement but during the process of writing this book chapter I came across and interesting find.  The retina is really part of the brain and just like the brain there are support cells called glia nestled in between the neurons. What I found out was that people had examined the optical properties of these glial cells (called Muller cells). The Muller cells stretch all the way from the outer part of the retina where the light hits it down to the photoreceptors. Amazingly, despite all of the stuff that needs to be present in the cell for that cell to live and function, these Muller cells are optically clear. In essence they function like optical cables sending the light safely down past all of those irregularly shaped cell bodies that would bounce the light in crazy ways from the surface of the retina to the photoreceptors such that each photon retains its relationship to the photon next to it.

To recap, the most important point to remember is that the photoreceptors are at the very back of the eye and that they are VERY hungry all the time. The RPE sits between the photoreceptors and their food source – the blood vessels. In my next post (which I promise will be this week) I will describe how diabetes screws this up.

Despite the popularity of “how to” books on transforming our lives we Americans really do not like life-style change. This is one reason there has been such hesitancy in setting up to screen large numbers of people for insulin resistance – the first sign of insipient type 2 diabetes. Previous trials in which pre-diabetic people have been identified have failed to stop their march into that state of full blown diabetes – underscoring the incredible difficulty in real life style change.

We do like to take pills, however. This may explain the success of the most recent clinical trial in which 207 pre-diabetic patients were given either placebo or else a low-dose combination of rosiglitazone and metformin. The double blind trial was funded by GlaxoSmithKline and just reported today in the Lancet by Dr. Bernard Zinman and colleagues. The patients were followed for almost 4 years. Forty one patients (39.4%) in the placebo group developed diabetes. Fourteen patients (13.6%) in the treatment group developed diabetes. A great many metabolic variables were examined and nothing really changed (at least that I picked up on). Weight was unchanged as well. No serious side effects were reported.

So it looks like we have a winner. My only question is how they got the acronym “CANOE” from rosiglitazone, metformin, and prediabetes. Perhaps some things should remain a mystery.

Insulin, like all other proteins, must undergo a bit of shaping before it is ready for business. Proteins are really just chains of amino acids (sometimes called polypeptide chains) that are arranged like beads on a string. Incredibly, these polypeptide chains simply fold in upon themselves to form the complex molecular machines that make everything happen within us. The biophysics of this process is under intense study. Sometimes that folding process is enough but sometimes it needs to be helped along with a bit of snipping. Insulin is one of those proteins that need some snipping. This snipping is performed by yet another string of amino acid beads that have folded in upon themselves to form an enzyme called a protease. The polypeptide chain gets cut in two very specific places to make three approximately equal pieces. The front and back piece get put together with some special chemical bonds (disulphide bonds) to help keep things folded properly while the middle piece gets tossed. We call the two pieces that get put together to make insulin the A chain and the B chain. The middle piece that gets tossed is called the C peptide. For years we considered the C peptide to be of no physiological use however that song is now changing its tune.

I was alerted to this by Bob Fenton, another diabetes blogger (http://bobsdiabetes. blogspot.com/). He sent me a piece from the Telegraph, a newspaper published in Briton which described the work of Dr. Karen Porter. I pulled up the research paper and found it to be quite interesting. Dr. Porter is looking at why patients with diabetes fare so poorly with heart disease. Not only do they need more procedures such as bypass surgery but the outcomes of these surgeries are often quite poor. For example, the saphenous vein (a big vein found in the thigh) is often used for coronary artery bypass grafts. The graft gets plugged surprisingly quickly when the patient has diabetes and is taking insulin; a process that gets the fancy name “intimal hyperplasia”. The plugging of the graft is not due to atherosclerotic plaque but rather due to the proliferation of the cells of the graft itself (hence the word, hyperplasia). The new cells can only grow inward and so the hole gets plugged and heart disease returns.

It is possible to examine theses cells in a tissue culture dish and this is what the research team did. They obtained bits of saphenous vein from non diabetic patients who had heart disease and were getting a coronary bypass graft (and volunteered for the study). These bits of tissue were placed into tissue culture dishes containing a liquid maintenance medium in the presence of either insulin or C-peptide or neither or both. Now it has been known for some time that insulin can act as a growth factor for some cells and others had demonstrated that insulin will promote the growth of the cells of the saphenous vein. What this group found was that C-peptide reversed the effect.

Insulin is cleaved within the secretory granule from which it will be released. Thus upon release, not only is insulin entering the blood stream but also an equal amount of C-peptide. Diabetes patients who do not make their own insulin do not get any C-peptide since it is not included in synthetic human insulin preparations. This leads to a lot of interesting and important questions. Would heart disease decrease for diabetes patients taking insulin if C-peptide was present? The present work suggests that after a saphenous vein graft cardiac bypass graft, C peptide might have a positive effect but we do not know how it will work for a patient whose heart is still healthy. As a pharmacologist, I would like to know how C-peptide works. Is there a separate receptor for C-peptide? Does C-peptide bind to some part of the insulin receptor and modify its function? Would the addition of C-peptide improve other diabetes complications?

At least some of these questions have been answered. A company called “Creative Peptides” is promoting the use of C-peptide in diabetes and has funded a clinical trial. The results were published in 2007 by Drs Karin Ekberg and colleagues from the Karolinska Institute in Stockholm. They found that a replacement dose of C-peptide resulted in an improvement in diabetic neuropathy. Others have shown that C-peptide can bind to membranes from endothelial cells, kidney cells, and nerve cells, indicating that a receptor for C-peptide exists and is probably different from the insulin receptor (which is found on many if not all cells). While the receptor has not yet been identified researchers have identified several signaling pathways that are altered when C-peptide is present. These result in the production of a chemical called nitric oxide (NO) which helps with blood flow as well as an increase in the activity of the pump that keeps the electrical gradient that powers neurons. C-peptide has also been shown to increase the secretion of neurotrophic factors which function to protect neurons. Within the symphony of the body, this is not a trivial part.

Can we expect to see C-peptide on the market any time soon? After mucking around on the web I found the beginnings of an answer in good old Wikipedia. A US company called Cebix has secured patents for the manufacture of C-peptide. According to the Cebix website they will be performing another phase II clinical trial which will start in 2011. Should you be interested in seeing if you qualify for this trial, keep an eye on the clinical trial web site www.clinicaltrials.gov. If indeed, insulin alone promotes a degree of discord, it is satisfying to know that harmony will be restored.

My first impression of the ARVO meeting: hot, humid, exciting. Approximately 12,000 vision researchers, ophthalmologists, and industry representatives descended on the Fort Lauderdale convention center for a week of information exchange. The meeting had everything from studies of the embryonic eye to studies of vision in the elderly.

Perhaps the most satisfying therapeutic story for diabetes involved the inhibition of the growth of new blood vessels – a process called angiogenesis. As I mentioned in my last post, high glucose causes a number of problems leading to thickening of the capillary membrane around the retina. This forms the basis for Diabetic Retinopathy (DR), one of the greatest causes of blindness in the developed world. It is assumed that thickening of the capillary membrane decreases oxygen permeability and leads to a state of tissue hypoxia. The tissue responds by calling out for new blood vessels. These new blood vessels push aside photoreceptors and leak fluid all over the retinal space. Blocking the growth of these vessels has been a goal of researchers for some time.

The search for drugs which block new vessel growth has been a “holy grail” of sorts for cancer researchers since the 1980s. This is because tumors release signals that attract growing blood vessels to supply additional nutrients to assist in tumor growth. It has taken quite some time (due to differences between the mouse model and human biology) but now we have arrived. It is clear that the major angiogenic signal is produced by a hormone called vascular endothelial growth factor (VEGF). The vascular endothelial cells create the tube that is the blood vessel. When VEGF binds to receptors found on the surface of a localized group of these cells they begin to break up and leave the tube. At first there is a short competition to see who will be the lead cell and who will follow. Then the lead cell (called the tip cell) begins to migrate towards the angiogenic signal with the following cells dividing to begin to create a new blood vessel. VEGF regulates most aspects of this complicated process, suggesting that this would be a good therapeutic target.

It was not until 2004 that the first VEGF inhibitor hit the market. Today the most popular forms of this therapy include Leucentis and Avastin. A host of newer molecules are making their way through clinical trials. All of them work by binding to VEGF molecules and keeping them from binding to VEGF receptors. They were originally approved for Age-related Macular Degeneration (AMD) and only fairly recently have been applied to DR. The results have been quite promising.

Here are the results from one study: the DA VINCI trial – chosen for the simple reason that they had nice handouts with all of the information so that I could write this at my leisure. All of the DR clinical trial data that I saw was comparable.

The study I am going to describe involves a synthetic protein that sort of looks like an antibody. Think of an antibody like the letter “Y”. The two top ends of the Y bind to a specific target while the base of the Y holds everything together. The linkage of two binding sites gives the molecule a lot of flexibility and increases its ability to bind to things. Researchers at Bayer Pharmaceuticals made use of this flexible structure; substituting binding regions of the VEGF receptor for the top parts of the Y while leaving the base of the Y intact. We have a name for this sort of construct. We call it an Fc fusion protein. At any rate, they called this new molecule VEGF Trap-Eye or VTE (not my favorite name).

This was a phase II clinical trial which means that the drug had already passed human safety tests and was now being evaluated in a small population for efficacy. Two hundred and twenty one patients were randomized to receive either laser photocoagulation or one of 4 doses of VTE. I should mention that laser photocoagulation is a rather clumsy method in which leaky blood vessels are closed by burning them shut. That was the state of the art treatment for many years. All patients had macular edema (water around the most critical visual region of the eye – the macula). The average age of the patients ranged from 60 to 64 with a slight preponderance of males (55 – 65%). The average HbA1c for each patient group ranged from 7.8 to 8.1. Several had earlier injections of either a different VEGF inhibitor or a steroid some time in the past however these were pretty much distributed equally among the groups. VTE was administered by intravitreous injection. This is fairly yucky – I saw several movies of surgeries and the needle is just poked right into the eye. Presumably patients are anesthetized. Patients were evaluated monthly and the report ended at the 6 month time point.

Improvements in visual acuity are sometimes reported in numbers of letters gained using the EDTRS system. This is the standard eye chart you see when you go to get your eyes checked. Each line has 5 letters and each subsequent line of letters gets smaller and smaller. The laser photocoagulation group gained an average of 2.5 letters. The various VTE dosing groups gained averages ranging from 8.5 – 11.4 letters. This is about two extra lines smaller and amounts to a pretty significant improvement in visual acuity.

Adverse events were present and need to be mentioned. These include conjunctival hemorrhage (excessive bleeding), increased intraocular pressure (think glaucoma), eye pain (that one is pretty obvious), ocular hypertension (increased blood pressure but specifically in the eye), and vitreous floaters (visible shapes that occlude your vision floating in the body of the eye). These were about the same for all groups including the laser coagulation group. There was a small increase in the number of people who developed increased intraocular pressure in all VTE groups suggesting to me that this one might be different from the laser treatment but then the laser group had more serious problems than the VTE groups.

All in all, this looks very promising. It is not a cure but it may give some folks enough vision to read – maybe even to drive. Sweet.

Of all the diabetic complications to fear – blindness may be the most scary and is certainly devastating when it occurs. Diabetic retinopathy causes from 12,000 to 24,000 cases of blindness each year according to the National Institutes of Diabetes and Digestive and Kidney Disease (NIDDK); one of the National Institutes of Health that funds much of diabetes research in the US. Perhaps 50% of newly diagnosed diabetes patients (we are talking type II here) have some degree of retinal damage. In part this is due to the very long time between onset of hyperglycemia associated with pre-diabetes and the actual diagnosis of the condition.

I bring up this topic now because next week is the national meeting of the Association for Research in Vision and Ophthalmology (ARVO) where some of the new information about diabetic retinopathy research and treatment will be presented. (A lot also gets presented at the American Diabetes Association annual meeting as well.) I will be attending and, time willing, I will try to file some reports on what I see and hear over the next week.

In preparation, let’s talk about the eye and about retinopathies. The eye is an outpouching of the brain. It is an incredible sensory organ that can detect just a few photons. We can divide the eye into the part that focuses light: the lens and the part that detects light: the retina. Each photoreceptor cell within the retina is sort of like a little electric circuit. It sends electrically charged small molecules called ions through tiny holes called ion channels. It is the movement of these ions that creates the electric circuit. Photons which pass through the photoreceptors are absorbed by a protein called rhodopsin and thus detected. When the photon hits rhodopsin the protein changes shape subtly and this initiates a signaling pathway in the photoreceptor cell that leads to the closing of those ion channels. This changes the electric current and voila – you see something. Vision, of course, requires a lot more information processing. That blip of electric current gets passed to a layer of intermediate nerve cells in the eye (amacrine and bipolar cells) where the signal from that piece of the visual field is compared to other bits of information coming in from neighboring regions and the information begins to be put together into larger pieces. These get passed to another neuron called the ganglion cell which sends the information back to the visual centers of the brain through the optic nerve.

Surprisingly, the retina appears to be constructed backwards. You would think that the photoreceptor cells would be facing outward towards the light and that the nerve cells that process the information would sit behind the photoreceptors. This is reversed. The photoreceptors are in the back of the eye and the light must pass through the ganglion cells and other nerve cells to get to the photoreceptors. Weird.

One reason that things may be set up this way is that photoreceptors need constant maintenance. I think that the electric current I described above takes a lot out of the photoreceptor. Indeed the retina is the most metabolically active tissue in the body. Rhodopsin sits within discs which are stacked like rings in a large cylinder. The tips of the photoreceptor cells are in close contact with another tissue at the very back of the eye called the retinal pigment epithelium (RPE). As the photoreceptors cells toss out their trash the RPE must gobble it up, keeping the environment clean. The RPE also reprocess several chemicals that the photoreceptors need to function. Thus the RPE are working as hard as the photoreceptors. Behind the RPE lie the blood vessels that supply all of those wonderful nutrients that keep the show running. This point ends up being very important for our understanding of how things go wrong for people with diabetes.

Remember that sugar is reactive. I’ve talked about this before. This is one reason why diabetes is so deadly. In the eye, a strange thing happens. Glucose as well as its derivative, sorbitol, causes the blood vessels behind the retina begin to thicken in spots. The thickening has an evil consequence. Since the photoreceptors are so metabolically active they cannot handle even a little loss in blood flow. Like us, when expenses get a bit too heavy, they begin to run up a debt. In this case the debt is in oxygen. Interestingly, when the tissues of the retina notice that they are running up an oxygen debt they activate special genes that are designed to initiate the growth of new blood vessels. One such gene encodes the growth factor VEGF (vascular endothelial growth factor). VEGF binds to receptors on the cells of these blood vessels and they respond by sprouting new branches. This, by itself would not be so bad, except the process does not stop. The blood vessels grow into the retina and disrupt the highly organized structure of the photoreceptors. Furthermore, the new blood vessels are quite leaky and fluid gets into the retina blocking photoreceptor access to light. The result, as you might imagine, is not good.

There is little in the way of treatments. Within the past few years drugs that block VEGF have hit the market and have helped. These include Avastin and Leucentis. Still, we have a long way to go.

At any rate, if I see something interesting and worth reporting during ARVO, you will ready about it here.

This is the 50^th anniversary of the birth control pill; a tiny thing that has revolutionized society. Taking the pill does tend to increase blood glucose levels so it might be useful to consider the ramifications of using this pregnancy avoidance tool while managing one’s diabetes. The pill essentially consists of some combination of the hormones estrogen and progesterone. These hormones provide important instructions to reproductive tissues in a carefully timed fashion. Birth control pills create a hormonal state that makes the body think it is already pregnant and blocks any new eggs developing. Thus actual pregnancy is avoided.

Probably the first thing you have focused on is this increase in blood glucose. How much are we talking about? Actually – not much. The amount of increase in non-diabetic women is considered by the American Diabetes Association not enough to be concerned about. For women with diabetes, however, the debate is spirited. One school of thought is that any increase in blood sugar is an increase in risk and should be concerning. The other school of thought, of course, is that the benefits of avoiding an unwanted pregnancy outweigh the minimal risk.

We have known for quite some time that birth control pills decrease insulin sensitivity and this is caused entirely by progesterone. The mechanism appears to be complicated in that progesterone seems to act at multiple levels in the insulin signaling pathway. Interestingly, the progesterone receptor, upon binding progesterone, travels to the nucleus of the cell and regulates the expression of numerous genes. Several of these genes target the insulin signaling pathway in a variety of ways suggesting that this is a very deliberate piece of evolutionary integration.

About a decade ago, a progesterone only pill was developed in response to potential cancer risks associated with estrogen. This has proved useful for women with diabetes as well since estrogen increases the rate of developing a type of diabetic complication known as macrovascular disease (heart attacks would be one example). Indeed the American College of Obstetricians and Gynecologists recommend that women who are diabetic and either over the age of 35 or have vascular disease should use a progesterone-only contraceptive. Interestingly, in epidemiological studies of diabetes incidence it was noted that there has been an increase in the number of cases of adolescent girls developing type 2 diabetes. The beginning of this increase corresponded suspiciously with the time at which the progesterone only pill was introduced, leading researchers to question whether or not there might be a connection.

In a large meta-analysis of the literature, a group found no evidence for any general increase in diabetes risk for non-diabetic women taking hormonal birth control pills. They mentioned, however, that the available studies were small and often poorly controlled. Indeed it seems as if this is an area of study that has been neglected. However, in a review of the literature focusing on injectable and implantable forms of hormonal therapy, I did find something interesting. In 2001 a group published a study of Navaho women using birth control. They compared women who used a progesterone only implant to those who used a combination progesterone/estrogen formulation. There was a clear increase in diabetes incidence for the women who used a progesterone only implant. Now there are two potentially important factors to consider here. First of all, Native Americans are much more prone to diabetes than Caucasians or the other races of human with whom we share this place. This may be due to different genetics, a different lifestyle of some combination of the two. The second important factor is that these women were quite overweight. We do not yet have a clear sense of the importance of this factor however it is likely that obesity places an increased stress on the insulin system and one can imagine that the very small stress of progesterone might have a greater consequence in this population.

Given the fattening of America, it would be a good thing for us to examine this issue a bit more carefully.

Cinnamon was so prized in the ancient world that it was considered fit as a gift for royalty or even the gods. It was considered to have medicinal properties and even to this day is thought to lower blood sugar and thus serve as a natural therapeutic for diabetes. In 2008 a group headed by Dr. William Baker at the University of Connecticut performed a meta-analysis of all known clinical trials involving cinnamon and diabetes and found, unfortunately, that there was no real effect. (Click here for the reference) If this is so, why are people still publishing papers in peer reviewed journals on cinnamon and diabetes?

The answer is that something in cinnamon does have an insulin-like effect and while it might not be powerful enough in its natural form to affect blood sugar levels sufficiently to rise above the clatter and noise of human clinical variability, a component of cinnamon may serve as a lead compound in a new class of therapeutics. If we could identify that component and understand its mechanism of action we might be able to provide that compound as a drug in a dose 100 or 1000 times more concentrated than would be found in cinnamon.

Examples of identification and extraction of natural compounds and using them as starting points for drug development are many. Consider the willow tree. Its bark was used by ancient healers for a variety of purposes and from that bark we ultimately purified aspirin. The yew tree has given us taxol, now an important chemotherapeutic compound. Red wine has given us resveritrol, another potential chemotherapeutic and antioxidant compound. I occasionally serve on our Cancer Center board to review grant applications and we received one application a few years ago proposing to study resveritrol. The author had translated each resveritrol dose into the equivalent of glasses of wine (to be administered to the mice). The average dose was something like 300 glasses worth. The thought of a mouse imbibing 300 glasses of wine was an amusing image but it also underscored the sheer impossibility of taking in that amount of the substance via drinking.. The proposal was quite good (as well as entertaining) and was funded.

At any rate, papers on cinnamon continue to be published. The most recent report is out of India. Dr. Anand and co-workers from the University of Delhi has examined a component of cinnamon called cinnamaldehyde. They found that, like the thiazolidinedione drug family (think Avandia), it increased the translocation of a glucose transporter in muscle to the cell surface. This allows glucose to leave the blood and enter muscle tissue – a major mechanism by which we all get our blood glucose stored. Furthermore, they found that it altered the expression and activity of enzymes involved in storing glucose as glycogen. Finally, they showed that if one creates diabetic rats using streptozocin (the drug destroys the beta cells of the pancreas and has been used extensively to create diabetes in this animal model), treatment with cinnamaldehyde improved blood glucose levels.

How does it work? They have not yet figured that out. We are left with an intriguing compound and we await with interest the next installment of the story. In the meantime, enjoy your cinnamon.

Type 2 diabetes might be controlled by diet and exercise but getting people to do that is tough. As a practical matter, most people cannot change their lives for something bad that will happen 7 to 10 years down the road when today has its own challenges to overcome. Thus most diabetic patients rely on drugs to lower their blood glucose levels. Luckily, a host of new drugs are being developed and we are seeing continual improvements in how blood glucose is controlled.

The latest addition to our armamentarium is Liraglutide (trade name Victoza). It was developed by Novo-Nordisk and was approved by the FDA early in 2010. It is a member of the class of drugs known as Incretins. Incretins are hormones that do all sorts of wonderful things for the diabetic patient including increase insulin sensitivity, decrease the rate of glucose production by the liver, and slow the rate of food absorption (to read more about incretins click here). Normally these hormones are rapidly degraded by the body, so what Novo-Nordisk did was to create something that would activate the appropriate hormone receptor but not get degraded so rapidly. They did a good job. The Liraglutide sticks around long enough in the body that one only needs to take it once per day. These sorts of things really help with compliance since these drugs are administered by injection like insulin.

The LEAD-6 clinical trial comparing Liraglutide to Exenatide (Byetta) was headed by Dr John Buse from the University of North Carolina at Chapel Hill and the results published in the Lancet in 2009. Four hundred and sixty four type 2 diabetes patients who were taking metformin and did not have well controlled blood glucose levels were randomized to receive either Byetta or Liraglutide. They took the drug for 26 weeks. The patients were predominantly Caucasian with approximately equal numbers of male and female participants. They were significantly overweight with an average BMI of 32.9 (obese).

The results of the study were quite good. Both groups saw a decrease in blood sugar as measured both as fasting blood glucose levels and by glycosylated hemoglobin (HbA1c). Since sugar binds to hemoglobin (glycosylation) and hemoglobin sticks around for about 90 days (the life span of a red blood cell), measuring HbA1c is a good average of blood glucose control over the past 2 – 3 months. Fasting blood glucose just measures how you are doing at that point in time. At any rate, the patients taking Liraglutide dropped by about 1.2% (approximately) while the patients taking Exenatide dropped about 0.8% (approximately). Now medical researchers have done a lot of work establishing at what level of blood glucose a patient is at risk for complications and what is a safe level. The magic number appears to be 6.5%. If you have diabetes and your HbA1c level is less than 6.5% your chances of developing complications are virtually nill. In this study about 35% of patients taking Liraglutide decreased their HbA1c levels below 6.5% while about 20% of patients taking Exenatide achieved the same level of control.

Furthermore, in a study that was just published in Diabetes Care, the trial was extended for another 14 weeks and the Exenatide group was switched to Liraglutide. Interestingly, by week 14, the two groups appeared identical. Thus it seems that patients can easily and safely switch from Exenatide to Liraglutide as needed.

Another important issue is nausea. This is the big downside to using incretins. Many patients report significant nausea (see Catherine Price’s blog for a personal description). In the Lancet article, incidence of nausea was measured for the two groups and while the two groups started out the same (around 15 – 16%) the Liraglutide group dropped to 2% while the Exenatide group stayed around 10%. Thus it looks like patients get used to Liraglutide more easily than Exenatide.

There is more risk associated with Liraglutide. About 5.1% of patients taking Liraglutide experienced a serious adverse effect while about 2.6% of patients taking Exenatide experienced the same level of problems. These problems were primarily GI disorders for both groups – this is a bit surprising given that the main issue is nausea with this class of therapy and that Liraglutide seemed to cause less nausea than Exenatide. There was 1 incidence of cancer in the Liraglutide group and 1 incidence of heart attack. In comparison there were 2 heart attacks and no cancers in the Exenatide group. To what extent did these drugs cause these problems? As for the GI side effects, I think it is highly likely. As for the cardiac and cancer effects – the data is not very clear. We will need to look at thousands of patients (as we did with Avandia) to get some decent numbers.

At present, in my opinion, Liraglutide looks like a good addition to our current therapies.

If you are taking Avandia or Actos and you have been reading about heart disease you may be concerned and you should be. As a class, these drugs increase your risk of heart disease and recent studies are confirming what we already suspected: Avandia is a bit worse on the heart than Actos.

However, there is something you can do to protect yourself. It seems that exercise does a very good job of reversing the problems caused by Avandia. I came across this clinical study last week and I wanted to share it with you.

The 1 year study was performed by a team of Greek doctors headed by Dr. Nikolaos Kadoglou and was published in the journal: Metabolism in November 2009. They chose 100 people in their late 50s or early 60s with type 2 diabetes who had not achieved good glycemic control with the combination of gliclazide (a sulfonylurea drug) and metformin. They were all overweight but were not taking any lipid lowering drugs and did not have any vascular complications. These patients were divided into 4 groups. The control group (we’ll call them the CO group) kept on as before. The next group received rosiglitazone (Avandia) in addition to their current therapy (let’s call them the RSG group). Group 3 exercised in addition to keeping up their original therapy (the EX group). Finally, the last group added both Avandia and exercise to their original therapy (the RSG+EX group). All patients were carefully examined before the start of the study to establish their fitness level as well as their lipid profiles, glycemic index, level of insulin resistance, and many other parameters. They were measured again after 1 year to provide the results of the study.

The exercise regimen started with a standard 45 min to 1 hour aerobic fitness class run at a local fitness center. The intensity of the exercise was tailored for each patient so that they were not in danger of hurting themselves or being asked to perform at an impossible level. Indeed the authors made the point that the exercise level began quite low and only slowly increased until individuals could achieve a reasonable level of effort (officially, 50% of V_O2 peak). After the first month the exercise was further tailored to the individual with some running and some walking or using an exercise bicycle. After 8 months, the patients were on their own with individual exercise programs and simply checked in periodically so that the researchers could see how they were doing. Out of the 100 patients, 11 dropped out of the study for a variety of reasons, none of which involved dislike of the exercise.

The results were quite impressive. Nobody lost weight but then we already know that weight loss cannot be achieved by exercise alone unless we are talking enormous amounts such as a multiday mountaineering expedition – not exactly the sort of thing you plan on doing any time soon. Glycemic control, as measured by the amount of glycosylated hemoglobin, was about 0.5% higher in the CO group. In the EX group it dropped 0.3%. In the RSG group it dropped 0.8% and in the RSG+EX group it dropped 1.4%.

Lipid profiles also responded favorably with exercise. As seen in other studies Avandia treatment (the RSG group) resulted in an increase in total and LDL cholesterol. For the groups that exercised, however, HDL levels (the good lipids) increased while LDL levels and cholesterol (the bad lipids) decreased. Also, various other measures of lipids that are somewhat more specialized such as ApoA and ApoB1 showed improvement but only in the groups that exercised. Measures of inflammation (inflammation increases insulin resistance) also showed marked improvements both with exercise and with Avandia. The combination of Avandia plus exercise markedly improved this parameter.

Another issue that increases the risk of a cardiac event is fluid retention. Increased fluid causes an increased workload for the heart and Avandia has effects on the kidney that increases fluid retention. This was seen in the current study. The CO group showed no significant change in body water content while the RSG group experienced a significant change of 2.4% (+/- 1.4%). When Avandia was combined with exercise (the RSG+EX group) the number dropped to 1.6% (+/- 1.2%) and was no longer statistically significant.

Blood pressure, another measure that is associated with increased cardiac risk, was increased in the CO group and decreased in the EX, RSG, and RSG+EX groups.

Perhaps the most interesting and surprising result from the study was that Avandia alone improved V_O2 max. This is a measure of aerobic capacity. Improving V_O2 max is the Holy Grail for anyone who is involved in a sport that involves lots of movement. Fly fishing probably doesn’t get easier but tennis or basketball or soccer certainly does. The RSG+EX group saw a synergistic improvement in V_O2 max which was much greater than the EX group.

So to sum up, the exercise groups performed about 2.5 to 3 hours of exercise a week for a year. They experienced marked improvements in insulin resistance, fasting glucose levels, lipid profiles and blood pressure. Avandia provided the expected improvements in glycemic control with the equally expected increases in fluid retention and cholesterol associated with increased cardiac risk. Exercise markedly reduced these cardiac risk factors while synergizing with exercise to improve glycemic control. Remarkably, Avandia actually improved the capacity of the study group making them more fit and capable of greater improvements in fitness.

Here are some questions. How much exercise do you need to do to achieve these benefits? Does Actos have the same properties or is this unique to Avandia? As usual, we end with the researchers’ mantra – “more work is necessary to unravel these important issues”. In the meantime, it wouldn’t hurt to go take a walk today.