Articles  |   August 2003
Editor's Message
Author Affiliations
  • Louis C. Haenel, DO
    Dr Haenel is head of the Division of Endocrinology and Metabolism, Department of Internal Medicine, John F. Kennedy Memorial Hospital, and a clinical associate professor of medicine at the University of Medicine and Dentistry of New Jersey<School of Osteopathic Medicine in Stratford, NJ.
Article Information
Endocrinology / Diabetes
Articles   |   August 2003
Editor's Message
The Journal of the American Osteopathic Association, August 2003, Vol. 103, Cov2. doi:
The Journal of the American Osteopathic Association, August 2003, Vol. 103, Cov2. doi:
As practicing clinicians, we now face one of the most challenging eras of diabetic management. We are confronted with a burgeoning population of potential patients who are becoming more sedentary and more obese. The problem of the metabolic syndrome, or the insulin-resistance syndrome, has reached epidemic proportions. It is estimated that 50 million Americans have some form of insulin resistance.1 A large percentage of these individuals will eventually go on to the development of type 2 diabetes mellitus (T2DM). Conservatively, there exist in the United States 18 to 20 million diabetics, many of whom have not had their disease diagnosed.1 Undoubtedly, this problem has at least partially arisen from our sedentary lifestyles with increasing use of computers and television and decreasing participation in physical activity. It has also been greatly compounded by our accessibility to rich fat-laden foods with extremely high glycemic indexes.1 
Physicians are being challenged to confront this problem and to make the necessary therapeutic adjustments in their patient populations to diminish the potential for not only progression to T2DM, but also to help in the reduction of insulin resistance, which carries a twofold to fourfold increased risk of mortality from macrovascular disease (ie, strokes and heart attacks) over the nondiabetic population. 
The The Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (ATP III)2 guidelines now allow us to clinically define insulin resistance syndrome and even code it for billing purposes. But, just establishing the diagnosis of insulin resistance syndrome or T2DM is not sufficient. 
As we now know from multiple studies, starting originally with patients with type 1 diabetes mellitus (T1DM) in the DDCT study3 and eventually the United Kingdom Prospective Diabetes Study,4,5 all these studies have clearly shown that in both T1DM and T2DM, improvement of the glycosylated hemoglobin (hemoglobin A1c) values over time has made significant strides in improving microvascular disease as it manifests itself in retinopathy, nephropathy, and neuropathy. The challenge to physicians is to be able to implement an algorithm or paradigm of therapy that will help bring patients into the ideal range. The therapeutic range is constantly being redefined and varies even now between the American Diabetes Association6 and the American Association of Clinical Endocrinologists and the American College of Endocrinology.7 
The lower the level of the A1c achieved, the better patients will fare. Even the UKPDS strongly suggests that improvement in the A1c level in the trial arm of those individuals using metformin would probably benefit from the standpoint of macrovascular complications, ie, cardiovascular disease.4 
For the staggering number of individuals who confront health care providers with these problems, therapeutic tools that help to facilitate proper glycemic control are now under development. Specifically, for the population with type 2 diabetes (ie, approximately 90% of all diabetic patients seen in clinical practice), lifestyle changes remain a vital and an integral part of a diabetes control program. The review of the nutritional guidelines and recommendations of the American Diabetes Association (ADA) by Carolyn Leontos, MS, RD, CDE, underscores the need for clinicians to supply the minimum ADA therapeutic goals and have the ability and the willingness to refer patients to diabetic nurse educators and registered dietitians. Thus, the diabetic population and perhaps even those with insulin resistance—most of whom are also obese—can benefit from the expertise of such health care professionals. Unfortunately, the recommended lifestyle changes are extremely difficult to implement and even more difficult to maintain. Realistically, it becomes difficult to get patients to comply long term with these stated objectives. 
We are indeed practicing in an exciting era with respect to the availability of pharmacologic modalities to help supplement basic lifestyle changes. Most older forms of therapy are still important and need to be used, but in appropriately selected patients. A patient who has significant glucose toxicity, even at initial onset, will require insulin therapy to reduce glucose toxicity and help to lower the toxic effect of sugar so as to enable effective introduction of other therapeutic modalities into the treatment program. Overall, the long-time standby insulin cannot be disregarded in many of the therapeutic arms that clinicians use. 
Fortunately, excellent insulin preparations are now available, as the contents of this supplement attest. The introduction of insulin glargine as a long-acting, nonpeaking type of basal insulin has brought new promise to both patients with T1DM and patients with T2DM. In the population with T1DM, it can be used as a single injection supplemented at mealtime with a short-acting insulin such as lispro or aspart. In the population with T2DM, insulin can also be used to maintain a basal level of glycemic control while adjunctive therapy with other pharmacologic agents is added. The use of the quick-acting insulin lispro or insulin aspart effects an extremely physiologic response and allows appropriate coverage of the glycemic surges that tend to occur after carbohydrate-rich meals. The peaks of these insulin preparations are much more in concert with the glycemic peaks that occur postprandially, and these insulin preparations can and should be given immediately before meals, allowing the peak activity, which occurs approximately 18 minutes after the injection, to attenuate the glucose peak. For the older regular insulin to attain a similar peak, the dose would have to be given approximately 1 hour before meals. 
Beyond insulin therapy are the secretagogues, which have been used for many decades. The newer secretagogues, the meglitinides, are extremely rapid-acting, very physiolgic pharmacologic agents that will lock onto the islet cell at a slightly different receptor than the older sulfonylureas, but through a similar mechanism, eventually opening the calcium channels to release stored insulin from the cells. Because of their short duration of activity and physiologic responses to glycemic rises, they become an important arm of our therapeutic regimen. 
The old standby sulfonylureas, especially the second-generation ones, still have utility. The ones that tend to have less duration of action, such as glimepiride and glipizide, are probably the most physiologic. They act in response to glucose surge and then allow insulin levels to drop. 
In the mid-1990s, the biguanides were reintroduced. They had been around for many decades in the form of phenformin, which was removed from the marketplace because of untoward lactic acidosis seen in patients with renal insufficiency. The metformin that was introduced in the United States has enabled us to achieve better diabetic control and at the same time, perhaps generate a little bit of weight loss, or at least no weight gain, while improving A1c levels. The mechanism(s) or the action of this compound are still not clear. Suffice it to say that the major efficacy of metformin appears to be in the downregulation of hepatic gluconeogenesis. Also, the use of this drug effectively prevents the liver (a major organ in the production of endogenous sugar) from raising glucose levels in people with T2DM. 
Perhaps the most exciting class of agents to be introduced in the past 4 or 5 years is the thiazoledinediones (TZDs). These agents have unique activity, working primarily through an intracellular peroxisome proliferator-activated gamma receptor (PPARgamma) agonistic effect in conjunction with insulin. Their hypoglycemic activity is well reported, and their staying power is extremely exciting. Unfortunately, these drugs were not around to be investigated at the inception of the United Kingdom Prospective Diabetes Study (UKPDS).4 
As UKPDS clearly demonstrates, regardless of the therapeutic arm used in the trial—insulin, secretagogues, or metformin—the hemoglobin A1c values eventually started to rise. This rise tended to occur at about 3.0 to 3.5 years after the initiation of therapy. We now believe that the TZDs have the staying power to maintain good diabetic control and lower A1c values for much longer periods, ie, outwards to 4 years with some of these drugs. They maintain good A1c levels, which are initially achieved within 3 to 6 months. The obvious implications with this type of long-term control is that it preserves islet cell function. 
Again, preliminary studies such the TRIPOD study8 would also point in that direction. Indirect measurements of islet cell function, such as can be demonstrated with euglycemic-hyperinsulinemic clamp studies and homeostasis model assessment mathematical studies in humans, strongly support the fact that these medications reduce insulin resistance and also indirectly indicate that they help preserve islet cells. Pancreatic biopsies in animal model studies show direct evidence of regranulation of beta cell tissue in the presence of at least some of the several TZDs studied. 
Beyond their efficacy in hypoglycemic effects, the TZDs have myriad nonhypoglycemic effects. Abundant literature now exists with respect to changes in endothelial smooth muscle cell thickness and reduction of free fatty acids and other potentially harmful substances released by the omental fat cells, effects that would have eventually aggravated endothelial function and lead to atherogenicity. The use of TZDs seem to significantly ameliorate all these effects. 
Similar drugs working through different mechanisms are also in development and will soon be introduced into our therapeutic armamentarium, as our ability to control diabetes through pharmacologic agents becomes better and better. 
The articles in this supplement help to give clinicians a better understanding of the type of physiologic mechanisms involved, particularly in T2DM. They offer some algorithms that can be instituted to maintain ideal control of the hemoglobin A1c level. 
Also not forgotten is T1DM. In addition to the use of insulin glargine in management of T1DM, ongoing studies are working on genetic manipulation, implantation of islet cells, more sophisticated insulin pumps that are structured to help in maintaining better glycemic control in patients with T1DM, those who unfortunately are afflicted so early in life with the multiple complications of this serious disease. 
The articles appearing in this issue are enlightening, succinct, readable, and extremely practical in the approaches they offer to diabetes management. The case scenarious offered by Jeffrey S. Freeman, DO, will help readers work through therapeutic modalities that offer promise in helping diabetic patients gain control of their disease. 
This is both an exciting and challenging era in diabetes management. With proper education of both clinicians and patients, diabetes can become much more manageable and both the macrovascular and microvascular complications to which this disease process is prone can be greatly improved. 
 Dr Haenel is on the speakers bureaus of Aventis Pharmaceuticals, Eli Lilly and Company, GlaxoSmithKiline, and Takeda Pharmaceuticals America, Inc.
 The contents of this JAOA Supplement were developed in part from lectures and discussion at a symposium, “The Faces of Diabetes,” implemented in accordance with the American College of Osteopathic Family Physicians and the American Osteopathic Association. The program was presented at the AOA's 108th Annual Convention and Scientific Seminar in Las Vegas, on October 7, 2002.
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