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Disclaimer: CME certification for these activities has expired. All information is pertinent to the timeframe in which it was released.

Diabetic Microvascular Complications: Are We Doing Enough?
Part I: Diabetic Peripheral Neuropathy

To delineate the multifactorial pathogenesis of diabetic microvascular complications, review pathways of disease progression, and present emerging data on future treatment options.

This activity is designed for neurologists, endocrinologists, diabetologists, and primary care physicians. No prerequisites required.

The Johns Hopkins University School of Medicine takes responsibility for the content,
quality, and scientific integrity of this CME activity. At the conclusion of this activity,
participants should be able to:

  • Discuss the impact and prevalence of diabetic microvascular complications, including retinopathy, nephropathy, and peripheral neuropathy.
  • Examine the multifactorial pathogenesis of microvascular damage.
  • Review different pathways of disease progression, and discuss the role of the protein kinase C-b pathway versus others in the development of microvascular complications.
  • Review current treatments for diabetic peripheral neuropathy.
  • Evaluate emerging data on future options for the treatment of the underlying processes of microvascular damage.

The Johns Hopkins University School of Medicine is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

The Johns Hopkins University School of Medicine designates this educational activity for a maximum of 2 category 1 credits toward the AMA Physician's Recognition Award.  Each physician should claim only those credits that he/she actually spent in the activity.

The estimated time to complete this educational activity:  2 hours.

Release date: June 15, 2004. Expiration date: June 15, 2006.

The opinions and recommendations expressed by faculty and other experts whose input is included in this program are their own. This enduring material is produced for educational purposes only. Use of Johns Hopkins University School of Medicine name implies review of educational format design and approach. Please review the complete prescribing information of specific drugs or combinations of drugs, including indications, contraindications, warnings, and adverse effects, before administering pharmacologic therapy to patients.

This program is supported by an unrestricted educational grant from Eli Lilly and Company.

Full Disclosure Policy Affecting CME Activities:
As a sponsor accredited by the Accreditation Council for Continuing Medical Education (ACCME), it is the policy of Johns Hopkins University School of Medicine to require the disclosure of the existence of any significant financial interest or any other relationship a faculty member or a sponsor has with the manufacturer(s) of any commercial product(s) discussed in an educational presentation. The Program Director and Participating Faculty reported the following:


Christopher D. Saudek, MD
Hugh P. McCormick Family Professor of Endocrinology and Metabolism
Johns Hopkins University School of Medicine
Director, Johns Hopkins Diabetes Center
Program Director,
General Clinical Research Center at Johns Hopkins
Baltimore, Maryland
Dr Saudek reports serving as a consultant to Eli Lilly and Company.


Rayaz A. Malik, MB.ChB, PhD, MRCP
Clinician Scientist (Vascular Medicine)
Senior Lecturer
Department of Medicine
University of Manchester
Consultant Physician
Manchester Royal Infirmary
Manchester, United Kingdom
Dr Malik reports receiving grants/research support from AstraZeneca PLC; and serving as a consultant to and receiving honoraria from AstraZeneca PLC, Takeda UK, and Pfizer Inc.

Aaron I. Vinik, MD, PhD
Director, Strelitz Diabetes Research Institutes
Eastern Virginia Medical School
Dr Vinik reports receiving grants/research support from Amgen, AstraZeneca LP, Athena, Boston Medical Technologies, Bristol-Myers Squibb Company, Eli Lilly and Company, Forest Laboratories, Genentech, GlaxoSmithKline, Guilford Pharmaceuticals, Knoll Pharmaceuticals, Merck & Co, Inc, Neurometrix, Pfizer Inc, Robert Wood Johnson Pharmaceutical Research Institute, Sankyo Pharma, Sigma Tau Research, Synergy Biosciences, LLC, Takeda, and TEVA Pharmaceutical Industries, LTD; and serving as a consultant to or on the speakers' bureau for Bristol-Myers Squibb Company, Eli Lilly and Company, Genentech, GlaxoSmithKline, Merck & Co, Inc, and Pfizer Inc.

In accordance with the ACCME Standards for Commercial Support, the audience is advised that one or more articles in this continuing medical education activity may contain reference(s) to unlabeled or unapproved uses of drugs or devices.

Faculty have indicated that they have not referenced unlabeled/unapproved uses of drugs or devices.

Advanced Studies in Medicine provides disclosure information from contributing authors, lead presenters, and participating faculty. Advanced Studies in Medicine does not provide disclosure information from authors of abstracts and poster presentations. The reader shall be advised that these contributors may or may not maintain financial relationships with pharmaceutical companies.

Diabetic Microvascular Complications: Are We Doing Enough?
Christopher D. Saudek, MD*

In 2002, a total of 18.2 million people in the United States (6.3% of the total population) were estimated to have diabetes, and a multitude of studies attest to the devastating—and growing—epidemic of diabetes. For both type 1 and type 2 diabetes, the long-term complications are the major cause of morbidity and mortality as well as cost. Generally speaking, these complications may be classified as either macrovascular (affecting large arteries) or microvascular (affecting the capillaries and small blood vessels). Both types add substantially to the cost of diabetes by both personal and societal measures. While macrovascular complications may get the most attention, especially in type 2 diabetes, microvascular complications are also a major risk in both types of diabetes. In fact, for a substantial number of people with type 2 diabetes, microvascular complications—retinopathy, nephropathy, or neuropathy—will be present at the time of diagnosis. The precise pathophysiologic mechanisms that cause microvascular complications are just beginning to be clarified. A central fact is that they correlate strongly with hyperglycemia. Current notions of pathogenesis will be emphasized in this treatise, but always in the context of the devastating effect microvascular complications may have on individuals with diabetes, and the aggregate cost to society.

Retinopathy causes between 12,000 to 24,000 new cases of blindness each year in the United States. According to the American Diabetes Association, nearly all patients who have type 1 diabetes for a period of 20 years will experience diabetic retinopathy. Up to 21% of patients with type 2 diabetes already show evidence of retinopathy at the time of diagnosis, and most of the others will eventually develop it. Nephropathy due to diabetes is the leading cause of end-stage renal disease in this country, and has a significant adverse effect on patient quality of life, morbidity, and mortality. Neuropathy is by far the most common diabetic microvascular complication, with approximately 60% to 70% of all people with diabetes suffering from it. In the more severe cases of diabetic peripheral neuropathy, the risk of lower-limb amputations is considerably increased. All of the diabetic microvascular complications therefore create a substantial impact on both the overall cost of managing diabetes and patient quality of life.

The current thought is that at the biochemical level, 4 major pathways of glucose metabolism may be involved in microvascular complications. These metabolic pathways can affect one another, however, and a specific understanding of the interactions between them will allow the design of specific treatments targeting microvascular disease.

This issue of Advanced Studies in Medicine begins with an interview with Dr Rayaz A. Malik, a specialist in neurophysiology as well as diabetes, provides us with a clinician interview in which he reviews the different pathways of disease progression, and discusses the role of the PKC pathway versus the other pathways in the development of diabetic microvascular complications.

I also participate in a clinician interview in which I discuss glycemic control, the current method for prevention of retinopathy, nephropathy, and neuropathy. Additionally, I review the few treatment approaches available beyond glycemic control to slow the progression of microvascular complications, as well as their efficacy, and discuss the need for new treatments.

A review article by Dr Aaron I. Vinik, a long-term and outstanding contributor in the area of diabetic neuropathy and other areas of diabetic research, discusses the emerging data on a new class of treatment—PKC-? inhibitors—that might contribute to  treatment, and describes how these agents affect the underlying processes of microvascular complications.

The review article is followed by 2 case studies. Dr Vinik presents a patient with an 18-year history of type 2 diabetes who presents to her primary care physician complaining of numbness and pain in both her feet. Dr Malik provides the second case study: a patient with type 1 diabetes who is admitted to the renal ward with acute onset pain and swelling in his right calf and deterioration in his renal function. These case studies illustrate some of the challenges seen in the management of diabetic microvascular complications.

Finally, an article by Dr Michael Brownlee presents the current medical knowledge on the multifactorial pathogenesis of microvascular complications. The discussion includes details on the 4 main hypotheses that have emerged to explain the mechanisms of hyperglycemia-induced vascular damage: the aldose reductase (or polyol pathway) theory, the advanced glycation end-product theory, the reactive oxygen intermediate theory, and the protein kinase C theory.

Finding strategies to help patients prevent or slow the development of diabetic microvascular complications is challenging at best. It is critical that we as clinicians continue to manage hyperglycemia aggressively in order to reduce the risk of the various microvascular complications. The new understanding of the pathogenesis of diabetic microvascular complications and the emergence of new targets for treatments offer hope that patients with diabetes may eventually experience improved health-related quality of life over the course of their disease and, possibly, improved clinical outcomes as well.

*Hugh P. McCormick Family Professor of Endocrinology and Metabolism, Johns Hopkins University School of Medicine; Director, Johns Hopkins Diabetes Center; Program Director, General Clinical Research Center at Johns Hopkins, Baltimore, Maryland.

Address correspondence to: Christopher D. Saudek, MD, Johns Hopkins University School of Medicine, Osler 576 Ð Endocrinology, 600 North Wolfe St, Baltimore, MD 21287. E-mail:

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