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Understanding the Relationship Between Hyperglycemia and Microvascular Complications

Jointly sponsored by The Dulaney Foundation and Diabetic Microvascular Complications Today. Release Date: August 2006. Expiration Date: August 31, 2007. This continuing medical education activity is supported by an educational grant from Eli Lilly and Company.

BY BERNARD ZINMAN, MD

STATEMENT OF NEED
The epidemic of diabetes in the United States affects 7% of the population, most of these have type 2 diabetes. Currently, 20.8 million Americans have diabetes and 6.2 million more have unrecognized diabetes. Diabetic retinopathy is the the most frequent late complication of type 1 diabetes. In fact, 100% of all patients with type 1 diabetes will develop diabetic retinopathy together with 60% of patients who have type 2 diabetes. Every incremental decrease in HbA1c significantly reduces the risk of mcrovascular complications.

TARGET AUDIENCE
This activity is designed for primary care physicians, endocrinologists, diabetologists, ophthalmologists and other practitioners who treat patients with diabetes and diabetic microvascular complications.

LEARNING OBJECTIVES
Upon successful completion of this learning program, the participant should be able to:
• Identify the major study questions from the DCCT trial.
• Discuss the findings from the DCCT and the EDIC trials.
• Describe what is meant by metabolic memory.
• Discuss the potential mechanisms by which hyperglycemia causes tissue damage.

METHOD OF INSTRUCTION
Participants should read the learning objectives and continuing medical education (CME) program in their entirety. After reviewing the material, they must complete the self-assessment test, which consists of a series of multiple-choice questions.

Participants have a choice of completing this activity online by visiting www.DiabeticMCToday.com; getting real-time results at www.CMEToday.net; or by using the print forms following this activity.

Upon completing the activity and achieving a passing score of ≥70% on the self-assessment test, participants will receive a CME credit letter awarding AMA/PRA Category 1 Credit™ 4 weeks after the registration and evaluation materials are received. The estimated time to complete this activity is 1 hour.

ACCREDITATION
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of The Dulaney Foundation and Diabetic Microvascular Complications Today.

The Dulaney Foundation designates this educational activity for a maximum of 1 AMA/PRA Category 1 Credit.™ Physicians should only claim credit commensurate with the extent of their participation in the activity.

DISCLOSURE
In accordance with the disclosure policies of The Dulaney Foundation and to conform with ACCME and FDA guidelines, all program faculty are required to disclose to the activity participants: (1) the existence of any financial interest or other relationships with the manufacturers of any commercial products/devices, or providers of commercial services that relate to the content of their presentation/material or the commercial contributors of this activity; and (2) identification of a commercial product/device that is unlabeled for use or an investigational use of a product/device not yet approved.

FACULTY DISCLOSURE DECLARATIONS
Dr. Zinman reports receiving grants/research support from Eli Lilly and Company, Novartis, GlaxoSmithKline (GSK) and Novo Nordisk. He discloses that he is a consultant for Amylin, Lilly, GSK, Merck, Novartis, Pfizer and Sanfi-Aventis.

FACULTY CREDENTIALS
Bernard Zinman, MD, is director, Leadership Sinai Centre for Diabetes, and professor of medicine, University of Toronto. He may be reached at zinman@mshri.on.ca.

INTRODUCTION
It is crucial that we as diabetolologists and endocrinologists who are on the front lines treating patients at high risk for the microvascular complications of diabetes have a close, and functioning relationship with our ophthalmologist colleagues.1

It is now clearly established that hyperglycemia is the initiating event responsible for the endothelial/metabolic dysfunction that leads to the development of neuropathy, retinopathy and nephropathy, as well as other vascular complications. Several glucose-mediated metabolic pathways have been postulated to be responsible for the intracellular events resulting in tissue damage.

A REVIEW OF THE DCCT TRIAL
Testing the glucose hypothesis in the context of diabetic complications has been a major focus of research. Many studies have shown the association between hyperglycemia and retinopathy. In the Diabetes Control and Complications Trial (DCCT), however, we determined prospectively if intensive diabetes treatment with the goal of near-normal glucose control would prevent or delay long-term complications of diabetes.

The major questions in the DCCT were:2
• Primary prevention — Will intensive therapy prevent the development of neuropathy, retinopathy and nephropathy in those with no complications?
• Secondary intervention — Will intensive therapy affect the progression of complications in those who already have problems?

The DCCT showed conclusively that a 2% reduction in HbA1c in the intensive control patients3 (Figure 1) resulted in a dramatic reduction in the rate of the development of retinopathy when compared with conventional treatment (Figure 2).3 At the 3-year point, there was a very rapid separation between the rate of the development of retinal complications among the intensively treated group when compared with conventional therapy.

An often-overlooked fact is that when you implement intensive therapy there may be a period where you have some worsening of retinopathy. We saw this in the secondary intervention cohort in the DCCT trial,3 and this same phenomenon has been shown in other older studies as well. Introducing intensive glucose control can transiently result in some worsening of retinopathy. Over time, however, there is a dramatic improvement in outcome with intensive therapy (Figure 3).

EDIC FOLLOW-UP TO DCCT
The long-term follow-up of the DCCT study is called the Epidemiology of Diabetes Interventions and Complications trial (EDIC). When the DCCT results were known and announced to our patients, the patients were informed that intensive therapy clearly had major advantages with respect to nerve, eye and kidney complications, and all participants should initiate intensive therapy. The conventionally treated study participants were now given intensive diabetes management training, and were put on insulin pumps or multiple daily injections. These participants improved their HbA1c and were returned to their usual clinical care. As part of the EDIC protocol the investigators followed these patients on an annual basis. Given that the original intensively treated patients were now seen less frequently, their HbA1c rose to approximately 8% and was similar in both groups.3,4

The DCCT/EDIC study provides us with the opportunity to determine the long-term impact of intensive therapy on both micovascular and macrovascular complications. Specifically, we can determine what will be the impact of 6.5 years of improved glycemic control on the subsequent development of complications.

METABOLIC MEMORY
The EDIC outcome data demonstrate that despite similar levels of control, the original intensive therapy group continued to have reduced rates of complication development. We called this phenomenon metabolic memory (Figure 4).5

This result applied to the outcomes of proliferative diabetic retinopathy as well as severe nonproliferative diabetic retinopathy (Figure 5) and clinically significant macular edema (Figure 6).4

Metabolic memory and diabetic complications appear to be an important phenomenon that applies generally to the complications of diabetes. Indeed, in late 2005 we described the same phenomenon in relationship to macrovascular disease.6 We documented a 58% reduction in clinically significant macrovascular disease outcomes in those individuals who were on originally intensive therapy.

The clinical message for patients with type 1 diabetes is that early intervention with intensive therapy should be the standard of care for preventing the long-term complications of diabetes. If intensive therapy is delayed, the momentum of complications is more difficult to slow.

Unfortunately, given our current tools for implementing intensive therapy, optimal glycemic control cannot be obtained in many patients with diabetes. In addition, the risk of increasing severe hypoglycemia remains as a significant barrier to intensifying diabetes control. In this context, there is a need for alternative therapies to reduce the impact of hyperglycemia on micro- and macrovascular complications.

ALTERNATIVE TREATMENTS
If we are going to consider alternate interventions for preventing or reducing diabetic microvascular complications, then we have to understand the underlying pathophysiology. We know that hyperglycemia is the initiating event that must be followed by other metabolic pathways. The potential pathways by which hyperglycemia-induced mitochondrial superoxide overproduction occurs include:7
• The polyol pathway, through increased sorbitol, fructose and its direct effect is hyperglycemia;
• The hexosamine pathway;
• The protein kinase C (PKC) pathway with an increase in diacylglycerol (DAG); and
• The advanced glycosylation endproduct (AGE) pathway.
Each of these pathways has been implicated as being key in the development of microvascular complications.

Recently there has been great interest in activation of PKC. Investigators have demonstrated that hyperglycemia increases the production of DAG and in turn, the beta and delta isoforms of PKC, resulting in a decrease in endothelial nitric oxide and an increase in endothelin 1. This then results in blood flow abnormalities — which can be visualized in the retina as an example — associated with an increase in vascular endothelial growth factor (VEGF) and changes in vascular permeability. Transforming growth factor (TGF) beta increases along with collagen and fibronectin, resulting in capillary occlusion, increases in plasminogen activator inhibitor (PAI) 1 and fibrinolysis, and vascular occlusion. Additional changes include an increase in interferon (INF) kappa beta and proinflammatory gene expression, an increase in nicotinamide adenine dinucleotide phosphate (NADPH), and an increase in reactive oxygen species (ROS), which has multiple effects.

There appears to be a unifying hypothesis that relates to the mitochondria. Increased glucose in the extracellular space crosses the cell membrane in cells where glucose transport is not dependent on insulin. The mitochondria are the intracellular organelles that play the principal role of producing energy. The increased glucose flux results in an increase in ROS, which can lead to DNA damage.

A recent example of a pharmacologic agent to block the effects of hyperglycemia on microvascular complication is the investigational PKC inhibitor ruboxistaurin. This agent has shown promise in early clinical trials. Ruboxistaurin limits PKC-beta overactivation and has been reported to have an impact on clinically significant retinal outcomes.8

Other pharmacologic approaches to improving microvasculr outcomes by blocking other metabolic pathways — aldose reductase inhibitors, AGE inhibitors and reduction of increased oxidative stress — have been studied and to date have not been successful.

CONCLUSION
Hyperglycemia is the principal cause of microvascular complications. Glycemic normalization is frequently difficult to achieve with current therapies and may also be associated with increased rates of severe hypoglycemia. We need to do everything we can to get the best possible control in our patients. Pharmacologic therapy to prevent the impact of hyperglycemia on target organs, however, still represents an important strategy for complications prevention.


1. The Eyes Have It: Preserving Vision in Patients with Diabetes. Presented as a live CME activity. June 12, 2006. Washington DC.
2. The DCCT Research Group. The Diabetes Control and Complications Trial (DCCT). Design and methodologic considerations for the feasibility phase. Diabetes. 1986;35:530-545.
3. The DCCT Research Group. The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. N Engl J Med. 1993;329:977-986.
4. The DCCT/EDIC Research Group. Retinopathy and nephropathy in patients with type 1 diabetes four years after a trial of intensive therapy. N Engl J Med. 2000;342:381-390.
5. The Writing Team for the DCCT/EDIC Research Group. Effect of intensive therapy on the microvascular complications of type 1 diabetes mellitus. JAMA. 2002;287:2563-2569.
6. The DCCT/EDIC Study Research Group. Intensive diabetes treatment and cardiovascular Disease in patients with type 1 diabetes. N Engl J Med. 2005;353:2643-2653.
7. Brownlee M. Biochemistry and molecular cell biology of diabetic complications. Nature. 2001;414:813-20.
8. Aiello LP. Effects of orally administered PKC-beta inhibitor ruboxistaurin on visual acuity in the PKC-DRS2 study. Presented at the Association for Research in Vision and Ophthalmology 2006 Annual Meeting. April 29 to May 4, 2006. Fort Lauderdale, Fla.
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