Highlights of the Second World Congress on the Insulin Resistance Syndrome

November 18-20, 2004; Los Angeles, California

Zachary T. Bloomgarden, MD

Disclosures

June 09, 2005

The Second World Congress on the Insulin Resistance Syndrome (IRS) addressed numerous aspects of what we now realize to be an increasingly complex clinical entity. Yehuda Handelsman, MD, Tarzana, California, organized and led the meeting, noting the importance of International Classification of Diseases, Ninth Revision ( ICD-9 ) diagnostic code 277.7, which allows the clinician to use IRS as a specific medical diagnosis.

Gerald Reaven, MD, Stanford, California, whose pioneering observations established the concept of IRS and who also played a major role at the meeting, raised the important theme of "what is the culprit?" In his presentation, he contrasted the 2 important elements of insulin resistance vs hyperinsulinemia. The dilemma of establishing which aspect of IRS is cause and which is effect was brought out in numerous, subsequent presentations. Arthur McCullough, MD, Cleveland, Ohio, questioned whether nonalcoholic fatty liver disease (NAFLD), an important illness associated with IRS (which he termed "a disease of our generation"), causes insulin resistance or whether insulin resistance causes fatty liver disease. He concluded that insulin resistance is primary, citing evidence that sensitizers may ameliorate NAFLD.

At the symposium on insulin resistance in childhood, Dennis M. Styne, MD, Davis, California, noted that "the world is catching up with us" in the prevalence of childhood obesity, and he asked, "Do we have the resolve to implement common sense measures while we increase research?" Sonia Caprio, MD, New Haven, Connecticut, clearly showed the association of the syndrome with obesity. But again, the question can be raised as to whether those children with underlying insulin resistance are more prone to developing the syndrome, as suggested by the elegant studies of Dr. Caprio and Silva Arslanian, MD, showing different abnormalities developing in obese children with different ethnicities.

In a symposium on the relationship between hypertension and IRS, Albert Rocchini, MD, Ann Arbor, Michigan, suggested that it is neither the case that insulin resistance causes hypertension nor is it the case that hypertension causes insulin resistance. He suggested that there is a common underlying factor -- activation of the sympathetic nervous system (SNS). However, Ele Ferrannini, MD, Pisa, Italy, described evidence of the inverse relationship between insulin sensitivity and blood pressure, suggesting that one can equally argue that SNS activation may cause insulin resistance and that insulin resistance (or hyperinsulinemia) may activate the SNS.

Questions of causality are of crucial importance. Richard C. Pasternak, MD, Boston, Massachusetts, reminded the audience that it is important to know whether insulin resistance causes atherosclerosis or a common factor causes both. "Until we understand this better, we won't know where we're going to intervene." Further addressing this point, Paul Jellinger, MD, Hollywood, Florida, commented that "we do not have, today, clear direction as to how to treat this syndrome [as a whole]," as opposed to our treatment of specific components of the syndrome.

Arya M. Sharma, MD, PhD, Hamilton, Ontario, Canada, described angiotensin II (Ang-II) as possibly being "the common molecule driving both insulin resistance and hypertension." Dr. Sharma reviewed the action of adipocytes in producing both angiotensinogen and the enzymatic machinery for Ang-II production, with Ang-II appearing to act physiologically in a fashion opposing peroxisome proliferator-activated receptor (PPAR)-gamma, and angiotensin receptor blockers (ARBs) appearing to have similar effects to those of thiazolidinediones. Philipp E. Scherer, PhD, Bronx, New York, gave a fascinating description of the role of the adipocyte secretory product adiponectin and of the relationship between adipocytes and inflammation, noting the "intense cross talk between the adipocyte and the macrophage." Professor Patrick Vallance, London, United Kingdom, gave an important description of the newly appreciated endogenous L-arginine derivative asymmetric dimethylarginine, which blocks the action of nitric oxide synthetase, the underlying part of the association between IRS and oxidative stress, which is controlled both by renal excretion and directly by metabolic degradation. Peter J. Grant, MD, Leeds, United Kingdom, discussed the relationship between insulin resistance and thrombosis, noting that thrombosis and inflammation "are actually the same process." He made fascinating observations about the physiologic process of prehibernation as a model for insulin resistance, noting its association with weight gain, increased insulin, insulin resistance, increased free fatty acids, and increased coagulation.

Analyzing the mechanism of gemfibrozil's benefit in the prevention of atherosclerosis in the Veterans' Administration HDL Intervention Trial, Sander Robins, MD, Boston, showed fascinating evidence that standard lipid measurements do not explain the drug's effect, but that a "reduction in LDL particle number clearly predicted a reduction in events," suggesting a potentially important approach to the treatment of dyslipidemia in IRS.

Fredrik Karpe, MD, PhD, Oxford, United Kingdom, discussed postprandial lipid metabolism and the differing postload triglyceride responses of persons with IRS, reviewing studies with rosiglitazone in which postprandial triglycerides decreased more rapidly after treatment. This may be another aspect of dyslipidemia, which is difficult to assess clinically but which is importantly related to atherosclerosis.

Rowan Chlebowski, MD, PhD, Los Angeles, California, discussed modifiers of insulin action and breast cancer risk, noting that obesity is associated with both increased risk of developing breast cancer and worse outcome among women who have the disease. George Blackburn, MD, PhD, Boston, discussed the interrelationship between obesity and cancer, suggesting that we are "on the road to adding cancer [to IRS]," and that "insulin resistance [produces] disproportionately increased risk."

In a symposium on the polycystic ovary syndrome (PCOS), which is emerging as an important subset of IRS, Richard Legro, MD, Hershey, Pennsylvania, reviewed the evidence from genetic studies suggesting that the tendency to hyperandrogenism is the common factor underlying many cases. This finding implies that in PCOS, insulin resistance may not itself cause the abnormality of androgen metabolism. However, in another example of the "which comes first" question, Dr. Reaven characterized PCOS as "an ovary that is responding to insulin by hypersecretion of androgens." Robert Norman, MD, Woodville, Australia, reminded us of the role of lifestyle modification in the treatment of PCOS, showing impressive evidence of the efficacy of this approach. He stated that regardless of physician prescribing leading to "metformin flowing all over the place," one must always consider diet and exercise as crucial to treatment, and one must ask, "Why does our advice so often fail?"

In further assessment of lifestyle intervention, Edward Horton, MD, Boston, asked, "Can we stop the progression to diabetes and cardiovascular disease?" He reviewed a number of studies suggesting that this is indeed possible and showed studies of the mechanism of this effect in which lifestyle intervention improved insulin sensitivity, with evidence of increase in flow-mediated vasodilatation, a measure of endothelial function. Complementing this presentation, Vivian Fonseca, MD, New Orleans, Louisiana, presented a rollercoaster of the myriad pharmaceutical approaches potentially effective in the IRS, including metformin, acarbose, thiazolidinediones, insulin secretagogues, angiotensin-converting enzyme inhibitors, ARBs, statins, fibrates, orlistat, insulin, and aspirin. Robert Misbin, MD, Rockville, Maryland, gave a thoughtful assessment of the challenge of developing drugs to treat insulin resistance, asking, "What is needed to treat the IRS itself rather than its components?" He suggested that we need to come to agreement about appropriate standards for the assessment of efficacy in the treatment of the IRS, which may require a study similar to the landmark Diabetes Complications and Control Trial. The approach to be tested needs to have acceptable risk profile, and then a sponsor must submit a New Drug Application, which is not a trivial point. Metformin in many ways has optimal characteristics but is only indicated in approved labeling for the treatment of diabetes and is now available as a generic. Therefore, Dr. Misbin stated, "No one has an interest in the pharmaceutical industry for developing further applications" for this agent, due to the great cost of such studies. Dr. Reaven, addressing the question of developing approaches to the treatment of the IRS based on current data, suggested that overweight persons with modest degrees of hypertriglyceridemia are at greatest risk of developing atherosclerosis, and at present would appear to be the group most requiring clinical treatment, perhaps in a study comparing a new agent with gemfibrozil.

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