These pages are best viewed with Netscape version 3.0 or higher or Internet Explorer version 3.0 or higher. When viewed with other browsers, some characters or attributes may not be rendered correctly.SUMMARY Insulin Resistance and Hyperglycemic Associated Risk Factors Session summary Jean-Pierre Després, PHD A constellation of factors contribute to the substantial increase in the risk of macrovascular disease that is well documented in type 2 diabetic patients. The hazard resulting from this complex, "minestrone soup" of metabolic alterations is such that ~75% of diabetic patients will eventually die from complications of coronary heart disease (CHD) (1). It is also well recognized that the cluster of risk factors found in type 2 diabetes is the consequence, at least to a certain extent, of the presence of an impaired sensitivity of various tissues (skeletal muscle, adipose tissue, liver, etc.) to insulin (2). The abnormalities found among individuals characterized by an impaired in vivo insulin action have been regrouped around a unifying concept: the insulin resistance syndrome (3). Because this syndrome can be observed long before the development of type 2 diabetes (4) and even among euglycemic subjects who may never convert to type 2 diabetes (2,3), it has been difficult to sort out the independent contributions of insulin resistance and of the related hyperinsulinemia from the deleterious impact of hyperglycemia on CHD risk in type 2 diabetic patients. Several aspects of the discussion that followed this session were related to this question. Furthermore, the contribution of nondiabetic hyperglycemia as an independent CHD risk factor (5) after control for all metabolic abnormalities found in type 2 diabetes remains uncertain (6,7). There also seems to be an exponential increase in CHD risk associated with diabetic hyperglycemia, and the identification of threshold values remains a matter of ongoing debate (7). Thus, the shape of the relationship between hyperglycemia and CHD is likely to be different from the one observed between insulin (as a crude marker of insulin resistance) and CHD, for which a continuous increase in risk has been suggested by some investigators (8,9). Another important clinical consequence of the insulin resistance syndrome is that a substantial increase in CHD risk can be observed even in the absence of traditional risk factors, such as hypercholesterolemia, hypertension, and smoking (1,10). Indeed, the contribution of conventional risk factors appears to account for only one-fourth of the excess CHD in diabetic individuals (10).Thus, the insulin resistance syndrome represents quite a challenge with considerable public health implications, and it raises questions regarding our current approaches for tracking and managing patients at high risk of CHD (11). Of course, it is undoubtedly of critical importance to identify and treat type 2 diabetic patients and to aim at the management of traditional risk factors when they are present. However, the prevalence of insulin resistance among normocholesterolemic patients with documented CHD (or at very high risk of CHD) is such that carriers of the syndrome should be identified and their condition properly treated. Obviously, this question was beyond the scope of the present meeting, but it should receive a great deal of attention. The numerous clustering alterations that can be found in type 2 diabetic, insulin-resistant patients could act in synergy or even in interaction with hyperglycemia to further increase CHD risk beyond the hazards of insulin resistance (1). As reviewed by Dr. Yudkin, not only do these abnormalities frequently include hypertension and a typical atherogenic dyslipidemic state (which has been described in this meeting by other speakers), but type 2 diabetes is also associated with a prothrombotic profile and with an impaired fibrinolysis (11). In his talk, Dr. Yudkin elegantly reviewed the evidence that the elevated plasminogen activator inhibitor 1 (PAI-1) levels found in type 2 diabetic patients could be induced by several factors, such as hyperinsulinemia, proinsulin-like molecules, triglyceride-rich lipoproteins, and oxidized LDL. It is also important to emphasize that PAI-1 levels are equally elevated in nondiabetic insulin-resistant subjects (12,13), a finding that raises the question of the independent contribution of hyperglycemia to this prothrombotic alteration. Dr. Yudkin also suggested that a damaged capillary endothelium and an impaired endothelium-dependent vasodilatation could play a role in the development of insulin resistance. He proposed that acute-phase cytokines could be involved in the altered coagulation and in the endothelial dysfunction of type 2 diabetes. These results led to the suggestion that a common primary factor, for which an expanded visceral adipose tissue mass could be a likely candidate, plays a significant role in the etiology of the alterations of the coagulation-fibrinolysis system found in insulin-resistant subjects. Indeed, it is more and more widely recognized that adipose tissue is an
important secretory organ (14). Thus, overexpression of PAI-1 and
of interleukin-6 by the expanded visceral adipose tissue mass of insulin-resistant, type 2
diabetic patients could contribute to the altered endothelial function, the procoagulant
state, and ischemic heart disease in these patients, whereas visceral obesity itself is
now recognized as an important correlate of the insulin resistance–dyslipidemic
syndrome (15). Which cell type (endothelial cells, stromal cells,
preadipocytes, inflammatory cells) contributes the most to interleukin-6 production by the
hypertrophied adipose tissue of type 2 diabetic patients is another issue that will have
to be further examined. The role of another cytokine, tumor necrosis factor- This question was, to a certain extent, examined by Dr. King. He brilliantly reviewed theoretical mechanisms by which hyperglycemia and insulin resistance could lead to macrovascular disease in diabetes. Dr. King showed the evidence explaining how hyperglycemia—or what could be described as the "diabetic milieu"—activates the diacylglycerol (DAG)–protein kinase C (PKC) pathway. The fact that glycation products and oxidants can also increase the DAG-PKC system was also addressed. Dr. King then reviewed his working hypothesis (17), stating that the activated DAG-PKC pathway could therefore represent a common mechanism by which secondary metabolic products of glucose could have deleterious effects on CHD, including the PKC-mediated impact of hyperglycemia on endothelial responsiveness. It was also proposed that the loss of insulin action (due to insulin resistance or insulin deficiency) could also enhance the atherosclerotic process because of the important role of insulin on vascular function. Dr. King's talk led to the description of a theoretical working model by which hyperglycemia and the loss of insulin vascular effect (due to resistance to or deficiency of the hormone) could be two major alterations that explain the substantially increased risk of cardiovascular disease found in diabetic patients (18). The two talks generated considerable discussion, which largely dealt with the identification of primary defects, their genetic or environmental origin, and the hierarchy of the complex relationships among the numerous CHD metabolic risk factors of type 2 diabetes. In all aspects examined, the contribution of hyperglycemia or of the "diabetic milieu," as opposed to insulin resistance, was an issue that required clarification. Dr. King's thesis regarding the anti-atherogenic properties of insulin generated considerable discussion and obviously implied selective insulin resistance, an issue for which additional data are needed. Indeed, we poorly understand how vascular cells would not develop resistance to insulin, as opposed to the skeletal muscle and adipose tissue. Dr. King therefore proposed that insulin could have multiple anti-atherogenic (e.g., effect on NO production) and atherogenic actions on the vascular cells. The loss of these anti-atherogenic effects in insulin resistance, combined with some potential atherogenic effects of marked hyperinsulinemia, would lead to the acceleration of the atherosclerotic process (18). Thus, this model would explain CHD both in insulin-deficient and in insulin-resistant (hyperinsulinemic) states. The synergy with other components of the "diabetic milieu," including hyperglycemia, will have to be examined in the context of this working hypothesis. There were also attempts by some participants to integrate the
inflammatory aspects addressed by Dr. Yudkin with Dr. King's data on the transgenic mice
overexpressing PKC- In summary, Drs. Yudkin and King allowed us to explore additional
features of the insulin resistance syndrome that could contribute to exacerbate CHD risk
in type 2 diabetic patients beyond the atherogenic dyslipidemia that includes
hypertriglyceridemia, low HDL cholesterol levels, increased concentration of
apolipoprotein B-associated lipoproteins, and an increased proportion of small dense LDL
particles. To what extent the enlarged visceral adipose tissue mass (a common feature of
insulin resistance) and the increased free fatty acid turnover could be the common
antecedents leading to insulin resistance and to increased PAI-1 (19)
and cytokine production is a question that requires further investigation. Regarding Dr.
King's unifying model, it is unlikely that the hyperinsulinemia of insulin resistance is
atherogenic by itself (8,9), although this
issue is not fully resolved (20). Meanwhile, hyperinsulinemia
could be considered as a marker, albeit imperfect, of a cluster of additional
athero-thrombotic abnormalities that may not be adequately described by the traditional
CHD risk factors currently assessed by clinicians. This point could even be more relevant
to nondiabetic individuals with normal Acknowledgments — Research of the author was supported by the Canadian Diabetes Association, the Medical Research Council of Canada, and the Quebec Heart and Stroke Foundation. References 2. Reaven GM: Pathophysiology of insulin resistance in human disease. Physiol Rev 75:473–486, 1995 3. Reaven GM: Role of insulin resistance in human disease. Diabetes 37:1595–1607, 1988 4. Haffner SM, Stern MP, Hazuda HP, Mitchell BD, Patterson JK: Cardiovascular risk factors in confirmed prediabetic individuals: does the clock for coronary heart disease start ticking before the onset of clinical diabetes? JAMA 263:2893–2898, 1990 5. Gerstein HC, Yusuf S: Dysglycemia and risk of cardiovascular disease. Lancet 347:949– 950, 1996 6. Barrett-Connor E: Does hyperglycemia really cause coronary heart disease? Diabetes Care 20:1620–1623, 1997 7. Jarrett RJ: The cardiovascular risk associated with impaired glucose tolerance. Diabet Med 3:S15–S19, 1996 8. Després JP, Lamarche B, Mauriège P, Cantin B, Dagenais GR, Moorjani S, Lupien PJ: Hyperinsulinemia as an independent risk factor for ischemic heart disease. N Engl J Med 334:952–957, 1996 9. Després JP, Lamarche B, Mauriège P, Cantin B, Lupien PJ, Dagenais GR: Risk factors for ischaemic heart disease: is it time to measure insulin? Eur Heart J 17:1453–1454, 1996 10. Pyörälä K, Laakso M, Uusitupa M: Diabetes and atherosclerosis: an epidemiologic view. Diabetes Metab Rev 3:463–524, 1987 11.Yudkin JS: Lipids, thrombosis and cardiovascular disease in diabetes. Proc Nutr Soc 56:273–280, 1997 12. Juhan-Vague I, Alessi MC, Vague P: Increased plasma plasminogen activator inhibitor 1 levels: a possible link between insulin resistance and athero-thrombosis. Diabetologia 34:457–462, 1991 13. Vague P, Raccah D, Scelles V: Hypofibrinolysis and the insulin resistance syndrome. Int J Obes 19:S11–S15, 1995 14. Flier JS: The adipocyte: storage depot or node on the energy information super highway? Cell 80:15–18, 1995 15. Després JP: Dyslipidemia and obesity. Ballière's Clin Endocrinol Metab 8:629–660, 1994 16. Ofei F, Hurel S, Newkirk J, Sopwith M, Taylor R:
Effects of an engineered human anti-TNF- 17. Koya D, King GL: Protein kinase C activation and the development of diabetic complications. Diabetes 47:859–866, 1998 18. Feener EP, King GL: Vascular dysfunction in diabetes mellitus. Lancet 350:SI9–SI13, 1997 19. Alessi MC, Peiretti F, Morange P, Henry M , Nalbone G, Juhan-Vague I: Production of plasminogen activator inhibitor-1 by human adipose tissue: possible link between visceral fat accumulation and vascular disease. Diabetes 46:860–867, 1997 20. Stout RW: Insulin and athroma: 20 year perspective. Diabetes Care 13:631–655, 1990 21. Laakso M: How good a marker is insulin level for insulin resistance? Am J Epidemiol 137:959–965, 1993 22. Gaudet D, Vohl MC, Perron P, Tremblay G, Gagné C, Lesiège D, Bergeron J, Moorjani S, Després JP: Relationships of abdominal obesity and hyperinsulinemia to angiographically assessed coronary artery disease in men with known mutations in the LDL receptor gene. Circulation 97:871–877, 1998 23. Howard G, O'Leary DH, Zaccaro D, Haffner S, Rewers M, Hamman R, Selby JV, Saad MF, Savage P, Bergman R, IRAS investigators: Insulin sensitivity and atherosclerosis. Circulation 93:1809–1817, 1996 24. Shinozaki K, Suzuki M, Ikebuchi M, Takaki H, Hara Y, Tsushima M, Harano Y: Insulin resistance associated with compensatory hyperinsulinemia as an independent risk factor for vasospastic angina. Circulation 92:1749–1757, 1995 From the Lipid Research Center, Laval University Medical Research Center, Ste-Foy, Canada. Address correspondence and reprint requests to Jean-Pierre Després, PhD, Lipid Research Center, Laval University Medical Research Center, 2705 Blvd., Laurier, Ste-Foy, PQ, Canada G1V 4G2. Received for publication 24 August 1998 and accepted in revised form 12 November 1998. Abbreviations: CHD, coronary heart disease; DAG, diacylglycerol; PAI-1, plasminogen activator inhibitor 1; PKC, protein kinase C. A table elsewhere in this issue shows conventional and Système International (SI) units and conversion factors for many substances. This article is based on presentations at a conference organized by the Indiana University Diabetes Research and Training Center. The conference and the publication of this article were made possible by an unrestricted educational grant from Eli Lilly and Company. Copyright © 1999 American Diabetes Association For Technical Issues contact webmaster@diabetes.org |
, is—as mentioned by Dr. Yudkin
in the discussion period—more controversial in humans (
2 isoform
specifically in the myocardium. These mice develop cardiac hypertrophy, cardiomyocyte
injuries, and fibrosis early in life. Both speakers appeared to agree that the evidence
for an inflammatory component in diabetic cardiomyopathy was weak. Dr. Yudkin also
wondered about the factor responsible for the unopposed mitogen-activated protein kinase
action in the common insulin-resistant state found in the abdominally obese or type 2
diabetic patient. Dr. King added that any alteration, either of genetic or of
environmental origin, that caused vasoconstriction could be responsible for this
phenomenon. The challenge in future studies will be to understand the complex interactions
among the numerous potential modulators of the DAG–mitogen-activated protein kinase
pathway in insulin resistance and type 2 diabetes.