Insulin resistance, inflammation, and the prediabetic state

doi:10.1016/S0002-9149(03)00612-X

The American Journal of Cardiology

Volume 92, Issue 4, Supplement 1, 18 August 2003, Pages 18-26

https://doi.org/10.1016/S0002-9149(03)00612-X Get rights and content

Abstract

Type 2 diabetes is associated with a marked increase in the incidence of coronary artery disease (CAD); however, the correlation between glycemia and CAD in patients with type 2 diabetes is only modestly positive. This relatively weak association between glycemia and CAD in subjects with diabetes may be caused by the existence of an atherogenic prediabetic state. In the San Antonio Heart Study, subjects who start with normal glucose tolerance and later develop type 2 diabetes have increased triglyceride levels, increased systolic blood pressure, and decreased levels of high-density lipoprotein cholesterol before the onset of type 2 diabetes. The basis for these atherogenic prediabetic changes may be related to insulin resistance rather than reduced insulin secretion. Recently, interest has focused on a possible role of fibrinolysis and increased subclinical inflammation, as determined by high-sensitivity C-reactive protein (CRP) levels. The Insulin Resistance Atherosclerosis Study found that insulin resistance, as determined by a frequently sampled glucose tolerance test, is significantly related to higher CRP levels, higher fibrinogen, and higher plasminogen activator inhibitor–1 (PAI-1) levels. The investigators also have shown that high PAI-1 and CRP levels are predictors of the development of type 2 diabetes. In addition, the Women's Health Study has shown that high CRP levels predict type 2 diabetes. Insulin-sensitizing interventions have been demonstrated to reduce these nontraditional risk factors. Rosiglitazone, an agent with insulin-sensitizing properties, decreases PAI-1 and CRP levels. Some of the adverse cardiovascular effects seen in patients with type 2 diabetes may be reversed by insulin-sensitizing agents.

Section snippets

Cross-sectional association of insulin resistance and cardiovascular risk factors

Subjects with type 2 diabetes who are insulin resistant have decreased insulin secretion and increased hepatic glucose production.12 Cross-sectionally, insulin resistance has been associated with a variety of risk factors for cardiovascular disease, including elevated triglyceride and small, dense low-density lipoprotein (LDL) cholesterol levels, and decreased high-density lipoprotein (HDL) cholesterol levels.13, 14 Insulin resistance has been associated with a number of nontraditional risk

Predictors of type 2 diabetes

Many studies have shown that increased insulin concentrations and obesity predict the development of type 2 diabetes in groups, such as the Hispanic, Polynesian, Japanese American, and Native American populations.29, 30, 31, 32 In Hispanic individuals in the San Antonio Heart Study, the incidence of type 2 diabetes was predicted by elevated fasting insulin levels and glucose concentrations, obesity, and increased upper-body fat distribution.30 These risk factors are also multivariate predictors

Cardiovascular risk factors in subjects before development of diabetes

Several studies have suggested that increased cardiovascular risk factors exist before the onset of type 2 diabetes.6, 7, 8, 9, 10, 11, 35 In an earlier report from the San Antonio Heart Study,10 subjects who had normal glucose tolerance at baseline and who later developed type 2 diabetes had increased triglyceride levels, decreased HDL cholesterol levels, and increased systolic blood pressure, despite similar body mass indexes and central adiposity. Glucose levels were slightly, but

Nontraditional predictors of type 2 diabetes

Multiple studies37, 38, 39, 40 have suggested that nontraditional risk factors, such as fibrinogen, CRP, and interleukin-6, may predict the development of type 2 diabetes (Table 3), as recently reviewed by Pradhan and Ridker.41 In some cases, these nontraditional risk factors are independent of possible confounding variables, such as obesity, although only IRAS has taken into account the effect of insulin resistance. These data can be interpreted in a number of ways. The simplest issue is

Effect of peroxisome proliferator-activated receptor–γ agonists on markers of inflammation and plasminogen activator inhibitor–1

The effect of peroxisome proliferator-activated receptor–γ (PPAR-γ) agonists on levels of CRP concentrations was evaluated in 357 subjects with type 2 diabetes.45 The average BMI was 30, the average duration of diabetes was 4.7 years, and the average hemoglobin A_1c level was 8.7%. Patients treated with rosiglitazone, either 4 mg/day or 8 mg/day for 26 weeks, demonstrated a statistically significant (p <0.05) decrease in CRP levels when compared with baseline and placebo (Figure 8). This did

Conclusions

Type 2 diabetes markedly increases the incidence of CAD, but glucose concentrations in type 2 diabetes are only modestly related to CAD. A possible explanation for the relatively weak effect of glycemia for CAD in diabetes is the existence of an atherogenic prediabetic state. Numerous studies have shown that subjects before diabetes have an adverse pattern of dyslipidemia and increased blood pressure. More recently, increased levels of inflammatory markers (eg, CRP levels and impaired

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Citation Excerpt :
Non-diabetic first degree relatives of T2DM have increased obesity, insulin resistance (IR) and increased prevalence of cardiovascular risk associated with metabolic syndrome [3]. Inflammation and inflammatory cytokines have been postulated to be important additional pathogenetic factors in the development of insulin resistance and T2DM.Whether inflammation causes insulin resistance, or an epiphenomenon of obesity itself, remains unresolved [4]. C-reactive protein (CRP), a nonspecific marker of the inflammatory response, is most consistently associated with the development of T2DM [5]; however a causal association remains unproven.
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Insulin resistance, inflammation, and the prediabetic state

Abstract

Section snippets

Cross-sectional association of insulin resistance and cardiovascular risk factors

Predictors of type 2 diabetes

Cardiovascular risk factors in subjects before development of diabetes

Nontraditional predictors of type 2 diabetes

Effect of peroxisome proliferator-activated receptor–γ agonists on markers of inflammation and plasminogen activator inhibitor–1

Conclusions

Atherosclerosis

Am J Med

Diabetes and glucose tolerance as risk factors for cardiovascular diseasethe Framingham Study

Diabetes Care

Mortality and coronary heart disease in subjects with type 2 diabetes and in nondiabetic subjects with and without prior myocardial infarction

N Engl J Med

NIDDM and its metabolic control predict coronary heart disease in elderly subjects

Diabetes

Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35)prospective observational study

BMJ

Association of systolic blood pressure with macrovascular and microvascular complications of type 2 diabetes (UKPDS 36)prospective observational study

BMJ

Glucose tolerance and mortalitycomparison of WHO and American Diabetes Association diagnostic criteria: European Diabetes Epidemiology Group. Diabetes Epidemiology: Collaborative Analysis of Diagnostic Criteria in Europe (DECODE)

Lancet

Major factors in the development of diabetes mellitus in 10,000 men

Arch Intern Med

Cardiovascular disease risk factors prior to the diagnosis of impaired glucose tolerance and non-insulin-dependent diabetes mellitus in a community of older adults

Am J Epidemiol

Cardiovascular risk factors as predictors of type 2 (non-insulin-dependent) diabetes mellitus in elderly subjects

Diabetologia

Cardiovascular risk factors in confirmed prediabetic individualsdoes the clock for coronary heart disease start ticking before the onset of clinical diabetes?

JAMA

Lilly Lecture 1987. The triumviratebeta-cell, muscle, liver: a collusion responsible for NIDDM

Diabetes

Insulin resistance and hyperinsulinemia in individuals with small, dense low-density lipoprotein particles

J Clin Invest

Relative contribution of insulin and its precursors to fibrinogen and PAI-1 in a large population with different states of glucose tolerancethe Insulin Resistance Atherosclerosis Study (IRAS)

Arterioscler Thromb Vasc Biol

C-reactive protein and other markers of inflammation in the prediction of cardiovascular disease in women

N Engl J Med

High-sensitivity C-reactive proteinpotential adjunct for global risk assessment in the primary prevention of cardiovascular disease

Circulation

Production of C-reactive protein and risk of coronary events in stable and unstable anginaEuropean Concerted Action on Thrombosis and Disabilities Angina Pectoris Study Group

Lancet

C-Reactive protein, a sensitive marker of inflammation, predicts future risk of coronary heart disease in initially healthy middle-aged menresults from the MONICA (Monitoring Trends and Determinants in Cardiovascular Disease) Augsburg Cohort Study, 1984 to 1992

Circulation

C reactive protein and its relation to cardiovascular risk factorsa population-based cross-sectional study

BMJ

Lifetime smoking exposure affects the association of C-reactive protein with cardiovascular disease risk factors and subclinical disease in healthy elderly subjects

Arterioscler Thromb Vasc Biol

C-reactive protein in healthy subjects. Associations with obesity, insulin resistance, and endothelial dysfunctiona potential role for cytokines originating from adipose tissue?

Arterioscler Thromb Vasc Biol

Chronic subclinical inflammation as part of the insulin resistance syndromethe Insulin Resistance Atherosclerosis Study (IRAS)

Circulation

Is type II diabetes mellitus a disease of the innate immune system?

Diabetologia