High cumulative insulin exposure: a risk factor of atherosclerosis in type 1 diabetes?

Muis, Marian J.; Bots, Michiel L.; Bilo, Henk J. G.; Hoogma, Roel P.L.M.; Hoekstra, J. B. L.; Grobbee, Diederick E.; Stolk, Ronald P.

doi:10.1016/j.atherosclerosis.2005.01.004

Cited by 33 publications

(23 citation statements)

References 58 publications

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“…Despite the fact that our study was not sufficiently powered to detect the diabetes-related differences in IMT which have been reported by Jarvisalo (7), we observed a thicker carotid intima media in the children receiving higher insulin doses (corrected for weight) as also observed in a survey of adult type 1 diabetic patients (15). Both these factors were negatively related to FMD.…”

Section: Endothelium and Sod In Diabetic Childrencontrasting

confidence: 46%

Impact of Oxidative Stress on the Endothelial Dysfunction of Children and Adolescents With Type 1 Diabetes Mellitus: Protection by Superoxide Dismutase?

et al. 2007

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Diabetes mellitus is associated with endothelial dysfunction and oxidative stress (OS). We investigated whether these abnormalities are interrelated in children and adolescents with type 1 diabetes mellitus (T1DM) and if early OS markers predictive of vascular dysfunction can be identified. Thirty-five T1DM patients were matched for sex, age, height, and weight with nondiabetic subjects as healthy controls (CO). Flow-mediated dilatation (FMD), carotid intima media thickness (IMT), and OS status in fasting blood were measured. Diabetic children had impaired FMD (6.68 Ϯ 1.98 versus 7.92 Ϯ 1.60% in CO, p ϭ 0.004), which was more pronounced in boys. The degree of FMD impairment was not related to the lower plasma levels of antioxidants or to the higher glucose, glycation, lipids, and peroxidation products. Erythrocyte superoxide dismutase activity, copper/zinc superoxide dismutase (Cu/Zn SOD), was higher in diabetic subjects (1008 Ϯ 224 versus 845 Ϯ 195 U/g Hb in CO, p ϭ 0.003) and was positively associated with FMD. After correcting for diabetes and gender, the subgroup of children with high Cu/Zn SOD (Ͼ955 U/g Hb) had a significantly better FMD (p ϭ 0.035). These results suggest that higher circulating Cu/Zn SOD could protect T1DM children and adolescents against endothelial dysfunction. Low Cu/Zn SOD is a potential early marker of susceptibility to diabetic vascular disease. (Pediatr Res 62: 456-461, 2007) D iabetes mellitus is an important risk factor for atherosclerosis and both the incidence and mortality of cardiovascular disease are increased in diabetic patients (1). Among the various pathophysiological mechanisms mediating the atherosclerotic process, both oxidative stress (OS) and endothelial dysfunction occur at an early stage in animal models of diabetes (2).Oxidative stress is defined as the change in the pro-oxidant/ antioxidant balance in favor of the former, potentially leading to biologic damage to macromolecules and cell dysfunction (3). As a result of hyperglycemia, excessive pro-oxidants (free radicals and reactive oxygen species) are formed via autooxidation of glucose, nonenzymatic glycation and formation of advanced glycation end products, increased flux through the polyol and hexosamine pathways, and activation of protein kinase C. These processes also lead to decreased antioxidant defenses. Brownlee (4) has linked all these abnormalities to the excessive production of superoxide by the mitochondria.In children with type 1 diabetes mellitus (T1DM), increased OS has been reported to be present even shortly after diagnosis (5). Other reports showed the parallelism between OS and abnormal markers of endothelial cell function (such as ESelectin and ICAM-1) in young T1DM patients, suggesting a link between these two abnormalities (6). Ultrasound testing of skin microcirculation and of brachial artery flow-mediated dilatation (FMD) have demonstrated early endothelial dysfunction in diabetic children and adolescents (7).Since it has been shown that foam cell accumulation in the vascular w...

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Section: Endothelium and Sod In Diabetic Childrencontrasting

confidence: 46%

Impact of Oxidative Stress on the Endothelial Dysfunction of Children and Adolescents With Type 1 Diabetes Mellitus: Protection by Superoxide Dismutase?

et al. 2007

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“…Thus, the significant associations observed in the age-and sex-adjusted models were no longer statistically significant after the adjustment for several confounders and the propensity score. Although some studies showed positive associations between the use of exogenous insulin and the development of CVD, findings from randomized controlled clinical trials showed that the benefits of tight glycemic control in reducing the risk of long-term complications of diabetes (i.e., retinopathy, nephropathy, and neuropathy) outweigh the possible harmful effects of exogenous insulin treatment (13,23). The University Group Diabetes Program showed no evidence that insulin treatment influenced the risk of CVD or mortality (24) in individuals with type 2 diabetes.…”

Section: Discussionmentioning

confidence: 99%

“…The rationale has been based on results from clinical and experimental studies that demonstrated the influence of exogenous insulin on arterial wall changes that ultimately contributed to the development of atherosclerosis (11)(12)(13). However, increased levels of endogenous insulin and the use of exogenous insulin have been associated with increased cardiovascular morbidity and mortality in some studies (3,5-7,9) but not in others (2, 14,15).…”

mentioning

confidence: 99%

Relationship of Glycemic Control, Exogenous Insulin, and C-Peptide Levels to Ischemic Heart Disease Mortality Over a 16-Year Period in People With Older-Onset Diabetes

et al. 2008

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OBJECTIVE—The purpose of this study was to examine the relationship of glycemic control and exogenous and endogenous insulin levels with all-cause and cause-specific mortality (ischemic heart disease and stroke) in an older-onset diabetic population. RESEARCH DESIGN AND METHODS—The Wisconsin Epidemiologic Study of Diabetic Retinopathy (WESDR) is an ongoing, prospective, population-based cohort study of individuals with diabetes first examined in 1980–1982. A stratified sample of all individuals with diabetes diagnosed at 30 years of age or older was labeled “older-onset” (n = 1,370). Those participating in the 1984–1986 examination phase (n = 1,007) were included in the analysis. Endogenous insulin was determined by measurements of plasma C-peptide (in nanomoles per liter), and exogenous insulin was calculated in units per kilogram per day. Glycemic control was determined by levels of glycosylated hemoglobin (HbA1). RESULTS—After 16 years of follow-up, 824 individuals died (all-cause mortality); 358 deaths involved ischemic heart disease and 137 involved stroke. C-peptide and HbA1 were significantly associated with all-cause and ischemic heart disease mortality in our study. The hazard ratio (95% CI) values for all-cause mortality were 1.12 (1.07–1.17) per 1% increase in HbA1, 1.20 (0.85–1.69) per 1 unit · kg−1 · day−1 increase in exogenous insulin, and 1.15 (1.04–1.29) per 1 nmol/l increase in C-peptide and for ischemic heart disease mortality were 1.14 (1.06–1.22), 1.50 (0.92–2.46), and 1.19 (1.02–1.39) for HbA1, exogenous insulin, and C-peptide, respectively, after adjusting for relevant confounders. C-peptide was associated with stroke mortality only among men (1.65 [1.07–2.53]). CONCLUSIONS—Our results show that individuals with higher endogenous insulin levels are at higher risk of all-cause, ischemic heart disease, and stroke mortality.

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“…We calculated the drug-specific daily doses as drug strength and a multiple of pills per day (PPD) which is a function of metric quantity. For those drugs (2) that were missing metric quantity, we assessed the vendor supplied cost-derived imputations from the prescription claims. The estimated values of metric quantity were not equivalent with either clinically-derived values or datadriven estimates for metric quantity.…”

Section: Assessment Of Exposure-response Relationships Using a Time-vmentioning

confidence: 99%

“…Advancing age, comorbid conditions, and cumulative drug exposures contribute to long-term health outcomes among persons with chronic diseases [1][2][3]. Historically, observational studies using administrative pharmacy claims characterize drug exposure as either dichotomized variables or as cumulative CrossMark ← Click for updates doi: 10.7243/2054-9911-3-2 exposure for drug class, combination regimens, or specific drugs [4].…”

Section: Introductionmentioning

confidence: 99%

Assessment of risk in longitudinal observational studies with time-varying drug exposures for treatment of a chronic disease

Youk¹,

Mundy²,

Laurent³

et al. 2015

Epidemiol Rep

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Background: Drug exposures can be continuous or intermittent with several competing exposures which can influence the analysis of exposure-response relationships in longitudinal observational data. Purpose: We report the in-depth application of research methods employed in a nested case-control study to assess risk for fracture among persons with human immunodeficiency virus (HIV) infection treated with antiretroviral (ARV) therapy. These pharmacoepidemiological research methods, extrapolated from occupational epidemiology, permitted detailed exposure-response analysis in longitudinal observational data sources. Methods: Multidrug administrative prescription claims data were reformatted to create time-varying, nonoverlapping drug exposure histories that preserved the information in the original prescriptions. We applied research methods from occupational health to estimate drug-class (N=5) and drug-specific (N=29) exposure summary measures associated with fracture events. Results: Using pharmacy claims from the Clinformatics™ DataMart Multiplan (IMPACT) database, a product of OptumInsight Life Sciences, Inc., 1,929,067 prescription histories from 30,405 ARV-treated HIV subjects were restructured retaining gaps and removing overlaps and encompassments in the prescription histories. Most subjects were dispensed at least three different ARV drugs; over 75% had prescription histories with at least one gap in prescriptions and 23.5% had over 65 prescription claims. Drug exposure summary metrics were computed from the restructured claims to determine time-varying exposureresponse relationships for individual ARV drug exposures and fractures. Conclusions: We report a research method to assess drug exposure using administrative prescription claims in observational data that goes beyond dichotomous or cumulative exposures measurements of HIV drug classes and specific ARV drugs. The time-varying measures derived here are easily applicable to other observational data sources such as drug exposures for other chronic diseases where prescription histories are complex and evolve over time.

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High cumulative insulin exposure: a risk factor of atherosclerosis in type 1 diabetes?

Cited by 33 publications

References 58 publications

Impact of Oxidative Stress on the Endothelial Dysfunction of Children and Adolescents With Type 1 Diabetes Mellitus: Protection by Superoxide Dismutase?

Impact of Oxidative Stress on the Endothelial Dysfunction of Children and Adolescents With Type 1 Diabetes Mellitus: Protection by Superoxide Dismutase?

Relationship of Glycemic Control, Exogenous Insulin, and C-Peptide Levels to Ischemic Heart Disease Mortality Over a 16-Year Period in People With Older-Onset Diabetes

Assessment of risk in longitudinal observational studies with time-varying drug exposures for treatment of a chronic disease

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