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Biomedical subjects

G M Reaven

Publications and source records attributed to G M Reaven.

At least 19 recordsLinked to original sources
PubMed2007

The relationship between insulin resistance and dyslipidaemia in cigarette smokers.

AIM: Considerable evidence shows that cigarette smokers tend to have the dyslipidemic pattern of high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentrations, a highly atherogenic lipoprotein profile also typical of the insulin-resistant state even in the absence of cigarette smoking. However, because cigarette smokers are frequently insulin resistant, it is unclear if this dyslipidaemia is secondary to smoking, per se, or simply to the fact that smokers tend to be insulin resistant. The present study was initiated to determine whether this dyslipidaemia prevalent in cigarette smokers and characteristic of insulin-resistant individuals is a function of cigarette smoking or of insulin resistance. METHODS: As measured using vertical auto profile-II methodology, the lipid and lipoprotein concentrations were compared in 34 cigarette smokers divided into insulin-sensitive and insulin-resistant subgroups. The two groups were similar in age and body mass index, differing only in their insulin-mediated glucose uptake as quantified by the steady-state plasma glucose concentration determined during the insulin suppression test. RESULTS: While levels of TG and very low-density lipoprotein cholesterol (VLDL-C) were significantly elevated in insulin-resistant cigarette smokers, total cholesterol (C), low-density lipoprotein cholesterol (LDL-C), narrow-density (ND) LDL-C, intermediate-density lipoprotein-C (IDL-C), HDL-C and non-HDL-C were not different in the two groups. The insulin-resistant smokers also had a preponderance of small, dense LDL particles, while the reverse was true of the insulin-sensitive cigarette smokers. CONCLUSIONS: These data suggest that the dyslipidaemia previously attributed to smoking occurs primarily in those smokers who are also insulin resistant.

Adult↗
PubMed2005

Insulin resistance, the insulin resistance syndrome, and cardiovascular disease.

Insulin-mediated glucose disposal varies widely in apparently healthy human beings, and the more insulin resistant an individual, the more insulin they must secrete in order to prevent the development of type 2 diabetes. However, the combination of insulin resistance and compensatory hyperinsulinemia increases the likelihood that an individual will be hypertensive, and have a dyslipidemia characterized by a high plasma triglyceride (TG) and low high-density lipoprotein cholesterol (HDL-C) concentration. These changes increase risk of cardiovascular disease (CVD), and in 1988, this cluster of related abnormalities was designated as comprising a syndrome (X). Several other clinical syndromes are now known to be associated with insulin resistance and compensatory hyperinsulinemia. For example, polycystic ovary syndrome appears to be secondary to insulin resistance and compensatory hyperinsulinemia. More recently, studies have shown that the prevalence of insulin resistance/hyperinsulinemia is increased in patients with nonalcoholic fatty liver disease, and there are reports that certain forms of cancer are more likely to occur in insulin resistant/hyperinsulinemic persons. Finally, there is substantial evidence of an association between insulin resistance/hyperinsulinemia, and sleep disordered breathing. Given the rapid increase in the number of clinical syndromes and abnormalities associated with insulin resistance/hyperinsulinemia, it seems reasonable to suggest that the cluster of these changes related to the defect in insulin action be subsumed under the term of the insulin resistance syndrome. In addition to the identification of additional clinical syndromes related to insulin resistance/hyperinsulinemia, a number of new risk factors have been recognized that would increase CVD risk in these individuals. Thus, in addition to a high TG and a low HDL-C, the atherogenic lipoprotein profile in insulin resistant/hyperinsulinemic individuals also includes the appearance of smaller and denser low density lipoprotein particles, and the enhanced postprandial accumulation of remnant lipoproteins; changes identified as increasing risk of CVD. Elevated plasma concentrations of plasminogen activator inhibitor-1 (PAI-1) have been shown to be associated with increased CVD, and there is evidence of a significant relationship between PAI-1 and fibrinogen levels and both insulin resistance and hyperinsulinemia. Evidence is also accumulating that sympathetic nervous system (SNS) activity is increased in insulin resistant, hyperinsulinemic individuals, and, along with the salt sensitivity associated with insulin resistance/hyperinsulinemia, increases the likelihood that these individuals will develop essential hypertension. The first step in the process of atherogenesis is the binding of mononuclear cells to the endothelium, and mononuclear cells isolated from insulin resistant/hyperinsulinemic individuals adhere with greater avidity. This process is modulated by adhesion molecules produced by endothelial cells, and there is a significant relationship between degree of insulin resistance and the plasma concentration of the several of these adhesion molecules. Further evidence of the relationship between insulin resistance and endothelial dysfunction is the finding that asymmetric dimethylarginine, an endogenous inhibitor of the enzyme nitric oxide synthase, is increased in insulin resistant/hyperinsulinemic individuals. Finally, plasma concentrations of several inflammatory markers are elevated in insulin resistant subjects. It is obvious that the cluster of abnormalities associated with insulin resistance and compensatory hyperinsulinemia contains many well-recognized CVD risk factors, choosing which one, or ones, that are primarily responsible for the accelerated atherogenesis that characterizes this syndrome is not a simple task. Indeed, efforts to try to do so by the use of multiple regression analysis of epidemiological data may be more misleading than helpful.

Animals↗
PubMed2003

What is the contribution of differences in three measures of tumor necrosis factor-alpha activity to insulin resistance in healthy volunteers?

To address the potential role that tumor necrosis factor-alpha (TNF-alpha) might play in modulation of insulin resistance in healthy, nondiabetic individuals, we compared plasma TNF-alpha and soluble TNF-alpha receptor 2 (sTNF-R2) concentrations, as well as TNF-alpha polymorphisms, in 94 healthy individuals, stratified into insulin-resistant (IR) and insulin-sensitive (IS) groups based on their plasma insulin concentrations 120 minutes after oral glucose on 2 occasions (1993 and 2000). The IR group (n = 50; 29 men and 21 women) was in the upper quartile and the IS group (n = 44; 24 men and 20 women) in the lowest quartile of the distribution of post-glucose challenge insulin concentrations in a large unselected population (>50 v <23 microU/mL). The IR group had significantly higher values for body mass index, waist-to-hip girth, fasting and post-glucose challenge insulin concentrations, and fasting triglyceride concentrations, and lower high-density lipoprotein cholesterol concentrations as compared to the IS group. Despite the fact that they were relatively more obese, and insulin-resistant, plasma concentrations of TNF-alpha were similar in the IR (1.6 +/- 0.6 pg/mL) and IS (1.7 +/- 0.6 pg/mL) groups, as were the concentrations (5.4 +/- 1.4 v 5.8 +/- 2.0 pg/mL) of sTNF-R2. Furthermore, TNF-alpha polymorphisms (detected by polymerase chain reaction [PCR]) were similar in the 2 groups, with essentially identical allelic frequencies of the 238 (10.3% v 9.4%) and 308 polymorphisms (17.9% v 18.7%). In conclusion, plasma TNF-alpha and sTNF-R2 concentrations, as well as TNF-alpha gene polymorphisms, were not different in healthy volunteers stratified into IR and IS groups on the basis of their plasma insulin response to an oral glucose challenge. Given these data, it does not appear that differences in TNF-alpha activity contribute to the marked variations in insulin action that occur in healthy individuals.

Aged↗
PubMed2003

Lipoprotein risk factors for cardiovascular disease in patients with type 2 diabetes mellitus treated with oral antihyperglycaemic agents.

AIMS: To compare lipoprotein risk factors for cardiovascular disease (CVD) in patients with type 2 diabetes mellitus (DM) treated with a sulphonylurea (SU) compound only, metformin (MET) only, or combined SU + MET. METHODS: The study population consisted of 62 patients with type 2 DM, whose antihyperglycaemic treatment program had been stable for at least 3 months, divided into three groups: 26 patients in the SU group, 17 patients in the MET group and 19 patients in the SU + MET group. None of the patients were taking lipid-lowering drugs. Fasting venous blood samples were taken to measure concentrations of glucose, total cholesterol, triglycerides (TG), high-density lipoprotein-cholesterol (HDL-C), low-density lipoprotein-cholesterol (LDL-C) and remnant lipoprotein-cholesterol (RLP-C) as well as for determination of LDL particle diameter. RESULTS: The three groups were similar in terms of age, gender, body mass index and fasting plasma glucose concentrations. Total cholesterol concentrations were significantly lower (p < 0.05 for trend) in those treated with SU + MET as compared with the other two groups. However, there were no significant differences between the three groups in their plasma concentrations of TG, LDL-C, HDL-C or RLP-C; furthermore, the proportion of individuals within each treatment group with small LDL particle diameter was also not different. CONCLUSIONS: The lipoprotein profile of patients with type 2 DM, matched for level of fasting hyperglycaemia, was similar irrespective of treatment with SU alone, MET alone or SU + MET. Thus, we could not identify any changes in lipoprotein metabolism that could account for differences in risk of CVD as a function of treatment.

Blood Glucose↗
PubMed2002

Evaluation of the quantitative insulin sensitivity check index as an estimate of insulin sensitivity in humans.

The goal of this study was to compare estimates of insulin resistance generated by the quantitative insulin sensitivity check index (QUICKI) with a direct measure of insulin-mediated glucose disposal in healthy, nondiabetic volunteers. For this purpose, the results of measurements of plasma glucose and insulin concentrations in 490 nondiabetic, healthy subjects were used to compute several surrogate estimates of insulin resistance, and these values were compared with a direct measure of insulin-mediated glucose disposal. The results of this analysis showed that estimates of insulin resistance derived from use of QUICKI were significantly correlated (r = -.60, P <.001) with direct measures of insulin-mediated glucose in the 490 subjects studied. It was also noted that QUICKI estimates of insulin resistance were highly correlated with fasting insulin concentrations (r = -.98) and the homeostasis model assessment for insulin resistance (HOMA-IR, r = -.99). On the other hand, the correlation between all 3 of the surrogate methods for estimating insulin resistance and the direct assessment of insulin-mediated glucose disposal was relatively weak, i.e., r =.61, r =.64, and r = -.60) for fasting insulin concentration, HOMA-IR, and QUICKI, respectively. The results of these comparisons do not provide support for the superiority of QUICKI over other commonly used surrogate measures of insulin resistance based upon use of fasting insulin concentration or equations utilizing fasting insulin and glucose concentration. Furthermore, none of the 3 surrogate estimates can account for more than approximately 40% of the variability of the difference in insulin-mediated glucose disposal measured directly in 490 healthy, nondiabetic volunteers.

Homeostasis↗
PubMed2002

Metformin treatment lowers asymmetric dimethylarginine concentrations in patients with type 2 diabetes.

This study was initiated to see if plasma asymmetric dimethylarginine (ADMA) concentrations decreased in hyperglycemic patients with type 2 diabetes following metformin treatment, either as monotherapy or following its addition to sulfonylurea-treated patients. Fasting plasma glucose, dimethylarginine, and L-arginine concentrations were measured before and 3 months after the administration of a maximally effective dose of metformin to 31 patients with type 2 diabetes in poor glycemic control (fasting plasma concentrations > 9.7 mmol/L), while being treated with either diet (n = 16) or a maximal amount of a sulfonylurea compound (n = 15). Fasting plasma glucose concentration (mean +/- SEM) decreased to a similar degree (P <.01) in patients treated with either metformin alone (12.4 +/- 0.5 to 9.5 +/- 0.5 mmol/L) or when it was added to a sulfonylurea compound (14.1 +/- 0.5 to 10.6 +/- 0.9 mmol/L). The improvement in glycemic control was associated with similar decreases (P <.01) in ADMA concentrations in metformin (1.65 +/- 0.21 to 1.18 +/- 0.13 micromol/L) and sulfonylurea + metformin-treated patients (1.75 +/- 0.13 to 1.19 +/- 0.08 micromol/L). Plasma L-arginine concentrations were similar in the 2 groups at baseline and did not change in response to metformin. Thus, metformin treatment was associated with a favorable increase in the plasma L-arginine/ADMA ratio. These results provide the first evidence that plasma ADMA concentrations decrease in association with improved glycemic control in patients with type 2 diabetes and demonstrate that the magnitude of the change in metformin-treated patients was similar, irrespective of whether it was used as monotherapy or in combination with sulfonylurea treatment.

Arginine↗
PubMed2001

Relationship between plasma insulin concentration and plasma remnant lipoprotein response to an oral fat load in patients with type 2 diabetes.

OBJECTIVES: The goal of this study was to evaluate the relative effects of hyperglycemia and hyperinsulinemia on postprandial remnant lipoprotein (RLP) concentrations in newly diagnosed type 2 diabetics. BACKGROUND: Increases in fasting RLP concentration have been described in type 2 diabetics, as well as in insulin-resistant nondiabetics. Given the atherogenicity of RLPs, we have extended these observations by assessing postprandial RLP concentrations and observing that hyperglycemia was necessary for the increase in RLP concentrations. METHODS: Patients with type 2 diabetes were subdivided on the basis of their plasma insulin response to oral glucose into hyperinsulinemic (H-DM) and normoinsulinemic (N-DM) groups of 15 patients each. Plasma triglyceride (TG), RLP-TG and RLP cholesterol (RLP-C) concentrations were determined before and 2 and 4 h after an oral fat load in these patients and 10 control (CTL) subjects. RESULTS: Plasma TG, RLP-TG and RLP-C concentrations peaked 2 h after the fat load in the CTL group, returning to baseline within 4 h. In contrast, concentrations of these variables increased throughout the 4-h study in both groups of patients with type 2 diabetes. Total integrated plasma RLP-TG and RLP-C responses above baseline after the oral fat load were significantly higher in the H-DM group compared with the CTL (p = 0.019 and 0.009, respectively) or N-DM (p = 0.026 and 0.029, respectively) groups. Post-heparin lipoprotein lipase activities and apo E phenotypes were similar in the H-DM and N-DM groups. CONCLUSIONS: Remnant lipoprotein response to an oral fat load is significantly increased in hyperinsulinemic patients with type 2 diabetes. These changes may increase the risk of coronary heart disease in these individuals.

Adult↗
PubMed2001

Improvement in insulin sensitivity followed by ovulation and pregnancy in a woman with polycystic ovary syndrome who was treated with rosiglitazone.

OBJECTIVE: To determine the metabolic and reproductive effectiveness of rosiglitazone in polycystic ovary syndrome (PCOS). DESIGN: Case report. SETTING: Academic clinical practice and General Clinical Research Center. PATIENT(S): A 25-year-old woman with PCOS. INTERVENTION(S): Rosiglitazone maleate, 4 mg daily for 5 months until conception. MAIN OUTCOME MEASURE(S): Insulin sensitivity by steady-state plasma glucose technique; serum androgens, progesterone, and hCG; and pelvic ultrasound images. RESULT(S): Rosiglitazone treatment for 5 months improved insulin sensitivity, lowered serum free testosterone, and resulted in spontaneous ovulation and conception. CONCLUSION(S): Rosiglitazone is a promising insulin sensitizer for treatment of PCOS. Clinical trials are warranted.

Adult↗
PubMed2001

Familial factors in the antihypertensive response to lisinopril.

BACKGROUND: Although it is widely recognized that there are familial elements in the pathogenesis of hypertension, remarkably little is known about the influence of family history on response to specific antihypertensive agents. METHODS: This study was designed to address that issue by comparing the depressor response to lisinopril in a dose range of 10 to 40 mg in 74 patients enrolled as sibling pairs. Because all patients were treated with lisinopril, ambulatory blood pressure monitoring (ABPM), an objective measure not influenced by the investigators, was used to assess the primary blood pressure (BP) outcome variable. RESULTS: Diastolic BP was highly correlated between sibling pairs at baseline (r = 0.476; P < .03) and on treatment (r = 0.524; P = .0021). Ethnicity/race had a striking influence on lisinopril dose and response rate. Among African American patients, 23 of 28 reached the top dose of 40 mg/day, whereas only 14 of 36 Caucasian patients reached that dose level. Among Caucasians, 92% responded, and only 48% of African Americans. Responders were characterized by being younger and heavier, having significantly lower microalbuminuria at baseline, higher baseline renal plasma flow (RPF), and higher urinary kallikrein. CONCLUSION: Among Caucasians, the presence of a hypertensive sibling predicts a striking therapeutic response to angiotensin converting enzyme inhibition.

Adolescent↗
PubMed2001

Insulin resistance, dietary cholesterol, and cholesterol concentration in postmenopausal women.

Questions remain concerning the effect of variations in cholesterol intake on plasma cholesterol concentration, as well as on the role of factors modulating the metabolic impact of this dietary intervention. To define the impact of wide variations in dietary cholesterol intake on plasma total and low-density lipoprotein (LDL) cholesterol concentrations, as well as testing the hypothesis that resistance to insulin-mediated glucose disposal would accentuate the increase in plasma total and LDL cholesterol concentrations in response to a given increment in dietary cholesterol intake, we performed a prospective, randomized study comparing diets varying in cholesterol content in 65 healthy, postmenopausal women, 31 defined as insulin-resistant and 34 as insulin-sensitive. The changes in total and LDL cholesterol in response to increments in dietary cholesterol of up to approximately 800 mg/day were modest in magnitude, without evidence of a statistically significant diet-induced increase in cholesterol concentration, or of any difference in the responses of insulin-resistant as compared with insulin-sensitive women. These results indicate that relatively large increments in dietary cholesterol intake had little effect on total or LDL cholesterol concentrations in healthy, postmenopausal women, irrespective of whether they were insulin-resistant or insulin-sensitive.

Apolipoproteins A↗
PubMed2001

Metabolic changes following sibutramine-assisted weight loss in obese individuals: role of plasma free fatty acids in the insulin resistance of obesity.

The relationship between insulin-mediated glucose disposal and daylong free fatty acid (FFA) concentrations before and after sibutramine-assisted weight loss was investigated in 24 healthy, normotensive, nondiabetic, obese women (body mass index [BMI] >30.0 kg/m(2)). The 24 volunteers were defined as being insulin-resistant (IR) or insulin-sensitive (IS) on the basis of their steady-state plasma glucose (SSPG) concentration in response to a 180-minute continuous intravenous infusion of octreotide, insulin, and glucose. The mean (+/- SEM) SSPG concentrations were significantly higher (P <.001) in the IR group (219 +/- 7 v 69 +/- 6 mg/dL) at baseline. The IR group also had significantly higher plasma glucose (P =.002), insulin (P <.001), and FFA (P =.02) concentrations measured at hourly intervals from 8 AM to 4 PM, before and after breakfast (8 AM) and lunch (noon). Weight loss in response to an energy-restricted diet for 4 months and sibutramine (15 mg/d) was comparable in the 2 experimental groups (8.6 +/- 1.3 v 7.9 +/- 1.4 kg). SSPG concentrations decreased significantly (P <.001) following weight loss (219 +/- 7 to 144 +/- mg/dL) in the IR group, but there was no change in the SSPG of the IS group (69 +/- 6 to 73 +/- 7 mg/dL. The improvement in insulin sensitivity in the IR group after weight loss was associated with a significant decline in daylong plasma glucose (P >.001) and insulin (P =.02) concentrations, without a weight-loss-associated decrease in daylong plasma FFA responses. In contrast, there was no significant change in plasma glucose, insulin, and FFA concentrations following weight loss in the IS group. These results indicate that daylong FFA concentrations vary substantially in obese individuals as a function of whether they are IR or IS. Furthermore the observation that the IR group was more insulin-sensitive after weight loss, associated with lower daylong insulin concentrations in the absence of a significant decrease in circulating FFA concentrations, suggests that resistance to insulin-mediated glucose disposal in obese individuals cannot be entirely due to high FFA levels.

Adipose Tissue↗
PubMed2001

Effect of insulin resistance on postprandial elevations of remnant lipoprotein concentrations in postmenopausal women.

BACKGROUND: Questions remain as to why postmenopausal women are at a higher risk of coronary artery disease (CAD) than are premenopausal women. Studies have shown that plasma concentrations of remnant lipoproteins (RLPs) are elevated in patients with CAD and that increases in plasma RLP concentrations may be related to variations in insulin-mediated glucose disposal. OBJECTIVE: We sought to evaluate the possibility that postprandial accumulation of plasma RLPs will be accentuated in insulin-resistant, postmenopausal women. DESIGN: Postmenopausal women were divided into insulin-sensitive (n = 15) and insulin-resistant (n = 15) groups according to their steady state plasma glucose concentrations in response to a 180-min infusion of octreotide, insulin, and glucose. Plasma insulin, triacylglycerol, and RLP-cholesterol concentrations were measured either hourly (insulin) or every 2 h (triacylglycerol and RLP cholesterol) for 8 h, before and after breakfast (0800) and lunch (1200). RESULTS: By selection, insulin-resistant women had higher steady state plasma glucose concentrations than did insulin-sensitive women (10.8 +/- 0.5 compared with 4.1 +/- 5 mmol/L, respectively; P < 0.001), associated with higher fasting triacylglycerol (1.58 +/- 0.04 compared with 1.00 +/- 0.03 mmol/L; P = 0.01) and lower HDL-cholesterol (1.06 +/- 0.08 compared with 1.34 +/- 0.05; P = 0.01) concentrations. In addition, measurements of daylong concentrations of insulin, triacylglycerol, and RLP cholesterol were also significantly greater in insulin-resistant than in insulin-sensitive women (P < 0.001). CONCLUSIONS: Postprandial accumulation of RLPs is accentuated in insulin-resistant, postmenopausal women. This may contribute to the increased risk of CAD in these individuals.

Blood Glucose↗
PubMed2001

Insulin resistance as a predictor of age-related diseases.

The current study was initiated to evaluate the ability of insulin resistance to predict a variety of age-related diseases. Baseline measurements of insulin resistance and related variables were made between 1988-1995 in 208 apparently healthy, nonobese (body mass index < 30 kg/m2) individuals, who were then evaluated 4-11 yr later (mean +/- SEM = 6.3 +/- 0.2 yr) for the appearance of the following age-related diseases: hypertension, coronary heart disease, stroke, cancer, and type 2 diabetes. The effect of insulin resistance on the development of clinical events was evaluated by dividing the study group into tertiles of insulin resistance at baseline and comparing the events in these 3 groups. Clinical endpoints (n = 40) were identified in 37 individuals (18%) of those evaluated, including 12 with hypertension, 3 with hypertension + type 2 diabetes, 9 with cancer, 7 with coronary heart disease, 4 with stroke, and 2 with type 2 diabetes. Twenty-eight out of the total 40 clinical events were seen in 25 individuals (36%) in the most insulin-resistant tertile, with the other 12 occurring in the group with an intermediate degree of insulin resistance. Furthermore, insulin resistance was an independent predictor of all clinical events, using both multiple logistic regression and Cox's proportional hazards analysis. The fact that an age-related clinical event developed in approximately 1 out of 3 healthy individuals in the upper tertile of insulin resistance at baseline, followed for an average of 6 yr, whereas no clinical events were observed in the most insulin-sensitive tertile, should serve as a strong stimulus to further efforts to define the role of insulin resistance in the genesis of age-related diseases.

Age Factors↗
PubMed2001

[Insulin resistance: why is it important to treat?].

The ability of insulin to stimulate muscle glucose disposal and inhibit adipose tissue lipolysis is impaired in patients with type 2 diabetes. The progression from normal glucose tolerance and/or impaired glucose tolerance to type 2 diabetes only occurs when insulin secretory function declines to a degree that circulating insulin concentrations are no longer able to overcome muscle and adipose tissue insulin resistance. Although, ambient plasma insulin concentrations are not sufficiently high to maintain euglycaemia in patients with type 2 diabetes, absolute plasma insulin concentrations in these individuals are as high, if not higher, than in nondiabetic subjects. Since the plasma concentrations of insulin, or free fatty acids (FFAs), or both, are elevated in patients with type 2 diabetes secondary to muscle and adipose tissue insulin resistance, hypertriglyceridaemia is common in these individuals. Improvement in glycaemic control with insulin or insulin secretagogues is achieved by raising plasma insulin concentrations to a level high enough to overcome the insulin resistance. This is not the case with thiazolidinediones (TZDs): glycaemic control is associated with lower plasma insulin concentration. Compounds that improve insulin sensitivity and lead to lower glucose and insulin concentrations may have unique clinical benefit in the treatment of patients with type 2 diabetes.

Adipose Tissue↗
PubMed2000

Hyperinsulinemia: the missing link among oxidative stress and age-related diseases?

Mounting evidence supports Harman's hypothesis that aging is caused by free radicals and oxidative stress. Although it is known that oxidant species are produced during metabolic reactions, it is largely unknown which factor(s), of physiological or pathophysiological significance, modulate their production in vivo. In this hypothesis paper, it is postulated that hyperinsulinemia may have such function and therefore promote aging, independently of elevations of glycemia. Hyperinsulinemia is secondary to impaired insulin stimulated glucose metabolism at the level of skeletal muscle (insulin resistance) and is seen in about one third of glucose tolerant humans following dietary carbohydrate intake. If other insulin-stimulated (or inhibited) pathways retain normal sensitivity to the hormone, hyperinsulinemia could, by its effects on antioxidative enzymes and on free radical generators, enhance oxidative stress. Other proaging effects of insulin involve the inhibition of proteasome and the stimulation of polyunsaturated fatty acid (PUFA) synthesis and of nitric oxide (NO). The hypothesis that hyperinsulinemia accelerates aging also offers a metabolic explanation for the life-prolonging effect of calorie restriction and of mutations decreasing the overall activity of insulin-like receptors in the nematode Caenorhabditis elegans.

Aging↗