Insulin response to oral glucose load is associated with coronary artery disease in subjects with normal glucose tolerance

AIM: The critical role of hyperinsulinemia, independent of hyperglycemia, in the pathogenesis of atherosclerosis has not been fully determined. We investigated the association between secretion patterns of insulin after oral glucose load and the severity of coronary artery disease (CAD) in patients with normal glucose tolerance (NGT). METHODS: We enrolled 116 subjects with NGT from 243 patients who had undergone coronary angiography and a standard 75-g oral glucose tolerance test. The patients were divided into 0-vessel, single-vessel and multi-vessel disease groups on the basis of the severity of CAD. RESULTS: The 2-h insulin levels in the multi-vessel disease group (p=0.005) and the single-vessel disease group (p<0.05) were significantly higher than those in the 0-vessel disease group. Multivariate analysis revealed that the levels of 2-h insulin were an independent variable for the presence of CAD (p=0.02) after adjustment for gender and the presence of each criterion of metabolic syndrome using the definition of the International Diabetes Federation. CONCLUSION: A slight but significant increase in prolonged insulin secretion, which is associated with the early stage of insulin resistance, in subjects with NGT, may play an important role in the pathogenesis of atherosclerosis.     

Insulin resistance and coronary artery disease

Summary The purpose of the present study was to quantitate insulin-mediated glucose disposal in normal glucose tolerant patients with angiographically documented coronary artery disease (CAD) and to define the pathways responsible for the insulin resistance. We studied 13 healthy, normal weight, normotensive subjects with angiographically documented CAD and 10 age-, weight-matched control subjects with an oral glucose tolerance test and a 2-h euglycaemic insulin (40 mU · m⁻²· min⁻¹) clamp with tritiated glucose and indirect calorimetry. Lean body mass was measured with tritiated water. All CAD and control subjects had a normal oral glucose tolerance test. Fasting plasma insulin concentration (66 ± 6 vs 42 ± 6 pmol/l, p < 0.05) and area under the plasma insulin curve following glucose ingestion (498 ± 54 vs 348 ± 42 pmol · l⁻¹· min⁻¹, p < 0.001) were increased in CAD vs control subjects. Insulin-mediated whole body glucose disposal (27.8 ± 3.9 vs 38.3 ± 4.4 μmol · kg fat free mass (FFM)⁻¹· min⁻¹, p < 0.01) was significantly decreased in CAD subjects and this was entirely due to diminished non-oxidative glucose disposal (8.9 ± 2.8 vs 20.0 ± 3.3 μmol · kg FFM⁻¹· min⁻¹, p < 0.001). The magnitude of insulin resistance was positively correlated with the severity of CAD (r = 0.480, p < 0.05). In the CAD subjects basal and insulin-mediated rates of glucose and lipid oxidation were normal and insulin caused a normal suppression of hepatic glucose production. In conclusion, subjects with angiographically documented CAD are characterized by moderate-severe insulin resistance and hyperinsulinaemia and should be included in the metabolic and cardiovascular cluster of disorders that comprise the insulin resistance syndrome or ’syndrome X'. [Diabetologia (1996) 39: 1345–1350] Received: 6 February 1996 and in revised form: 29 May 1996     

Inflammatory response to percutaneous coronary intervention in stable coronary artery disease

Percutaneous coronary intervention (PCI) can be regarded as a model for mechanical induced plaque rupture. The objective of this study was to evaluate the inflammatory response to PCI in stable coronary artery disease (CAD) by analysing plasma levels of a wide range of inflammatory mediators. Consecutively, we included 36 patients with stable angina pectoris after successful revascularization by PCI with implantation of a bare metal stent (BMS) or a drug eluting stent (DES). Patients were followed for 7 days with serial measurements of inflammatory mediators in plasma. C-reactive protein (CRP) and Pentraxin 3 showed a statistical significant early increase after PCI peaking at 3 days and 3 h, respectively. Vascular cell adhesion molecule-1 (VCAM-1) increased significantly with a peak at 3 days, while E-selectin showed a statistical significant gradual decrease. Markers of platelet mediated inflammation showed increasing (CD40 ligand) and decreasing (P-selectin) levels after PCI. While monocyte chemoattractant protein, CCL21 and CXCL16 increased rapidly in response to PCI, Interleukin-8, CCL19 and RANTES decreased. Patients with DES had significantly lower levels of VCAM-1 and RANTES compared to those with BMS. A femoral access site was associated with higher CRP levels than a radial access site. The use of glycoprotein-IIb/IIIa-inhibitors was associated with significantly higher CD40L and RANTES levels. Our findings underscore the complex nature of the inflammatory responses during PCI in stable CAD, and suggest that simultaneous measurements of several markers may be needed to characterize these PCI-related responses. The responses were only in a minor degree influenced by stent type, access site and the use of glycoprotein-IIb/IIIa-inhibitors.     

Insulin resistance affects endothelium-dependent acetylcholine-induced coronary artery response.

AIMS: This study was designed to investigate the relationship between insulin resistance and the acetylcholine-induced endothelium-dependent coronary artery response in patients without angiographically significant atherosclerotic coronary artery disease and to elucidate the pathophysiological significance of insulin resistance in the early stages of coronary atherosclerosis. METHODS AND RESULTS: Insulin resistance was calculated from fasting plasma glucose and insulin concentration using homeostasis model assessment in 40 patients suspected of having ischaemic heart disease, but without angiographic evidence of atherosclerotic coronary artery disease defined as a discrete stenosis or intimal irregularity. They were selected for an acetylcholine provocation test in both left and right coronary arteries. The homeostasis model assessment level was higher in 16 acetylcholine-positive patients than in 24 acetylcholine-negative patients (1.84+/-1.24 vs 0.72+/-0.62, P<0.01). Comparisons of the percentage change in vessel lumen diameter after the acetylcholine test in each of proximal, mid and distal segments of three coronary arteries among the three groups of low (less than 0.7; n=13), intermediate (0.7 to 1.4; n=13), and high homeostasis model assessment level (more than 1.4; n=14) revealed that a higher level resulted in a worse acetylcholine-induced constrictive response in coronary arteries. CONCLUSION: These results suggest that there is an association between high insulin resistance and coronary vascular endothelial cell dysfunction, and that insulin resistance may be an indicator of early stage coronary artery atherosclerosis not detectable by angiography.     

Insulin and growth hormone responses to glucose loading in treated acromegalics

Summary The insulin and growth hormone responses to oral glucose load (100 g) in 23 acronaegalic patients, previously treated by external irradiation, are described. Based on current clinical findings, sixteen acromegalics were considered inactive and seven patients active. Two of the latter were treated diabetics. Thirteen healthy, non-obese subjects formed the control group. Five inactive acromegalics had blood glucose values exceeding the upper limits of normal after the glucose load. Both the inactive and active acromegalics had hyperinsulinemia in the fasting state and after glucose load. The observation of an exaggerated serum insulin response to glucose load in clinically inactive acromegalics suggested that chronically elevated levels of circulating growth hormone may have led to permanent changes in the responsiveness of the pancreatic islets to glucose stimulation. The mean fasting value of serum growth hormone was about the same in the controls and the inactive acromegalics; the latter did not show suppression in serum growth hormone levels after glucose load.Research Fellow, Medical Research Council of Canada     

Impaired chronotropic response to beta-stimulation in chronic coronary artery disease

A male patient with angiographically verified coronary artery disease and poor cardioacceleration upon physical exercise was studied to detect the defect in sinus node function. The intrinsic fire-off rate of the node was normal as assessed by atrial pacing and pharmacologic interventions. The response of plasma catecholamines to exercise was normal. The infusion of isoprenaline either alone or after inhibition of phosphodiesterase by theophylline resulted in poor cardioacceleration. The plasma levels of cyclic adenosine monophosphate (cyclic AMP) after both isoprenaline and glucagon challenge were within normal limits. Plasma free fatty acids were adequately increased by isoprenaline stimulation. Damage to the sinus node betareceptors was the most plausible explanation for the limited chronotropic response despite normal sinus rhythm.     

Variable response to clopidogrel in patients with coronary artery disease

Antiplatelet drug resistance is a multifactorial phenomenon that affects a large number of cardiovascular patients with symptomatic coronary artery disease. Although unique definitions for aspirin and clopidogrel resistance are missing, there is growing evidence for a clinical importance of response to antiplatelet therapy. The prevalence for aspirin and clopidogrel resistance has been reported to be between 5 and 30% in literature. Moreover, recent data suggest a high rate of dual antiplatelet drug resistance. Although there are convincing data about an association of aspirin resistance and clinical outcome, little is known about the clinical relevance of clopidogrel hyporesponsiveness. This article reviews the evidence for the clinical impact of antiplatelet drug resistance, with particular attention on the clinical outcome of clopidogrel low response according to current clinical data. Additional systematic studies are needed to evaluate the effects of alternative antiplatelet therapies in patients identified as low responders.     

Studies in prediabetes. Insulin response to oral glucose,intravenous tolbutamide and rapid intravenous glucose infusion in genetic prediabetics

Summary Twenty-two non-obese genetic prediabetics (offspring with both parents diabetic) were compared with 34 normal volunteers, closely matched by age and weight, in their response to three standardized stimuli: oral glucose tolerance test (with 100 g of glucose), intravenous tolbutamide tolerance test (1 g) and rapid intravenous glucose infusion (0.33 g/kg body weight). Blood sugar, immunoreactive insulin and non-esterified fatty acids (N.E.F.A.) were estimated in both groups in the fasting state and at different time intervals during each of the three tests. — Results showed no significant differences (either in carbohydrate tolerance or in the behaviour of the N.E.F.A. levels) between normals and prediabetics at any time in the course of the selected tests. Plasma immunoreactive insulin fasting levels were also closely comparable in both groups, no significantly different insulin release in normals and prediabetics being elicited either by the oral glucose load or by the intravenous tolbutamide injection. However, the rapid intravenous glucose infusion brings about a markedly diminished insulin secretion in the prediabetic group limited to the very early response phase. — Our results strongly support the idea that an impaired ability to secrete insulin under the specific stimulus of the intravenous glucose is a distinguishing feature of the pancreatic beta cell in those humans pre-disposed to diabetes mellitus.

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Untersuchungen zum Prädiabetes. Insulinausschüttung nach oraler Glucosezufuhr und intravenösen Gaben von Tolbutamid und schnell injizierter Glucose bei genetischen Prädiabetikern

Zusammenfassung Die Reaktion von 22 normalgewichtigen genetischen Prädiabetikern, deren beide Elternteile Diabetiker waren, wurde mit der von 34 stoffwechselgesunden Freiwilligen entsprechenden Alters und Gewichtes verglichen. Als standardisierte Stimulationsmethoden dienten: der orale Glucosetoleranztest (100 g Glucose), der i.v. Tolbutamid-Toleranztest (1 g) und die schnelle i.v. Injektion von 0.33 g Glucose/kg Körpergewicht. Die Spiegel des Blutzuckers, des immunreaktiven Insulins und der unveresterten Fettsäuren (NEFA) wurden bei beiden Gruppen im Nüchternzustand und zu verschiedenen Zeiten während der 3 Tests bestimmt.-Die Resultate zeigten keine signifikanten Unterschiede in bezug auf die Kohlenhydrat-Toleranz und das Verhalten der NEFA zu irgend einem Zeitpunkt der benutzten Tests bei Normalpersonen und Prädiabetikern. Bei enger Übereinstimmung der Nüchternspiegel des plasma-immunreaktiven Insulins fanden sich auch keine signifikanten Unterschiede in der Ausschüttung nach oraler Glucosegabe oder i.v. Tolbutamidinjektion. Dagegen ergab sich nach schneller i.v. Glucoseinjektion eine deutlich verringerte Insulinfreisetzung bei der Gruppe der Prädiabetiker, die sich jedoch auf die Frühphase beschränkte. — Unsere Resultate sprechen durchaus dafür, daß eine verringerte Kapazität zur Ihsulinausschüttung nach dem spezifischen Reiz der i.v. Glucosebelastung ein Charakteristikum der Pankreas--Zelle der Menschen darstellt, die zum Diabetes mellitus prädisponiert sind.

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Etude du prédiabète. Réponse de Vinsuline au glucose oral, au tolbutamide intraveineux et à la rapide infusion intraveineuse de glucose chez des sujets génétiquement prédiabétiques

Résumé Vingt-deux sujets non-obèses, génétiquement prédiabétiques (issus de deux parents diabétiques) ont été comparés à 34 sujets normaux de même âge et de même poids, en ce qui concerne leur réponse à trois stimuli standardisés: test de tolérance au glucose oral (avec 100 g de glucose), test de tolérance au tolbutamide intraveineux (1 g) et rapide infusion intraveineuse de glucose (0.33 g/kg de poids corporel). La glycémie, l'insuline immunoréactive et les acides gras non-estérifLés (NEFA) ont été mesurés dans les deux groupes à l'état de jeûne et à différents intervalles de temps au cours de chacun des trois tests.-Les résultats n'ont montré de différence significative ni dans la tolérance aux hydrates de carbone, ni dans le comportement des taux de NEFA entre les sujets normaux et les prédiabétiques, à aucun moment au cours des tests choisis. Les taux à jeun d'insuline plasmatique immunoréactive étaient également étroitement comparables dans les deux groupes; ni la charge orale de glucose, ni l'injection intraveineuse de tolbutamide ne provoquait une libération d'insuline significativement différente chez les sujets normaux et les prédiabétiques. Cependant, la rapide infusion intraveineuse de glucose provoquait une sécrétion d'insuline nettement diminuée dans le groupe prédiabétique qui était plutôt limitée à la phase de réponse très précoce.-Nos résultats confirment fortement l'idée qu'une capacité diminuée à sécréter de l'insuline sous l'influence du stimulus spécifique constitué par la charge brutale de glucose intraveineux est un trait plutôt caractéristique de la cellule bêta pancréatique chez ces sujets qui sont fortement prédisposés au diabète sucré.

     

Insulin metabolism is a major factor responsible for high or low peripheral insulin levels in response to oral glucose loading in the healthy man

In the present study we evaluated C-peptide peripheral levels after an oral glucose load in 30 healthy subjects (18 females, 12 males, aged from 15 to 55) with high or low insulin response to glucose challenge in order to clarify whether or not their beta-cell secretion rate keeps pace with peripheral insulin levels. Moreover, by the study of the relations between C-peptide and insulin in peripheral blood, we had an insight into the extent of insulin metabolism. On the basis of an insulin incremental area higher or lower than the mean +/- 1 SD after a 100-gram oral glucose load, 6 subjects were classified as 'high insulin responders' and 6 other subjects as 'low insulin responders'. Their insulin incremental area after glucose averaged 0.25 +/- 0.01 nmol X 1-1 X min and 0.078 +/- 0.005 nmol X 1-1 X min, respectively (p less than 0.001). The two groups were matched for sex, age and body weight. The glycemic profile after oral glucose load was higher in low insulin responders than in high insulin responders. C-peptide concentrations after glucose load were similar in the two groups, as well as C-peptide incremental areas (0.92 +/- 0.12 vs. 0.74 +/- 0.08 nmol X l-1 X min in high insulin responders and low insulin responders, respectively). The molar ratios of C-peptide to insulin after oral glucose load, as well as the relations between the incremental areas of the two peptides, were significantly lower in high insulin responders than in low insulin responders.(ABSTRACT TRUNCATED AT 250 WORDS)     

Impaired HDL response to fat in men with coronary artery disease

A low HDL cholesterol is found frequently in subjects with premature coronary artery disease. We speculated that individuals with a normal total cholesterol and coronary artery disease have an impaired HDL response to dietary fat. Twenty-one men with recently diagnosed coronary artery disease and total plasma cholesterol of <6 mmol/l were matched by age, weight and cholesterol with 26 men with no personal or family history of coronary artery disease. They were placed sequentially on a 25% fat diet for 2 weeks, a high carbohydrate supplement which reduced fat to 16% of energy for 3 weeks and a high monounsaturated fat supplement which increased fat to 35% for a final 3-week period. Half of the subjects underwent an intravenous glucose tolerance test at the end of the intervention periods. The high fat supplement increased HDL cholesterol from 0.79 to 0.89 mmol/l in the men with coronary artery disease while HDL increased from 0.88 to 1.05 mmol/l in the control group (P<0.05 for group difference). Plasma triglyceride fell by 0.79 and 0.45 mmol/l in cases and controls respectively (P<0.05 for group difference). LDL cholesterol fell by 0.2 mmol/l in both groups. Men with coronary artery disease had an enhanced insulin response during the intravenous glucose tolerance test (P<0.03) particularly in the low fat phase. Thus men with premature coronary artery disease and a low HDL cholesterol appear to have an impaired elevation of HDL cholesterol in response to dietary fat, and insulin resistance may underlie this response.     

Blood glucose and platelet-dependent thrombosis in patients with coronary artery disease

OBJECTIVES: To investigate the influence of blood glucose on platelet-dependent thrombosis (PDT). BACKGROUND: Elevated blood glucose is a predictor of adverse cardiovascular risk independent of a diagnosis of diabetes, possibly due to adverse effects promoting thrombosis. The effects of blood glucose on PDT have not been characterized. METHODS: An ex vivo extracorporeal perfusion protocol was used to measure PDT in 42 patients with stable coronary artery disease (CAD). The Badimon chamber was perfused with unanticoagulated venous blood and PDT evaluated using computerized morphometry. Whole blood impedance aggregometry and flow cytometry evaluated platelet aggregation and P-selectin expression, respectively. RESULTS: Using a multivariate stepwise regression model, blood glucose was the best independent predictor of PDT (R2 = 0.19, p < 0.008), followed by apolipoprotein B (R2 = 0.18, p = 0.002) and intracellular magnesium levels (R2 = 0.12, p = 0.02). Platelet-dependent thrombosis was significantly greater in patients with blood glucose >, compared with <, the median value of 4.9 mmol/l (159 +/- 141 vs. 67 +/- 69 microm2/mm, p < 0.01). Neither platelet aggregation nor P-selectin expression was significantly different between the two groups. Insulin levels correlated with blood glucose (r = 0.56, p = 0.0003), but were not independently associated with either PDT, platelet aggregation or P-selectin expression. A two-way analysis of variance demonstrated an interaction between insulin (>126 pmol/l) and blood glucose (>4.9 mmol/l) in modulating PDT (F [1,38] = 8.5, p < 0.006). CONCLUSIONS: Blood glucose is an independent predictor of PDT in stable CAD patients. The relationship is evident even in the range of blood glucose levels considered normal, indicating that the risk associated with blood glucose may be continuous and graded. These findings suggest that the increased CAD risk associated with elevated blood glucose may be, in part, related to enhanced platelet-mediated thrombogenesis.