Ivana Zavaroni

Effect of fructose feeding on insulin secretion and insulin action in the rat

Insulin secretion and insulin action were studied in rats fed either a diet containing (as percent of calories) 66% fructose, 22% protein, and 12% fat, or standard rat chow (60% vegetable starch, 29% protein, 11% fat) for 7 days. Plasma glucose concentration following either an oral glucose or fructose load (180 mg/100 g body weight) were slightly higher in the fructose-fed rats, and this was associated with a much greater elevation of plasma insulin concentrations. The ability of insulin to stimulate disposal of glucose load was determined during the continuous infusion of epinephrine, propranolol, glucose, and insulin. Under these condtions the steady state plasma insulin levels were the same in the two groups of rats, whereas the steady state plasma glucose levels were almost twice as high in the fructose fed rats. Thus, fructose feeding for 7 days resulted in an increase in the insulin response to an oral carbohydrate challenge, as well as to a loss of normal insulin sensitivity.

Hyperinsulinemia in a normal population as a predictor of non—insulin-dependent diabetes mellitus, hypertension, and coronary heart disease: The barilla factory revisited

The study was initiated to evaluate the ability of hyperinsulinemia (as a surrogate measure of insulin resistance) to predict the development in a previously healthy population of three putative outcomes of this abnormality--glucose intolerance, hypertension, and coronary heart disease (CHD). The study involved defining the incidence at which these changes occurred between 1981 and 1993 to 1996 in 647 individuals who were free of any disease when initially studied. The study population consisted of approximately 90% of the subjects evaluated in 1981, divided into quartiles on the basis of the plasma insulin response to a glucose challenge as determined in 1981. The results indicated that the 25% of the population with the highest insulin response in 1981 had significant (P < .001) increases in the incidence of impaired glucose tolerance (IGT) or type 2 diabetes (eightfold), hypertension (twofold), or CHD (threefold). Furthermore, the ability of hyperinsulinemia to predict the three clinical endpoints was independent of differences in age, gender, or body mass index (BMI). Finally, if CHD is considered the clinical endpoint, multiple logistic regression analysis indicates that the values for plasma triglyceride (TG) and mean arterial blood pressure ([MAP] as measured in 1981) also predict the development of CHD. These results indicate that the untoward clinical effects of insulin resistance and/or compensatory hyperinsulinemia, glucose intolerance, hypertension, and CHD clearly can develop in less than 15 years.

Mechanism of insulin resistance in fructose-fed rats

Previous results from our laboratory demonstrated that chronic administration of fructose to normal rats led to both hyperinsulinemia and in vivo insulin resistance. To localize the major tissue site of insulin resistance in fructose-fed animals, we compared glucose uptake by perfused hindlimb skeletal muscle and liver from rats fed either a 60% fructose diet or laboratory chow. Glucose uptake by perfused muscle from chow and fructose-fed rats was comparable at perfusate insulin levels of 0 microunit/ml (15.2 versus 15.5 microliters/min/g muscle), 100 microunits/ml (18.3 versus 19.8), and greater than 500 microunits/ml (35.5 versus 33.4). In contrast, glucose outflow from livers of fructose-fed rats was significantly greater (p less than .02) than chow-fed animals perfused in the absence of added insulin (52.1 versus 36.5 mumol/g). Furthermore, the ability of insulin to suppress glucose outflow was less in livers from fructose-fed rats at perfusate insulin level of 165 microunits/ml (13.2 versus 41.4% as well as at insulin concentration greater than 900 microunits/ml, (32.5% versus 62.2%). These findings suggest that the insulin resistance resulting from chronic fructose feeding is due to the diminished ability of insulin to suppress hepatic glucose output, and not to a decrease in insulin-stimulated glucose uptake by muscle.

Prevalence of hyperinsulinaemia in patients with high blood pressure

Abstract. A total of 41 patients with hypertension were identified in a survey of 732 healthy factory workers. Twenty‐three of these individuals were receiving antihypertensive medication, whereas 18 cases were newly discovered. Plasma glucose and insulin responses to oral glucose and fasting plasma triglyceride (TG), cholesterol, and high‐density‐lipoprotein (HDL) cholesterol concentrations of these 41 individuals were compared with those of 41 other factor workers, with normal blood pressure, matched with the hypertensive group in terms of gender, age, degree of obesity, job in the factory, and leisure‐time activity. Patients with hypertension had significantly higher plasma glucose (P < 0.05) and insulin (P < 0.05) concentrations in response to oral glucose, as well as a higher plasma TG concentration (P < 0.05). Similar findings were obtained when the treated and untreated hypertensive groups were analysed separately and compared with their respective control groups. However, there were no differences between the treated and untreated hypertensive groups. Ninety per cent of the normotensive group had a plasma insulin concentration of < 500 pmol l−1 2 h after the glucose load. Using this value as the criterion for definition of hyperinsulinaemia, 41% of the patients with high blood pressure were hyperinsulinaemic. In addition to meeting this cut‐off point, the patients with hypertension and hyperinsulinaemia were also glucose intolerant and dyslipidaemic. In conclusion, approximately 50% of an unselected group of patients with hypertension were hyperinsulinaemic. Insulin levels were comparable in treated and untreated patients with high blood pressure, and hyperinsulinaemic patients also tended to be glucose intolerant and dyslipidaemic.

Association of Insulin Resistance, Hyperleptinemia, and Impaired Nitric Oxide Release With In-Stent Restenosis in Patients Undergoing Coronary Stenting

Background—Previously undiagnosed diabetes, impaired glucose tolerance, and insulin resistance are common in patients with acute myocardial infarction and coronary heart disease (CHD) and might be involved in early restenosis after stent implantation. To evaluate whether markers of insulin resistance syndrome, including leptin, and endothelial dysfunction are related to increased rate of early restenosis, we studied nondiabetic patients with CHD after successful coronary stenting. Methods and Results—Both patients with CHD undergoing coronary stenting (120 patients) and control subjects (58 patients) were submitted to an oral glucose tolerance test (OGTT). Fasting leptin levels and fasting and postglucose load insulin sensitivity were assessed. Endothelial function was measured by nitrite and nitrate release (NOx) during OGTT. More than 50% of patients treated with stent implantation presented impaired glucose tolerance or type 2 diabetes, which was previously undiagnosed. These patients also had higher glucose, insulin, and leptin levels than control subjects. Among the stented patients, insulin and leptin levels were higher in patients with restenosis than in patients without restenosis. A significant increase in NOx levels was found during OGTT both in patients without restenosis and in control subjects. On the contrary, NOx profiles were blunted in patients with restenosis. At multiple regression analysis, only &Dgr;AUC-NOx areas and insulin sensitivity index showed an independent correlation with the minimal lumen diameter at follow-up. Conclusions—We demonstrated that insulin resistance and endothelial dysfunction are independent predictors of early restenosis after coronary stenting.

Total antioxidant capacity of the diet is inversely and independently related to plasma concentration of high-sensitivity C-reactive protein in adult Italian subjects

Inflammation, a risk factor for cardiovascular disease, is associated with low plasma levels of antioxidant vitamins. In addition to vitamins, other antioxidants modulate the synthesis of inflammatory markers in vitro and contribute to the total antioxidant capacity (TAC) of a diet. However, the relationship between dietary TAC and markers of inflammation has never been evaluated in vivo. We investigated the relationship between dietary TAC and markers of systemic (high-sensitivity C-reactive protein (hs-CRP), leucocytes) and vascular (soluble intercellular cell adhesion molecule-1) inflammation in 243 non-diabetic subjects. General Linear Model (GLM) analysis showed a significant (P=0.005) inverse relationship between hs-CRP and quartiles of energy-adjusted dietary TAC, even when recognized modulating factors of inflammation, namely alcohol, fibre, vitamin C, alpha-tocopherol, beta-carotene, BMI, waist circumference, HDL-cholesterol, hypertension, insulin sensitivity and plasma beta-carotene, were included in the model as covariates (P=0.004). The relationship was stronger for subjects with hypertension (P=0.013 v. P=0.109 for normotensive individuals). Among dietary factors, TAC was significantly higher (5.3 (sd 3.0) v. 4.9 (sd 2.7) mmol Trolox/d; P=0.026) in subjects with low plasma hs-CRP (range: 0.0-4.1 mg/l) than in subjects with high plasma hs-CRP (range: 4.2-27.8 mg/l). We conclude that dietary TAC is inversely and independently correlated with plasma concentrations of hs-CRP and this could be one of the mechanisms explaining the protective effects against CVD of antioxidant-rich foods such as fruits, whole cereals and red wine. This could be of particular significance for subjects with high blood pressure.

Evidence for an independent relationship between plasma insulin and concentration of high density lipoprotein cholesterol and triglyceride

Increased plasma insulin and triglycerides and decreased high density lipoprotein concentrations are primary risk factors in the development of coronary artery disease. The aim of the present study was to verify whether there was an independent relationship between plasma insulin levels and both HDL cholesterol and triglyceride in a worker population of 607 subjects, 389 men and 218 women, aged 23-73 years. An oral glucose tolerance test (75 g) was performed. Plasma glucose, insulin, triglyceride and HDL cholesterol were measured at fasting, plasma glucose and insulin were determined also 1 h and 2 h after glucose load. The results, examined separately in men and women documented a significant negative relationship between plasma insulin and HDL cholesterol level, as well as pointing out that both HDL cholesterol and insulin are significantly correlated to degree of hypertriglyceridemia, degree of obesity and level of glucose tolerance. The partial correlation coefficients between HDL cholesterol and plasma insulin levels at fasting in men and post-glucose load in women, demonstrated an independent relationship between increased plasma insulin and decreased plasma HDL concentration. However, the strongest relationship, revealed by partial correlation coefficient analysis, was between the degree of hyperinsulinemia and hypertriglyceridemia.

Decreased hepatic insulin extraction in subjects with mild glucose intolerance

The fact that hyperinsulinemia occurs in simple obesity and mild glucose intolerance has been well established. Altered hepatic insulin extraction may influence the levels of circulating hormone. The simultaneous measurement of insulin and C-peptide concentrations in peripheral blood enables an in vivo estimation of hepatic insulin removal. To evaluate hepatic insulin extraction, insulin and C-peptide responses to oral glucose were studied in 176 obese and nonobese subjects with normal, impaired, or diabetic glucose tolerance. Insulin levels as well as insulin incremental areas in glucose intolerant subjects were significantly higher than in weight-matched controls. The levels of C-peptide as well as C-peptide incremental areas were only slightly enhanced in subjects with impaired glucose tolerance, whereas they were reduced in subjects with diabetic tolerance. The molar ratios of C-peptide to insulin, both in the fasting state and after ingestion of glucose, as well as the relationship between the incremental areas of the two peptides were used as measures of hepatic insulin extraction. They were significantly reduced in glucose intolerant subjects and, to a lesser extent, in nondiabetic obese subjects. These results indicate that peripheral hyperinsulinemia in subjects with simple obesity or impaired glucose tolerance is a result of both pancreatic hypersecretion and diminished hepatic insulin extraction. In subjects with a more severe degree of glucose intolerance, decreased hepatic insulin removal is the primary cause of hyperinsulinemia.

Changes in insulin and lipid metabolism in males with asymptomatic hyperuricaemia

Abstract. Objectives. To define the effect of asymptomatic hyperuricaemia on various facets of glucose, insulin, and lipoprotein metabolism.

Studies of the mechanism of fructose-induced hypertriglyceridemia in the rat☆

Carbohydrate-induced hypertriglyceridemia is easily produced in the rat, and fructose has been shown to be particularly potent in this regard. In this study we have compared the effects of feeding rats diets high (66% of total calories) in fructose or glucose on various aspects of carbohydrate and lipid metabolism. The results confirmed previous observations that fructose (456 +/- 276 mg/dl) was more potent (p less than 0.001) in raising plasma TG concentration than was glucose (242 +/- 13 mg/dl), and indicated that the difference in magnitude of hypertriglyceridemia produced by the two carbohydrates was closely related to the ability of the test diets to increase VLDL-TG secretion (r = 0.85, p less than 0.001). Both glucose and fructose feeding led to comparable degrees of hyperinsulinemia, and plasma TG concentrations increased before hyperinsulinemia evolved in fructose-fed rats. Therefore, it was concluded that fructose can act directly on the liver to increase VLDL-TG secretion, and that fructose-induced hypertriglyceridemia can occur in the absence of hyperinsulinemia. On the other hand, the rise in plasma TG concentration produced by fructose was reduced dramatically in exercise-trained rats, and this was associated with a decrease in plasma insulin concentration. Based upon these observations, we suggest that fructose feeding produces hypertriglyceridemia by directly stimulating hepatic VLDL-TG secretion, as well as by producing insulin resistance and hyperinsulinemia, and that it is the combined effect of these two separate actions which accounts for the magnitude of fructose-induced hypertriglyceridemia.