Endothelial Cells in Physiology and in the Pathophysiology of Vascular Disorders

The clinical implications of endothelial dysfunction.

While virtually absent in our diet a few hundred years ago, fructose has now become a major constituent of our modern diet. Our main sources of fructose are sucrose from beet or cane, high fructose corn syrup, fruits, and honey. Fructose has the same chemical formula as glucose (C(6)H(12)O(6)), but its metabolism differs markedly from that of glucose due to its almost complete hepatic extraction and rapid hepatic conversion into glucose, glycogen, lactate, and fat. Fructose was initially thought to be advisable for patients with diabetes due to its low glycemic index. However, chronically high consumption of fructose in rodents leads to hepatic and extrahepatic insulin resistance, obesity, type 2 diabetes mellitus, and high blood pressure. The evidence is less compelling in humans, but high fructose intake has indeed been shown to cause dyslipidemia and to impair hepatic insulin sensitivity. Hepatic de novo lipogenesis and lipotoxicity, oxidative stress, and hyperuricemia have all been proposed as mechanisms responsible for these adverse metabolic effects of fructose. Although there is compelling evidence that very high fructose intake can have deleterious metabolic effects in humans as in rodents, the role of fructose in the development of the current epidemic of metabolic disorders remains controversial. Epidemiological studies show growing evidence that consumption of sweetened beverages (containing either sucrose or a mixture of glucose and fructose) is associated with a high energy intake, increased body weight, and the occurrence of metabolic and cardiovascular disorders. There is, however, no unequivocal evidence that fructose intake at moderate doses is directly related with adverse metabolic effects. There has also been much concern that consumption of free fructose, as provided in high fructose corn syrup, may cause more adverse effects than consumption of fructose consumed with sucrose. There is, however, no direct evidence for more serious metabolic consequences of high fructose corn syrup versus sucrose consumption.

http://www.perishablepundit.com/docs/fructose-and-obesity.pdf

Metabolic Effects of Fructose and the Worldwide Increase in Obesity

Environmental factors and diet are generally believed to be accelerators of obesity and hypertension, but they are not the underlying cause Our animal model of obesity and hypertension is based on the observation that impaired fetal growth has long-term clinical consequences that are induced by fetal programming Using fetal undernutrition throughout pregnancy, we investigated whether the effects of fetal programming on adult obesity and hypertension are mediated by changes in insulin and leptin action and whether increased appetite may be a behavioral trigger of adult disease Virgin Wistar rats were time mated and randomly assigned to receive food either ad libitum (AD group) or at 30% of ad libitum intake, or undernutrition (UN group) Offspring from UN mothers were significantly smaller at birth than AD offspring At weaning, offspring were assigned to one of two diets [a control diet or a hypercaloric (30% fat) diet] Food intake in offspring from UN mothers was significantly elevated at an early postnatal age It increased further with advancing age and was amplified by hypercaloric nutrition UN offspring also showed elevated systolic blood pressure and markedly increased fasting plasma insulin and leptin concentrations This study is the first to demonstrate that profound adult hyperphagia is a consequence of fetal programming and a key contributing factor in adult pathophysiology We hypothesize that hyperinsulinism and hyperleptinemia play a key role in the etiology of hyperphagia, obesity, and hypertension as a consequence of altered fetal development

https://www.physiology.org/doi/pdf/10.1152/ajpendo.2000.279.1.E83

Fetal origins of hyperphagia, obesity, and hypertension and postnatal amplification by hypercaloric nutrition

To examine the association of low-grade systemic inflammation with diabetes, as well as its heterogeneity across subgroups, we designed a case-cohort study representing the ∼9-year experience of 10,275 Atherosclerosis Risk in Communities Study participants. Analytes were measured on stored plasma of 581 incident cases of diabetes and 572 noncases. Statistically significant hazard ratios of developing diabetes for those in the fourth (versus first) quartile of inflammation markers, adjusted for age, sex, ethnicity, study center, parental history of diabetes, and hypertension, ranged from 1.9 to 2.8 for sialic acid, orosomucoid, interleukin-6, and C-reactive protein. After additional adjustment for BMI, waist-to-hip ratio, and fasting glucose and insulin, only the interleukin-6 association remained statistically significant (HR = 1.6, 1.01–2.7). Exclusion of GAD antibody-positive individuals changed associations minimally. An overall inflammation score based on these four markers plus white cell count and fibrinogen predicted diabetes in whites but not African Americans (interaction P = 0.005) and in nonsmokers but not smokers (interaction P = 0.13). The fully adjusted hazard ratio comparing white nonsmokers with score extremes was 3.7 ( P for linear trend = 0.008). In conclusion, a low-grade inflammation predicts incident type 2 diabetes. The association is absent in smokers and African-Americans.

https://diabetes.diabetesjournals.org/content/diabetes/52/7/1799.full.pdf

Low-grade systemic inflammation and the development of type 2 diabetes: the atherosclerosis risk in communities study.

To test the hypothesis that obesity/insulin resistance impairs both endothelium-dependent vasodilation and insulin-mediated augmentation of endothelium-dependent vasodilation, we studied leg blood flow (LBF) responses to graded intrafemoral artery infusions of methacholine chloride (MCh) or sodium nitroprusside (SNP) during saline infusion and euglycemic hyperinsulinemia in lean insulin-sensitive controls (C), in obese insulin-resistant subjects (OB), and in subjects with non-insulin-dependent diabetes mellitus (NIDDM). MCh induced increments in LBF were approximately 40% and 55% lower in OB and NIDDM, respectively, as compared with C (P < 0.05). Euglycemic hyperinsulinemia augmented the LBF response to MCh by - 50% in C (P < 0.05 vs saline) but not in OB and NIDDM. SNP caused comparable increments in LBF in all groups. Regression analysis revealed a significant inverse correlation between the maximal LBF change in response to MCh and body fat content. Thus, obesity/insulin resistance is associated with (a) blunted endothelium-dependent, but normal endothelium-independent vasodilation and (b) failure of euglycemic hyperinsulinemia to augment endothelium-dependent vasodilation. Therefore, obese/insulin-resistant subjects are characterized by endothelial dysfunction and endothelial resistance to insulin's effect on enhancement of endothelium-dependent vasodilation. This endothelial dysfunction could contribute to the increased risk of atherosclerosis in obese insulin-resistant subjects.

/pdf/obesity-insulin-resistance-is-associated-with-endothelial-d98v09rlo3.pdf

Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

Whether insulin-mediated vasodilation is important in determining insulin's overall action to stimulate glucose uptake is unknown. To this end, we measured leg glucose uptake during euglycemic hyperinsulinemic clamps performed at two insulin doses (40 mU/m2 per min, n = 6 and 120 mU/m2 per min, n = 15) alone and during a superimposed intrafemoral artery infusion of GN-monomethyl-L-arginine (L-NMMA) designed to blunt insulin-mediated vasodilation. During the higher dose study, hyperinsulinemia resulted in about a twofold rise in basal leg blood flow from 0.24 +/- 0.02 to 0.45 +/- 0.05 liter/min, P < 0.0001. L-NMMA infusion resulted in a net 21% reduction in leg glucose uptake from 114 +/- 18 mg/min to 85 +/- 13 mg/min, P < 0.001. We also found a significant relationship between the rate of insulin-stimulated whole body glucose uptake and the magnitude of flow dependent glucose uptake (r = 0.57, P = 0.02). Data obtained during the lower dose insulin infusion resulted in similar findings. In conclusion, in healthy lean subjects, insulin-stimulated muscle blood flow contributes to both insulin responsiveness and insulin sensitivity. The most insulin-sensitive subjects appear to be the most reliant on muscle perfusion for insulin action. Insulin-mediated vasodilation is an important physiological determinant of insulin action.

/pdf/insulin-mediated-skeletal-muscle-vasodilation-contributes-to-1ora3wi9b1.pdf

Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans.

Background

Amylin is a peptide co-secreted with insulin by pancreatic β-cells. A role for amylin in the pathogenesis of type 2 diabetes mellitus (DM2) has been suggested by in vitro and in vivo studies indicating an effect of amylin to cause insulin resistance and/or inhibit insulin secretion.



Methods

We have determined the effect of endogenous amylin on insulin secretion and insulin action in humans by performing 4-h hyperglycemic clamps during infusion of placebo or a specific amylin receptor antagonist (ARA) in paired, double-blinded, crossover studies. We studied nine healthy lean, ten healthy obese (BMI>27) and ten obesity-matched DM2 subjects.



Results

Infusion of ARA alone had no effect on basal insulin, glucose or glucose turnover in any group. Under combined hyperglycemia and ARA infusion, lean subjects displayed a 32% augmentation in insulin levels [AUC 33 565±3556 (placebo) to 44 562±1379 (ARA) pmol/l/min, p<0.01]. The concomitant increase in glucose disposal rate (GDR) was proportionate, indicating no change in insulin sensitivity (ISI 27.7±2.7 vs 27.3±2.1, p=NS). In obese subjects, basal insulin and the rise in insulin during the clamp were greater (AUC I 44% increase from 82 054±15 407 to 117 922±27 085, p<0.01), and also accompanied by a proportionate rise in GDR reflecting an unchanged insulin sensitivity (ISI 12.1±2.9 vs 10.8±3.0, p=NS). In lean and obese subjects, the C-peptide response to hyperglycemia was also augmented by ARA (p=0.007). No effect of ARA on insulin secretion or action was observed in diabetic subjects.



Conclusions

The present data are consistent with an effect of endogenous amylin on the β-cell to modulate and/or restrain insulin secretion, and indicate that endogenous amylin does not affect insulin action. These observations provide the first human evidence that amylin plays a role in the modulation of insulin secretion. Copyright © 2002 John Wiley & Sons, Ltd.

Rosalind Leaming

Papers

Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

Insulin-mediated skeletal muscle vasodilation contributes to both insulin sensitivity and responsiveness in lean humans.

Role of amylin in insulin secretion and action in humans: antagonist studies across the spectrum of insulin sensitivity.