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      Adaptation of β-Cell and Endothelial Function to Carbohydrate Loading: Influence of Insulin Resistance

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          Abstract

          High-carbohydrate diets have been associated with β-cell strain, dyslipidemia, and endothelial dysfunction. We examined how β-cell and endothelial function adapt to carbohydrate overloading and the influence of insulin resistance. On sequential days in randomized order, nondiabetic subjects (classified as insulin-sensitive [IS] [ n = 64] or insulin-resistant [IR] [ n = 79] by euglycemic clamp) received four mixed meals over 14 h with either standard (300 kcal) or double carbohydrate content. β-Cell function was reconstructed by mathematical modeling; brachial artery flow-mediated dilation (FMD) was measured before and after each meal. Compared with IS, IR subjects showed higher glycemia and insulin hypersecretion due to greater β-cell glucose and rate sensitivity; potentiation of insulin secretion, however, was impaired. Circulating free fatty acids (FFAs) were less suppressed in IR than IS subjects. Baseline FMD was reduced in IR, and postprandial FMD attenuation occurred after each meal, particularly with high carbohydrate, similarly in IR and IS. Throughout the two study days, higher FFA levels were significantly associated with lower (incretin-induced) potentiation and impaired FMD. In nondiabetic individuals, enhanced glucose sensitivity and potentiation upregulate the insulin secretory response to carbohydrate overloading. With insulin resistance, this adaptation is impaired. Defective suppression of endogenous FFA is one common link between impaired potentiation and vascular endothelial dysfunction.

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          Most cited references 31

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          The biology of incretin hormones.

          Gut peptides, exemplified by glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) are secreted in a nutrient-dependent manner and stimulate glucose-dependent insulin secretion. Both GIP and GLP-1 also promote beta cell proliferation and inhibit apoptosis, leading to expansion of beta cell mass. GLP-1, but not GIP, controls glycemia via additional actions on glucose sensors, inhibition of gastric emptying, food intake and glucagon secretion. Furthermore, GLP-1, unlike GIP, potently stimulates insulin secretion and reduces blood glucose in human subjects with type 2 diabetes. This article summarizes current concepts of incretin action and highlights the potential therapeutic utility of GLP-1 receptor agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors for the treatment of type 2 diabetes.
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            Obesity/insulin resistance is associated with endothelial dysfunction. Implications for the syndrome of insulin resistance.

            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.
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              Prognostic value of coronary vascular endothelial dysfunction.

              Whether patients at increased risk can be identified from a relatively low-risk population by coronary vascular function testing remains unknown. We investigated the relationship between coronary endothelial function and the occurrence of acute unpredictable cardiovascular events (cardiovascular death, myocardial infarction, stroke, and unstable angina) in patients with and without coronary atherosclerosis (CAD). We measured the change in coronary vascular resistance (DeltaCVR) and epicardial diameter with intracoronary acetylcholine (ACh, 15 micro g/min) to test endothelium-dependent function and sodium nitroprusside (20 micro g/min) and adenosine (2.2 mg/min) to test endothelium-independent vascular function in 308 patients undergoing cardiac catheterization (132 with and 176 without CAD). Patients underwent clinical follow-up for a mean of 46+/-3 months. Acute vascular events occurred in 35 patients. After multivariate analysis that included CAD and conventional risk factors for atherosclerosis, DeltaCVR with ACh (P=0.02) and epicardial constriction with ACh (P=0.003), together with increasing age, CAD, and body mass index, were independent predictors of adverse events. Thus, patients in the tertile with the best microvascular responses with ACh and those with epicardial dilation with ACh had improved survival by Kaplan-Meier analyses in the total population, as did those in the subset without CAD. Similar improvement in survival was also observed when all adverse events, including revascularization, were considered. Endothelium-independent responses were not predictive of outcome. Epicardial and microvascular coronary endothelial dysfunction independently predict acute cardiovascular events in patients with and without CAD, providing both functional and prognostic information that complements angiographic and risk factor assessment.
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                Author and article information

                Journal
                Diabetes
                Diabetes
                diabetes
                diabetes
                Diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                July 2015
                09 March 2015
                : 64
                : 7
                : 2550-2559
                Affiliations
                1Behavioral Medicine Research Center, University of Miami, Miami, FL
                2Division of Endocrinology, Diabetes, and Metabolism, Miller School of Medicine, University of Miami, Miami, FL
                3Department of Psychology, University of Miami, Coral Gables, FL
                4Translational Research Institute for Metabolism and Diabetes, Florida Hospital, Orlando, FL
                5National Research Council Institute of Biomedical Engineering, Padua, Italy
                6Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
                7National Research Council Institute of Clinical Physiology, Pisa, Italy
                Author notes
                Corresponding author: Ele Ferrannini, ferranni@ 123456ifc.cnr.it .
                Article
                0106
                10.2337/db15-0106
                4477346
                25754957
                © 2015 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
                Page count
                Pages: 10
                Product
                Funding
                Funded by: NHLBI
                Award ID: HL081817
                Categories
                Pathophysiology

                Endocrinology & Diabetes

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