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      Portal Vein Glucose Sensors Do Not Play a Major Role in Modulating Physiological Responses to Insulin-Induced Hypoglycemia in Humans

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          Abstract

          OBJECTIVE—Experimental data from animal studies indicate that portal vein glucose sensors play a key role in the responses to slow-fall hypoglycemia. However, their role in modulating these responses in humans is not well understood. The aim of the present study was to examine in humans the potential role of portal vein glucose sensors in physiological responses to insulin-induced hypoglycemia mimicking the slow fall of insulin-treated diabetic subjects.

          RESEARCH DESIGN AND METHODS—Ten nondiabetic subjects were studied on two different occasions during intravenous insulin (2 mU · kg −1 · min −1) plus variable glucose for 160 minutes. In both studies, after 60 min of normal plasma glucose concentrations, hypoglycemia (47 mg/dl) was induced slowly (60 min) and maintained for 60 min. Hypoglycemia was preceded by the ingestion of either oral placebo or glucose (28 g) given at 30 min.

          RESULTS—Plasma glucose and insulin were not different with either placebo or glucose ( P > 0.2). Similarly, counterregulatory hormones, substrates, and symptoms were not different with either placebo or glucose. The Stroop color and colored words subtest of the Stroop test deteriorated less ( P < 0.05) with glucose than placebo.

          CONCLUSIONS—In contrast to animals, in humans, prevention of portal hypoglycemia with oral glucose from the beginning of insulin-induced slow-fall hypoglycemia has no effect on sympathoadrenal and symptomatic responses to hypoglycemia.

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          Most cited references32

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          Metabolic endotoxemia initiates obesity and insulin resistance.

          Diabetes and obesity are two metabolic diseases characterized by insulin resistance and a low-grade inflammation. Seeking an inflammatory factor causative of the onset of insulin resistance, obesity, and diabetes, we have identified bacterial lipopolysaccharide (LPS) as a triggering factor. We found that normal endotoxemia increased or decreased during the fed or fasted state, respectively, on a nutritional basis and that a 4-week high-fat diet chronically increased plasma LPS concentration two to three times, a threshold that we have defined as metabolic endotoxemia. Importantly, a high-fat diet increased the proportion of an LPS-containing microbiota in the gut. When metabolic endotoxemia was induced for 4 weeks in mice through continuous subcutaneous infusion of LPS, fasted glycemia and insulinemia and whole-body, liver, and adipose tissue weight gain were increased to a similar extent as in high-fat-fed mice. In addition, adipose tissue F4/80-positive cells and markers of inflammation, and liver triglyceride content, were increased. Furthermore, liver, but not whole-body, insulin resistance was detected in LPS-infused mice. CD14 mutant mice resisted most of the LPS and high-fat diet-induced features of metabolic diseases. This new finding demonstrates that metabolic endotoxemia dysregulates the inflammatory tone and triggers body weight gain and diabetes. We conclude that the LPS/CD14 system sets the tone of insulin sensitivity and the onset of diabetes and obesity. Lowering plasma LPS concentration could be a potent strategy for the control of metabolic diseases.
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            Diabetes

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              Glucagon-like peptide-1 receptor is involved in learning and neuroprotection.

              Glucagon-like peptide-1 (GLP-1) is a gut peptide that, together with its receptor, GLP-1R, is expressed in the brain. Here we show that intracerebroventricular (i.c.v.) GLP-1 and [Ser(2)]exendin(1-9) (HSEGTFTSD; homologous to a conserved domain in the glucagon/GLP-1 family) enhance associative and spatial learning through GLP-1R. [Ser(2)]exendin(1-9), but not GLP-1, is also active when administered peripherally. GLP-1R-deficient mice have a phenotype characterized by a learning deficit that is restored after hippocampal Glp1r gene transfer. In addition, rats overexpressing GLP-1R in the hippocampus show improved learning and memory. GLP-1R-deficient mice also have enhanced seizure severity and neuronal injury after kainate administration, with an intermediate phenotype in heterozygotes and phenotypic correction after Glp1r gene transfer in hippocampal somatic cells. Systemic administration of [Ser(2)]exendin(1-9) in wild-type animals prevents kainate-induced apoptosis of hippocampal neurons. Brain GLP-1R represents a promising new target for both cognitive-enhancing and neuroprotective agents.
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                Author and article information

                Journal
                Diabetes
                diabetes
                Diabetes
                American Diabetes Association
                0012-1797
                1939-327X
                January 2009
                : 58
                : 1
                : 194-202
                Affiliations
                [1]From the Department of Internal Medicine, University of Perugia, Perugia, Italy
                Author notes

                Corresponding author: Prof. Geremia B. Bolli, gbolli@ 123456unipg.it

                Article
                581194
                10.2337/db08-0641
                2606871
                18852332
                e8d00a88-c0dd-4b67-881d-00e2a360d9e0
                Copyright © 2009, 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.

                History
                : 14 May 2008
                : 2 October 2008
                Categories
                Pathophysiology

                Endocrinology & Diabetes
                Endocrinology & Diabetes

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