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      CPR-IR is an insulin resistance index that is minimally affected by hepatic insulin clearance—A preliminary research

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          Abstract

          Background

          Increased hepatic insulin clearance (HIC) is important in the pathophysiology of type 2 diabetes mellitus (T2DM). The aim of this study is to analyze an effective insulin resistance (IR) index that is minimally affected by HIC.

          Methods

          Our study involved 20 participants with T2DM and 21 healthy participants without diabetes (Non-DM). Participants underwent a meal tolerance test from which plasma glucose, insulin and serum C-peptide immunoreactivity (CPR) were measured, and HOMA-IR and HIC were calculated. Participants then underwent a hyperinsulinemic-euglycemic clamp from which the glucose disposal rate (GDR) was measured.

          Results

          The index CPR-IR = 20/(fasting CPR × fasting plasma glucose) was correlated more strongly with GDR, than was HOMA-IR, and CPR-IR could be used to estimate GDR. In T2DM participants with HIC below the median, HOMA-IR and CPR-IR were equally well correlated with GDR. In T2DM with high HIC, CPR-IR correlated with GDR while HOMA-IR did not. In Non-DM, CPR-IR and HOMA-IR were equally well correlated with GDR regardless of HIC. The mean HIC value in T2DM was significantly higher than that of Non-DM.

          Conclusions

          CPR-IR could be a simple and effective index of insulin resistance for patients with type 2 diabetes that is minimally affected by HIC.

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          Most cited references22

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          Insulin sensitivity indices obtained from oral glucose tolerance testing: comparison with the euglycemic insulin clamp.

          Several methods have been proposed to evaluate insulin sensitivity from the data obtained from the oral glucose tolerance test (OGTT). However, the validity of these indices has not been rigorously evaluated by comparing them with the direct measurement of insulin sensitivity obtained with the euglycemic insulin clamp technique. In this study, we compare various insulin sensitivity indices derived from the OGTT with whole-body insulin sensitivity measured by the euglycemic insulin clamp technique. In this study, 153 subjects (66 men and 87 women, aged 18-71 years, BMI 20-65 kg/m2) with varying degrees of glucose tolerance (62 subjects with normal glucose tolerance, 31 subjects with impaired glucose tolerance, and 60 subjects with type 2 diabetes) were studied. After a 10-h overnight fast, all subjects underwent, in random order, a 75-g OGTT and a euglycemic insulin clamp, which was performed with the infusion of [3-3H]glucose. The indices of insulin sensitivity derived from OGTT data and the euglycemic insulin clamp were compared by correlation analysis. The mean plasma glucose concentration divided by the mean plasma insulin concentration during the OGTT displayed no correlation with the rate of whole-body glucose disposal during the euglycemic insulin clamp (r = -0.02, NS). From the OGTT, we developed an index of whole-body insulin sensitivity (10,000/square root of [fasting glucose x fasting insulin] x [mean glucose x mean insulin during OGTT]), which is highly correlated (r = 0.73, P < 0.0001) with the rate of whole-body glucose disposal during the euglycemic insulin clamp. Previous methods used to derive an index of insulin sensitivity from the OGTT have relied on the ratio of plasma glucose to insulin concentration during the OGTT. Our results demonstrate the limitations of such an approach. We have derived a novel estimate of insulin sensitivity that is simple to calculate and provides a reasonable approximation of whole-body insulin sensitivity from the OGTT.
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            Quantitative insulin sensitivity check index: a simple, accurate method for assessing insulin sensitivity in humans.

            Insulin resistance plays an important role in the pathophysiology of diabetes and is associated with obesity and other cardiovascular risk factors. The "gold standard" glucose clamp and minimal model analysis are two established methods for determining insulin sensitivity in vivo, but neither is easily implemented in large studies. Thus, it is of interest to develop a simple, accurate method for assessing insulin sensitivity that is useful for clinical investigations. We performed both hyperinsulinemic isoglycemic glucose clamp and insulin-modified frequently sampled iv glucose tolerance tests on 28 nonobese, 13 obese, and 15 type 2 diabetic subjects. We obtained correlations between indexes of insulin sensitivity from glucose clamp studies (SI(Clamp)) and minimal model analysis (SI(MM)) that were comparable to previous reports (r = 0.57). We performed a sensitivity analysis on our data and discovered that physiological steady state values [i.e. fasting insulin (I(0)) and glucose (G(0))] contain critical information about insulin sensitivity. We defined a quantitative insulin sensitivity check index (QUICKI = 1/[log(I(0)) + log(G(0))]) that has substantially better correlation with SI(Clamp) (r = 0.78) than the correlation we observed between SI(MM) and SI(Clamp). Moreover, we observed a comparable overall correlation between QUICKI and SI(Clamp) in a totally independent group of 21 obese and 14 nonobese subjects from another institution. We conclude that QUICKI is an index of insulin sensitivity obtained from a fasting blood sample that may be useful for clinical research.
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              Identification and cloning of a beta-cell-specific zinc transporter, ZnT-8, localized into insulin secretory granules.

              SLC30A8, a novel member of the zinc transporter (ZnT) family, was identified by searching the human genomic and expressed sequence tag (EST) databases with the amino acid sequence of all known human ZnT. The protein (369 amino acids) predicted from this gene, ZnT-8, contains six transmembrane domains and a histidine-rich loop between transmembrane domains IV and V, like the other ZnT proteins. We demonstrated by RT-PCR on cDNA libraries and human tissue extracts that the ZnT-8 gene is solely transcribed in the pancreas, mainly in the islets of Langerhans. The gene, named SLC30A8, was cloned and sequenced. Confocal immunofluorescence analysis revealed that a ZnT-8-EGFP (enhanced green fluorescent protein) fusion product colocalized with insulin in the secretory pathway granules of the insulin-secreting INS-1 cells. Exposure of the ZnT-8-EGFP stably expressing HeLa cells to 75 micromol/l zinc caused an accumulation of zinc in intracellular vesicles compared with cells expressing EGFP alone. These results identified ZnT-8 as a ZnT specific to the pancreas and expressed in beta-cells. Because ZnT-8 facilitates the accumulation of zinc from the cytoplasm into intracellular vesicles, ZnT-8 may be a major component for providing zinc to insulin maturation and/or storage processes in insulin-secreting pancreatic beta-cells.
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                Author and article information

                Contributors
                Role: ConceptualizationRole: Data curationRole: Formal analysisRole: Funding acquisitionRole: InvestigationRole: MethodologyRole: Project administrationRole: ResourcesRole: SoftwareRole: VisualizationRole: Writing – original draft
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Investigation
                Role: Methodology
                Role: Supervision
                Role: SupervisionRole: Writing – review & editing
                Role: Supervision
                Role: Funding acquisitionRole: SupervisionRole: Writing – review & editing
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, CA USA )
                1932-6203
                23 May 2018
                2018
                : 13
                : 5
                : e0197663
                Affiliations
                [1 ] Division of Cardiovascular Medicine, Endocrinology and Metabolism, Department of Molecular Medicine and Therapeutics, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
                [2 ] School of Health Science, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
                [3 ] Division of Molecular Pharmacology, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
                [4 ] Department of Regional Medicine, Tottori University Faculty of Medicine, Yonago, Tottori, Japan
                Shanghai Diabetes Institute, CHINA
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Author information
                http://orcid.org/0000-0003-3713-6617
                Article
                PONE-D-18-08178
                10.1371/journal.pone.0197663
                5965889
                29791512
                29c18f4d-247b-493c-8d37-52fd8fea9ca5
                © 2018 Okura et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 16 March 2018
                : 7 May 2018
                Page count
                Figures: 1, Tables: 4, Pages: 12
                Funding
                Funded by: JSPS KAKENHI Grant-in-Aid for Scientific Research (C)
                Award ID: Grant Number 16K08935
                Award Recipient :
                This work was supported by a JSPS KAKENHI Grant-in-Aid for Scientific Research (C) grant number 16K08935 (2016-2019), JSPS KAKENHI Grant-in-Aid for Young Scientists (B) grant number 26870373 (2014–2015), the Japan Diabetes Foundation (2013), grants for young researchers from the Japan Association for Diabetes Education and Care (2013, 2014), Tottori University Faculty of Medicine Research Grant (2013) and Tottori University Hospital Research Grant (2013). This work also supported by the MSD research grant (2013, 2015).
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