For Publishers
DiscoveryMetadataPeer reviewHostingPublishing
For Researchers
JoinPublishReviewCollect
Register
Blog
About
Search
Advanced search
My ScienceOpen
Search
For Publishers
For Researchers
Blog
About
51
views
40
references
 Top references
cited by
29
    
0 reviews
 Review
0
comments
 Comment
0
recommends
+1 Recommend
0 collections
    0
    shares
      61
      similar
       All similar
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

      Detailed Physiologic Characterization Reveals Diverse Mechanisms for Novel Genetic Loci Regulating Glucose and Insulin Metabolism in Humans

      research-article
      Author(s): 1 , 2 , 3 , 4 , 5 , 6 , 7 , 8 , 5 , 6 , 3 , 9 , 10 , 11 , 10 , 2 , 10 , 12 , 13 , 14 , 9 , 15 , 16 , 12 , 17 , 18 , 19 , 15 , 15 , 20 , 20 , 15 , 21 , 22 , 23 , 16 , 24 , 25 , 26 , 20 , 27 , 28 , 28 , 7 , 29 , 15 , 15 , 30 , 31 , 32 , 33 , 20 , 16 , 9 , 9 , 19 , 15 , 14 , 25 , 34 , 35 , 36 , 19 , 37 , 35 , 23 , 14 , 32 , 10 , 31 , 3 , 11 , 38 , 5 , 6 , 39 , 7 , 12 , 40 , 30 , 38 , 41 , 42 , on behalf of the MAGIC investigators
      Publication date (Electronic):
      Journal: Diabetes
      Publisher: American Diabetes Association

      Read this article at

      ScienceOpenPublisherPMC
      Bookmark
          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          OBJECTIVE

          Recent genome-wide association studies have revealed loci associated with glucose and insulin-related traits. We aimed to characterize 19 such loci using detailed measures of insulin processing, secretion, and sensitivity to help elucidate their role in regulation of glucose control, insulin secretion and/or action.

          RESEARCH DESIGN AND METHODS

          We investigated associations of loci identified by the Meta-Analyses of Glucose and Insulin-related traits Consortium (MAGIC) with circulating proinsulin, measures of insulin secretion and sensitivity from oral glucose tolerance tests (OGTTs), euglycemic clamps, insulin suppression tests, or frequently sampled intravenous glucose tolerance tests in nondiabetic humans ( n = 29,084).

          RESULTS

          The glucose-raising allele in MADD was associated with abnormal insulin processing (a dramatic effect on higher proinsulin levels, but no association with insulinogenic index) at extremely persuasive levels of statistical significance ( P = 2.1 × 10 −71). Defects in insulin processing and insulin secretion were seen in glucose-raising allele carriers at TCF7L2, SCL30A8, GIPR, and C2CD4B. Abnormalities in early insulin secretion were suggested in glucose-raising allele carriers at MTNR1B, GCK, FADS1, DGKB, and PROX1 (lower insulinogenic index; no association with proinsulin or insulin sensitivity). Two loci previously associated with fasting insulin ( GCKR and IGF1) were associated with OGTT-derived insulin sensitivity indices in a consistent direction.

          CONCLUSIONS

          Genetic loci identified through their effect on hyperglycemia and/or hyperinsulinemia demonstrate considerable heterogeneity in associations with measures of insulin processing, secretion, and sensitivity. Our findings emphasize the importance of detailed physiological characterization of such loci for improved understanding of pathways associated with alterations in glucose homeostasis and eventually type 2 diabetes.

          Related collections

          Most cited references40

          • Record: found
          • Abstract: found
          • Article: not found

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

          M. Matsuda, R DeFronzo (1999)
          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.
          Article 0 comments Cited 952 times – based on 0 reviews     Review now
            Bookmark
            • Record: found
            • Abstract: found
            • Article: not found

            Glucose clamp technique: a method for quantifying insulin secretion and resistance.

            Christian R. Andres, Stephanie J. Tobin, R. DeFronzo (1979)
            Methods for the quantification of beta-cell sensitivity to glucose (hyperglycemic clamp technique) and of tissue sensitivity to insulin (euglycemic insulin clamp technique) are described. Hyperglycemic clamp technique. The plasma glucose concentration is acutely raised to 125 mg/dl above basal levels by a priming infusion of glucose. The desired hyperglycemic plateau is subsequently maintained by adjustment of a variable glucose infusion, based on the negative feedback principle. Because the plasma glucose concentration is held constant, the glucose infusion rate is an index of glucose metabolism. Under these conditions of constant hyperglycemia, the plasma insulin response is biphasic with an early burst of insulin release during the first 6 min followed by a gradually progressive increase in plasma insulin concentration. Euglycemic insulin clamp technique. The plasma insulin concentration is acutely raised and maintained at approximately 100 muU/ml by a prime-continuous infusion of insulin. The plasma glucose concentration is held constant at basal levels by a variable glucose infusion using the negative feedback principle. Under these steady-state conditions of euglycemia, the glucose infusion rate equals glucose uptake by all the tissues in the body and is therefore a measure of tissue sensitivity to exogenous insulin.
            Article 0 comments Cited 566 times – based on 0 reviews     Review now
              Bookmark
              • Record: found
              • Abstract: found
              • Article: not found

              The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes.

              S E Kahn (2003)
              The relative contributions of insulin resistance and beta-cell dysfunction to the pathophysiology of Type 2 diabetes have been debated extensively. The concept that a feedback loop governs the interaction of the insulin-sensitive tissues and the beta cell as well as the elucidation of the hyperbolic relationship between insulin sensitivity and insulin secretion explains why insulin-resistant subjects exhibit markedly increased insulin responses while those who are insulin-sensitive have low responses. Consideration of this hyperbolic relationship has helped identify the critical role of beta-cell dysfunction in the development of Type 2 diabetes and the demonstration of reduced beta-cell function in high risk subjects. Furthermore, assessments in a number of ethnic groups emphasise that beta-cell function is a major determinant of oral glucose tolerance in subjects with normal and reduced glucose tolerance and that in all populations the progression from normal to impaired glucose tolerance and subsequently to Type 2 diabetes is associated with declining insulin sensitivity and beta-cell function. The genetic and molecular basis for these reductions in insulin sensitivity and beta-cell function are not fully understood but it does seem that body-fat distribution and especially intra-abdominal fat are major determinants of insulin resistance while reductions in beta-cell mass contribute to beta-cell dysfunction. Based on our greater understanding of the relative roles of insulin resistance and beta-cell dysfunction in Type 2 diabetes, we can anticipate advances in the identification of genes contributing to the development of the disease as well as approaches to the treatment and prevention of Type 2 diabetes.
              Article 0 comments Cited 459 times – based on 0 reviews     Review now
                Bookmark
                All references

                Author and article information

                Journal
                Journal ID (nlm-ta): Diabetes
                Journal ID (hwp): diabetes
                Journal ID (pmc): diabetes
                Journal ID (publisher-id): Diabetes
                Title: Diabetes
                Publisher: American Diabetes Association
                ISSN (Print): 0012-1797
                ISSN (Electronic): 1939-327X
                Publication date (Print): May 2010
                Publication date (Electronic): 25 February 2010
                Volume: 59
                Issue: 5
                Pages: 1266-1275
                Author notes
                Corresponding authors: Erik Ingelsson, erik.ingelsson@ 123456ki.se ; Leif Groop, Leif.Groop@ 123456med.lu.se ; Richard M. Watanabe, rwatanab@ 123456usc.edu ; Jose C. Florez, jcflorez@ 123456partners.org .

                *The complete list of authors' affiliations can be found in the appendix.

                E.I., C.L., and M.-F.H. contributed equally to this article.

                Article
                Publisher ID: 1568
                DOI: 10.2337/db09-1568
                PMC ID: 2857908
                PubMed ID: 20185807
                SO-VID: 92667eee-c880-4856-b8ae-2edaf641f07b
                Copyright © © 2010 by the American Diabetes Association.
                License:

                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
                Date received : 26 October 2009
                Date accepted : 18 February 2010
                Categories
                Subject: Original Article
                Subject: Genetics

                ScienceOpen disciplines: Endocrinology & Diabetes
                Data availability:
                ScienceOpen disciplines: Endocrinology & Diabetes

                Comments

                Comment on this article

                scite_

                Similar content61

                See all similar

                Cited by84

                See all cited by

                Most referenced authors1,899

                See all reference authors