Domenico Tricò1,2, Andrea Natali1, Silva Arslanian3,4, Andrea Mari5, Ele Ferrannini6. 1. Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy. 2. Institute of Life Sciences, Sant'Anna School of Advanced Studies, Pisa, Italy. 3. Center for Pediatric Research in Obesity and Metabolism, UPMC Children's Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA. 4. Division of Pediatric Endocrinology, Diabetes and Metabolism, Children's Hospital of Pittsburgh, University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, USA. 5. Institute of Neuroscience, National Research Council, Padua, Italy. 6. Institute of Clinical Physiology, National Research Council, Pisa, Italy.
Abstract
BACKGROUND: Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS: In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS: Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION: Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING: The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
BACKGROUND:Excessive insulin secretion may lead to glucose dysregulation. Our aim was to identify primary (independent of insulin resistance) insulin hypersecretion in subjects with normal glucose tolerance and its role in the progression of dysglycemia. METHODS: In 1,168 adults, insulin secretion rate (ISR) and β cell function were estimated by C-peptide modeling during an oral glucose tolerance test (OGTT) and an i.v. glucose tolerance test. Whole-body insulin sensitivity was measured by a hyperinsulinemic-euglycemic clamp. After regressing ISR on insulin sensitivity, subjects in the upper tertile of the distribution of residuals were defined as primary hypersecretors. This approach was applied to a biethnic cohort of 182 obese adolescents, who received an OGTT, a hyperglycemic, and a euglycemic clamp. RESULTS: Adult hypersecretors showed older age, more familial diabetes, sedentary lifestyle, increased fat mass, and worse lipid profile compared with the rest of the cohort, despite virtually identical BMI and insulin sensitivity. Insulin secretion was increased by 53% due to enhanced (+23%) β cell glucose sensitivity. Despite the resulting hyperinsulinemia, glucose tolerance was worse in hypersecretors among both adults and adolescents, coupled with higher indices of liver insulin resistance and increased availability of gluconeogenic substrates. At the 3-year follow-up, adult hypersecretors had increased incidence of impaired glucose tolerance/type 2 diabetes. CONCLUSION: Primary insulin hypersecretion, independent of insulin resistance, is associated with a worse clinical and metabolic phenotype in adults and adolescents and predicts deterioration of glucose control over time. FUNDING: The relationship between insulin sensitivity and cardiovascular disease (RISC) Study was partly supported by EU grant QLG1-CT-2001-01252.
Authors: S A Hills; B Balkau; S W Coppack; J M Dekker; A Mari; A Natali; M Walker; E Ferrannini Journal: Diabetologia Date: 2004-02-14 Impact factor: 10.122
Authors: Lovisa E Johansson; Ulf Lindblad; Charlotte A Larsson; Lennart Råstam; Martin Ridderstråle Journal: Eur J Endocrinol Date: 2008-08-26 Impact factor: 6.664
Authors: S M Haffner; R D'Agostino; M F Saad; M Rewers; L Mykkänen; J Selby; G Howard; P J Savage; R F Hamman; L E Wagenknecht Journal: Diabetes Date: 1996-06 Impact factor: 9.461
Authors: P Sbraccia; M D'Adamo; F Leonetti; S Caiola; P Iozzo; A Giaccari; A Buongiorno; G Tamburrano Journal: Diabetologia Date: 1996-02 Impact factor: 10.122
Authors: Evan P Taddeo; Nour Alsabeeh; Siyouneh Baghdasarian; Jakob D Wikstrom; Eleni Ritou; Samuel Sereda; Karel Erion; Jin Li; Linsey Stiles; Muhamad Abdulla; Zachary Swanson; Joshua J Wilhelm; Melena D Bellin; Richard G Kibbey; Marc Liesa; Orian S Shirihai Journal: Diabetes Date: 2019-11-18 Impact factor: 9.461
Authors: Kristina M Utzschneider; Mark T Tripputi; Alexandra Kozedub; Kieren J Mather; Kristen J Nadeau; Sharon L Edelstein; Tamara S Hannon; Silva A Arslanian; Melanie Cree-Green; Thomas A Buchanan; Sonia Caprio; Andrea Mari Journal: Pediatr Diabetes Date: 2020-10-14 Impact factor: 4.866
Authors: Stephan van Vliet; Han-Chow E Koh; Bruce W Patterson; Mihoko Yoshino; Richard LaForest; Robert J Gropler; Samuel Klein; Bettina Mittendorfer Journal: Diabetes Date: 2020-07-10 Impact factor: 9.461
Authors: Gordon I Smith; David C Polidori; Mihoko Yoshino; Monica L Kearney; Bruce W Patterson; Bettina Mittendorfer; Samuel Klein Journal: J Clin Invest Date: 2020-06-01 Impact factor: 14.808