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Role of the ENPP1 K121Q Polymorphism on Glucose Homeostasis

¹Unit of Endocrinology, Department of Internal and Specialistic Medicine, University of Catania Medical School, Garibaldi Hospital, Catania, Italy
²Research Unit of Diabetes and Endocrine Diseases, CSS Scientific Institute, San Giovanni Rotondo, Italy
³CSS-Mendel Institute, Rome, Italy
⁴Bambino Gesù Pediatric Hospital, Research Institute IRCCS, Rome, Italy
⁵Unit of Biostatistics, Department of Clinical Pharmacology and Epidemiology, "Consorzio Mario Negri Sud", S. Maria Imbaro, Chieti, Italy
⁶Unit of Endocrinology, CSS Scientific Institute, San Giovanni Rotondo, Italy
⁷Department of Clinical Sciences, "Sapienza" University, Rome, Italy

Objective: To study the role of the ENPP1 Q121 variant on glucose homeostasis in Whites from Italy.

Research Design and Methods: Case-control studies in 764 adults (i.e. from two independent samples of 289 non-obese and 485 obese individuals) and 240 overweight/obese children undergoing OGTT. Early-phase insulin secretion and insulin sensitivity (i.e. the insulinogenic index, IGI and the insulin sensitivity index, ISI) and their interplay (i.e. the disposition index, DI) were calculated.

Results: Adult subjects. Glucose profiles during OGTT were significantly (p=2·10^–2) different across K121Q genotype groups, being higher in QQ vs. KK individuals (p=5·10^–2). The IGI, was significantly reduced in QQ (18.5±3.4) as compared to both KK (31.6±1.0; p=2.2·10^–7) and KQ (30.5±1.5; p=3.2·10^–6) individuals. KQ individuals also showed a reduced ISI as compared to KK subjects (p=3.6·10^–2). The DI was lower in QQ carriers vs. KQ and KK individuals (p=8·10^–3 and 4·10^–4, respectively) and in KQ vs. KK individuals (p=3·10^–2).

Overweight/obese children. Data obtained in this sample were very similar to those observed in adults with QQ individuals showing, as compared to KQ and KK subjects, reduced IGI (p=7·10^–3 and 2·10^–2, respectively) and DI (p=2·10^–2 and 7·10^–3, respectively).

Conclusions: Homozygous carriers of the ENPP1 Q121 variant are characterized by an altered glucose homeostasis. Reduced early-phase insulin secretion and inefficient interplay between insulin secretion and sensitivity, which occur at early ages, are major determinants of this defect.

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