Abstract
ObjectiveThe Williams-Beuren syndrome (WS) is associated with impaired glucose metabolism (IGM) early in adulthood. However, the pathophysiology of IGM remains poorly defined, due to the lack of longitudinal studies investigating the contribution of β-cell dysfunction and impaired insulin sensitivity. This study aimed at assessing incidence of IGM and the underlying mechanisms in WS adults.MethodsThis observational, longitudinal (5-year), cohort study enrolled thirty-one consecutive WS subjects attending a tertiary referral center. An oral glucose tolerance test (OGTT) was performed yearly and used to classify patients as normal or IGM, including impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT) and diabetes mellitus (DM), and to calculate surrogate measures of insulin secretion and/or sensitivity.ResultsIGM patients were 18 (58.1%, three DM) at baseline and 19 (61.3%, five DM) at end-of-follow-up. However, 13 individuals changed category of glucose homeostasis in both directions during follow-up (8 progressors, 5 regressors) and 18 did not (8 non-progressors, 10 non-regressors). New cases of IGM and DM were 11.1 and 2.53 per 100 persons-year, respectively, and were treated non-pharmacologically. In the whole cohort and, to a higher extent, in progressors, indices of early-phase insulin secretion and insulin sensitivity decreased significantly from baseline to end-of-follow-up, with concurrent reduction of the oral disposition index and insulin secretion-sensitivity index-2 (ISSI-2), compensating insulin secretion for the level of insulin resistance. No baseline measure independently predicted progression, which correlated with change from baseline in ISSI-2. Compared with patients with normal glucose homeostasis, IGT subjects had impaired insulin sensitivity, whereas insulin secretion was reduced only in those with IFG+IGT or DM.ConclusionsIGM incidence is high in young adults with WS, suggesting the need of early screening and timed intervention. As in classical type 2 diabetes, impaired insulin sensitivity and β-cell dysfunction contribute, in this sequence, to progression to IGM and DM.
Highlights
Several genetic disorders are accompanied by an increased incidence of diabetes mellitus (DM)
No baseline measure independently predicted progression, which correlated with change from baseline in insulin secretion-sensitivity index-2 (ISSI-2)
impaired glucose metabolism (IGM) incidence is high in young adults with Williams-Beuren syndrome (WS), suggesting the need of early screening and timed intervention
Summary
Several genetic disorders are accompanied by an increased incidence of diabetes mellitus (DM). DM is not invariably present in individuals suffering from these syndromes and, when present, it is often diagnosed only by performing an oral glucose tolerance test (OGTT) Though rare, these disorders may provide insight into the pathophysiology of the common forms of DM, especially type 2 DM. Adults with WS are typically limited in their ability to live independently or work in competitive employment settings, due to the persistence into adulthood of physical and mental health problems and the emergence of new medical issues such as audiological, dental, and endocrine abnormalities These individuals frequently develop IGM, comprising impaired fasting glucose (IFG), impaired glucose tolerance (IGT), and DM, early in the adulthood. Two genes mapping to the WSCR have been considered as possible “diabetogenic hits”, syntaxin-1A (STX-1A) [10] and Max-like protein X interacting protein like (MLXIPL, formerly WSCR 14 and known as carbohydrate-responsive element-binding protein, ChREBP) [11]
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