Impaired glucose metabolism in subjects with the Williams-Beuren syndrome. A five-year follow-up cohort study

Objective. The 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 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. Methods. This 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. Results. IGM 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. Conclusions. IGM 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

Real world effectiveness of subcutaneous semaglutide in type 2 diabetes: A retrospective, cohort study (Sema-MiDiab01)

IntroductionAim of the present study was to evaluate the real-world impact of once-weekly (OW) subcutaneous semaglutide on different end-points indicative of metabolic control, cardiovascular risk factors, and beta-cell function in type 2 diabetes (T2D).MethodsThis was a retrospective, observational study conducted in 5 diabetes clinics in Italy. Changes in HbA1c, fasting blood glucose (FBG), body weight, blood pressure, lipid profile, renal function, and beta-cell function (HOMA-B) during 12 months were evaluated.ResultsOverall, 594 patients (97% GLP-1RA naïve) were identified (mean age 63.9 ± 9.5 years, 58.7% men, diabetes duration 11.4 ± 8.0 years). After 6 months of treatment with OW semaglutide, HbA1c levels were reduced by 0.90%, FBG by 26 mg/dl, and body weight by 3.43 kg. Systolic blood pressure, total and LDL-cholesterol significantly improved. Benefits were sustained at 12 months. Renal safety was documented. HOMA-B increased from 40.2% to 57.8% after 6 months (p<0.0001).DiscussionThe study highlighted benefits of semaglutide on metabolic control, multiple CV risk factors, and renal safety in the real-world. Semaglutide seems to be an advisable option for preservation of β-cell function and early evidence suggests it might have a role in modifying insulin resistance (HOMA-IR), the pathogenetic basis of prediabetes and T2D

Central role of the β-cell in driving regression of diabetes after liver transplantation in cirrhotic patients

Background & Aims: Diabetes occurring as a direct consequence of loss of liver function is usually characterized by non-diabetic fasting plasma glucose (FPG) and haemoglobin A 1c (HbA 1c ) levels and should regress after orthotopic liver transplantation (OLT). This observational, longitudinal study investigated the relationship between the time-courses of changes in all 3 direct determinants of glucose regulation, i.e., β-cell function, insulin clearance and insulin sensitivity, and diabetes regression after OLT. Methods: Eighty cirrhotic patients with non-diabetic FPG and HbA 1c levels underwent an extended oral glucose tolerance test (OGTT) before and 3, 6, 12 and 24 months after OLT. The OGTT data were analysed with a mathematical model to estimate derivative control (DC) and proportional control (PC) of β-cell function and insulin clearance (which determine insulin bioavailability), and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. Results: At baseline, 36 patients were diabetic (45%) and 44 were non-diabetic (55%). Over the 2-year follow-up, 23 diabetic patients (63.9%) regressed to non-diabetic glucose regulation, whereas 13 did not (36.1%); moreover, 4 non-diabetic individuals progressed to diabetes (9.1%), whereas 40 did not (90.9%). Both DC and PC increased in regressors (from month 3 and 24, respectively) and decreased in progressors, whereas they remained stable in non-regressors and only PC decreased in non-progressors. Insulin clearance increased in all groups, apart from progressors. Likewise, OGIS-2 h improved at month 3 in all groups, but thereafter it continued to improve only in regressors, whereas it returned to baseline values in the other groups. Conclusions: Increased insulin bioavailability driven by improved β-cell function plays a central role in favouring diabetes regression after OLT, in the presence of a sustained improvement of insulin sensitivity. Lay summary: Diabetes occurring in cirrhosis as a direct consequence of loss of liver function should regress after transplantation of a new functioning liver, though the pathophysiological mechanisms are unclear. This is the first study evaluating the contribution of all 3 direct determinants of insulin-dependent glucose regulation using a sophisticated mathematical model. Results show that β-cell function is the key process governing favourable or detrimental changes in glucose regulation in cirrhotic patients undergoing transplantation, pointing to the need to develop therapies to sustain β-cell function in these individuals. Trial registration: ClinicalTrials.gov, NCT02038517

Contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes. Role of severity of liver disease

Background & Aims This study evaluated the contribution of β-cell dysfunction and insulin resistance to cirrhosis-associated diabetes. Methods One-hundred and sixty cirrhotic patients with normal fasting plasma glucose (FPG), three with impaired fasting glucose and seven with untreated diabetes mellitus (DM) underwent an extended oral glucose tolerance test (OGTT). The OGTT data were analyzed with a Minimal Model to estimate dynamic (derivative) control (DC) and static (proportional) control (PC) of β-cell function, and with the Oral Glucose Insulin Sensitivity (OGIS)-2 h index to estimate insulin sensitivity. Results Twenty-six patients (15.6%) had normal glucose tolerance (NGT), 60 (35.8%) had impaired glucose tolerance (IGT), and 84 (48.6%) had DM. DC was significantly reduced in DM vs. NGT and IGT patients. PC was significantly impaired in DM and IGT vs. NGT patients and in DM vs. IGT subjects. The OGIS-2 h index was significantly reduced to a similar extent in DM and IGT vs. NGT patients. Patients with Child-Pugh class B and C cirrhosis had reduced DC and PC, but not OGIS-2 h values, as compared with subjects in class A. Moreover, Child-Pugh class/score was an independent predictor of β-cell function even after adjustment for glucose tolerance. Conclusions Abnormalities of glucose tolerance occur frequently in cirrhosis even in patients with normal FPG, thereby supporting the importance of performing an OGTT. Transition from IGT to DM is driven primarily by β-cell dysfunction. Insulin secretion worsens in parallel with the severity of liver disease, thus suggesting a detrimental effect of liver failure on pancreatic islets on its own

Metabolic syndrome after liver transplantation: Short-term prevalence and pre- and post-operative risk factors

Background: The metabolic syndrome is a common condition among liver transplanted patients and contributes to morbidity and mortality by favouring the development of cardiovascular diseases. Aims: This prospective study assessed the prevalence of metabolic syndrome in the first year after orthotopic liver transplantation, the associated pre-operative and post-operative risk factors and the influence of nutritional factors. Methods: 84 cirrhotic patients (75% male, mean age 53.9 +/- 9.3 years) were evaluated at baseline and after liver transplantation. Metabolic syndrome was defined according to 2004 Adult Treatment Panel-III criteria. Nutritional habits were assessed using 3-day food records. Results: Prevalence of metabolic syndrome before orthotopic liver transplantation was 14/84 (16.6%); at 3, 6 and 12 months post-orthotopic liver transplantation it was 27/84 (32.1%), 30/84 (35.7%), and 32/81 (39.5%), respectively. Diabetes, family history of diabetes, and excess body weight at baseline independently correlated with incidence of metabolic syndrome. After orthotopic liver transplantation, patients with metabolic syndrome showed a higher increase in the intake of total energy and saturated fats and a higher prevalence of complications, especially cardiovascular events, than subjects without metabolic syndrome. Conclusion: Occurrence of metabolic syndrome is an early phenomenon after liver transplantation. Preoperative and post-operative factors predispose patients to metabolic syndrome, which may be reduced by controlling modifiable risk factors, such as body weight and dietary intake. (C) 2013 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved

Changes in glucose homeostasis from baseline to end-of-follow-up.

<p>Changes in glucose homeostasis from baseline to end-of-follow-up.</p

Metabolic profiles of WS patients not known for type 2 DM (30 out of 31) at baseline and end-of-follow-up.

<p>Metabolic profiles of WS patients not known for type 2 DM (30 out of 31) at baseline and end-of-follow-up.</p

Changes in BMI category from baseline to end-of-follow-up.

<p>Changes in BMI category from baseline to end-of-follow-up.</p

Changes in CPGI relative to changes in MI in progressors (red; n = 8) and non-progressors (blue; n = 8).

<p>The lines represent the prediction line and the lower and upper limits of the 95% confidence interval of the regression between CPGI and MI as derived from a reference population with NFG/NGT. CPGI = C-peptidogenic Index; MI = Composite Insulin Sensitivity Index or Matsuda Index; NFG = normal fasting glucose; NGT = normal glucose tolerance.</p

eATP and autoimmune diabetes

Purpose of review: The purine nucleotide adenosine triphosphate (ATP) is released into extracellular spaces as extracellular ATP (eATP) as a consequence of cell injury or death and activates the purinergic receptors. Once released, eATP may facilitate T-lymphocyte activation and differentiation. The purpose of this review is to elucidate the role of ATP-mediated signaling in the immunological events related to type 1 diabetes (T1D). Recent findings: T lymphocytes mediate immune response during the onset of T1D and promote pancreatic islet or whole pancreas rejection in transplantation. Recent data suggest a potential role for eATP in early steps of T1D onset and of allograft rejection. In different preclinical experimental models and clinical trials, several drugs targeting purinergic signaling have been employed to abrogate lymphocyte activation and differentiation, thus representing an achievable treatment to prevent/revert T1D or to induce long-term islet allograft function. Summary: In preclinical and clinical settings, eATP-signaling inhibition induces immune tolerance in autoimmune disease and in allotransplantation. In this view, the purinergic system may represent a novel therapeutic target for auto- and allo-immunity