Publications by authors named "Andrea De Gaetano"

63 Publications

A mathematical model of food intake.

Math Biosci Eng 2021 01;18(2):1238-1279

Department of Mathematics, Faculty of Science, Mahidol University, Bangkok 10400, Thailand.

The metabolic, hormonal and psychological determinants of the feeding behavior in humans are numerous and complex. A plausible model of the initiation, continuation and cessation of meals taking into account the most relevant such determinants would be very useful in simulating food intake over hours to days, thus providing input into existing models of nutrient absorption and metabolism. In the present work, a meal model is proposed, incorporating stomach distension, glycemic variations, ghrelin dynamics, cultural habits and influences on the initiation and continuation of meals, reflecting a combination of hedonic and appetite components. Given a set of parameter values (portraying a single subject), the timing and size of meals are stochastic. The model parameters are calibrated so as to reflect established medical knowledge on data of food intake from the National Health and Nutrition Examination Survey (NHANES) database during years 2015 and 2016.
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http://dx.doi.org/10.3934/mbe.2021067DOI Listing
January 2021

A quasi-equilibrium reduced model of pancreatic insulin secretion.

J Math Biol 2021 Mar 1;82(4):25. Epub 2021 Mar 1.

CNR-IASI Biomathematics Laboratory (BioMatLab), Rome, Italy.

Much attention has been devoted in the last few decades to mathematical models of insulin secretion, in order to better understand the regulation of glycemia and its derangements. The glucose-insulin homeostatic mechanism is so complex and gives rise to such diverse behavior following perturbations that different models had been published, which reproduced the results of single experiments. More recently, a unifying model of pancreatic insulin secretion was proposed, which is able to account, with a single value of the (meta)parameters, for the wide array of clinically observed behavior. This model explicitly represented the pulsatile nature of the many pancreatic hormone-secreting firing units: the price to pay for its flexibility and performance is the very high dimensionality (hundreds of thousand equations) of the corresponding dynamical system. Clearly, it would be desirable to reduce this model to a much simpler form while retaining its power to reproduce heterogeneous phenomena. The present work reviews the qualitative behavior of this pancreas pulsatile model and offers some insight into its reduction in equilibrium and quasi-equilibrium conditions, also considering single-shot (non-repeated) glucose jumps from an approximately resting condition (such as would occur in standard Intra-Venous bolus dosing of glucose during diabetes diagnostic maneuvers). The resulting quasi-steady-state model can be further endowed with additional lower-order dynamics to also approximate transient behavior. Although a more accurate reduction of the original pulsatile model is left to further investigation, numerical results confirm the biomedical applicability of the formulation already obtained.
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http://dx.doi.org/10.1007/s00285-021-01575-5DOI Listing
March 2021

Metabolic surgery versus conventional medical therapy in patients with type 2 diabetes: 10-year follow-up of an open-label, single-centre, randomised controlled trial.

Lancet 2021 01;397(10271):293-304

Division of Diabetes and Nutritional Sciences, Faculty of Life Sciences and Medicine, King's College London, London, UK; Department of Diabetes, Bariatric and Metabolic Surgery, King's College Hospital, London, UK.

Background: No data from randomised controlled trials of metabolic surgery for diabetes are available beyond 5 years of follow-up. We aimed to assess 10-year follow-up after surgery compared with medical therapy for the treatment of type 2 diabetes.

Methods: We did a 10-year follow-up study of an open-label, single-centre (tertiary hospital in Rome, Italy), randomised controlled trial, in which patients with type 2 diabetes (baseline duration >5 years; glycated haemoglobin [HbA] >7·0%, and body-mass index ≥35 kg/m) were randomly assigned (1:1:1) to medical therapy, Roux-en-Y gastric bypass (RYGB), or biliopancreatic diversion (BPD) by a computerised system. The primary endpoint of the study was diabetes remission at 2 years (HbA <6·5% and fasting glycaemia <5·55 mmol/L without ongoing medication for at least 1 year). In the 10-year analysis, durability of diabetes remission was analysed by intention to treat (ITT). This study is registered with ClinicalTrials.gov, NCT00888836.

Findings: Between April 30, 2009, and Oct 31, 2011, of 72 patients assessed for eligibility, 60 were included. The 10-year follow-up rate was 95·0% (57 of 60). Of all patients who were surgically treated, 15 (37·5%) maintained diabetes remission throughout the 10-year period. Specifically, 10-year remission rates in the ITT population were 5·5% for medical therapy (95% CI 1·0-25·7; one participant went into remission after crossover to surgery), 50·0% for BPD (29·9-70·1), and 25·0% for RYGB (11·2-46·9; p=0·0082). 20 (58·8%) of 34 participants who were observed to be in remission at 2 years had a relapse of hyperglycaemia during the follow-up period (BPD 52·6% [95% CI 31·7-72·7]; RYGB 66·7% [41·7-84·8]). All individuals with relapse, however, maintained adequate glycaemic control at 10 years (mean HbA 6·7% [SD 0·2]). Participants in the RYGB and BPD groups had fewer diabetes-related complications than those in the medical therapy group (relative risk 0·07 [95% CI 0·01-0·48] for both comparisons). Serious adverse events occurred more frequently among participants in the BPD group (odds ratio [OR] for BPD vs medical therapy 2·7 [95% CI 1·3-5·6]; OR for RYGB vs medical therapy 0·7 [0·3-1·9]).

Interpretation: Metabolic surgery is more effective than conventional medical therapy in the long-term control of type 2 diabetes. Clinicians and policy makers should ensure that metabolic surgery is appropriately considered in the management of patients with obesity and type 2 diabetes.

Funding: Fondazione Policlinico Universitario Agostino Gemelli IRCCS.
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http://dx.doi.org/10.1016/S0140-6736(20)32649-0DOI Listing
January 2021

A Simple Cardiovascular Model for the Study of Hemorrhagic Shock.

Comput Math Methods Med 2020 24;2020:7936895. Epub 2020 Dec 24.

National Research Council of Italy, Institute for Biomedical Research and Innovation, Via Ugo La Malfa, 153, 90146 Palermo, Italy.

Hemorrhagic shock is the number one cause of death on the battlefield and in civilian trauma as well. Mathematical modeling has been applied in this context for decades; however, the formulation of a satisfactory model that is both practical and effective has yet to be achieved. This paper introduces an upgraded version of the 2007 Zenker model for hemorrhagic shock termed the ZenCur model that allows for a better description of the time course of relevant observations. Our study provides a simple but realistic mathematical description of cardiovascular dynamics that may be useful in the assessment and prognosis of hemorrhagic shock. This model is capable of replicating the changes in mean arterial pressure, heart rate, and cardiac output after the onset of bleeding (as observed in four experimental laboratory animals) and achieves a reasonable compromise between an overly detailed depiction of relevant mechanisms, on the one hand, and model simplicity, on the other. The former would require considerable simulations and entail burdensome interpretations. From a clinical standpoint, the goals of the new model are to predict survival and optimize the timing of therapy, in both civilian and military scenarios.
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http://dx.doi.org/10.1155/2020/7936895DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7781723PMC
December 2020

Pioglitazone and bariatric surgery are the most effective treatments for non-alcoholic steatohepatitis: A hierarchical network meta-analysis.

Diabetes Obes Metab 2021 Apr 15;23(4):980-990. Epub 2021 Jan 15.

Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy.

Aims: To compare different treatments for non-alcoholic steatohepatitis (NASH) and to determine an effectiveness hierarchy.

Materials And Methods: We conducted a systematic review and Bayesian network meta-analysis including randomized controlled trials or prospective trials with at least 6 months' follow-up and histologically proven NASH in adult participants. Monte Carlo simulations were performed, each generating 10 000 data points, and results are reported as medians and 95% credibility intervals (CrIs). A meta-regression was conducted to find the effects of body mass index (BMI) decrement or reduction of homeostatic model assessment of insulin resistance (HOMA-IR) index on non-alcoholic fatty liver disease activity score (NAS) change.

Results: The review identified 48 eligible trials comprising 2356 adults (55.6% men). Data were pooled using a random-effects model. The most effective treatments in terms of NAS reduction per semester were pioglitazone and Roux-en-Y gastric bypass (RYGB; -1.50 [95% CrI -2.08, -1.00] for pioglitazione and -1.00 [95% CrI -1.70, -0.32] for RYGB). Pioglitazone was also the best therapy for steatosis and lobular inflammation reduction. RYGB was the best treatment for hepatocellular ballooning reduction, whereas antioxidants appeared to be best for fibrosis improvement. For each 1% decrement in BMI, NAS was reduced by 1.3% (β = 1.28%, P = 0.01). Conversely, a 1% reduction of HOMA-IR index reduced NAS by 0.3% (β = 0.31%, P < 0.001). Treatments that were regarded as promising, such as elafibranor, simtuzumab, selonsertib, cenicriviroc, obeticholic acid and liraglutide, did not reduce either NAS or liver fibrosis significantly.

Conclusions: Pioglitazione and RYGB are the most effective therapies for NASH. Antioxidants may be effective in reducing liver fibrosis. Weight loss and improvement of hepatic insulin resistance are promising approaches in the treatment of NASH.
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http://dx.doi.org/10.1111/dom.14304DOI Listing
April 2021

Comparison between two different cardiovascular models during a hemorrhagic shock scenario.

Math Biosci Eng 2020 07;17(5):5027-5058

CNR-IASI BioMatLab (Biomathematics Laboratory), UCSC Largo A. Gemelli 8, 00168 Rome, Italy.

Hemorrhagic shock is a form of hypovolemic shock determined by rapid and large loss of intravascular blood volume and represents the first cause of death in the world, whether on the battlefield or in civilian traumatology. For this, the ability to prevent hemorrhagic shock remains one of the greatest challenges in the medical and engineering fields. The use of mathematical models of the cardiocirculatory system has improved the capacity, on one hand, to predict the risk of hemorrhagic shock and, on the other, to determine efficient treatment strategies. In this paper, a comparison between two mathematical models that simulate several hemorrhagic scenarios is presented. The models considered are the Guyton and the Zenker model. In the vast panorama of existing cardiovascular mathematical models, we decided to compare these two models because they seem to be at the extremes as regards the complexity and the detail of information that they analyze. The Guyton model is a complex and highly structured model that represents a milestone in the study of the cardiovascular system; the Zenker model is a more recent one, developed in 2007, that is relatively simple and easy to implement. The comparison between the two models offers new prospects for the improvement of mathematical models of the cardiovascular system that may prove more effective in the study of hemorrhagic shock.
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http://dx.doi.org/10.3934/mbe.2020272DOI Listing
July 2020

A revised Sorensen model: Simulating glycemic and insulinemic response to oral and intra-venous glucose load.

PLoS One 2020 14;15(8):e0237215. Epub 2020 Aug 14.

Institute of System Analysis and Informatics (IASI) "A. Ruberti", National Research Council (CNR), Rome, Italy.

In 1978, Thomas J. Sorensen defended a thesis in chemical engineering at the University of California, Berkeley, where he proposed an extensive model of glucose-insulin control, model which was thereafter widely employed for virtual patient simulation. The original model, and even more so its subsequent implementations by other Authors, presented however a few imprecisions in reporting the correct model equations and parameter values. The goal of the present work is to revise the original Sorensen's model, to clearly summarize its defining equations, to supplement it with a missing gastrio-intestinal glucose absorption and to make an implementation of the revised model available on-line to the scientific community.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0237215PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7428140PMC
October 2020

Insulin sensitivity depends on the route of glucose administration.

Diabetologia 2020 07 8;63(7):1382-1395. Epub 2020 May 8.

Steno Diabetes Center, Gentofte, Denmark.

Aims/hypothesis: The small intestine plays an important role in hepatic and whole-body insulin sensitivity, as shown by bariatric surgery. Our goal was to study whether routes and dose of glucose administration have an acute impact on insulin sensitivity. The primary endpoint of this proof-of-concept study was the difference in insulin-mediated metabolic clearance rate (MCR/I) of glucose between the oral and intravenous routes of glucose administration. Secondary endpoints were differences in insulin effect on proteolysis, ketogenesis, lipolysis and glucagon levels.

Methods: In this parallel cohort study, we administered multiple oral glucose loads to 23 participants (aged between 18 and 65 years) with morbid obesity and with normal or impaired glucose tolerance or type 2 diabetes. In a different session, we administered isoglycaemic intravenous glucose infusions (IGIVI) to match the plasma glucose levels observed during the oral challenges. Glucose rate of appearance (R) and disappearance (R) and endogenous glucose production (EGP) were calculated by infusing [6,6-H]glucose with or without oral [U-C]glucose. Plasma small polar metabolites were measured by gas chromatography and time-of-flight mass spectrometry. Lipids were measured by ultra-HPLC and quadrupole mass spectrometry. Glucagon-like peptide-1, insulin, C-peptide and glucagon were also measured. Participants, caregivers, people doing measurements or examinations, and people assessing the outcomes were unblinded to group assignment.

Results: Glucose MCR/I was significantly higher during IGIVI than during oral glucose administration, independently of glycaemic status (12 ± 6 for IGIVI vs 7.4 ± 3 ml min kg per nmol/l for oral, p< 0.001 from paired t test). Insulin secretion was higher during oral administration than during IGIVI (p< 0.001). The disposition index was significantly lower during the oral procedure: 4260 ± 1820 vs 5000 ± 2360 (ml min kg (nmol/l) pmol/min; p = 0.005). Insulin clearance was significantly higher when glucose was infused rather than ingested (2.53 ± 0.82 vs 2.16 ± 0.49 l/min in intravenous and oral procedure, respectively, p = 0.006). The efficacy of insulin in inhibiting lipolysis and proteolysis was decreased after oral glucose loads. A heat map diagram showed a different pattern for the metabolites between the two routes of glucose administration.

Conclusions/interpretation: Our study shows that insulin sensitivity depends on the route of glucose administration, the oral route leading to increased insulin secretion and compensatory insulin resistance compared with the intravenous route. The efficacy of insulin in blocking lipolysis and protein breakdown is lower after oral glucose loads vs the intravenous route. Our findings suggest that, while the glucose-mediated incretin release is followed by an increase in insulin release, the effect of the released insulin is limited by an increase in insulin resistance.

Trial Registration: ClinicalTrials.gov NCT03223129. Graphical abstract.
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http://dx.doi.org/10.1007/s00125-020-05157-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7286868PMC
July 2020

A novel fast-slow model of diabetes progression: Insights into mechanisms of response to the interventions in the Diabetes Prevention Program.

PLoS One 2019 10;14(10):e0222833. Epub 2019 Oct 10.

Lilly Research Laboratories, Eli Lilly and Company, Lilly Corporate Center, Indianapolis, Indiana, United States of America.

Several models for the long-term development of T2DM already exist, focusing on the dynamics of the interaction between glycemia, insulinemia and β-cell mass. Current models consider representative (fasting or daily average) glycemia and insulinemia as characterizing the compensation state of the subject at some instant in slow time. This implies that only these representative levels can be followed through time and that the role of fast glycemic oscillations is neglected. An improved model (DPM15) for the long-term progression of T2DM is proposed, introducing separate peripheral and hepatic (liver and kidney) insulin actions. The DPM15 model no longer uses near-equilibrium approximation to separate fast and slow time scales, but rather describes, at each step in slow time, a complete day in the life of the virtual subject in fast time. The model can thus represent both fasting and postprandial glycemic levels and describe the effect of interventions acting on insulin-enhanced tissue glucose disposal or on insulin-inhibited hepatic glucose output, as well as on insulin secretion and β-cell replicating ability. The model can simulate long-term variations of commonly used clinical indices (HOMA-B, HOMA-IR, insulinogenic index) as well as of Oral Glucose Tolerance or Euglycemic Hyperinsulinemic Clamp test results. The model has been calibrated against observational data from the Diabetes Prevention Program study: it shows good adaptation to observations as a function of very plausible values of the parameters describing the effect of such interventions as Placebo, Intensive LifeStyle and Metformin administration.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0222833PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6786566PMC
March 2020

Consistency of compact and extended models of glucose-insulin homeostasis: The role of variable pancreatic reserve.

PLoS One 2019 15;14(2):e0211331. Epub 2019 Feb 15.

CNR-IASI BioMatLab, Consiglio Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica, Laboratorio di Biomatematica (Italian National Research Council - Institute for System Analysis and Computer Science - Biomathematics Laboratory), UCSC Largo A. Gemelli 8, Rome, Italy.

Published compact and extended models of the glucose-insulin physiologic control system are compared, in order to understand why a specific functional form of the compact model proved to be necessary for a satisfactory representation of acute perturbation experiments such as the Intra Venous Glucose Tolerance Test (IVGTT). A spectrum of IVGTT's of virtual subjects ranging from normal to IFG to IGT to frank T2DM were simulated using an extended model incorporating the population-of-controllers paradigm originally hypothesized by Grodsky, and proven to be able to capture a wide array of experimental results from heterogeneous perturbation procedures. The simulated IVGTT's were then fitted with the Single-Delay Model (SDM), a compact model with only six free parameters, previously shown to be very effective in delivering precise estimates of insulin sensitivity and secretion during an IVGTT. Comparison of the generating, extended-model parameter values with the obtained compact model estimates shows that the functional form of the nonlinear insulin-secretion term, empirically found to be necessary for the compact model to satisfactorily fit clinical observations, captures the pancreatic reserve level of the simulated virtual patients. This result supports the validity of the compact model as a meaningful analysis tool for the clinical assessment of insulin sensitivity.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0211331PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6377092PMC
November 2019

Incidence of Hypoglycemia After Gastric Bypass vs Sleeve Gastrectomy: A Randomized Trial.

J Clin Endocrinol Metab 2018 06;103(6):2136-2146

Department of Internal Medicine, Catholic University, Rome, Italy.

Context: We compared the incidence of hypoglycemia after Roux-en-Y gastric bypass (RYGB) vs sleeve gastrectomy (SG).

Design, Setting, And Main Outcome Measures: Randomized, open-label trial conducted at the outpatient obesity clinic in a university hospital in Rome, Italy. The primary aim was the incidence of reactive hypoglycemia (<3.1 mmol/L after 75-g oral glucose load) at 1 year after surgery. Secondary aims were hypoglycemia under everyday life conditions, insulin sensitivity, insulin secretion, and lipid profile.

Results: Of 175 eligible patients, 120 were randomized 1:1 to RYGB or SG; 117 (93%) completed the 12-month follow-up. Reactive hypoglycemia was detected in 14% and 29% of SG and RYGB patients (P = 0.079), respectively, with the effect of treatment in multivariate analysis significant at P = 0.018. Daily hypoglycemic episodes during continuous glucose monitoring did not differ between groups (P = 0.75). Four of 59 RYGB subjects (6.8%) had 1 to 3 hospitalizations for symptomatic hypoglycemia vs 0 in SG. The static β-cell glucose sensitivity index increased after both treatments (P < 0.001), but the dynamic β-cell glucose sensitivity index increased significantly in SG (P = 0.008) and decreased in RYGB (P = 0.004 for time × treatment interaction). Whole-body insulin sensitivity increased about 10-fold in both groups.

Conclusions: We show that reactive hypoglycemia is no less common after SG and is not a safer option than RYGB, but RYGB is associated with more severe hypoglycemic episodes. This is likely due to the lack of improvement of β-cell sensitivity to changes in circulating glucose after RYGB, which determines an inappropriately high insulin secretion.
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http://dx.doi.org/10.1210/jc.2017-01695DOI Listing
June 2018

Simulation of Trauma Incidents : Modelling the Evolution of Patients and Resources.

J Med Syst 2016 Nov 21;40(11):234. Epub 2016 Sep 21.

CNR-IASI Biomathematics Laboratory (BioMatLab), Largo A. Gemelli 8, 00168, Rome, Italy.

Mathematical modeling and simulation with medical applications has gained much interest in the last few years, mainly due to the widespread availability of low-cost technology and computational power. This paper presents an integrated platform for the in-silico simulation of trauma incidents, based on a suite of interacting mathematical models. The models cover the generation of a scenario for an incident, a model of physiological evolution of the affected individuals, including the possible effect of the treatment, and a model of evolution in time of the required medical resources. The problem of optimal resource allocation is also investigated. Model parameters have been identified according to the expertise of medical doctors and by reviewing some related literature. The models have been implemented and exposed as web services, while some software clients have been built for the purpose of testing. Due to its extendability, our integrated platform highlights the potential of model-based simulation in different health-related fields, such as emergency medicine and personal health systems. Modifications of the models are already being used in the context of two funded projects, aiming at evaluating the response of health systems to major incidents with and without model-based decision support.
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http://dx.doi.org/10.1007/s10916-016-0599-xDOI Listing
November 2016

A Simple, Realistic Stochastic Model of Gastric Emptying.

PLoS One 2016 8;11(4):e0153297. Epub 2016 Apr 8.

Department of Mathematics, Mahidol University, Bangkok 10400, Thailand.

Several models of Gastric Emptying (GE) have been employed in the past to represent the rate of delivery of stomach contents to the duodenum and jejunum. These models have all used a deterministic form (algebraic equations or ordinary differential equations), considering GE as a continuous, smooth process in time. However, GE is known to occur as a sequence of spurts, irregular both in size and in timing. Hence, we formulate a simple stochastic process model, able to represent the irregular decrements of gastric contents after a meal. The model is calibrated on existing literature data and provides consistent predictions of the observed variability in the emptying trajectories. This approach may be useful in metabolic modeling, since it describes well and explains the apparently heterogeneous GE experimental results in situations where common gastric mechanics across subjects would be expected.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0153297PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4825969PMC
August 2016

Determinants of Diabetes Remission and Glycemic Control After Bariatric Surgery.

Diabetes Care 2016 Jan 1;39(1):166-74. Epub 2015 Dec 1.

Obesity Research Unit, Department of General Practice, and Baker IDI Heart and Diabetes Institute, Monash University, Melbourne, Victoria, Australia.

Objective: Eligibility criteria for bariatric surgery in diabetes include BMI ≥35 kg/m(2) and poorly controlled glycemia. However, BMI does not predict diabetes remission, and thus, predictors need to be identified.

Research Design And Methods: Seven hundred twenty-seven patients were included in a database merged from the Swedish Obese Subjects (SOS) study and two randomized controlled studies, with 415 surgical and 312 medical patients in total. Bariatric operations were divided into gastric only (GO) and gastric plus diversion (GD).

Results: Sixty-four percent of patients in the surgical arm and 15.0% in the medical arm experienced diabetes remission (P < 0.001). GO yielded 60% remission, and GD yielded 76% remission. The best predictors of diabetes remission were lower baseline glycemia and shorter diabetes duration. However, when operation type was considered, GD predicted a higher likelihood of remission and greater weight loss. Patients in remission (responders) lost more weight (25% vs. 17%) and waist circumference (18% vs. 13%) and experienced better insulin sensitivity than nonresponders.

Conclusions: Surgery is more effective than medical treatment in achieving diabetes remission and tighter glycemic control. Shorter diabetes duration, lower fasting glycemia before surgery, and GD versus GO procedures independently predict higher rates of remission, whereas baseline HbA1c and waist circumference predict improved glycemic control. The results show the advantage of an early operation together with better controlled glycemia on diabetes remission independently of BMI.
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http://dx.doi.org/10.2337/dc15-0575DOI Listing
January 2016

A Unifying Organ Model of Pancreatic Insulin Secretion.

PLoS One 2015 10;10(11):e0142344. Epub 2015 Nov 10.

CNR-IASI BioMatLab (Italian National Research Council - Institute of Analysis, Systems and Computer Science - Biomathematics Laboratory), UCSC Largo A. Gemelli 8, 00168 Rome, Italy.

The secretion of insulin by the pancreas has been the object of much attention over the past several decades. Insulin is known to be secreted by pancreatic β-cells in response to hyperglycemia: its blood concentrations however exhibit both high-frequency (period approx. 10 minutes) and low-frequency oscillations (period approx. 1.5 hours). Furthermore, characteristic insulin secretory response to challenge maneuvers have been described, such as frequency entrainment upon sinusoidal glycemic stimulation; substantial insulin peaks following minimal glucose administration; progressively strengthened insulin secretion response after repeated administration of the same amount of glucose; insulin and glucose characteristic curves after Intra-Venous administration of glucose boli in healthy and pre-diabetic subjects as well as in Type 2 Diabetes Mellitus. Previous modeling of β-cell physiology has been mainly directed to the intracellular chain of events giving rise to single-cell or cell-cluster hormone release oscillations, but the large size, long period and complex morphology of the diverse responses to whole-body glucose stimuli has not yet been coherently explained. Starting with the seminal work of Grodsky it was hypothesized that the population of pancreatic β-cells, possibly functionally aggregated in islets of Langerhans, could be viewed as a set of independent, similar, but not identical controllers (firing units) with distributed functional parameters. The present work shows how a single model based on a population of independent islet controllers can reproduce very closely a diverse array of actually observed experimental results, with the same set of working parameters. The model's success in reproducing a diverse array of experiments implies that, in order to understand the macroscopic behaviour of the endocrine pancreas in regulating glycemia, there is no need to hypothesize intrapancreatic pacemakers, influences between different islets of Langerhans, glycolitic-induced oscillations or β-cell sensitivity to the rate of change of glycemia.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0142344PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4640662PMC
June 2016

A glycemia-structured population model.

J Math Biol 2016 07 6;73(1):39-62. Epub 2015 Oct 6.

BioMatLab, IASI-CNR, Rome, Italy.

Structured models are population models in which the individuals are characterized with respect to the value of some variable of interest, called the structure variable. In the present paper, we propose a glycemia-structured population model, based on a linear partial differential equation with variable coefficients. The model is characterized by three rate functions: a new-adult population glycemic profile, a glycemia-dependent mortality rate and a glycemia-dependent average worsening rate. First, we formally analyze some properties of the solution, the transient behavior and the equilibrium distribution. Then, we identify the key parameters and functions of the model from real-life data and we hypothesize some plausible modifications of the rate functions to obtain a more beneficial steady-state behavior. The interest of the model is that, while it summarizes the evolution of diabetes in the population in a completely different way with respect to previously published Monte Carlo aggregations of individual-based models, it does appear to offer a good approximation of observed reality and of the features expected in the clinical setting. The model can offer insights in pharmaceutical research and be used to assess possible public health intervention strategies.
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http://dx.doi.org/10.1007/s00285-015-0935-7DOI Listing
July 2016

Bariatric-metabolic surgery versus conventional medical treatment in obese patients with type 2 diabetes: 5 year follow-up of an open-label, single-centre, randomised controlled trial.

Lancet 2015 Sep;386(9997):964-73

Metabolic and Bariatric Surgery, King's College London, London, UK.

Background: Randomised controlled trials have shown that bariatric surgery is more effective than conventional treatment for the short-term control of type-2 diabetes. However, published studies are characterised by a relatively short follow-up. We aimed to assess 5 year outcomes from our randomised trial designed to compare surgery with conventional medical treatment for the treatment of type 2 diabetes in obese patients.

Methods: We did our open-label, randomised controlled trial at one diabetes centre in Italy. Patients aged 30-60 years with a body-mass index of 35 kg/m(2) or more and a history of type 2 diabetes lasting at least 5 years were randomly assigned (1:1:1), via a computer-generated randomisation procedure, to receive either medical treatment or surgery by Roux-en-Y gastric bypass or biliopancreatic diversion. Participants were aware of treatment allocation before the operation and study investigators were aware from the point of randomisation. The primary endpoint was the rate of diabetes remission at 2 years, defined as a glycated haemaglobin A1c (HbA1c) concentration of 6·5% or less (≤47·5 mmol/mol) and a fasting glucose concentration of 5·6 mmol/L or less without active pharmacological treatment for 1 year. Here we analyse glycaemic and metabolic control, cardiovascular risk, medication use, quality of life, and long-term complications 5 years after randomisation. Analysis was by intention to treat for the primary endpoint and by per protocol for the 5 year follow-up. This study is registered with ClinicalTrials.gov, number NCT00888836.

Findings: Between April 27, 2009, and Oct 31, 2009, we randomly assigned 60 patients to receive either medical treatment (n=20) or surgery by gastric bypass (n=20) or biliopancreatic diversion (n=20); 53 (88%) patients completed 5 years' follow-up. Overall, 19 (50%) of the 38 surgical patients (seven [37%] of 19 in the gastric bypass group and 12 [63%] of 19 in the bilipancreatic diversion group) maintained diabetes remission at 5 years, compared with none of the 15 medically treated patients (p=0·0007). We recorded relapse of hyperglycaemia in eight (53%) of the 15 patients who achieved 2 year remission in the gastric bypass group and seven (37%) of the 19 patients who achieved 2 year remission in the biliopancreatic diversion group. Eight (42%) patients who underwent gastric bypass and 13 (68%) patients who underwent biliopancreatic diversion had an HbA1c concentration of 6·5% or less (≤47·5 mmol/mol) with or without medication, compared with four (27%) medically treated patients (p=0·0457). Surgical patients lost more weight than medically treated patients, but weight changes did not predict diabetes remission or relapse after surgery. Both surgical procedures were associated with significantly lower plasma lipids, cardiovascular risk, and medication use. Five major complications of diabetes (including one fatal myocardial infarction) arose in four (27%) patients in the medical group compared with only one complication in the gastric bypass group and no complications in the biliopancreatic diversion group. No late complications or deaths occurred in the surgery groups. Nutritional side-effects were noted mainly after biliopancreatic diversion.

Interpretation: Surgery is more effective than medical treatment for the long-term control of obese patients with type 2 diabetes and should be considered in the treatment algorithm of this disease. However, continued monitoring of glycaemic control is warranted because of potential relapse of hyperglycaemia.

Funding: Catholic University of Rome.
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http://dx.doi.org/10.1016/S0140-6736(15)00075-6DOI Listing
September 2015

A stochastic delay differential model of cerebral autoregulation.

PLoS One 2015 1;10(4):e0118456. Epub 2015 Apr 1.

Consiglio Nazionale delle Ricerche, Istituto di Analisi dei Sistemi ed Informatica "Antonio Ruberti", Rome, Italy.

Mathematical models of the cardiovascular system and of cerebral autoregulation (CAR) have been employed for several years in order to describe the time course of pressures and flows changes subsequent to postural changes. The assessment of the degree of efficiency of cerebral auto regulation has indeed importance in the prognosis of such conditions as cerebro-vascular accidents or Alzheimer. In the quest for a simple but realistic mathematical description of cardiovascular control, which may be fitted onto non-invasive experimental observations after postural changes, the present work proposes a first version of an empirical Stochastic Delay Differential Equations (SDDEs) model. The model consists of a total of four SDDEs and two ancillary algebraic equations, incorporates four distinct delayed controls from the brain onto different components of the circulation, and is able to accurately capture the time course of mean arterial pressure and cerebral blood flow velocity signals, reproducing observed auto-correlated error around the expected drift.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0118456PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4382334PMC
December 2015

Effect of indoor nitrogen dioxide on lung function in urban environment.

Environ Res 2015 Apr 13;138:8-16. Epub 2015 Feb 13.

National Research Council of Italy, Institute of Biomedicine and Molecular Immunology, Palermo, Italy.

Background: High levels of indoor NO2 are associated with increased asthma symptoms and decreased expiratory peak flows in children. We investigated the association of exposure to domestic indoor NO2, objectively measured in winter and spring, with respiratory symptoms and lung function in a sample of adolescents from a southern Mediterranean area.

Methods: From a large school population sample (n=2150) participating in an epidemiological survey in the urban area of the City of Palermo (southern Italy), a sub-sample of 303 adolescents was selected which furnished an enriched sample for cases of current asthma. All subjects were evaluated by a health questionnaire, skin prick tests and spirometry. One-week indoor NO2 monitoring of their homes was performed by diffusive sampling during spring and again during winter.

Results: We found that about 25% of subjects were exposed to indoor NO2 levels higher than the 40µg/m(3) World Health Organization limit, during both spring and winter. Moreover, subjects exposed to the highest indoor NO2 concentrations had increased frequency of current asthma (p=0.005), wheeze episodes in the last 12 months (p<0.001), chronic phlegm (p=0.013), and rhinoconjunctivitis (p=0.008). Finally, subjects with a personal history of wheeze ever had poorer respiratory function (FEF25-75%, p=0.01) when exposed to higher indoor NO2 concentrations.

Conclusions: Home exposure to high indoor NO2 levels frequently occurs in adolescents living in a southern Mediterranean urban area and is significantly associated with the risks for increased frequency of both respiratory symptoms and reduced lung function.
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http://dx.doi.org/10.1016/j.envres.2015.01.023DOI Listing
April 2015

Predictors of remission of diabetes mellitus in severely obese individuals undergoing bariatric surgery: do BMI or procedure choice matter? A meta-analysis.

Ann Surg 2015 Mar;261(3):459-67

*CNR-Institute of Systems Analysis and Computer Science (IASI) BioMatLab, Rome, Italy; and †Department of Internal Medicine, Università Cattolica S. Cuore, Rome, Italy.

Objective: To compare diabetes remission after bariatric surgery in subjects with body mass index (BMI) of 35 kg/m2 or more or BMI of less than 35 kg/m to determine which predictors are best.

Background: BMI is currently the only selection criterion for bariatric surgery in diabetic subjects. Many studies have challenged BMI for predicting diabetes remission.

Methods: Data sources were PubMed, Cochrane Library, and EMBASE databases from January 1980 to June 2013. The selected studies were randomized controlled trials, controlled clinical trials, or cohort studies with 10 or more patients per arm. Of 1437 screened articles, 94 studies were included with 94,579 patients undergoing surgical procedures (4944 with type 2 diabetes mellitus). Weight, BMI, glycated hemoglobin A1c, fasting glucose, and insulin were abstracted by 2 independent reviewers. The effect size was the percent diabetes remission.

Results: Meta-analysis was performed for BMI less than 35 kg/m2 (group 1) and BMI 35 kg/m2 or more (group 2). Diabetes remission was 72% [95% confidence interval (CI), 65-80] in group 1 and 71% (95% CI, 65-77) in group 2. Diabetes resolution was 89% (95% CI, 83-94) after biliopancreatic diversion, 77% (95% CI, 72-82) after Roux-en-Y bypass, 62% (95% CI, 46-79) after gastric banding, and 60% (95% CI, 51-70) after sleeve gastrectomy. The only significant predictor of glycated hemoglobin A1c reduction was waist circumference, lower baseline waist associating with higher reduction.

Conclusions: Bariatric surgery determines similar diabetes remission rates in patients with BMI of 35 kg/m2 or more or BMI of less than 35 kg/m2. Baseline BMI is unrelated to diabetes remission. The association of baseline waist circumference with glycated hemoglobin A1c reduction is likely due to selection bias. Bariatric or metabolic effects of the surgical procedures appear independent, and different indices are needed to predict them.
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http://dx.doi.org/10.1097/SLA.0000000000000863DOI Listing
March 2015

Nasal high-flow versus Venturi mask oxygen therapy after extubation. Effects on oxygenation, comfort, and clinical outcome.

Am J Respir Crit Care Med 2014 Aug;190(3):282-8

1 Department of Anesthesiology and Intensive Care, Agostino Gemelli Hospital, Università Cattolica del Sacro Cuore, Rome, Italy.

Rationale: Oxygen is commonly administered after extubation. Although several devices are available, data about their clinical efficacy are scarce.

Objectives: To compare the effects of the Venturi mask and the nasal high-flow (NHF) therapy on PaO2/FiO2SET ratio after extubation. Secondary endpoints were to assess effects on patient discomfort, adverse events, and clinical outcomes.

Methods: Randomized, controlled, open-label trial on 105 patients with a PaO2/FiO2 ratio less than or equal to 300 immediately before extubation. The Venturi mask (n = 52) or NHF (n = 53) were applied for 48 hours postextubation.

Measurements And Main Results: PaO2/FiO2SET, patient discomfort caused by the interface and by symptoms of airways dryness (on a 10-point numerical rating scale), interface displacements, oxygen desaturations, need for ventilator support, and reintubation were assessed up to 48 hours after extubation. From the 24th hour, PaO2/FiO2SET was higher with the NHF (287 ± 74 vs. 247 ± 81 at 24 h; P = 0.03). Discomfort related both to the interface and to airways dryness was better with NHF (respectively, 2.6 ± 2.2 vs. 5.1 ± 3.3 at 24 h, P = 0.006; 2.2 ± 1.8 vs. 3.7 ± 2.4 at 24 h, P = 0.002). Fewer patients had interface displacements (32% vs. 56%; P = 0.01), oxygen desaturations (40% vs. 75%; P < 0.001), required reintubation (4% vs. 21%; P = 0.01), or any form of ventilator support (7% vs. 35%; P < 0.001) in the NHF group.

Conclusions: Compared with the Venturi mask, NHF results in better oxygenation for the same set FiO2 after extubation. Use of NHF is associated with better comfort, fewer desaturations and interface displacements, and a lower reintubation rate. Clinical trial registered with www.clinicaltrials.gov (NCT 01575353).
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http://dx.doi.org/10.1164/rccm.201402-0364OCDOI Listing
August 2014

Mathematical modeling of renal tubular glucose absorption after glucose load.

PLoS One 2014 29;9(1):e86963. Epub 2014 Jan 29.

Department of Internal Medicine; Università Cattolica S. Cuore, Rome, Italy.

A partial differential Progressive Tubular Reabsorption (PTR) model, describing renal tubular glucose reabsorption and urinary glucose excretion following a glucose load perturbation, is proposed and fitted to experimental data from five subjects. For each subject the Glomerular Filtration Rate was estimated and both blood and urine glucose were sampled following an Intra-Venous glucose bolus. The PTR model was compared with a model representing the conventional Renal Threshold Hypothesis (RTH). A delay bladder compartment was introduced in both formulations. For the RTH model, the average threshold for glycosuria varied between 9.90 ± 4.50 mmol/L and 10.63 ± 3.64 mmol/L (mean ± Standard Deviation) under different hypotheses; the corresponding average maximal transport rates varied between 0.48 ± 0.45 mmol/min (86.29 ± 81.22 mg/min) and 0.50 ± 0.42 mmol/min (90.62 ± 76.15 mg/min). For the PTR Model, the average maximal transports rates varied between 0.61 ± 0.52 mmol/min (109.57 ± 93.77 mg/min) and 0.83 ± 0.95 mmol/min (150.13 ± 171.85 mg/min). The time spent by glucose inside the tubules before entering the bladder compartment varied between 1.66 ± 0.73 min and 2.45 ± 1.01 min. The PTR model proved much better than RTH at fitting observations, by correctly reproducing the delay of variations of glycosuria with respect to the driving glycemia, and by predicting non-zero urinary glucose elimination at low glycemias. This model is useful when studying both transients and steady-state glucose elimination as well as in assessing drug-related changes in renal glucose excretion.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0086963PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906102PMC
September 2014

Routine OGTT: a robust model including incretin effect for precise identification of insulin sensitivity and secretion in a single individual.

PLoS One 2013 29;8(8):e70875. Epub 2013 Aug 29.

Institute of System Analysis and Informatics (IASI) A. Ruberti, National Research Council (CNR), Rome, Italy.

In order to provide a method for precise identification of insulin sensitivity from clinical Oral Glucose Tolerance Test (OGTT) observations, a relatively simple mathematical model (Simple Interdependent glucose/insulin MOdel SIMO) for the OGTT, which coherently incorporates commonly accepted physiological assumptions (incretin effect and saturating glucose-driven insulin secretion) has been developed. OGTT data from 78 patients in five different glucose tolerance groups were analyzed: normal glucose tolerance (NGT), impaired glucose tolerance (IGT), impaired fasting glucose (IFG), IFG+IGT, and Type 2 Diabetes Mellitus (T2DM). A comparison with the 2011 Salinari (COntinuos GI tract MOdel, COMO) and the 2002 Dalla Man (Dalla Man MOdel, DMMO) models was made with particular attention to insulin sensitivity indices ISCOMO, ISDMMO and kxgi (the insulin sensitivity index for SIMO). ANOVA on kxgi values across groups resulted significant overall (P<0.001), and post-hoc comparisons highlighted the presence of three different groups: NGT (8.62×10(-5)±9.36×10(-5) min(-1)pM(-1)), IFG (5.30×10(-5)±5.18×10(-5)) and combined IGT, IFG+IGT and T2DM (2.09×10(-5)±1.95×10(-5), 2.38×10(-5)±2.28×10(-5) and 2.38×10(-5)±2.09×10(-5) respectively). No significance was obtained when comparing ISCOMO or ISDMMO across groups. Moreover, kxgi presented the lowest sample average coefficient of variation over the five groups (25.43%), with average CVs for ISCOMO and ISDMMO of 70.32% and 57.75% respectively; kxgi also presented the strongest correlations with all considered empirical measures of insulin sensitivity. While COMO and DMMO appear over-parameterized for fitting single-subject clinical OGTT data, SIMO provides a robust, precise, physiologically plausible estimate of insulin sensitivity, with which habitual empirical insulin sensitivity indices correlate well. The kxgi index, reflecting insulin secretion dependency on glycemia, also significantly differentiates clinically diverse subject groups. The SIMO model may therefore be of value for the quantification of glucose homeostasis from clinical OGTT data.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0070875PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3756988PMC
April 2014

Mathematical modeling of the glucose-insulin system: a review.

Math Biosci 2013 Aug 1;244(2):69-81. Epub 2013 Jun 1.

BioMatLab, IASI "A. Ruberti", National Council of Researches, UCSC Largo A. Gemelli 8, 00168 Rome, Italy.

Mathematical modeling of the glucose-insulin feedback system is necessary to the understanding of the homeostatic control, to analyze experimental data, to identify and quantify relevant biophysical parameters, to design clinical trials and to evaluate diabetes prevention or disease modification therapies. Much work has been made over the last 30years, and the time now seems ripe to provide a comprehensive review. The one here proposed is focused on the most important clinical/experimental tests performed to understand the mechanism of glucose homeostasis. The review proceeds from models of pancreatic insulin production, with a coarser/finer level of detail ranging over cellular and subcellular scales, to short-term organ/tissue models accounting for the intra-venous and the oral glucose tolerance tests as well as for the euglycemic hyperinsulinemic clamp, to total-body, long-term diabetes models aiming to represent disease progression in terms of β-cell population dynamics over a long period of years.
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http://dx.doi.org/10.1016/j.mbs.2013.05.006DOI Listing
August 2013

Effects of transoral gastroplasty on glucose homeostasis in obese subjects.

J Clin Endocrinol Metab 2013 May 29;98(5):1901-10. Epub 2013 Mar 29.

Department of Internal Medicine, Catholic University, Rome, Italy.

Context And Objective: Transoral gastroplasty (TOGA) is a safe and less invasive procedure than traditional bariatric surgery. We studied the effects of TOGA on the risk of progression from prediabetes to overt type 2 diabetes mellitus (T2DM) or on regression from diabetes or prediabetes to a lower risk category.

Design And Setting: Prospective, observational study (October 2008 to October 2010) performed at Catholic University, Rome, Italy. Fifty consecutive subjects 18-60 years old, 35 ≥ body mass index < 55 kg/m², were enrolled. Glucose tolerance, insulin sensitivity, and secretion were studied at baseline and 1 week and 1, 6, and 12 months after TOGA. Plasma glucagon-like peptide-1 (GLP-1), glucose-dependent insulinotropic peptide (GIP), and ghrelin levels were measured.

Results: Forty-three patients (86%) completed the 1-year postoperative follow-up. Patients lost 16.90% of baseline weight (P level × factor time <0.001). Body mass index decreased from 42.24 ± 3.43 to 34.65 ± 4.58 kg/m² (P < .001). Twenty-three patients (53.5%) were diagnosed as normal glucose tolerance (NGT) before treatment, 2 (4.6%) were impaired fasting glucose (IFG), 12 (27.9%) were impaired glucose tolerance (IGT), 1 (2.3%) had both IFG and IGT, and 5 (11.6%) had T2DM. At 1-year posttreatment, the percentages changed to 86.0% NGT, 2.3% IFG, 11.6% IGT, 0% IFG plus IGT, and 0% T2DM, respectively. Peripheral insulin resistance and homeostasis model of assessment-insulin resistance improved significantly. Fasting glucose-dependent insulinotropic peptide and ghrelin decreased from 316.9 ± 143.1 to 156.2 ± 68.2 pg/mL (P < .001) and from 630.6 ± 52.1 to 456.7 ± 73.1 pg/mL (P < .001), respectively, whereas GLP-1 increased from 16.2 ± 4.9 to 23.7 ± 9.5 pg/mL (P < .001).

Conclusions: TOGA induced glucose disposal improvement with regression of diabetes to NGT or IGT and regression of IGT and IFG to NGT in half of the cases. Regressors showed a much larger increase of GLP-1 levels than progressors.
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http://dx.doi.org/10.1210/jc.2013-2418DOI Listing
May 2013

Double-blind, randomized study evaluating the glycemic and anti-inflammatory effects of subcutaneous LY2189102, a neutralizing IL-1β antibody, in patients with type 2 diabetes.

Diabetes Care 2013 Aug 20;36(8):2239-46. Epub 2013 Mar 20.

1Chorus, Lilly Research Laboratories, Eli Lilly & Company, Indianapolis, Indiana, USA

Objective: Inflammation is associated with pancreatic β-cell apoptosis and reduced insulin sensitivity. Literature suggests that interleukin (IL)-1β may contribute to the pathogenesis of type 2 diabetes mellitus (T2DM). This study aimed to determine the efficacy, safety, and tolerability of LY2189102, a neutralizing IL-1β antibody, in T2DM patients.

Research Design And Methods: Phase II, randomized, double-blind, parallel, placebo-controlled study of subcutaneous LY2189102 (0.6, 18, and 180 mg) administered weekly for 12 weeks in T2DM patients on diet and exercise, with or without approved antidiabetic medications.

Results: LY2189102 reduced HbA1c at 12 weeks (adjusted mean differences versus placebo: -0.27, -0.38 and -0.25% for 0.6, 18 and 180 mg doses, respectively), and fasting glucose at multiple time points compared with placebo. LY2189102 also reduced postprandial glycemia, and inflammatory biomarkers, including hs-CRP and IL-6. LY2189102 was generally well tolerated.

Conclusions: Weekly subcutaneous LY2189102 for 12 weeks was well tolerated, modestly reduced HbA1c and fasting glucose, and demonstrated significant anti-inflammatory effects in T2DM patients. Neutralizing IL-1β holds promise as a convenient adjuvant treatment for T2DM.
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http://dx.doi.org/10.2337/dc12-1835DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3714510PMC
August 2013

Twenty-four hour energy expenditure and skeletal muscle gene expression changes after bariatric surgery.

J Clin Endocrinol Metab 2013 Feb 22;98(2):E321-7. Epub 2013 Jan 22.

Department of Surgery, Catholic University, 00168 Rome, Italy.

Context: Obesity is characterized by decreased insulin-stimulated glucose uptake in muscle and shift from glucose to lipid oxidation, the so-called metabolic inflexibility. Biliopancreatic diversion (BPD), a mainly malabsorptive bariatric operation, determines a prompt improvement of insulin resistance, but the mechanisms are still unclear.

Objective: We aimed to estimate the response of glucose transporter 4 (GLUT4) and hexokinase-II (HKII) gene expression to hyperinsulinemia before and after surgical treatment with a BPD or dietary-induced weight loss. The association with 24-hour energy expenditure and its different components-diet-induced thermogenesis (DIT), resting energy expenditure, physical activity (PA) of daily living, and physical exercise-was also determined. DESIGN, SETTING, AND MAIN OUTCOME MEASURES: Case-control study: 20 subjects, BPD vs diet-induced weight loss. Four subjects withdrew in the surgical arm and 1 subject withdrew in the dietary arm. Insulin sensitivity was measured by the euglycemic-hyperinsulinemic clamp. Energy expenditure was assessed by indirect calorimetry over 24 hours. Muscle biopsies were obtained during the clamp to measure gene expression: GLUT4 and HKII.

Results: Insulin sensitivity increased significantly (P < .01) only after BPD (0.101 ± 0.012 to 0.204 ± 0.033 μmol/kg/min/pM). Enhanced GLUT4 and HKII mRNA levels were observed after surgery (P < .0001 and P = .021, respectively), whereas they were not affected by diet-induced weight loss. Carbohydrate oxidation (P = .0027), DIT (P = .033), PA (P = .036), and energy expenditure during the exercise (P = .017) increased only in the BPD group.

Conclusions: BPD improved impaired glucose metabolism and insulin resistance through increased glucose uptake, glycogen synthesis, and glucose oxidation. Furthermore, the concomitant increase in DIT, PA, and exercise in BPD patients may partly explain their ability to sustained long-term weight loss and may contribute to the improved insulin sensitivity.
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http://dx.doi.org/10.1210/jc.2012-2876DOI Listing
February 2013

Protocol for a randomised clinical study comparing the effect of Roux-en-Y gastric bypass and sleeve gastrectomy on reactive hypoglycaemia in morbidly obese subjects.

BMJ Open 2012 19;2(6). Epub 2012 Nov 19.

Department of Internal Medicine, Catholic University, Rome, Italy.

Introduction: Roux-en-Y gastric bypass (RYGB) is the most performed bariatric operation. Reactive hypoglycaemia is a frequent late complication occurring in about 72% of RYGB patients, which can present with various intensities up to the serious form of neuroglycopaenia. However, it seems to occur also after sleeve gastrectomy (SG) although much more rarely.

Methods And Analysis: A single centre, open, 1-year randomised trial to compare the incidence of hypoglycaemia after RYGB or SG. A secondary objective is the assessment of the comparative ability of the two surgical procedures in determining the improvement or normalisation of insulin sensitivity, given the established relevance of insulin resistance in the cardiometabolic syndrome of obesity.

Ethics And Dissemination: The study will be published and presented to international meetings and, due to the safety issue, it will represent a relevant information for national healthcare systems. The protocol was approved by the Catholic University Ethical Committee (A1534/CE/2012). Clinicaltrials.gov Registration n. NCT01581801.
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http://dx.doi.org/10.1136/bmjopen-2012-002184DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3533087PMC
November 2012

A geometrical approach to the PKPD modelling of inhaled bronchodilators.

J Pharmacokinet Pharmacodyn 2012 Oct 17;39(5):415-28. Epub 2012 Jul 17.

Consiglio Nazionale Delle Ricerche, Istituto di Analisi Dei Sistemi ed Informatica A. Ruberti, Viale Manzoni, 30, 00185, Rome, Italy.

The present work introduces a new method to model the pharmacokinetics (PK) and pharmacodynamics (PD) of an inhaled dose of bronchodilator, alternative to classic compartmental representations or computational fluid dynamics. A five compartment PK model comprising alimentary tract absorption (gut), bronchial tree mucosa, bronchial muscles, plasma, and elimination/excretion pathways has been developed. Many anatomical and physiological features of the bronchial tree depend on bronchial generation or on mean distance from the larynx. Among these are diameters, resistances, and receptor density, which determine together the local response to the inhaled drug; integrating these local responses over the whole bronchial tree allows an approximation of total bronchodilator response and airflow resistance. While the PK part of the model reflects classical compartmental assumptions, the PD part adds a simplified geometrical and functional description of the bronchial tree to a typical empirical model of local effect on bronchial muscle, leading to the direct computation of the approximate forced expiratory volume in 1 s (FEV(1)). In the present work the construction of the model is detailed, with reference to literature data. Simulation of a hypothetical asthmatic subject is employed to illustrate the behaviour of the model in representing the evolution over time of the distribution and pharmacological effect of an inhaled dose of a bronchodilator. The relevance of particle size and drug formulation diffusivity on therapeutic efficacy is discussed.
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http://dx.doi.org/10.1007/s10928-012-9259-zDOI Listing
October 2012