Marco Orsini Federici

Nonlinear model predictive control of glucose concentration in subjects with type 1 diabetes

A nonlinear model predictive controller has been developed to maintain normoglycemia in subjects with type 1 diabetes during fasting conditions such as during overnight fast. The controller employs a compartment model, which represents the glucoregulatory system and includes submodels representing absorption of subcutaneously administered short-acting insulin Lispro and gut absorption. The controller uses Bayesian parameter estimation to determine time-varying model parameters. Moving target trajectory facilitates slow, controlled normalization of elevated glucose levels and faster normalization of low glucose values. The predictive capabilities of the model have been evaluated using data from 15 clinical experiments in subjects with type 1 diabetes. The experiments employed intravenous glucose sampling (every 15 min) and subcutaneous infusion of insulin Lispro by insulin pump (modified also every 15 min). The model gave glucose predictions with a mean square error proportionally related to the prediction horizon with the value of 0.2 mmol L(-1) per 15 min. The assessment of clinical utility of model-based glucose predictions using Clarke error grid analysis gave 95% of values in zone A and the remaining 5% of values in zone B for glucose predictions up to 60 min (n = 1674). In conclusion, adaptive nonlinear model predictive control is promising for the control of glucose concentration during fasting conditions in subjects with type 1 diabetes.

Closing the Loop: The Adicol Experience

The objective of the project Advanced Insulin Infusion using a Control Loop (ADICOL) was to develop a treatment system that continuously measures and controls the glucose concentration in subjects with type 1 diabetes. The modular concept of the ADICOLs extracorporeal artificial pancreas consisted of a minimally invasive subcutaneous glucose system, a handheld PocketPC computer, and an insulin pump (D-Tron, Disetronic, Burgdorf, Switzerland) delivering subcutaneously insulin lispro. The present paper describes a subset of ADICOL activities focusing on the development of a glucose controller for semi-closed-loop control, an in silico testing environment, clinical testing, and system integration. An incremental approach was adopted to evaluate experimentally a model predictive glucose controller. A feasibility study was followed by efficacy studies of increasing complexity. The ADICOL project demonstrated feasibility of a semi-closed-loop glucose control during fasting and fed conditions with a wearable, modular extracorporeal artificial pancreas.

A model of the endogenous glucose balance incorporating the characteristics of glucose transporters

This paper describes the development and preliminary test of a model of the endogenous glucose balance that incorporates the characteristics of the glucose transporters GLUT1, GLUT3 and GLUT4. In the modeling process the model is parameterized with nine parameters that are subsequently estimated from data in the literature on the hepatic- and endogenous- balances at various combinations of blood glucose and insulin levels. The ability of the resulting endogenous balance to fit blood glucose measured from patients was tested on 20 patients. The fit obtained with this model compared favorably with the fit obtained with the endogenous balance currently incorporated in the DIAS system.

Privacy impact assessment in the design of transnational public health information systems: the BIRO project

Objectives: To foster the development of a privacy-protective, sustainable cross-border information system in the framework of a European public health project. Materials and methods: A targeted privacy impact assessment was implemented to identify the best architecture for a European information system for diabetes directly tapping into clinical registries. Four steps were used to provide input to software designers and developers: a structured literature search, analysis of data flow scenarios or options, creation of an ad hoc questionnaire and conduction of a Delphi procedure. Results: The literature search identified a core set of relevant papers on privacy (n = 11). Technicians envisaged three candidate system architectures, with associated data flows, to source an information flow questionnaire that was submitted to the Delphi panel for the selection of the best architecture. A detailed scheme envisaging an “aggregation by group of patients” was finally chosen, based upon the exchange of finely tuned summary tables. Conclusions: Public health information systems should be carefully engineered only after a clear strategy for privacy protection has been planned, to avoid breaching current regulations and future concerns and to optimise the development of statistical routines. The BIRO (Best Information Through Regional Outcomes) project delivers a specific method of privacy impact assessment that can be conveniently used in similar situations across Europe.

The Artificial Pancreas

In type 1 diabetes an absolute deficiency of insulin secretion requires exogenous insulin supply to guarantee the patients life avoiding ketoacidotic coma and to prevent the chronic complications of diabetes. In order to obtain a more physiological replacement therapy different approaches have been pursued since the early 70s to create an artificial wearable pancreas able to deliver insulin according to the blood glucose values as determined by continuous monitoring. Four components are considered essential for the realisation of an artificial pancreas: the sampling system, the glucose sensor, the mathematical models and the related algorithms for the calculation of the insulin doses and the infusion system for the insulin delivery. At present the still unsolved issues are mainly represented by the availability of reliable continuous glucose monitor and control algorithms, while the new technologies allow for the miniaturisation of the system.

Ketone bodies monitoring

Abstract Diabetic ketoacidosis (DK) is a serious acute complication in type 1 diabetic patients caused by insulin deficiency. The early detection of insulin deprivation represents therefore an important element in routine clinical practice, especially in ketone prone subjects such as CSII (continuous subcutaneous insulin infusion) treated subjects. Different methods have been developed for ketone bodies (KB) monitoring: urine dipsticks, laboratory readings, capillary β-hydroxybutirate (BOHB) meters. Urine dipsticks are not recommended for KB monitoring because they measure only acetoacetate and not BOBH the most prevalent ketone during DK. Laboratory methods are more reliable but not useful for self monitoring. Capillary BOHB represents the most suitable method for KB monitoring in home settings. Several experiences demonstrated the accuracy and reliability of this method at different degree of ketosis and their efficacy in detecting and managing the course of DKA. A recent experience, conducted by our group, investigated the efficacy of the dynamic evaluation of capillary BOBH levels, irrespectively of the absolute value, for early detection of insulin deprivation in CSII treated subjects. Results indicated that dynamic evaluation of capillary BOHB appears as a more rapid and accurate indicator of early insulin deprivation than blood glucose and could be used for targeting effectively insulin therapy in the restoration phase.

Impaired endothelial antithrombotic activity following short-term interruption of continuous subcutaneous insulin infusion in type1 diabetic patients

Review of literature has shown an increased rate of thrombotic complications in diabetic patients with frequent episodes of hyperketonemia. However, the mechanisms by which ketosis promotes vascular disease in diabetic patients are unclear. It was the aim of this study to investigate early changes in haemostatic parameters and oxidative stress markers during the hyperketonemic status which follows the interruption of continuous subcutaneous insulin infusion (CSII) in type I diabetic patients. Eight CSII-treated type I diabetic patients underwent a 4-hour pump arrest. Blood glucose, insulin and 3-hydroxybutirate were measured to verify the metabolic response. A vein-occlusive (VO) test was performed for the determination of tPA and PAI-1 activities and their antigen levels before and after the CSII arrest. Coagulation factor VII and VIII were evaluated by one-stage PT and PTT method, respectively. TF, vWF, tPA and PAI-1 antigens were determined by ELISA, whereas tPA and PAI-1 activities using chromogenic methods. Plasma malondialdehyde (MDA) and protein carbonyl groups (PCG) levels were determined by HPLC and spectrophotometry, respectively. After the insulin deprivation phase, post-VO tPA antigen level significantly decreased (P = 0.0391), whereas TF and post-VO PAI-1 activity and antigen levels significantly increased (P = 0.0156 and P = 0.0234, respectively). Plasma MDA and PCG levels were 1.88-fold and 1.74-fold higher than baseline values, respectively. In conclusion, the impairment of the fibrinolytic potential and the increases in TF, MDA and PCG levels may enhance the risk of both arterial and venous thrombosis during ketosis. Thus, early detection of hyperketonemia in DM patients could contribute to the prevention of life-threatening vascular events.

The Umbria Diabetes Register

The project PROMODR (Progressive Model of Diabetes Register) funded by an Italian Ministry of Health grant, aimed at the realisation of a prototype regional registry for diabetes mellitus and its validation in a pilot experience. Primary data sources are the General Practitioners (GPs) and the Diabetes Centres (DCs) of the Umbria region already equipped with electronic medical records (EMR). A minimum registry data set was created consisting of personal data, metabolic indices, late diabetic complications and therapy. The GPs EMR system was modified in order to automatically identify, extract encrypt and send via e-mail to a central regional server the administrative and clinical data related to the diabetic patients. At this level the data are merged with the information derived by the DCs. The functionality of the prototype has been evaluated in a pilot experience consisting of two consecutive phases: the first collecting data from 7 GPs covering different areas of the region and a population of around 10680 inhabitants and the second one involving 13 DCs. Data from more than 12000 diabetic subjects were collected. Different examples indicators have been calculated. This pilot study showed an accurate functionality of the prototype without major errors in all the different phases of data collection and transmission.

Diabetes registers and prevention strategies: towards an active use of health information

Recent experiences in the use of diabetes registers show their ability to improve population health in a region. In the framework of the Umbria registry, we have defined general criteria for the development of a comprehensive model including new directions for active use of health information. General functions of the diabetes register have been designed for a range of stakeholders. Large scale data linkage is used to extract study cohorts and add information content to the register. Multidimensional/multilevel analysis is directly applied to define high risk strata on the basis of multiple individual, structural, contextual (ecological) and service-related components. Target subjects can be used to design specific interventions for the prevention of diabetic complications. The enhanced version of the Umbria Register involves a large group of institutional partners in a new program for clinical governance. Agreed routine health system evaluation now regards diabetes indicators as a high priority area. The data model supports information exchange across a network of national and international partners, contributing to the definition of a common benchmarking system. The present work shows that principles of evidence-based medicine can be used to underpin new ways of active use of health information. Involving policy makers and health professionals in the research and development of diabetes registers will be increasingly crucial to capture all opportunities arising from a wide application.

National survey on the execution of the oral glucose tolerance test (OGTT) in a representative cohort of Italian laboratories

Abstract Background: Recently revised diagnostic criteria for diabetes mellitus and the lack of universal agreement on the methodology for the screening and diagnosis of gestational diabetes mellitus (GDM) still generate inconsistency in execution of the oral glucose tolerance test (OGTT). The aim of the present survey was to evaluate the adherence of Italian laboratories to the internationally accepted guidelines in carrying out the OGTT for the diagnosis of diabetes in the general population and for the screening of GDM. Methods: A questionnaire was designed to investigate the following issues related to the OGTT: 1) the relationship between laboratories and diabetes centres for the definition of standard protocols; 2) the amount of glucose administered; 3) the number and timing of blood samples; 4) the procedures used for the screening and diagnosis of GDM; and 5) reference to WHO guidelines for the interpretation of the results. The questionnaire was administered to 400 specialists in laboratory medicine working in public or private laboratories nationwide participating in the “Italian External Evaluation of Quality in Laboratory Medicine” Study Group. Results: The survey was completed in the period from June to September 2003. In the observation period, 241 questionnaires were returned by specialists working in laboratories scattered throughout 15 out of the 20 Italian regions. Only 50% of the laboratories performed the OGTT according to protocols defined in agreement with local reference diabetes centres. OGTT using 75g of glucose in adults and 1.75g/kg for children as recommended by WHO was performed by 87.1% of the laboratories. WHO indications to collect samples at baseline and at 120min were followed by 33.2% of the centres. Higher variability was highlighted with respect to the methodology for GDM screening: 49.8% of the laboratories always adopted the two-step procedure consisting of a glucose challenge test (GCT) and subsequent OGTT in positive cases; 4.9% performed the 100-g OGTT with four blood samples; 1.6% the 75-g OGTT with two blood samples; and 2.7% the 75-g OGTT with four blood samples. More than 30% of the centres referred to different diagnostic schemes, 62% of which used individually chosen procedures amongst those reported above, 19% used only the GCT and no subsequent OGTT in positive cases, and 18.4% used a variety of completely different, arbitrarily chosen methods. Finally, only 25.6% of the laboratories referred to the WHO limits for interpretation of the results. Conclusions: For the Italian laboratories investigated, relevant variability was highlighted for performance of the OGTT in general and GDM screening in particular. A variable relationship between laboratories and diabetes centres was also detected, which might represent a relevant indicator for the need for rationalisation or standardisation of the method for performing an OGTT. These data highlight the need for greater collaboration between these different bodies. We suggest that other similar investigations should be carried out in other countries within the framework of the IFCC Global Campaign on Diabetes Mellitus.