Robust strategies for glucose control in type 1 diabetes

[EN] Type 1 diabetes mellitus is a chronic and incurable disease that affects millions of people all around the world. Its main characteristic is the destruction (totally or partially) of the beta cells of the pancreas. These cells are in charge of producing insulin, main hormone implied in the control of blood glucose. Keeping high levels of blood glucose for a long time has negative health effects, causing different kinds of complications. For that reason patients with type 1 diabetes mellitus need to receive insulin in an exogenous way. Since 1921 when insulin was first isolated to be used in humans and first glucose monitoring techniques were developed, many advances have been done in clinical treatment with insulin. Currently 2 main research lines focused on improving the quality of life of diabetic patients are opened. The first one is concentrated on the research of stem cells to replace damaged beta cells and the second one has a more technological orientation. This second line focuses on the development of new insulin analogs to allow emulating with higher fidelity the endogenous pancreas secretion, the development of new noninvasive continuous glucose monitoring systems and insulin pumps capable of administering different insulin profiles and the use of decision-support tools and telemedicine. The most important challenge the scientific community has to overcome is the development of an artificial pancreas, that is, to develop algorithms that allow an automatic control of blood glucose. The main difficulty avoiding a tight glucose control is the high variability found in glucose metabolism. This fact is especially important during meal compensation. This variability, together with the delay in subcutaneous insulin absorption and action causes controller overcorrection that leads to late hypoglycemia (the most important acute complication of insulin treatment). The proposals of this work pay special attention to overcome these difficulties. In that way interval models are used to represent the patient physiology and to be able to take into account parametric uncertainty. This type of strategy has been used in both the open loop proposal for insulin dosage and the closed loop algorithm. Moreover the idea behind the design of this last proposal is to avoid controller overcorrection to minimize hypoglycemia while adding robustness against glucose sensor failures and over/under- estimation of meal carbohydrates. The algorithms proposed have been validated both in simulation and in clinical trials.[ES] La diabetes mellitus tipo 1 es una enfermedad crónica e incurable que afecta a millones de personas en todo el mundo. Se caracteriza por una destrucción total o parcial de las células beta del páncreas. Estas células son las encargadas de producir la insulina, hormona principal en el control de glucosa en sangre. Valores altos de glucosa en la sangre mantenidos en el tiempo afectan negativamente a la salud, provocando complicaciones de diversa índole. Es por eso que los pacientes con diabetes mellitus tipo 1 necesitan recibir insulina de forma exógena. Desde que se consiguiera en 1921 aislar la insulina para poder utilizarla en clínica humana, y se empezaran a desarrollar las primeras técnicas de monitorización de glucemia, se han producido grandes avances en el tratamiento con insulina. Actualmente, las líneas de investigación que se están siguiendo en relación a la mejora de la calidad de vida de los pacientes diabéticos, tienen fundamentalmente 2 vertientes: una primera que se centra en la investigación en células madre para la reposición de las células beta y una segunda vertiente de carácter más tecnológico. Dentro de esta segunda vertiente, están abiertas varias líneas de investigación, entre las que se encuentran el desarrollo de nuevos análogos de insulina que permitan emular más fielmente la secreción endógena del páncreas, el desarrollo de monitores continuos de glucosa no invasivos, bombas de insulina capaces de administrar distintos perfiles de insulina y la inclusión de sistemas de ayuda a la decisión y telemedicina. El mayor reto al que se enfrentan los investigadores es el de conseguir desarrollar un páncreas artificial, es decir, desarrollar algoritmos que permitan disponer de un control automático de la glucosa. La principal barrera que se encuentra para conseguir un control riguroso de la glucosa es la alta variabilidad que presenta su metabolismo. Esto es especialmente significativo durante la compensación de las comidas. Esta variabilidad junto con el retraso en la absorción y actuación de la insulina administrada de forma subcutánea favorece la aparición de hipoglucemias tardías (complicación aguda más importante del tratamiento con insulina) a consecuencia de la sobreactuación del controlador. Las propuestas presentadas en este trabajo hacen especial hincapié en sobrellevar estas dificultades. Así, se utilizan modelos intervalares para representar la fisiología del paciente, y poder tener en cuenta la incertidumbre en sus parámetros. Este tipo de estrategia se ha utilizado tanto en la propuesta de dosificación automática en lazo abierto como en el algoritmo en lazo cerrado. Además la principal idea de diseño de esta última propuesta es evitar la sobreactuación del controlador evitando hipoglucemias y añadiendo robustez ante fallos en el sensor de glucosa y en la estimación de las comidas. Los algoritmos propuestos han sido validados en simulación y en clínica.[CA] La diabetis mellitus tipus 1 és una malaltia crònica i incurable que afecta milions de persones en tot el món. Es caracteritza per una destrucció total o parcial de les cèl.lules beta del pàncrees. Aquestes cèl.lules són les encarregades de produir la insulina, hormona principal en el control de glucosa en sang. Valors alts de glucosa en la sang mantinguts en el temps afecten negativament la salut, provocant complicacions de diversa índole. És per això que els pacients amb diabetis mellitus tipus 1 necessiten rebre insulina de forma exògena. Des que s'aconseguís en 1921 aïllar la insulina per a poder utilitzar-la en clínica humana, i es començaren a desenrotllar les primeres tècniques de monitorització de glucèmia, s'han produït grans avanços en el tractament amb insulina. Actualment, les línies d'investigació que s'estan seguint en relació a la millora de la qualitat de vida dels pacients diabètics, tenen fonamentalment 2 vessants: un primer que es centra en la investigació de cèl.lules mare per a la reposició de les cèl.lules beta i un segon vessant de caràcter més tecnològic. Dins d' aquest segon vessant, estan obertes diverses línies d'investigació, entre les que es troben el desenrotllament de nous anàlegs d'insulina que permeten emular més fidelment la secreció del pàncrees, el desenrotllament de monitors continus de glucosa no invasius, bombes d'insulina capaces d'administrar distints perfils d'insulina i la inclusió de sistemes d'ajuda a la decisió i telemedicina. El major repte al què s'enfronten els investigadors és el d'aconseguir desenrotllar un pàncrees artificial, és a dir, desenrotllar algoritmes que permeten disposar d'un control automàtic de la glucosa. La principal barrera que es troba per a aconseguir un control rigorós de la glucosa és l'alta variabilitat que presenta el seu metabolisme. Açò és especialment significatiu durant la compensació dels menjars. Aquesta variabilitat junt amb el retard en l'absorció i actuació de la insulina administrada de forma subcutània afavorix l'aparició d'hipoglucèmies tardanes (complicació aguda més important del tractament amb insulina) a conseqüència de la sobreactuació del controlador. Les propostes presentades en aquest treball fan especial insistència en suportar aquestes dificultats. Així, s'utilitzen models intervalares per a representar la fisiologia del pacient, i poder tindre en compte la incertesa en els seus paràmetres. Aquest tipus d'estratègia s'ha utilitzat tant en la proposta de dosificació automàtica en llaç obert com en l' algoritme en llaç tancat. A més, la principal idea de disseny d'aquesta última proposta és evitar la sobreactuació del controlador evitant hipoglucèmies i afegint robustesa.Revert Tomás, A. (2015). Robust strategies for glucose control in type 1 diabetes [Tesis doctoral no publicada]. Universitat Politècnica de València. https://doi.org/10.4995/Thesis/10251/56001TESI

Closed-loop insulin delivery in adults with type 1 diabetes

Achieving tight glucose control safely in type 1 diabetes with currently available methods of insulin delivery is challenging. Aggressive regimens carry an increased risk of hypoglycaemia, particularly overnight. Both alcohol consumption and exercise predispose further to low glucose levels. The demands are even greater in pregnancy where, in addition to limiting hypoglycaemia, avoidance of postprandial hyperglycaemia is critical to minimising adverse obstetric outcomes. The aim of my studies was to evaluate feasibility and safety of a closed-loop or ’artificial pancreas’ system linking insulin delivery with continuous glucose monitoring (CGM), in adults with type 1 diabetes in a controlled setting. Three randomised crossover studies compared closed-loop insulin delivery with conventional insulin pump therapy on two separate occasions, matched in meals and activities. During closed-loop visits, CGM values were entered into a computer containing a model predictive control algorithm which advised on basal insulin infusion for subcutaneous delivery, every 15 minutes. During control visits, usual insulin pump regimen was continued. The feasibility study evaluated overnight closed-loop in 12 adults (seven females, mean age 37.7 years, HbA1c 7.8%) following 60g- carbohydrate evening meal. A follow-up study assessed overnight closed-loop in 12 further adults (seven females, mean age 37.2 years, HbA1c 7.8%) following 100g-carbohydrate meal and (mean 564 ml) white wine. The third study evaluated 24 hours of closed-loop in 12 pregnant women (mean age 32.9 years, 19 to 23 weeks gestation, HbA1c 6.4%) during normal daily activities, including low and moderate intensity exercise. Activity and glucose levels were also measured during free-living. CGM performance during exercise was evaluated. Overnight closed-loop insulin delivery in adults, compared with conventional pump therapy, increased time spent with plasma glucose in target range (3.9−8.0 mmol/l) following both standard meal (81% versus 57%; p = 0.012) and large meal accompanied by alcohol (70% versus 46%; p = 0.012). Glycaemic variability, and time spent in hypo- and hyper- glycaemia were lowered. In pregnant women, day and night closed-loop insulin delivery was as effective as usual pump regimen (81% versus 81% time spent with plasma glucose 3.5−7.8 mmol/l; p = 0.754). Hypoglycaemia occurred following exercise, although closed-loop prevented nocturnal episodes. Glycaemic control during free-living was suboptimal, compared with controlled diet and exercise conditions. Accuracy of CGM was lower during exercise. In conclusion, these studies confirm the feasibility and efficacy of overnight closed-loop insulin delivery in adults with type 1 diabetes. Closed-loop is safe during pregnancy and may be beneficial in women with suboptimal glycaemic control. Meals and physical activity currently limit optimal daytime use of closed-loop

Faculty Publications and Creative Works 2001

One of the ways in which we recognize our faculty at the University of New Mexico is through Faculty Publications & Creative Works. An annual publication, it highlights our faculty\u27s scholarly and creative activities and achievements and serves as a compendium of UNM faculty efforts during the 2001 calendar year. Faculty Publications & Creative Works strives to illustrate the depth and breadth of research activities performed throughout our University\u27s laboratories, studios and classrooms. We believe that the communication of individual research is a significant method of sharing concepts and thoughts and ultimately inspiring the birth of new ideas. In support of this, UNM faculty during 2001 produced over 2,299* works, including 1,685 scholarly papers and articles, 69 books, 269 book chapters, 184 reviews, 86 creative works and 6 patented works. We are proud of the accomplishments of our faculty which are in part reflected in this book, which illustrates the diversity of intellectual pursuits in support of research and education at the University of New Mexico