Reverse correlation between urine nitric oxide metabolites and insulin resistance in patients with type 2 diabetes mellitus.
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We studied the possible relationship between nitric oxide (NO) production and insulin resistance in patients with type 2 diabetes mellitus. Urine NO metabolites (NOx) were measured as an index for NO production by HPLC combined with a Cd column, Griess reaction and a spectrophotometer in 403 healthy control subjects and 102 hospitalized patients with type 2 diabetes. Glucose infusion rate (GIR) was measured as a reverse index for insulin resistance by euglycemic glucose clamp study using an artificial pancreas in 20 of 102 diabetic patients. Urine NOx was lower in the patients with type 2 diabetes than in healthy control subjects (mean+/-SE: 3.18 +/-0.02 versus 3.25 +/-0.01 log[-micromol/gCr], p<0.01). Urine NOx was correlated with body mass index (BMI) in 102 diabetic patients (r= -0.372, p<0.001), but not related to either age, sex, fasting plasma glucose, HbA1c or blood pressure. Urine NOx was correlated with GIR independent of BMI in 20 diabetic patients (r=0.774, P<0.0001). These findings suggest that NO production is closely related with insulin resistance in patients with type 2 diabetes. (+info)
Close relationship of tissue plasminogen activator-plasminogen activator inhibitor-1 complex with multiple organ dysfunction syndrome investigated by means of the artificial pancreas.
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BACKGROUND: Glucose tolerance (GT) has not been taken into consideration in investigations concerning relationships between coagulopathy and multiple organ dysfunction syndrome (MODS), and endothelial cell activation/endothelial cell injury (ECA/ECI) in septic patients, although coagulopathy is known to be influenced by blood glucose level. We investigated those relationships under strict blood glucose control and evaluation of GT with the glucose clamp method by means of the artificial pancreas in nine septic patients with glucose intolerance. The relationships between GT and blood stress related hormone levels (SRH) were also investigated. METHODS: The amount of metabolized glucose (M value), as the parameter of GT, was measured by the euglycemic hyperinsulinemic glucose clamp method, in which the blood glucose level was clamped at 80 mg/dl under a continuous insulin infusion rate of 1.12 mU/kg per min, using the artificial pancreas, STG-22. Multiple organ failure (MOF) score was calculated using the MOF criteria of Japanese Association for Critical Care Medicine. Regarding coagulopathy, the following parameters were used: disseminated intravascular coagulation (DIC) score (calculated from the DIC criteria of the Ministry of Health and Welfare of Japan) and the parameters used for calculating DIC score, protein-C, protein-S, plasminogen, antithrombin III (AT-III), plasminogen activator inhibitor-1 (PAI-1), and tissue plasminogen activator-PAI-1 (tPA-PAI-1) complex. Thrombomodulin (TM) was measured as the indicator of ECI. RESULTS: There were no significant correlations between M value and SRH, parameters indicating coagulopathy and the MOF score. The MOF score and blood TM levels were positively correlated with DIC score, thrombin-AT-III complex and tPA-PAI-1 complex, and negatively correlated with blood platelet count. CONCLUSIONS: GT was not significantly related to SRH, coagulopathy and MODS under strict blood glucose control. Hypercoagulability was closely related to MODS and ECI. Among the parameters indicating coagulopathy, tPA-PAI-1 complex, which is considered to originate from ECA, seemed to be a sensitive parameter of MODS and ECI, and might be a predictive marker of MODS. The treatment for reducing hypercoagulability and ECA/ECI were thought to be justified as one of the therapies for acutely ill septic patients. (+info)
Incorporation of sulfonylurea into N-isopropylacrylamide as an extracellular matrix for an artificial pancreas.
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High-molecular-weight N-isopropylacrylamide copolymers with small amounts of sulfonylurea (SU, typically 2-4 mol% in the feed) were synthesized by free radical polymerization in benzene. SU-incorporated polymer solutions (5, 6, 8, and 10% w/v) in a culture medium (pH 7.4, 0.15 M ionic strength) with islet cells were mixed and poured into Millicells which supported gel formation. In order to increase the gelation temperature, the SU-incorporated copolymer gel, p(NiPAAm-co-SU), was blended with the p(NiPAAm-co-AAc) polymer at a ratio of 4 to 96. Interaction between the islet cells and the synthetic matrix of SU-incorporated copolymer gel resulted in effective cell viability and such cell functions as insulin secretion. To verify the specific interaction between the SU (K+ channel closer)-incorporated copolymer and islet cells, the cells were pretreated with diazoxide, an agonist of the ATP-sensitive K+ channel (K+ channel opener), before interaction between the polymer and islet cells. This treatment suppressed the action of SU on the islet cells. The results from this study provide evidence that the SU-incorporated copolymer stimulated insulin secretion by specific interaction between SU moieties in the polymer and the islet cells. (+info)
Caged pancreatic islet for IDDM.
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The goals of this research are to improve the functionality (insulin secretion rate and pattern) and to expand the life-span of immunoprotected pancreatic islets. The low functionality (less than 15% of the insulin release rate of native islets in pancreas) required a large number of islets within the implant, which causes complications in surgery and discomfort for patients. The limited life-span of the islets in a biohybrid artificial pancreas (BAP) may require frequent cell reseeding and cause further supply problems in islet transplantation. Improved islet functionality and prolonged life-span will minimize the volume of the BAP by reducing the number of islets needed for diabetic patients to achieve normoglycaemia and reduce problems associated with islet supply. It is hypothesized in this research that 1) by mimicking facilitated oxygen transport in avascular tissues, the immunoprotected islets release a higher amount of insulin, recover their intrinsic biphasic release pattern, and prolong their life-span, and 2) insulinotropic agents further promote insulin secretion from islets. Based on these hypotheses, a new BAP system will be designed which contains the water-soluble polymeric conjugates of oxygen carriers (or oxygen binding vehicles) and islet stimulants of sulfonylurea compounds and glucagon-like insulinotropic peptide-1 with entrapped islets in the BAP. The research examines their effects on islet viability, the amount of insulin secretion, the insulin release profile, and the life-span of immunoprotected pancreatic islets. Especially, the combined synergy effects of both hypotheses will be emphasized. The successful results in improving functionality and life-span of islets entrapped in an immunoprotected membrane can be applied in the delivery of microencapsulated therapeutic cells and to the miniaturization of a BAP. In addition, the approaches proposed in this research will provide a potential solution to the shortage problem of human cell or tissue sources. (+info)
Insulin therapy and carbohydrate counting.
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Nutritional management is one of the cornerstones of diabetes care. Many studies have been performed on the correlation between nature and amount of carbohydrate in meal intake and insulin delivery by artificial pancreas in Type 1 diabetic patients. In fact consistency in the amount and source of carbohydrate intake from day to day is associated with improved blood glucose control in people with Type 1 diabetes. Many methods of counting carbohydrate have been used and many are still commonly used in paediatric practice (exchange, portion/serving, grams, glycemic index, carbohydrate/insulin ratio). Carbohydrate counting is a meal planning approach with patients with Type 1 diabetes mellitus that focuses on carbohydrate as the primary nutrient affecting postprandial glycemic response. The aim of this paper is to review published data on the significance of carbohydrate counting on meeting outcome goals and allowing flexibility in food choices. (+info)
Modeling of encapsulated cell systems.
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Tissue engineered substitutes consisting of cells in biocompatible materials undergo remodeling with time as a result of cell growth and death processes. With inert matrices that do not directly influence cell growth, remodeling is driven mainly by the concentration of dissolved oxygen (DO). Insulin-secreting cell lines encapsulated in alginate-based beads and used as a pancreatic substitute represent such a case. Beads undergo remodeling with time so that an initially homogeneous distribution of cells is eventually replaced by a dense peripheral ring of primarily viable cells, whereas inner cells are mostly necrotic. This paper develops and analyzes a mathematical model of an encapsulated cell system of spherical geometry that tracks the viable and dead cell densities and the concentration of DO within the construct as functions of radial position and time. Model simulations are compared with experimental histology data on cell distribution. Correlations are then developed between the average intrabead DO concentration (AIDO) and the total viable cell number, as well as between AIDO and the radial cell and DO distributions in beads. As AIDO can be measured experimentally by incorporating a perfluorocarbon emulsion in the beads and acquiring (19)F nuclear magnetic resonance (NMR) spectroscopic data, these correlations can be used to track the remodeling that occurs in the construct in vitro and potentially in vivo. The usefulness of mathematical models in describing the dynamic changes that occur in tissue constructs with time, and the value of these models at obtaining additional information on the system when used interactively with experimental measurements, are discussed. (+info)
AIM: Restoration of long-term normal blood glucose control in diabetic patients supports the elaboration of an artificial beta cell. The possibility of implantation of the three crucial components of such a system (insulin delivery device, glucose sensor and controller) is analyzed. METHODS: The Long-Term Sensor System project, aiming at a fully implantable artificial beta cell, assessed the feasibility of glucose control by the combined implantation of a pump for peritoneal insulin delivery and a central intravenous glucose sensor close to the right atrium, connected via a subcutaneous lead. It was initiated in 10 Type 1 diabetic patients in our clinic from 2000. Data obtained during this experience are reviewed and confronted to reported closed-loop trials using other approaches. RESULTS: No significant complication related to prolonged implantation of intravenous sensors occurred and the combined implants were well tolerated. Glucose measurement by the intravenous sensors correlated well with meter values (r=0.83-0.93, with a mean absolute deviation of 16.5%) and accuracy has been sustained for an average duration of 9 months. Uploading of pump electronics by algorithms designed for closed-loop insulin delivery allowed in-patient 48 hour-trials aiming at automated glucose control. Glucose control was similar to that reported by investigations combining subcutaneous sensors to wearable pumps for subcutaneous insulin infusion. The benefits of more physiological insulin kinetics due to intra-peritoneal delivery have been hampered by the slow response time of intravenous sensors. CONCLUSION: Although the concept of a fully implantable artificial beta cell has been validated as feasible, the limited performance in achieving glucose control requests improvements in the sensor structure to increase its longevity and decrease sensor delay. (+info)
Progress in the treatment of diabetes type 1 and 2.
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In the last years an increased incidence of diabetes was observed in the whole world. It was estimated that in the year 2030 there will be around 300 million patients with diabetes. Diabetes, especially not adequately treated, develops serious chronic complications. The main aim of the therapy in diabetes is, as we know, to achieve a stable normoglycemia, normal levels of HbA1c, the prevention or inhibition of the progression of late consequences of diabetes. In the paper the authors discuss new more perfect insulins which enable a better imitation of the physiological rhythm of insulin secretion, the therapy with personal insulin pumps, the more perfect equipment for the appreciation and monitoring of the metabolic control. The authors present also the actual data about the transplantation of the pancreas, the islets and recently the beta cells alone. They enumerate also the inclusion and exclusion criteria for transplantation. The gene therapy is mentioned. The present possibilities of the therapy of type 2 diabetes are presented. It is stressed that in the year 2006 for the first time an expert crew was appointed to elaborate a prevention and therapeutical program for diabetes in Poland. The program was accepted by the Ministry of Health for realisation in the years 2006-2008. The authors conclude that in the recent years an enormous progress in the prevention, diagnostics and therapy in diabetes has been achieved. However, the time which should elapse to the moment when the complete success would be achieved is dependent on the further scientific progress the intensity of investigations in the whole world. (+info)