Als Typ-3-Diabetes werden persistierende Hyperglykämien bezeichnet, welche im Rahmen von Krankheiten auftreten, die nicht dem Typ-1-, Typ-2- oder Gestationsdiabetes zuzuordnen sind [1, 2]. Dazu gehören monogenetische Störungen der Betazellfunktion wie bei MODY (Maturity Onset Diabetes of the Young), Erkrankungen des exokrinen Pankreas, genetische Defekte der Insulinwirkung, medikamentös-chemisch induzierter Diabetes, Endokrinopathien und Infektionen. Hinzu kommen weitere genetische Syndrome, die mit Diabetes assoziiert sein können. Die Therapie orientiert sich am Patienten und den erfahrungsgemäß bei der jeweiligen Störung wirksamen Optionen.

This paper introduces an improved physiological animal model with diabetic Gottingen minipigs, which focuses on the application of human therapy devices and metabolic system analysis. Based on measurement data-sets collected by metabolic test procedures, a new mathematical minipig model is developed. The model consists of 16 differential equations and describes the diabetic porcine glucose metabolism according to the human model published by Sorensen. In the future, the mathematical model will be used as a basis for controller design and the physiological model for experimental control performance evaluation. (C) 2014 Elsevier Ltd. All rights reserved.

Pancreatic islet transplantation stabilises glycaemic control in type 1 diabetes mellitus patients with neuroglycopoenia, despite them not achieving insulin independence because of limited graft function. However, the extent and underlying metabolic pathways of restored glucose counterregulation are unknown. We therefore compared systemic glucose turnover, including lactate gluconeogenesis (GN) and muscle glucose uptake, in individuals with type 1 diabetes who were transplant recipients with partial graft function (T1DM/ITx+), matched non-transplanted individuals with type 1 diabetes (T1DM/ITx−) and matched healthy non-diabetic individuals.

A method for optimal continuous insulin therapy for diabetes patients has been sought since the early 1970s. Although technical and medical advances have been made, a fully automated artificial pancreas to replace the functions of the natural organ is still a research aim. This review compares recent control algorithms for type 1 diabetic patients which automatically connect continuous glucose monitoring and insulin injection, without patient intervention. Black-box model and gray-box model based control strategies are described and their performances are evaluated, with a focus on their feasibility of implementation in a real-life situation. In conclusion, a satisfactory control strategy has not yet been proposed, mainly because most control algorithms rely on continuous blood glucose measurement which is not yet available. Modeling the effect of glucose ingestion as an external disturbance on the time evolution of blood glucose concentration, is now the norm for the control community. In contrast, the effects of physical activity on the metabolic system is not yet fully understood and remain an open issue. Moreover, clinical studies on evaluation of control performance are scarce. Therefore, research on blood glucose control needs to concentrate on advanced patient modeling, control optimization and control performance evaluation under realistic patient-oriented conditions. (C) 2012 Elsevier Ltd. All rights reserved.

A method for optimal continuous insulin therapy for diabetes patients has been sought since the early 1970s. Although technical and medical advances have been made, a fully automated artificial pancreas to replace the functions of the natural organ is still a research aim. This review compares recent control algorithms for type 1 diabetic patients which automatically connect continuous glucose monitoring and insulin injection, without patient intervention. Black-box model and gray-box model based control strategies are described and their performances are evaluated, with a focus on their feasibility of implementation in a real-life situation. In conclusion, a satisfactory control strategy has not yet been proposed, mainly because most control algorithms rely on continuous blood glucose measurement which is not yet available. Modeling the effect of glucose ingestion as an external disturbance on the time evolution of blood glucose concentration, is now the norm for the control community. In contrast, the effects of physical activity on the metabolic system is not yet fully understood and remain an open issue. Moreover, clinical studies on evaluation of control performance are scarce. Therefore, research on blood glucose control needs to concentrate on advanced patient modeling, control optimization and control performance evaluation under realistic patient-oriented conditions.

The current epidemic of diabetes with its overwhelming burden on our healthcare system requires better therapeutic strategies. Here we present a promising novel approach for a curative strategy that may be accessible for all insulin-dependent diabetes patients. We designed a subcutaneous implantable bioartificial pancreas (BAP)-the "β-Air"-that is able to overcome critical challenges in current clinical islet transplantation protocols: adequate oxygen supply to the graft and protection of donor islets against the host immune system. The system consists of islets of Langerhans immobilized in an alginate hydrogel, a gas chamber, a gas permeable membrane, an external membrane, and a mechanical support. The minimally invasive implantable device, refueled with oxygen via subdermally implanted access ports, completely normalized diabetic indicators of glycemic control (blood glucose intravenous glucose tolerance test and HbA1c) in streptozotocin-induced diabetic rats for periods up to 6 months. The functionality of the device was dependent on oxygen supply to the device as the grafts failed when oxygen supply was ceased. In addition, we showed that the device is immuno-protective as it allowed for survival of not only isografts but also of allografts. Histological examination of the explanted devices demonstrated morphologically and functionally intact islets; the surrounding tissue was without signs of inflammation and showed visual evidence of vasculature at the site of implantation. Further increase in islets loading density will justify the translation of the system to clinical trials, opening up the potential for a novel approach in diabetes therapy.

This article presents initial results of a chemically induced diabetic swine model. A Gottingen minipig was equipped with a commercially available subcutaneous measuring glucose sensor and an insulin pump. Blood and subcutaneous glucose concentrations were observed during healthy and diabetic periods. Induction of stable diabetes mellitus by Streptozocin injection was confirmed by oral glucose tolerance test. The measurements showed, that blood glucose level in Gottingen minipigs is in a similar range, albeit discretely lower compared to human subjects. Subcutaneous and intravenous glucose concentration were similar but differing. In the future, it seems to be reasonable to use a swine model as intermediate translational step between in-silica and human trials for the validation of control algorithms for blood glucose control.

Islet transplantation is a feasible therapeutic alternative for metabolically labile patients with type 1 diabetes. The primary therapeutic target is stable glycemic control and prevention of complications associated with diabetes by reconstitution of endogenous insulin secretion. However, critical shortage of donor organs, gradual loss in graft function over time, and chronic need for immunosuppression limit the indication for islet transplantation to a small group of patients. Here we present a promising approach to address these limitations by utilization of a macrochamber specially engineered for islet transplantation. The s.c. implantable device allows for controlled and adequate oxygen supply and provides immunological protection of donor islets against the host immune system. The minimally invasive implantable chamber normalized blood glucose in streptozotocin-induced diabetic rodents for up to 3 mo. Sufficient graft function depended on oxygen supply. Pretreatment with the growth hormone-releasing hormone (GHRH) agonist, JI-36, significantly enhanced graft function by improving glucose tolerance and increasing β-cell insulin reserve in rats thereby allowing for a reduction of the islet mass required for metabolic control. As a result of hypervascularization of the tissue surrounding the device, no relevant delay in insulin response to glucose changes has been observed. Consequently, this system opens up a fundamental strategy for therapy of diabetes and may provide a promising avenue for future approaches to xenotransplantation.

Liu et al. make several comments and suggestions (1) on our publication (2) in which we studied primarily the role of hypothalamic releasing hormones corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone on islet function. The occurrence of HSD enzymes in rodent and human pancreatic islets has been shown by various groups. Although most of these groups have studied and discussed the role of 11β-HSD1 and steroid action with respect to β-cell function and insulin release, one study suggests a primary role of α-cells in pancreatic islets (3). Our study (2) demonstrated mRNA and protein expression of 11β-HSD1 in rodent and human islets and in β-cell line INS-1, as well as steroid regulation in INS-1 cells. Analysis of expression of mRNA for human and rat 11β-HSD1 and 11β-HSD2 was performed with sequence-specific primers and further quantified by real-time PCR.

Relativ häufig tritt nach einer Transplantation ein Diabetes mellitus auf. Die Bedeutung dieses Posttransplantationsdiabetes wird oft unterschätzt. Er erhöht sowohl die Mortalität als auch die Rate an Transplantatversagen signifikant. Die Störung des Glukosestoffwechsels wird häufig erst spät entdeckt. Dabei ist ein frühzeitiges, konsequentes Eingreifen nötig, um Komplikationen zu reduzieren. Bereits vor der Aufnahme auf eine Transplantationswarteliste sollte ein oraler Glukosetoleranztest durchgeführt werden. Die Therapie orientiert sich an den Leitlinien für Erwachsene mit Diabetes mellitus Typ 2. Ergänzend stehen transplantationsspezifische Möglichkeiten zur Verfügung, die aber nur in enger Absprache von Hausarzt, Diabetologen und Transplantationsmediziner gewählt werden sollten. Der vorliegende Beitrag erläutert die pathogenetischen Besonderheiten des Posttransplantationsdiabetes sowie das diagnostische und therapeutische Vorgehen.

Drug Prescribing for Patients with Chronic Kidney Disease in General Practice: a Cross-Sectional Study

Corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH), primarily characterized as neuroregulators of the hypothalamic-pituitary-adrenal axis, directly influence tissue-specific receptor-systems for CRH and GHRH in the endocrine pancreas. Here, we demonstrate the expression of mRNA for CRH and CRH-receptor type 1 (CRHR1) and of protein for CRHR1 in rat and human pancreatic islets and rat insulinoma cells. Activation of CRHR1 and GHRH-receptor significantly increased cell proliferation and reduced cell apoptosis. CRH stimulated both cellular content and release of insulin in rat islet and insulinoma cells. At the ultrastructural level, CRHR1 stimulation revealed a more active metabolic state with enlarged mitochondria. Moreover, glucocorticoids that promote glucose production are balanced by both 11b-hydroxysteroid dehydrogenase (11β-HSD) isoforms; 11β-HSD–type-1 and 11β-HSD–type-2. We demonstrated expression of mRNA for 11β-HSD-1 and 11β-HSD-2 and protein for 11β-HSD-1 in rat and human pancreatic islets and insulinoma cells. Quantitative real-time PCR revealed that stimulation of CRHR1 and GHRH-receptor affects the metabolism of insulinoma cells by down-regulating 11β-HSD-1 and up-regulating 11β-HSD-2. The 11β-HSD enzyme activity was analyzed by measuring the production of cortisol from cortisone. Similarly, activation of CRHR1 resulted in reduced cortisol levels, indicating either decreased 11β-HSD-1 enzyme activity or increased 11β-HSD-2 enzyme activity; thus, activation of CRHR1 alters the glucocorticoid balance toward the inactive form. These data indicate that functional receptor systems for hypothalamic-releasing hormone agonists exist within the endocrine pancreas and influence synthesis of insulin and the pancreatic glucocorticoid shuttle. Agonists of CRHR1 and GHRH-receptor, therefore, may play an important role as novel therapeutic tools in the treatment of diabetes mellitus.

Islet cell transplantation has considerable potential as a cure for type 1 diabetes, but recurrent autoimmunity and allograft rejection in which both cytokines play an important role are major obstacles. Using a new approach considering confounders by regression analysis, we investigated circulating cytokines and their association with graft function in type 1 diabetes patients who underwent either simultaneous islet kidney (SIK) or islet after kidney (IAK) transplantation. After transplantation, interleukin (IL)-10 was lower in SIK recipients with subsequent loss of graft function in comparison to recipients maintaining graft function. Before transplantation, high IL-13 and IL-18 concentrations were prospectively associated for subsequent loss of graft function in IAK recipients, whereas in SIK recipients, high macrophage migration inhibitory factor (MIF) concentrations were associated with subsequent loss of graft function. Circulating cytokines are associated with islet graft function in patients with long-standing type 1 diabetes when considering confounders.

During pregnancy, the pancreatic islets undergo major structural and functional changes in response to increased peripheral resistance to insulin. In this study, we investigated the adaptive changes of the pancreatic islet beta-cell mass during pregnancy in rats, and explored profiles of islet gene expression at various stages of pregnancy. Some differentially expressed genes were verified by RT-PCR and Real-time PCR. Our results showed that compared with the non-pregnant control group, insulin synthesis, glucose-stimulated insulin secretion, islet beta-cell proliferation, and islet size were all increased in pregnant rats. The study also demonstrated that expression of several-hundred islet genes were changed during pregnancy, especially at day 14.5. The differentially expressed genes identified were distributed into eight main categories according to their biological functions: (1) genes involved in apoptosis or tumor; (2) genes related to binding; (3) genes involved in metabolism; (4) genes related to cell cycle; (5) genes for signal transducer activity; (6) genes related to structural molecule activity; (7) genes involved in transcription regulator activity; (8) genes for transporter activity. Among these genes, regenerating islet-derived 3 alpha (Reg3a) was remarkably increased during pregnancy. We hypothesize that differentially expressed genes may play an important role in adaptation of pancreatic islets during pregnancy in rats. In addition, the markedly increased expression of gene Reg3a is probably related to islet regeneration.

Therapeutic strategies for transplantation of pancreatic islet cells are urgently needed to expand beta-cell mass by stimulating islet cell proliferation and/or prolonging islet cell survival. Control of the islets by different growth factors provides a potential venue for augmenting beta-cell mass. In the present study, we show the expression of the biologically active splice variant-1 (SV-1) of growth hormone-releasing hormone (GHRH) receptor in rat insulinoma (INS-1) cells as well as in rat and human pancreatic islets. In studies in vitro of INS-1 cells, the GHRH agonist JI-36 caused a significant increase in cell proliferation and a reduction of cell apoptosis. JI-36 increased islet size and glucose-stimulated insulin secretion in isolated rat islets after 48-72 h. At the ultrastructural level, INS-1 cells treated with agonist JI-36 revealed a metabolic active stimulation state with increased cytoplasm. Coincubation with the GHRH antagonist MIA-602 reversed the actions of the agonist JI-36, indicating the specificity of this agonist. In vivo, the function of pancreatic islets was assessed by transplantation of rat islets under the kidney capsule of streptozotocin-induced diabetic non-obese diabetic-severe combined immunodeficiency (NOD-SCID) mice. Islets treated with GHRH agonist JI-36 were able to achieve normoglycemia earlier and more consistently than untreated islets. Furthermore, in contrast to diabetic animals transplanted with untreated islets, insulin response to an i.p. glucose tolerance test (IPGTT) in animals receiving islets treated with agonist Jl-36 was comparable to that of normal healthy mice. In conclusion, our study provides evidence that agonists of GHRH represent a promising pharmacological therapy aimed at promoting islet graft growth and proliferation in diabetic patients.