16,261 research outputs found

    Functional deficits precede structural lesions in mice with high-fat diet-induced diabetic retinopathy

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    Obesity predisposes to human type 2 diabetes, the most common cause of diabetic retinopathy. To determine if high-fat diet–induced diabetes in mice can model retinal disease, we weaned mice to chow or a high-fat diet and tested the hypothesis that diet-induced metabolic disease promotes retinopathy. Compared with controls, mice fed a diet providing 42% of energy as fat developed obesity-related glucose intolerance by 6 months. There was no evidence of microvascular disease until 12 months, when trypsin digests and dye leakage assays showed high fat–fed mice had greater atrophic capillaries, pericyte ghosts, and permeability than controls. However, electroretinographic dysfunction began at 6 months in high fat–fed mice, manifested by increased latencies and reduced amplitudes of oscillatory potentials compared with controls. These electroretinographic abnormalities were correlated with glucose intolerance. Unexpectedly, retinas from high fat–fed mice manifested striking induction of stress kinase and neural inflammasome activation at 3 months, before the development of systemic glucose intolerance, electroretinographic defects, or microvascular disease. These results suggest that retinal disease in the diabetic milieu may progress through inflammatory and neuroretinal stages long before the development of vascular lesions representing the classic hallmark of diabetic retinopathy, establishing a model for assessing novel interventions to treat eye disease

    Impact of Sleep and Circadian Disruption on Energy Balance and Diabetes: A Summary of Workshop Discussions

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    A workshop was held at the National Institute for Diabetes and Digestive and Kidney Diseases with a focus on the impact of sleep and circadian disruption on energy balance and diabetes. The workshop identified a number of key principles for research in this area and a number of specific opportunities. Studies in this area would be facilitated by active collaboration between investigators in sleep/circadian research and investigators in metabolism/diabetes. There is a need to translate the elegant findings from basic research into improving the metabolic health of the American public. There is also a need for investigators studying the impact of sleep/circadian disruption in humans to move beyond measurements of insulin and glucose and conduct more in-depth phenotyping. There is also a need for the assessments of sleep and circadian rhythms as well as assessments for sleep-disordered breathing to be incorporated into all ongoing cohort studies related to diabetes risk. Studies in humans need to complement the elegant short-term laboratory-based human studies of simulated short sleep and shift work etc. with studies in subjects in the general population with these disorders. It is conceivable that chronic adaptations occur, and if so, the mechanisms by which they occur needs to be identified and understood. Particular areas of opportunity that are ready for translation are studies to address whether CPAP treatment of patients with pre-diabetes and obstructive sleep apnea (OSA) prevents or delays the onset of diabetes and whether temporal restricted feeding has the same impact on obesity rates in humans as it does in mice

    Class III PI3K regulates organismal glucose homeostasis by providing negative feedback on hepatic insulin signalling.

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    Defective hepatic insulin receptor (IR) signalling is a pathogenic manifestation of metabolic disorders including obesity and diabetes. The endo/lysosomal trafficking system may coordinate insulin action and nutrient homeostasis by endocytosis of IR and the autophagic control of intracellular nutrient levels. Here we show that class III PI3K--a master regulator of endocytosis, endosomal sorting and autophagy--provides negative feedback on hepatic insulin signalling. The ultraviolet radiation resistance-associated gene protein (UVRAG)-associated class III PI3K complex interacts with IR and is stimulated by insulin treatment. Acute and chronic depletion of hepatic Vps15, the regulatory subunit of class III PI3K, increases insulin sensitivity and Akt signalling, an effect that requires functional IR. This is reflected by FoxO1-dependent transcriptional defects and blunted gluconeogenesis in Vps15 mutant cells. On depletion of Vps15, the metabolic syndrome in genetic and diet-induced models of insulin resistance and diabetes is alleviated. Thus, feedback regulation of IR trafficking and function by class III PI3K may be a therapeutic target in metabolic conditions of insulin resistance

    Overregulation of Health Care: Musings on Disruptive Innovation Theory

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    Disruptive innovation theory provides one lens through which to describe how regulations may stifle innovation and increase costs. Basing their discussion on this theory, Curtis and Schulman consider some of the effects that regulatory controls may have on innovation in the health sector

    Overregulation of Health Care: Musings on Disruptive Innovation Theory

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    Disruptive innovation theory provides one lens through which to describe how regulations may stifle innovation and increase costs. Basing their discussion on this theory, Curtis and Schulman consider some of the effects that regulatory controls may have on innovation in the health sector

    Mathematical investigation of diabetically impaired ultradian oscillations in the glucose-insulin regulation

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    We study the effect of diabetic deficiencies on the production of an oscillatory ultradian regime using a deterministic nonlinear model which incorporates two physiological delays. It is shown that insulin resistance impairs the production of oscillations by dampening the ultradian cycles. Four strategies for restoring healthy regulation are explored. Through the introduction of an instantaneous glucose-dependent insulin response, explicit conditions for the existence of periodic solutions in the linearised model are formulated, significantly reducing the complexity of identifying an oscillatory regime. The model is thus shown to be suitable for representing the effect of diabetes on the oscillatory regulation and for investigating pathways to reinstating a physiological healthy regime

    Amplitude and frequency variation in nonlinear glucose dynamics with multiple delays via periodic perturbation

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    Characterising the glycemic response to a glucose stimulus is an essential tool for detecting deficiencies in humans such as diabetes. In the presence of a constant glucose infusion in healthy individuals, it is known that this control leads to slow oscillations as a result of feedback mechanisms at the organ and tissue level. In this paper, we provide a novel quantitative description of the dependence of this oscillatory response on the physiological functions. This is achieved through the study of a model of the ultradian oscillations in glucose-insulin regulation which takes the form of a nonlinear system of equations with two discrete delays. While studying the behaviour of solutions in such systems can be mathematically challenging due to their nonlinear structure and non-local nature, a particular attention is given to the periodic solutions of the model. These arise from a Hopf bifurcation which is induced by an external glucose stimulus and the joint contributions of delays in pancreatic insulin release and hepatic glycogenesis. The effect of each physiological subsystem on the amplitude and period of the oscillations is exhibited by performing a perturbative analysis of its periodic solutions. It is shown that assuming the commensurateness of delays enables the Hopf bifurcation curve to be characterised by studying roots of linear combinations of Chebyshev polynomials. The resulting expressions provide an invaluable tool for studying the interplay between physiological functions and delays in producing an oscillatory regime, as well as relevant information for glycemic control strategies

    Inhibition of Y1 receptor signaling improves islet transplant outcome

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    Failure to secrete sufficient quantities of insulin is a pathological feature of type-1 and type-2 diabetes, and also reduces the success of islet cell transplantation. Here we demonstrate that Y1 receptor signaling inhibits insulin release in β-cells, and show that this can be pharmacologically exploited to boost insulin secretion. Transplanting islets with Y1 receptor deficiency accelerates the normalization of hyperglycemia in chemically induced diabetic recipient mice, which can also be achieved by short-term pharmacological blockade of Y1 receptors in transplanted mouse and human islets. Furthermore, treatment of non-obese diabetic mice with a Y1 receptor antagonist delays the onset of diabetes. Mechanistically, Y1 receptor signaling inhibits the production of cAMP in islets, which via CREB mediated pathways results in the down-regulation of several key enzymes in glycolysis and ATP production. Thus, manipulating Y1 receptor signaling in β-cells offers a unique therapeutic opportunity for correcting insulin deficiency as it occurs in the pathological state of type-1 diabetes as well as during islet transplantation.Islet transplantation is considered one of the potential treatments for T1DM but limited islet survival and their impaired function pose limitations to this approach. Here Loh et al. show that the Y1 receptor is expressed in β- cells and inhibition of its signalling, both genetic and pharmacological, improves mouse and human islet function.info:eu-repo/semantics/publishe

    MP Modeling of Glucose-Insulin Interactions in the Intravenous Glucose Tolerance Test

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    The Intra Venous Glucose Tolerance Test (IVGTT) is an experimental pro- cedure in which a challenge bolus of glucose is administered intra-venously and plasma glucose and insulin concentrations are then frequently sampled. An open problem is to construct a model representing simultaneously the entire control system. In the last three decades, several models appeared in the literature. One of the mostly used one is known as the minimal model, which has been challenged by the dynamical model. However, both the models have not escape from criticisms and drawbacks. In this paper we apply Metabolic P systems theory for developing new physiologically based models of the glucose-insulin system which can be applied to the Intra Venous Glucose Tolerance Test. We considered ten data-sets obtained from literature and for each of them we found an MP model which ts the data and explains the regulations of the dynamics. Finally, further analysis are planned in order to de ne common patterns which explain, in general, the action of the glucose-insulin control system
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