Abstract
Pancreatic islet transplantation has become an established approach to β-cell replacement therapy for the treatment of insulin-deficient diabetes. Recent progress in techniques for islet ...isolation, islet culture, and peritransplant management of the islet transplant recipient has resulted in substantial improvements in metabolic and safety outcomes for patients. For patients requiring total or subtotal pancreatectomy for benign disease of the pancreas, isolation of islets from the diseased pancreas with intrahepatic transplantation of autologous islets can prevent or ameliorate postsurgical diabetes, and for patients previously experiencing painful recurrent acute or chronic pancreatitis, quality of life is substantially improved. For patients with type 1 diabetes or insulin-deficient forms of pancreatogenic (type 3c) diabetes, isolation of islets from a deceased donor pancreas with intrahepatic transplantation of allogeneic islets can ameliorate problematic hypoglycemia, stabilize glycemic lability, and maintain on-target glycemic control, consequently with improved quality of life, and often without the requirement for insulin therapy. Because the metabolic benefits are dependent on the numbers of islets transplanted that survive engraftment, recipients of autoislets are limited to receive the number of islets isolated from their own pancreas, whereas recipients of alloislets may receive islets isolated from more than one donor pancreas. The development of alternative sources of islet cells for transplantation, whether from autologous, allogeneic, or xenogeneic tissues, is an active area of investigation that promises to expand access and indications for islet transplantation in the future treatment of diabetes.
Reactive oxygen species (ROS) are formed by virtually all tissues. In normal concentrations they facilitate many physiologic activities, but in excess they cause oxidative stress and tissue damage. ...Local antioxidant enzyme synthesis in cells is regulated by the cytoplasmic KEAP-1/Nrf2 complex, which is stimulated by ROS, to release Nrf2 for entry into the nucleus, where it upregulates antioxidant gene expression. Major antioxidant enzymes include glutathione peroxidase (GPx), catalase (CAT), superoxide dismutases (SOD), hemoxygenases (HO), and peroxiredoxins (Prdx). Notably, the pancreatic islet β-cell does not express GPx or CAT, which puts it at greater risk for ROS damage caused by postprandial hyperglycemia. Experimentally, overexpression of GPx in β-cell lines and isolated islets, as well as in vivo studies using genetic models of type 2 diabetes (T2D), has demonstrated enhanced protection against hyperglycemia and oxidative stress. Oral treatment of diabetic rodents with ebselen, a GPx mimetic that is approved for human clinical use, reproduced these findings. Prdx detoxify hydrogen peroxide and reduce lipid peroxides. This suggests that pharmacologic development of more potent, β-cell-specific antioxidants could be valuable as a treatment for oxidative stress due to postprandial hyperglycemia in early T2D in humans.
Abstract
Thyroid dysfunction and diabetes mellitus are closely linked. Several studies have documented the increased prevalence of thyroid disorders in patients with diabetes mellitus and vice versa. ...This review critically discusses the different underlying mechanisms linking type 1 and 2 diabetes and thyroid dysfunction to demonstrate that the association of these two common disorders is unlikely a simple coincidence. We assess the current state of knowledge on the central and peripheral control of thyroid hormone on food intake and glucose and lipid metabolism in target tissues (such as liver, white and brown adipose tissue, pancreatic β cells, and skeletal muscle) to explain the mechanism linking overt and subclinical hypothyroidism to type 2 diabetes and metabolic syndrome. We also elucidate the common susceptibility genes and the pathogenetic mechanisms contributing to the autoimmune mechanism involved in the onset of type 1 diabetes mellitus and autoimmune thyroid disorders. An untreated thyroid dysfunction can impair the metabolic control of diabetic patients, and this association can have important repercussions on the outcome of both of these disorders. Therefore, we offer recommendations for the diagnosis, management, and screening of thyroid disorders in patients with diabetes mellitus, including the treatment of diabetic patients planning a pregnancy. We also discuss the major causes of failure to achieve an optimal management of thyroid dysfunction in diabetic patients and provide recommendations for assessing and treating these disorders during therapy with antidiabetic drugs. An algorithm for a correct approach of these disorders when linked is also provided.
This perspective examines the proposition that chronically elevated blood glucose levels caused by type 2 diabetes (T2D) harm body tissues by locally generating reactive oxygen species (ROS). A ...feed-forward scenario is described in which the initial onset of defective beta cell function T2D becomes sustained and causes chronic elevations in blood glucose, which flood metabolic pathways throughout the body, giving rise to abnormally high local levels of ROS. Most cells can defend themselves via a full complement of antioxidant enzymes that are activated by ROS. However, the beta cell itself does not contain catalase or glutathione peroxidases and thereby runs a greater risk of ROS-induced damage. In this review, previously published experiments are revisited to examine the concept that chronic hyperglycemia can lead to oxidative stress in the beta cell, how this relates to the absence of beta cell glutathione peroxidase (GPx) activity, and whether this deficiency might be ameliorated by genetic enrichment of beta cell GPx and by oral antioxidants, including ebselen, a GPx mimetic.
Glucagon is a peptide hormone that is produced primarily by the alpha cells in the islet of Langerhans in the pancreas, but also in intestinal enteroendocrine cells and in some neurons. Approximately ...100 years ago, several research groups discovered that pancreatic extracts would cause a brief rise in blood glucose before they observed the decrease in glucose attributed to insulin. An overall description of the regulation of glucagon secretion requires the inclusion of its sibling insulin because they both are made primarily by the islet and they both regulate each other in different ways. For example, glucagon stimulates insulin secretion, whereas insulin suppresses glucagon secretion. The mechanism of action of glucagon on insulin secretion has been identified as a trimeric guanine nucleotide-binding protein (G-protein)-mediated event. The manner in which insulin suppresses glucagon release from the alpha cell is thought to be highly dependent on the peri-portal circulation of the islet through which blood flows downstream from beta cells to alpha cells. In this scenario, it is via the circulation that insulin is thought to suppress the release of glucagon. However, high levels of glucose also have been shown to suppress glucagon secretion. Consequently, the glucose-lowering effect of insulin may be additive to the direct effects of insulin to suppress alpha cell function, so that in vivo both the discontinuation of the insulin signal and the condition of low glucose jointly are responsible for induction of glucagon secretion.
Glucotoxicity, lipotoxicity, and glucolipotoxicity are secondary phenomena that are proposed to play a role in all forms of type 2 diabetes. The underlying concept is that once the primary ...pathogenesis of diabetes is established, probably involving both genetic and environmental forces, hyperglycemia and very commonly hyperlipidemia ensue and thereafter exert additional damaging or toxic effects on the β-cell. In addition to their contribution to the deterioration of β-cell function after the onset of the disease, elevations of plasma fatty acid levels that often accompany insulin resistance may, as glucose levels begin to rise outside of the normal range, also play a pathogenic role in the early stages of the disease. Because hyperglycemia is a prerequisite for lipotoxicity to occur, the term glucolipotoxicity, rather than lipotoxicity, is more appropriate to describe deleterious effects of lipids on β-cell function. In vitro and in vivo evidence supporting the concept of glucotoxicity is presented first, as well as a description of the underlying mechanisms with an emphasis on the role of oxidative stress. Second, we discuss the functional manifestations of glucolipotoxicity on insulin secretion, insulin gene expression, and β-cell death, and the role of glucose in the mechanisms of glucolipotoxicity. Finally, we attempt to define the role of these phenomena in the natural history of β-cell compensation, decompensation, and failure during the course of type 2 diabetes.
Direct measurements of neutrino mass Formaggio, Joseph A.; de Gouvêa, André Luiz C.; Robertson, R.G. Hamish
Physics reports,
06/2021, Letnik:
914, Številka:
C
Journal Article
Recenzirano
Odprti dostop
The turn of the 21st century witnessed a sudden shift in our fundamental understanding of particle physics. While the minimal Standard Model predicts that neutrino masses are exactly zero, the ...discovery of neutrino oscillations proved the Standard Model wrong. Neutrino oscillation measurements, however, shed light neither on the scale of neutrino masses, nor on the mechanism by which those are generated. The neutrino mass scale is most directly accessed by studying the energy spectrum generated by beta decay or electron capture — a technique dating back to Enrico Fermi’s formulation of radioactive decay. In this Article, we review the methods and techniques – both past and present – aimed at measuring neutrino masses kinematically. We focus on recent experimental developments that have emerged in the past decade, overview the spectral refinements that are essential in the treatment of the most sensitive experiments, and give a simple yet effective protocol for estimating the sensitivity. Finally, we provide an outlook of what future experiments might be able to achieve.
Solar Neutrinos: Status and Prospects Haxton, W.C; Hamish Robertson, R.G; Serenelli, Aldo M
Annual review of astronomy and astrophysics,
08/2013, Letnik:
51, Številka:
1
Journal Article
Recenzirano
Odprti dostop
We describe the current status of solar neutrino measurements and of the theory-both neutrino physics and solar astrophysics-employed in interpreting measurements. Important recent developments ...include Super-Kamiokande's determination of the ν−e elastic scattering rate for
8
B neutrinos to 3%; the latest Sudbury Neutrino Observatory (SNO) global analysis in which the inclusion of low-energy data from SNO I and II significantly narrowed the range of allowed values for the neutrino mixing angle
θ
12
; Borexino results for both the
7
Be and proton-electron-proton (pep) neutrino fluxes, the first direct measurements constraining the rate of proton-proton (pp) I and pp II burning in the Sun; global reanalyses of solar neutrino data that take into account new reactor results on
θ
13
; a new decadal evaluation of the nuclear physics of the pp chain and CNO cycle defining best values and uncertainties in the nuclear microphysics input to solar models; recognition of an emerging discrepancy between two tests of solar metallicity, helioseismological mappings of the sound speed in the solar interior, and analyses of the metal photoabsorption lines based on our best current description of the Sun's photosphere; a new round of standard solar model calculations optimized to agree either with helioseismology or with the new photospheric analysis; and, motivated by the solar abundance problem, the development of nonstandard, accreting solar models, in order to investigate possible consequences of the metal segregation that occurred in the proto-solar disk. We review this progress and describe how new experiments such as SNO+ could help us further exploit neutrinos as a unique probe of stellar interiors.
When cooled, insects first lose their ability to perform coordinated movements (CT
) after which they enter chill coma (chill coma onset, CCO). Both these behaviours are popular measures of cold ...tolerance that correlate remarkably well with species distribution. To identify and understand the neuromuscular impairment that causes CT
and CCO we used inter- and intraspecific model systems of
species that have varying cold tolerance as a consequence of adaptation or cold acclimation. Our results demonstrate that CT
and CCO correlate strongly with a spreading depolarization (SD) within the central nervous system (CNS). We show that this SD is associated with a rapid increase in extracellular K
within the CNS causing neuronal depolarization that silences the CNS. The CNS shutdown is likely to be caused by a mismatch between passive and active ion transport within the CNS and in a different set of experiments we examine inter- and intraspecific differences in sensitivity to SD events during anoxic exposure. These experiments show that cold adapted or acclimated flies are better able to maintain ionoregulatory balance when active transport is compromised within the CNS. Combined, we demonstrate that a key mechanism underlying chill coma entry of
is CNS shutdown, and the ability to prevent this CNS shutdown is therefore an important component of acute cold tolerance, thermal adaptation and cold acclimation in insects.
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