Kathrin Maedler

Bio: Kathrin Maedler is an academic researcher from University of Bremen. The author has contributed to research in topics: Pancreatic islets & Beta cell. The author has an hindex of 41, co-authored 102 publications receiving 8045 citations. Previous affiliations of Kathrin Maedler include University of California, Los Angeles & University of Zurich.

Glucose-induced β cell production of IL-1β contributes to glucotoxicity in human pancreatic islets

Abstract: In type 2 diabetes, chronic hyperglycemia is suggested to be detrimental to pancreatic beta cells, causing impaired insulin secretion. IL-1beta is a proinflammatory cytokine acting during the autoimmune process of type 1 diabetes. IL-1beta inhibits beta cell function and promotes Fas-triggered apoptosis in part by activating the transcription factor NF-kappaB. Recently, we have shown that increased glucose concentrations also induce Fas expression and beta cell apoptosis in human islets. The aim of the present study was to test the hypothesis that IL-1beta may mediate the deleterious effects of high glucose on human beta cells. In vitro exposure of islets from nondiabetic organ donors to high glucose levels resulted in increased production and release of IL-1beta, followed by NF-kappaB activation, Fas upregulation, DNA fragmentation, and impaired beta cell function. The IL-1 receptor antagonist protected cultured human islets from these deleterious effects. beta cells themselves were identified as the islet cellular source of glucose-induced IL-1beta. In vivo, IL-1beta-producing beta cells were observed in pancreatic sections of type 2 diabetic patients but not in nondiabetic control subjects. Similarly, IL-1beta was induced in beta cells of the gerbil Psammomys obesus during development of diabetes. Treatment of the animals with phlorizin normalized plasma glucose and prevented beta cell expression of IL-1beta. These findings implicate an inflammatory process in the pathogenesis of glucotoxicity in type 2 diabetes and identify the IL-1beta/NF-kappaB pathway as a target to preserve beta cell mass and function in this condition.

Distinct Effects of Saturated and Monounsaturated Fatty Acids on β-Cell Turnover and Function

Abstract: Glucotoxicity and lipotoxicity contribute to the impaired beta-cell function observed in type 2 diabetes. Here we examine the effect of saturated and unsaturated fatty acids at different glucose concentrations on beta-cell proliferation and apoptosis. Adult rat pancreatic islets were cultured onto plates coated with extracellular matrix derived from bovine corneal endothelial cells. Exposure of islets to saturated fatty acid (0.5 mmol/l palmitic acid) in medium containing 5.5, 11.1, or 33.3 mmol/l glucose for 4 days resulted in a five- to ninefold increase of beta-cell DNA fragmentation. In contrast, monounsaturated palmitoleic acid alone (0.5 mmol/l) or in combination with palmitic acid (0.25 or 0.5 mmol/l each) did not affect DNA fragmentation. Increasing concentrations of glucose promoted beta-cell proliferation that was dramatically reduced by palmitic acid. Palmitoleic acid enhanced the proliferation activity in medium containing 5.5 mmol/l glucose but had no additional effect at higher glucose concentrations (11.1 and 33.3 mmol/l). The cell-permeable ceramide analog C2-ceramide mimicked both the palmitic acid-induced beta-cell apoptosis and decrease in proliferation. Moreover, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on beta-cell viability. Additionally, palmitic acid but not palmitoleic acid decreased the expression of the mitochondrial adenine nucleotide translocator and induced release of cytochrome c from the mitochondria into the cytosol. Finally, palmitoleic acid improved beta-cell-secretory function that was reduced by palmitic acid. Taken together, these results suggest that the lipotoxic effect of the saturated palmitic acid involves an increased apoptosis rate coupled with reduced proliferation capacity of beta-cells and impaired insulin secretion. The deleterious effect of palmitate on beta-cell turnover is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway. In contrast, the monounsaturated palmitoleic acid does not affect beta-cell apoptosis, yet it promotes beta-cell proliferation at low glucose concentrations, counteracting the negative effects of palmitic acid as well as improving beta-cell function.

Monounsaturated Fatty Acids Prevent the Deleterious Effects of Palmitate and High Glucose on Human Pancreatic β-Cell Turnover and Function

Abstract: Glucotoxicity and lipotoxicity contribute to the impaired β-cell function observed in type 2 diabetes. Here we examine the effect of saturated and monounsaturated fatty acids at different glucose concentrations on human β-cell turnover and secretory function. Exposure of cultured human islets to saturated fatty acid and/or to an elevated glucose concentration for 4 days increased β-cell DNA fragmentation and decreased β-cell proliferation. In contrast, the monounsaturated palmitoleic acid or oleic acid did not affect DNA fragmentation and induced β-cell proliferation. Moreover, each monounsaturated fatty acid prevented the deleterious effects of both palmitic acid and high glucose concentration. The cell-permeable ceramide analogue C 2 -ceramide mimicked both the palmitic acid-induced β-cell apoptosis and decrease in proliferation. Furthermore, the ceramide synthetase inhibitor fumonisin B1 blocked the deleterious effects of palmitic acid on β-cell turnover. In addition, palmitic acid decreased Bcl-2 expression and induced release of cytochrome c from the mitochondria into the cytosol, which was prevented by fumonisin B1 and by oleic acid. Finally, each monounsaturated fatty acid improved β-cell secretory function that was reduced by palmitic acid and by high glucose. Thus, in human islets, the saturated palmitic acid and elevated glucose concentration induce β-cell apoptosis, decrease β-cell proliferation, and impair β-cell function, which can be prevented by monounsaturated fatty acids. The deleterious effect of palmitic acid is mediated via formation of ceramide and activation of the apoptotic mitochondrial pathway, whereas Bcl-2 may contribute to the protective effect of monounsaturated fatty acids.

Inflammatory mediators and islet β-cell failure: a link between type 1 and type 2 diabetes

Abstract: Pancreatic islet β-cell death occurs in type 1 and 2 diabetes mellitus, leading to absolute or relative insulin deficiency. β-cell death in type 1 diabetes is due predominantly to autoimmunity. In type 2 diabetes β-cell death occurs as the combined consequence of increased circulating glucose and saturated fatty acids together with adipocyte secreted factors and chronic activation of the innate immune system. In both diabetes types intra-islet inflammatory mediators seem to trigger a final common pathway leading to β-cell apoptosis. Therefore anti-inflammatory therapeutic approaches designed to block β-cell apoptosis could be a significant new development in type 1 and 2 diabetes.

Mechanisms of β-Cell Death in Type 2 Diabetes

Abstract: A decrease in the number of functional insulin-producing β-cells contributes to the pathophysiology of type 2 diabetes. Opinions diverge regarding the relative contribution of a decrease in β-cell mass versus an intrinsic defect in the secretory machinery. Here we review the evidence that glucose, dyslipidemia, cytokines, leptin, autoimmunity, and some sulfonylureas may contribute to the maladaptation of β-cells. With respect to these causal factors, we focus on Fas, the ATP-sensitive K + channel, insulin receptor substrate 2, oxidative stress, nuclear factor-κB, endoplasmic reticulum stress, and mitochondrial dysfunction as their respective mechanisms of action. Interestingly, most of these factors are involved in inflammatory processes in addition to playing a role in both the regulation of β-cell secretory function and cell turnover. Thus, the mechanisms regulating β-cell proliferation, apoptosis, and function are inseparable processes.

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Abstract: Since the outbreak of severe acute respiratory syndrome (SARS) 18 years ago, a large number of SARS-related coronaviruses (SARSr-CoVs) have been discovered in their natural reservoir host, bats1–4. Previous studies have shown that some bat SARSr-CoVs have the potential to infect humans5–7. Here we report the identification and characterization of a new coronavirus (2019-nCoV), which caused an epidemic of acute respiratory syndrome in humans in Wuhan, China. The epidemic, which started on 12 December 2019, had caused 2,794 laboratory-confirmed infections including 80 deaths by 26 January 2020. Full-length genome sequences were obtained from five patients at an early stage of the outbreak. The sequences are almost identical and share 79.6% sequence identity to SARS-CoV. Furthermore, we show that 2019-nCoV is 96% identical at the whole-genome level to a bat coronavirus. Pairwise protein sequence analysis of seven conserved non-structural proteins domains show that this virus belongs to the species of SARSr-CoV. In addition, 2019-nCoV virus isolated from the bronchoalveolar lavage fluid of a critically ill patient could be neutralized by sera from several patients. Notably, we confirmed that 2019-nCoV uses the same cell entry receptor—angiotensin converting enzyme II (ACE2)—as SARS-CoV. Characterization of full-length genome sequences from patients infected with a new coronavirus (2019-nCoV) shows that the sequences are nearly identical and indicates that the virus is related to a bat coronavirus.

Inflammatory Mechanisms in Obesity

Abstract: The modern rise in obesity and its strong association with insulin resistance and type 2 diabetes have elicited interest in the underlying mechanisms of these pathologies. The discovery that obesity itself results in an inflammatory state in metabolic tissues ushered in a research field that examines the inflammatory mechanisms in obesity. Here, we summarize the unique features of this metabolic inflammatory state, termed metaflammation and defined as low-grade, chronic inflammation orchestrated by metabolic cells in response to excess nutrients and energy. We explore the effects of such inflammation in metabolic tissues including adipose, liver, muscle, pancreas, and brain and its contribution to insulin resistance and metabolic dysfunction. Another area in which many unknowns still exist is the origin or mechanism of initiation of inflammatory signaling in obesity. We discuss signals or triggers to the inflammatory response, including the possibility of endoplasmic reticulum stress as an important contributor to metaflammation. Finally, we examine anti-inflammatory therapies for their potential in the treatment of obesity-related insulin resistance and glucose intolerance.

Immunological and Inflammatory Functions of the Interleukin-1 Family

Abstract: More than any other cytokine family, the interleukin (IL)-1 family is closely linked to the innate immune response. This linkage became evident upon the discovery that the cytoplasmic domain of the IL-1 receptor type I is highly homologous to the cytoplasmic domains of all Toll-like receptors (TLRs). Thus, fundamental inflammatory responses such as the induction of cyclooxygenase type 2, increased expression of adhesion molecules, or synthesis of nitric oxide are indistinguishable responses of both IL-1 and TLR ligands. Both families nonspecifically affect antigen recognition and lymphocyte function. IL-1β is the most studied member of the IL-1 family because of its role in mediating autoinflammatory diseases. Although the TLR and IL-1 families evolved to assist in host defense against infection, unlike the TLR family, the IL-1 family also includes members that suppress inflammation, both specifically within the IL-1 family but also nonspecifically for TLR ligands and the innate immune response.

Type 2 diabetes as an inflammatory disease.

Abstract: Components of the immune system are altered in obesity and type 2 diabetes (T2D), with the most apparent changes occurring in adipose tissue, the liver, pancreatic islets, the vasculature and circulating leukocytes. These immunological changes include altered levels of specific cytokines and chemokines, changes in the number and activation state of various leukocyte populations and increased apoptosis and tissue fibrosis. Together, these changes suggest that inflammation participates in the pathogenesis of T2D. Preliminary results from clinical trials with salicylates and interleukin-1 antagonists support this notion and have opened the door for immunomodulatory strategies for the treatment of T2D that simultaneously lower blood glucose levels and potentially reduce the severity and prevalence of the associated complications of this disease.

Mammalian caspases: structure ,a ctivation ,s ubstrates, and functions during apoptosis

Abstract: ■ Abstract Apoptosis is a genetically programmed, morphologically distinct form of cell death that can be triggered by a variety of physiological and pathological stimuli. Studies performed over the past 10 years have demonstrated that proteases play critical roles in initiation and execution of this process. The caspases, a family of cysteine-dependent aspartate-directed proteases, are prominent among the death proteases. Caspases are synthesized as relatively inactive zymogens that become activated by scaffold-mediated transactivation or by cleavage via upstream proteases in an intracellular cascade. Regulation of caspase activation and activity occurs at several different levels: ( a) Zymogen gene transcription is regulated; ( b) antiapoptotic members of the Bcl-2 family and other cellular polypeptides block proximity-induced activation of certain procaspases; and ( c) certain cellular inhibitor of apoptosis proteins (cIAPs) can bind to and inhibit active caspases. Once activated, caspases cleave a variety of intracellular polypeptides, including major structural elements of the cytoplasm and nucleus, components of the DNA repair machinery, and a number of protein kinases. Collectively, these scissions disrupt survival pathways and disassemble important architectural components of the cell, contributing to the stereotypic morphological and biochemical changes that characterize apoptotic cell death.