Showing papers by "Andreas L. Birkenfeld published in 2016"
TL;DR: Recent advances regarding understanding the role of the various cells of the innate and adaptive immunity in NASH development and progression are summarized, and possible future therapeutic options and tools to interfere with disease progression are discussed.
Abstract: The low grade inflammatory state present in obesity promotes the progression of Non-Alcoholic Fatty Liver Disease (NAFLD). In Non-Alcoholic Steatohepatitis (NASH), augmented hepatic steatosis is accompanied by aberrant intrahepatic inflammation and exacerbated hepatocellular injury. NASH is an important disorder and can lead to fibrosis, cirrhosis and even neoplasia. The pathology of NASH involves a complex network of mechanisms, including increased infiltration of different subsets of immune cells, such as monocytes, T-lymphocytes and neutrophils, to the liver, as well as activation and in situ expansion of liver resident cells such as Kupffer cells or stellate cells. In this review, we summarize recent advances regarding understanding the role of the various cells of the innate and adaptive immunity in NASH development and progression, and discuss possible future therapeutic options and tools to interfere with disease progression.
104 citations
TL;DR: The hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, is supported, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.
Abstract: Hypophosphatemia can lead to muscle weakness and respiratory and heart failure, but the mechanism is unknown. To address this question, we noninvasively assessed rates of muscle ATP synthesis in hypophosphatemic mice by using in vivo saturation transfer [31P]-magnetic resonance spectroscopy. By using this approach, we found that basal and insulin-stimulated rates of muscle ATP synthetic flux (VATP) and plasma inorganic phosphate (Pi) were reduced by 50% in mice with diet-induced hypophosphatemia as well as in sodium-dependent Pi transporter solute carrier family 34, member 1 (NaPi2a)-knockout (NaPi2a-/-) mice compared with their wild-type littermate controls. Rates of VATP normalized in both hypophosphatemic groups after restoring plasma Pi concentrations. Furthermore, VATP was directly related to cellular and mitochondrial Pi uptake in L6 and RC13 rodent myocytes and isolated muscle mitochondria. Similar findings were observed in a patient with chronic hypophosphatemia as a result of a mutation in SLC34A3 who had a 50% reduction in both serum Pi content and muscle VATP After oral Pi repletion and normalization of serum Pi levels, muscle VATP completely normalized in the patient. Taken together, these data support the hypothesis that decreased muscle ATP synthesis, in part, may be caused by low blood Pi concentrations, which may explain some aspects of muscle weakness observed in patients with hypophosphatemia.-Pesta, D. H., Tsirigotis, D. N., Befroy, D. E., Caballero, D., Jurczak, M. J., Rahimi, Y., Cline, G. W., Dufour, S., Birkenfeld, A. L., Rothman, D. L., Carpenter, T. O., Insogna, K., Petersen, K. F., Bergwitz, C., Shulman, G. I. Hypophosphatemia promotes lower rates of muscle ATP synthesis.
70 citations
TL;DR: From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease and it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity.
Abstract: In ancient Greek medicine the concept of a distinct syndrome (going together) was used to label 'a group of signs and symptoms' that occur together and 'characterize a particular abnormality and condition'. The (dys)metabolic syndrome is a common cluster of five pre-morbid metabolic-vascular risk factors or diseases associated with increased cardiovascular morbidity, fatty liver disease and risk of cancer. The risk for major complications such as cardiovascular diseases, NASH and some cancers develops along a continuum of risk factors into clinical diseases. Therefore we still include hyperglycemia, visceral obesity, dyslipidemia and hypertension as diagnostic traits in the definition according to the term 'deadly quartet'. From the beginning elevated blood pressure and hyperglycemia were core traits of the metabolic syndrome associated with endothelial dysfunction and increased risk of cardiovascular disease. Thus metabolic and vascular abnormalities are in extricable linked. Therefore it seems reasonable to extend the term to metabolic-vascular syndrome (MVS) to signal the clinical relevance and related risk of multimorbidity. This has important implications for integrated diagnostics and therapeutic approach. According to the definition of a syndrome the rapid global rise in the prevalence of all traits and comorbidities of the MVS is mainly caused by rapid changes in life-style and sociocultural transition resp. with over- and malnutrition, low physical activity and social stress as a common soil.
32 citations
TL;DR: The evidence from accomplished trials analyzing factors influencing mortality in patients with T2DM is reviewed to provide some recommendations for targets and treatment in the European region and to identify HbA1c-levels between 6.5 % and 7 % are associated with the lowest impact on mortality.
Abstract: We aimed to review and summarize the evidence from accomplished trials analyzing factors influencing mortality in patients with T2DM and to provide some recommendations for targets and treatment in the European region. The following databases were searched for relevant trials: PubMed and the Cochrane Library. Of 3.806 citations, 134 trials met our inclusion criteria. Results: The reduction in lifetime for 65 + −years-old patients having less than 10 years T2DM amounts to 1.8 years. Having T2DM for more than 10 years lifetime will be reduced by 2.7 years. However, the lifetime shortening factor of T2DM will even be stronger for 40 + −years-old patients at onset. Males will lose 11.6 years of life and 18.6 QUALYs. T2DM among females will reduce life by 14 QUALYs by 22 years. From a statistical point of view, the highest mortality rate will occur in an over 55-years-old European smoking and non-compliant diabetic woman with alcohol abuse living in a rural area with a low level of education and a low socio-economic status. Furthermore, other co-morbidities such as cardiovascular diseases, gout, and depression affect mortality. Additionally, mortality will increase with a BMI over 35 and also with a BMI under 20–25. This refers to the obesity paradox indicating a higher mortality rate among normal weight patients with T2DM compared to overweight patients with T2DM. HbA1c-levels between 6.5 % and 7 % are associated with the lowest impact on mortality.
30 citations
TL;DR: It is shown, for the first time to the authors' knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients.
Abstract: Stress hyperglycaemia (SHG) is a common complication in sepsis associated with poor outcome. Chemerin is an adipocytokine associated with inflammation and impaired glucose homeostasis in metabolic diseases such as type 2 diabetes (T2D). We aimed to investigate how alterations of circulating chemerin levels and corresponding visceral adipose tissue (VAT) expression are linked to glucose metabolism and prognosis in sepsis. Clinical data and tissue samples were taken from a cross-sectional study including control, T2D and sepsis patients, all undergoing laparotomy. A second independent patient cohort of patients with sepsis was included to evaluate associations with prognosis. This was complemented by a murine model of peritoneal infection and a high-fat diet. We analysed circulating chemerin by enzyme-linked immunosorbent assay and VAT messenger RNA (mRNA) expression by real-time polymerase chain reaction. Circulating chemerin was increased in sepsis 1.69-fold compared with controls (p = 0.012) and 1.47-fold compared with T2D (p = 0.03). Otherwise, chemerin VAT mRNA expression was decreased in patients with sepsis (p = 0.006) and in septic diabetic animals (p = 0.009). Circulating chemerin correlated significantly with intra-operative glucose (r = 0.662; p = 0.01) and in trend with fasting glucose (r = 0.528; p = 0.052). After adjusting for body mass index or haemoglobin A1c, chemerin correlated in trend with insulin resistance evaluated using the logarithmised homeostasis model assessment of insulin resistance (r = 0.539, p = 0.071; r = 0.553, p = 0.062). Chemerin was positively associated with Acute Physiology and Chronic Health Evaluation II score in patients with sepsis (p = 0.036) and with clinical severity in septic mice (p = 0.031). In an independent study population, we confirmed association of chemerin with glucose levels in multivariate linear regression analysis (β = 0.556, p = 0.013). In patients with sepsis with SHG, non-survivors had significantly lower chemerin levels than survivors (0.38-fold, p = 0.006), while in patients without SHG, non-survivors had higher chemerin levels, not reaching significance (1.64-fold, p = 0.089). No difference was apparent in patients with pre-existing T2D (p = 0.44). We show, for the first time to our knowledge, that chemerin is increased in sepsis and that it associates with impaired glucose metabolism and survival in these patients. It could be further evaluated as a biomarker to stratify mortality risk of patients with SHG.
23 citations
TL;DR: A large number of genetic polymorphisms have been described affecting the response to treatment with OADs and extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas.
Abstract: Type 2 diabetes mellitus (T2DM) is a fast progressing disease reaching pandemic proportions. T2DM is specifically harmful because of its severe secondary complications. In the course of the disease, most patients require treatment with oral antidiabetic drugs (OADs), for which a relatively large number of different options are available. The growing number of individuals affected by T2DM as well as marked interindividual differences in the response to treatment call for individualized therapeutic regimens that can maximize treatment efficacy and thus reduce side effects and costs. A large number of genetic polymorphisms have been described affecting the response to treatment with OADs; in this review, we summarize the most recent advances in this area of research. Extensive evidence exists for polymorphisms affecting pharmacokinetics and pharmacodynamics of biguanides and sulfonylureas. Data on incretin-based medications as well as the new class of sodium/glucose cotransporter 2 (SGLT2) inhibitors are just starting to emerge. With diabetes being a known comorbidity of several psychiatric disorders, we also review genetic polymorphisms possibly responsible for a common treatment response in both conditions. For all drug classes reviewed here, large prospective trials are necessary in order to consolidate the existing evidence and derive treatment schemes based on individual genetic traits.
19 citations
TL;DR: Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.
Abstract: Objective As the obesity pandemic continues to expand, novel molecular targets to reduce obesity-related insulin resistance and Type 2 Diabetes (T2D) continue to be needed. We have recently shown that obesity is associated with reactivated liver Notch signaling, which, in turn, increases hepatic insulin resistance, opening up therapeutic avenues for Notch inhibitors to be repurposed for T2D. Herein, we tested the systemic effects of γ-secretase inhibitors (GSIs), which prevent endogenous Notch activation, and confirmed these effects through creation and characterization of two different adipocyte-specific Notch loss-of-function mouse models through genetic ablation of the Notch transcriptional effector Rbp-Jk ( A-Rbpj ) and the obligate γ-secretase component Nicastrin ( A-Nicastrin ). Methods Glucose homeostasis and both local adipose and systemic insulin sensitivity were examined in GSI-treated, A-Rbpj and A-Nicastrin mice, as well as vehicle-treated or control littermates, with complementary in vitro studies in primary hepatocytes and 3T3-L1 adipocytes. Results GSI-treatment increases hepatic insulin sensitivity in obese mice but leads to reciprocal lowering of adipose glucose disposal. While A-Rbpj mice show normal body weight, adipose development and mass and unchanged adipose insulin sensitivity as control littermates, A-Nicastrin mice are relatively insulin-resistant, mirroring the GSI effect on adipose insulin action. Conclusions Notch signaling is dispensable for normal adipocyte function, but adipocyte-specific γ-secretase blockade reduces adipose insulin sensitivity, suggesting that specific Notch inhibitors would be preferable to GSIs for application in T2D.
16 citations
TL;DR: This special Guest issue comprises articles of prominent scientists, many of whom collaborators of Prof. Hanefeld, working in medical research areas / fields related to metabolic syndrome.
Abstract: Markolf Hanefeld, MD, Dr. hc. PhD, is Professor of Internal Medicine, Endocrinology and Diabetology (Diabetologist DDG) In honor of Professor Markolf Hanefeld’s 80th birthday, a special symposium had been held in Dresden, Germany, where Prof. Hanefeld spent most of his professional career. This special Guest issue comprises articles of prominent scientists, many of whom collaborators of Prof. Hanefeld, working in medical research areas / fields related to metabolic syndrome. Prof. Hanefeld started his outstanding academic career in the early sixties at the Medical Academy ‘Carl Gustav Carus’ in Dresden, at a time when the wall was build up in Berlin. Dresden had a long tradition of structured diabetes care with the first outpatient department in Europe initiated by O. Rostoski in 1923. Under the guidance of his teacher H. Haller, this group started comprehensive studies on the interaction of non-alcoholic fatty liver and metabolic dysregulation with the major finding that fatty liver was intricately connected with abnormal glucose tolerance, dyslipidemia, hyperuricemia and obesity [1]. On this basis, together with W. Leonhardt, Prof. Hanefeld in 1981 published the first comprehensive definition of the metabolic syndrome as a cluster of metabolic diseases and hypertension with increased risk of diabetes mellitus and cardiovascular disease (CVD) [2]. The emphasis of this concept, which is valid until today, was on an integrated approach for diagnostics and therapy with lifestyle intervention as a common tool to prevent diabetesmellitus and CVD in people with the metabolic syndrome. In parallel with the UK-PDS, Prof. Hanefeld initiated the Diabetes Intervention Study (DIS) in patients with newly diagnosed type 2 diabetes, to evaluate the efficacy of life style intervention and risk factor control on cardiovascular outcome. This study, with postprandial (pp) measurements, identified the quality of pp glucose control, pp triglycerides and blood pressure as independent risk factors for CVD and all cause mortality [3, 4]. * Andreas L. Birkenfeld Andreas.birkenfeld@uniklinikum-dresden.de
12 citations
TL;DR: According to the authors, ketones improve myocardial work efficiency and function specifically in the failing heart, and evidence suggests that in heart failure, ketone use by the heart …
Abstract: In a recent issue of Diabetes Care , Ferrannini et al. (1) postulated a “thrifty substrate” hypothesis suggesting that the benefit in heart failure outcomes in patients treated with the sodium–glucose cotransporter 2 (SGLT2) inhibitor empagliflozin in the BI 10773 (Empagliflozin) Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG OUTCOME) trial is at least in part due to a switch in myocardial substrate metabolism away from fat and glucose oxidation toward an “energy-efficient super fuel like ketone bodies” (2). According to the authors, ketones improve myocardial work efficiency and function specifically in the failing heart (1,2). Indeed, evidence suggests that in heart failure, ketone use by the heart …
2 citations