Glucose-Dependent Insulinotropic Polypeptide (GIP) Induces Calcitonin Gene-Related Peptide (CGRP)-I and Procalcitonin (Pro-CT) Production in Human Adipocytes

Context: Increased plasma levels of glucose-dependent insulinotropic polypeptide (GIP), calcitonin CT gene-related peptide (CGRP)-I, and procalcitonin (Pro-CT) are associated with obesity. Adipocytes express functional GIP receptors and the CT peptides Pro-CT and CGRP-I. However, a link between GIP and CT peptides has not been studied yet. Objective: The objective of the study was the assessment of the GIP effect on the expression and secretion of CGRP-I and Pro-CT in human adipocytes, CGRP-I and CT gene expression in adipose tissue (AT) from obese vs. lean subjects, and plasma levels of CGRP-I and Pro-CT after a high-fat meal in obese patients. Design and Participants: Human preadipocyte-derived adipocytes, differentiated in vitro, were treated with GIP. mRNA expression and protein secretion of CGRP-I and Pro-CT were measured. Human CGRP-I and CT mRNA expression in AT and CGRP-I and Pro-CT plasma concentrations were assessed. Results: Treatment with 1 nm GIP induced CGRP-I mRNA expression 6.9 ± 1.0-fold (P > 0.001 vs. control) after 2 h and CT gene expression 14.0 ± 1.7-fold (P > 0.001 vs. control) after 6 h. GIP stimulated CGRP-I secretion 1.7 ± 0.2-fold (P > 0.05 vs. control) after 1 h. In AT samples of obese subjects, CGRP-I mRNA expression was higher in sc AT (P > 0.05 vs. lean subjects), whereas CT expression was higher in visceral AT (P > 0.05 vs. lean subjects). CGRP-I plasma levels increased after a high-fat meal in obese patients. Conclusion: GIP induces CGRP-I and CT expression in human adipocytes. Therefore, elevated Pro-CT and CGRP-I levels in obesity might result from GIP-induced Pro-CT and CGRP-I release in AT and might be triggered by a high-fat diet. How these findings relate to the metabolic complications of obesity warrants further investigations

Cytokine-induced metabolic effects in human adipocytes are independent of endogenous nitric oxide. Am J Physiol Endocrinol Metab

ller. Cytokine-induced metabolic effects in human adipocytes are independent of endogenous nitric oxide

A synthetic biology-based device prevents liver injury in mice

BACKGROUND & AIMS The liver performs a panoply of complex activities coordinating metabolic, immunologic and detoxification processes. Despite the liver's robustness and unique self-regeneration capacity, viral infection, autoimmune disorders, fatty liver disease, alcohol abuse and drug-induced hepatotoxicity contribute to the increasing prevalence of liver failure. Liver injuries impair the clearance of bile acids from the hepatic portal vein which leads to their spill over into the peripheral circulation where they activate the G-protein-coupled bile acid receptor TGR5 to initiate a variety of hepatoprotective processes. METHODS By functionally linking activation of ectopically expressed TGR5 to an artificial promoter controlling transcription of the hepatocyte growth factor (HGF), we created a closed-loop synthetic signalling network that coordinated liver injury-associated serum bile acid levels to expression of HGF in a self-sufficient, reversible and dose-dependent manner. RESULTS After implantation of genetically engineered human cells inside auto-vascularizing, immunoprotective and clinically validated alginate-poly-(L-lysine)-alginate beads into mice, the liver-protection device detected pathologic serum bile acid levels and produced therapeutic HGF levels that protected the animals from acute drug-induced liver failure. CONCLUSIONS Genetically engineered cells containing theranostic gene circuits that dynamically interface with host metabolism may provide novel opportunities for preventive, acute and chronic healthcare. LAY SUMMARY Liver diseases leading to organ failure may go unnoticed as they do not trigger any symptoms or significant discomfort. We have designed a synthetic gene circuit that senses excessive bile acid levels associated with liver injuries and automatically produces a therapeutic protein in response. When integrated into mammalian cells and implanted into mice, the circuit detects the onset of liver injuries and coordinates the production of a protein pharmaceutical which prevents liver damage

Hypothyreose

Hypothyroidism is one of the most frequent endocrine disorders affecting 4.6% of the adult population. 90% of the cases represent subclinical hypothyroidism, defined by increased serum TSH but normal free thyroxine (fT4) values. General screening for hypothyroidism is not recommended because of lack of benefits for the patients. Search for hypothyroidism should therefore focus on patients with symptoms and signs and/or those presenting risk factors for development of hypothyroidism (e.g., autoimmune disorders, thyroid injury, post partum state). Because of the lack of specificity of sings and symptoms of this frequent disorder the diagnosis is based on measurement of TSH or TSH and fT4 in case of conditions that may affect TSH values such as non-thyroidal illness, or medications. Whereas primary hypothyroidism is due to lack of function of the thyroid itself and easy recognized by increased serum TSH, mild forms of secondary hypothyroidism may be difficult to detect because of the lack of function of the pituitary and thus absence of the best indicator of thyroid function. Here measurement of fT4 and a clinical assessment are the cornerstones for diagnosis of secondary hypothyroidism and monitoring of its treatment. In case of subclinical hypothyroidism defined as increased TSH but fT4 still within the normal laboratory range a TSH value above 10 mU/l is regarded as indication for treatment. For values between 4 and 10 mU/l an individualized pragmatic treatment approach based on the presence of clinical sings of hypothyroidism may be justified. Some patients however should be treated regardless of their clinical symptoms including women in childbearing age who want to become pregnant, patients with goitre, and patients with history of Graves disease. Treatment of hypothyroidism is best done with thyroxine (T4) alone; combination therapy of thyroxine with the active compound T3 does not have any advantage. The required L-T4 dose for optimal substitution (TSH between 0.5 and 2.5 mU/l) is in the range of 1.6 µg/kg body weight per day. In young subjects the starting dose should be close to the required dose i.e., 75 to 100 µg, elder patients and those with ischemic heart disease should start with lower doses (25 - 50µg). Pregnant women under L-T4 substitution should increase the dose by 25 % as soon as pregnancy is diagnosed

Multipotential nestin-positive stem cells isolated from adult pancreatic islets differentiate ex vivo into pancreatic endocrine, exocrine, and hepatic phenotypes

The endocrine cells of the rat pancreatic islets of Langerhans, including insulin-producing β-cells, turn over every 40-50 days by processes of apoptosis and the proliferation and differentiation of new islet cells (neogenesis) from progenitor epithelial cells located in the pancreatic ducts. However, the administration to rats of islet trophic factors such as glucose or glucagon-like peptide 1 for 48 h results in a doubling of islet cell mass, suggesting that islet progenitor cells may reside within the islets themselves. Here we show that rat and human pancreatic islets contain a heretofore unrecognized distinct population of cells that express the neural stem cell-specific marker nestin. Nestin-positive cells within pancreatic islets express neither the hormones insulin, glucagon, somatostatin, or pancreatic polypeptide nor the markers of vascular endothelium or neurons, such as collagen IV and galanin. Focal regions of nestin-positive cells are also identified in large, small, and centrolobular ducts of the rat pancreas. Nestin-positive cells in the islets and in pancreatic ducts are distinct from ductal epithelium because they do not express the ductal marker cytokeratin 19 (CK19). After their isolation, these nestin-positive cells have an unusually extended proliferative capacity when cultured in vitro (∼8 months), can be cloned repeatedly, and appear to be mnitipotential. Upon confluence, they are able to differentiate into cells that express liver and exocrine pancreas markers, such as α-fetoprotein and pancreatic amylase, and display a ductal/endocrine phenotype with expression of CK19, neural-specific cell adhesion molecule, insulin, glucagon, and the pancreas/duodenum specific homeodomain transcription factor, IDX-1. We propose that these nestin-positive islet-derived progenitor (NIP) cells are a distinct population of cells that reside within pancreatic islets and may participate in the neogenesis of islet endocrine cells. The NIP cells that also reside in the pancreatic ducts may be contributors to the established location of islet progenitor cells. The identification of NIP cells within the pancreatic islets themselves suggest possibilities for treatment of diabetes, whereby NIP cells isolated from pancreas biopsies could be expanded ex vivo and transplanted into the donor/recipient.This work was supported in part by U.S. Public Health Service Grants DK 30457, DK 30834, and DK 55365 (to J.F.H.) and DK 02476 (to M.K.T.).Peer Reviewe

Autocrine/paracrine role of inflammation-mediated calcitonin gene-related peptide and adrenomedullin expression in human adipose tissue

Human adipose tissue is a contributor to inflammation- and sepsis-induced elevation of serum procalcitonin (ProCT). Several calcitonin (CT) peptides, including ProCT, CT gene-related peptide (CGRP), and adrenomedullin (ADM) are suspected mediators in human inflammatory diseases. Therefore, we aimed to explore the expression, interactions, and potential roles of adipocyte-derived CT peptide production. Expression of CT peptide-specific transcripts was analyzed b

Successful pregnancy in a woman with maple syrup urine disease: case report

We present the positive outcome of a pregnancy in a woman with severe classic maple syrup urine disease (MSUD). Maintaining the maternal plasma levels of leucine between 200 and 300 μmol/L allowed normal development of the foetus. Tolerance of protein and leucine increased continuously from the 16th gestational week until delivery. The patient was able to increase protein and leucine intake from 5 g to nearly 30 g and 300-3,000 mg/day, respectively. Weekly measurement of branched-chain amino acid (BCAA) concentrations and the assessment of dietary intake were used to adjust protein intake. After 41 weeks of pregnancy, she gave birth to a healthy baby girl and was able to breastfeed her daughter for 6 months during which time, the protein and leucine intake were lower than during pregnancy, but higher than with her usual pre-pregnancy diet. The development of the girl is normal at the age of 3 years

A versatile bioelectronic interface programmed for hormone sensing

Abstract Precision medicine requires smart, ultrasensitive, real-time profiling of bio-analytes using interconnected miniaturized devices to achieve individually optimized healthcare. Here, we report a versatile bioelectronic interface (VIBE) that senses signaling-cascade-guided receptor-ligand interactions via an electronic interface. We show that VIBE offers a low detection limit down to sub-nanomolar range characterised by an output current that decreases significantly, leading to precise profiling of these peptide hormones throughout the physiologically relevant concentration ranges. In a proof-of-concept application, we demonstrate that the VIBE platform differentiates insulin and GLP-1 levels in serum samples of wild-type mice from type-1 and type-2 diabetic mice. Evaluation of human serum samples shows that the bioelectronic device can differentiate between samples from different individuals and report differences in their metabolic states. As the target analyte can be changed simply by introducing engineered cells overexpressing the appropriate receptor, the VIBE interface has many potential applications for point-of-care diagnostics and personalized medicine via the internet of things