Biology of Incretins: GLP-1 and GIP

Context Epidemiological studies have indicated an inverse association between cardiorespiratory fitness (CRF) and coronary heart disease (CHD) or all-cause mortality in healthy participants. Objective To define quantitative relationships between CRF and CHD events, cardiovascular disease (CVD) events, or all-cause mortality in healthy men and women. Data Sources and Study Selection A systematic literature search was conducted for observational cohort studies using MEDLINE (1966 to December 31, 2008) and EMBASE (1980 to December 31, 2008). The Medical Subject Headings search terms used included exercise tolerance, exercise test, exercise/physiology, physical fitness, oxygen consumption, cardiovascular diseases, myocardial ischemia, mortality, mortalities, death, fatality, fatal, incidence, or morbidity. Studies reporting associations of baseline CRF with CHD events, CVD events, or all-cause mortality in healthy participants were included. Data Extraction Two authors independently extracted relevant data. CRF was estimated as maximal aerobic capacity (MAC) expressed in metabolic equivalent (MET) units. Participants were categorized as low CRF ( Data Synthesis Data were obtained from 33 eligible studies (all-cause mortality, 102 980 participants and 6910 cases; CHD/CVD, 84 323 participants and 4485 cases). Pooled RRs of all-cause mortality and CHD/CVD events per 1-MET higher level of MAC (corresponding to 1-km/h higher running/jogging speed) were 0.87 (95% confidence interval [CI], 0.84-0.90) and 0.85 (95% CI, 0.82-0.88), respectively. Compared with participants with high CRF, those with low CRF had an RR for all-cause mortality of 1.70 (95% CI, 1.51-1.92; P  Conclusions Better CRF was associated with lower risk of all-cause mortality and CHD/CVD. Participants with a MAC of 7.9 METs or more had substantially lower rates of all-cause mortality and CHD/CVD events compared with those with a MAC of less 7.9 METs.

https://jamanetwork.com/journals/jama/articlepdf/1108396/jcr90003_2024_2035.pdf

Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events in Healthy Men and Women: A Meta-analysis

ENDOTHELIN-1 was initially identified as a 21-residue potent vasoconstrictor peptide produced by vascular endothelial cells, but was subsequently found to have many effects on both vascular and non-vascular tissues1,2. The discovery of three isopeptides of the endothelin family3, ET-1, ET-2 and ET-3, each possessing a diverse set of pharmacological activities of different potency, suggested the existence of several different endothelin receptor subtypes3–7. Endothelins may elicit biological responses by various signal-transduction mechanisms, including the G protein-coupled activation of phospholipase C and the activation of voltage-dependent Ca2+ channels8–10. Thus, different subtypes of the endothelin receptor may use different signal-transduction mechanisms. Here we report the cloning of a complementary DNA encoding one subtype belonging to the superf amily of G protein-coupled receptors. COS-7 cells transfected with the cDNA express specific and high-affinity binding sites for endothelins, responding to binding by the production of inositol phosphates and a transient increase in the concentration of intracellular free Ca2+. The three endothelin isopeptides are roughly equipotent in displacing 125I-labelled ET-1 binding and causing Ca2+ mobilization. A messenger RNA corresponding to the cDNA is detected in many rat tissues including the brain, kidney and lung but not in vascular smooth muscle cells. These results indicate that this cDNA encodes a 'nonselective' subtype of the receptor which is different from the vascular smooth muscle receptor.

/pdf/cloning-of-a-cdna-encoding-a-non-isopeptide-selective-3gy557fhn1.pdf

Cloning of a cDNA encoding a non-isopeptide-selective subtype of the endothelin receptor.

High-mobility group box 1 protein (HMGB1), which previously was thought to function only as a nuclear factor that enhances transcription, was recently discovered to be a crucial cytokine that mediates the response to infection, injury and inflammation. These observations have led to the emergence of a new field in immunology that is focused on understanding the mechanisms of HMGB1 release, its biological activities and its pathological effects in sepsis, arthritis, cancer and other diseases. Here, we discuss these features of HMGB1 and summarize recent advances that have led to the preclinical development of therapeutics that modulate HMGB1 release and activity.

High-mobility group box 1 protein (HMGB1): nuclear weapon in the immune arsenal.

Interest has been recently rekindled in short chain fatty acids (SCFAs) with the emergence of prebiotics and probiotics aimed at improving colonic and systemic health Dietary carbohydrates, specifically resistant starches and dietary fiber, are substrates for fermentation that produce SCFAs, primarily acetate, propionate, and butyrate, as end products The rate and amount of SCFA production depends on the species and amounts of microflora present in the colon, the substrate source and gut transit time SCFAs are readily absorbed Butyrate is the major energy source for colonocytes Propionate is largely taken up by the liver Acetate enters the peripheral circulation to be metabolized by peripheral tissues Specific SCFA may reduce the risk of developing gastrointestinal disorders, cancer, and cardiovascular disease Acetate is the principal SCFA in the colon, and after absorption it has been shown to increase cholesterol synthesis However, propionate, a gluconeogenerator, has been shown to inhibit cholesterol synthesis Therefore, substrates that can decrease the acetate: propionate ratio may reduce serum lipids and possibly cardiovascular disease risk Butyrate has been studied for its role in nourishing the colonic mucosa and in the prevention of cancer of the colon, by promoting cell differentiation, cell-cycle arrest and apoptosis of transformed colonocytes; inhibiting the enzyme histone deacetylase and decreasing the transformation of primary to secondary bile acids as a result of colonic acidification Therefore, a greater increase in SCFA production and potentially a greater delivery of SCFA, specifically butyrate, to the distal colon may result in a protective effect Butyrate irrigation (enema) has also been suggested in the treatment of colitis More human studies are now needed, especially, given the diverse nature of carbohydrate substrates and the SCFA patterns resulting from their fermentation Short-term and long-term human studies are particularly required on SCFAs in relation to markers of cancer risk These studies will be key to the success of dietary recommendations to maximize colonic disease prevention

Colonic health: fermentation and short chain fatty acids.

The incorporation of [14C]glycine to hepatic purines increased proving the increased rate of de novo purine biosynthesis in rat liver after bilateral adrenalectomy in comparison to sham-operated controls. In the liver of adrenalectomized animals 24 hours after adrenalectomy when the rate of de novo purine biosynthesis is increased above control by 70% there was a 200% increase of 5-phosphoribosyl 1-pyrophosphate (PRPP) concentration. The concentrations of purine ribonucleotides showed a 33 and a 24% decrease of ATP and GTP, and 245 and 38% increase of AMP and ADP respectively associated with the unchanged total adenine and guanine nucleotide concentration and a 18% decrease of adenylate energy charge. The specific activity of amidophosphoribosyltransferase (ATase) was not changed. The replacement with corticosterone acetate to adrenalectomized animals for 24 hours partially restored the rate of de novo purine biosynthesis and the concentrations of purine ribonucleotides.

Mechanism of Increased Rate of De Novo Purine Biosynthesis in Rat Liver after Bilateral Adrenalectomy

Effect of insulin on the proline transport activity in cultured fibroblasts from patients with Werner syndrome.

1. 1. Six hours after oral administration in rat liver, diisopropyl 1,3-dithiol-2-ylidenemalonate (malotilate) decreased AMP concentrations by 60% with unchanged total adenine nucleotide concentrations and significantly increased adenylate energy charges of 0.87 in comparison to those of 0.81 in vehicle administered control animals. 2. 2. Twelve hours after incubation in primary cultured rat hepatocytes, malotilate decreased AMP concentrations by 18% and increased ATP and GTP concentrations by 13 and 18% respectively with significantly increased adenylate energy charges of 0.89 in comparison to 0.87 in vehicle control. 3. 3. Increased adenylate energy charges by malotilate coincided with the initiation of increases in protein and de novo purine synthesis in vivo, and are associated with the increased rate of de novo purine synthesis in vitro.

Increased adenylate energy charges in rat liver or primary cultured rat hepatocytes by diisopropyl 1,3-dithiol-2-ylidenemalonate.

Amidophosphoribosyltransferase (ATase) (E.C.2.1.2.14) is presumably a rate-limiting enzyme in de novo purine synthetic pathway under a skillful regulatory system, although 5-phosphoribosyl 1-pyrophosphate (PRPP) synthetase is another possibility. The present study was designed to investigate the rate-limiting quality of ATase by artificially controlling expression of its activity, and to test the complementality of ATase-deficiency with a foreign ATase gene in mammalian cells. The experimental scheme, as in Fig. 1, was composed of production of a recombinant plasmid between an E. coli ATase gene and a glucocorticoid-responsive promoter and its transfection into a strain of Chinese hamster ovary fibroblasts which is deficient in ATase (CHO ade-A). Transfectants were cultured in the presence or absence of glucocorticoid, and were examined as to the complementality of de novo purine and DNA synthesis in purine-free medium with dexamethasone (DEX). The expression of E. coli ATase was also examined by northern, western analysis, and ATase activity.

Controllable expression of an E. coli amidophosphoribosyltransferase (ATase) gene in ATase-deficient mammalian fibroblasts--a basic model for gene therapy.

老人のWeber-Christian病は希である.我々は1年以上にわたり周期的に生ずる高熱,発疹,全身倦怠感,意識障害等の症状を呈した67才の男性を皮膚生検像,試験開腹を含む各種の検索の結果, Weber-Christian病と診断した.本患者は加えて,発熱時に120mEq/l程度の低Na血症を呈した.この原因は間脳-下垂体の機能異常によるglucocorticoid分泌不全により, SIADH様状態を呈したためと診断した.その他の下垂体機能異常として,低血糖刺激に対するGH分泌低下, TRHによるPRLの過剰分泌, TSHの遅延分泌反応を認めた. ACTH分泌は低血糖刺激および発熱には反応しないが,メトピロンには反応した.これらの結果に併せ, CTスキャン等の検討では脳の萎縮しか見い出せなかつたことより,視床下部における機能的異常が最も考えられた.この視床下部異常や意識障害という脳の機能異常とWeber-Christian病との直接的因果関係は証明できなかつた.しかしながら文献的考察から,原因の一つとして脳の退行変性により生じた脂肪に脂肪織炎が生じた可能性が示唆された.

Kamejiro Yamashita

Papers

Mechanism of Increased Rate of De Novo Purine Biosynthesis in Rat Liver after Bilateral Adrenalectomy

Effect of insulin on the proline transport activity in cultured fibroblasts from patients with Werner syndrome.

Increased adenylate energy charges in rat liver or primary cultured rat hepatocytes by diisopropyl 1,3-dithiol-2-ylidenemalonate.

Controllable expression of an E. coli amidophosphoribosyltransferase (ATase) gene in ATase-deficient mammalian fibroblasts--a basic model for gene therapy.

[A case of chronic relapsing febrile nodular panniculitis (Weber-Christian disease) associated with pituitary dysfunction (author's transl)].