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.

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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 rates of de novo purine and protein synthesis were assessed in vivo in rat liver after bolus administration of glucagon. The specific activity of hepatic purines and the specific activity ratio of hepatic purine/protein were used as an index of the rate of de novo purine synthesis and the rate relative to protein. Glucagon at doses of 0.01 mg to 0.1 mg/200 g body weight (BW), administered as an intravenous bolus, inhibited dose-dependently the rate of de novo purine synthesis and the rate relative to protein although it increased dose-dependently the hepatic concentration of 5-phosphoribosyl 1-pyrophosphate (PRPP). The inhibition of the rate of de novo purine synthesis recovered to control levels during the period between 60 and 90 minutes after glucagon administration. Dibutyryl cyclic AMP (Bt2 cAMP) partially mimicked this effect of glucagon in that it did not increase the rate of de novo purine synthesis in spite of increased concentrations of PRPP. These results suggest that an intravenous bolus of glucagon inhibits the rate of de novo purine synthesis through increasing cAMP concentration. The data are consistent with inhibition of amidophosphoribosyltransferase (ATase) in spite of increased PRPP concentrations.

In vivo inhibition of the rate of de novo purine synthesis in rat liver by glucagon.

A study relating to gastrin release from gastrinoma cells by neuromedin is and C-terminal decapeptide of gastrin releasing peptide (GRP-10) has not yet been reported. Therefore, we studied the effects of neuromedin B and GRP-10 on gastrin release from cultured dispersed cells prepared from both the primary tumor in the pancreas and the metastatic tumor in the liver from a case of malignant Zollinger-Ellison syndrome. Both the primary and metastatic tumors obtained by a curative operation contained similar concentrations of gastrin and glucagon, whereas the primary tumor contained 10 times more insulin than the metastatic tumor. Gastrin release from cultured cells of both tumors was suppressed by 0.1 and 10nM neuromedin B and tended to be suppressed by 0.1-10nM GRP-10. However, insulin release from cultured cells of the pancreatic tumor was stimulated by GRP-10, but not by neuromedin B. These results might suggest that receptor function for the bombesin family peptides is abnormal in gastrinoma cells in both primary and metastatic tumors, and that a major source of insulin secretary cells is the contaminated normal islet cells in the primary tumor.

https://www.jstage.jst.go.jp/article/endocrj1954/37/6/37_6_857/_pdf

Effects of neuromedin B and GRP-10 on gastrin and insulin release from cultured tumor cells of a malignant gastrinoma.

In an attempt to study the influence of vitamin D metabolites on PTH secretion, serum calcium and urinary excretion of cAMP were sequentially measured in conscious perfused rats, and the effects of a single iv injection of the metabolites on these paramenters were examined. Four hours after the administration of 0.25μg/kg (0.6 nmol/kg, probably a physiological dose) of 1α, 25-dihydroxycholecalciferol [1α, 25 (OH) 2D3], the urinary excretion of cAMP decreased to a level compatible with that of parathyroidectomized rats (-60% of the initial value; P<0.05) and this level was sustained for nearly 24h. Serum concentrations of calcium (total and ionized) did not change. In parathyroidectomized rats which were continuously infused with bovine PTH (1U/h), the vitamin D metabolite had no significant effect on the urinary excretion of cAMP. 24R, 25-dihydroxcholecalciferol (12.5μg/kg) had no significant effect either on the urinary excretion of cAMP or on serum calcium.These results suggest that in rats, a physiological dose of 1α, 25 (OH) 2D3 inhibits PTH secretion without causing a significant rise iu serum calcium, reflecting a feedback mechanism between active vitamin D metabolite, 1α, 25 (OH) 2D3 and the parathyroid glands.

Kamejiro Yamashita

Papers

In vivo inhibition of the rate of de novo purine synthesis in rat liver by glucagon.

Effects of neuromedin B and GRP-10 on gastrin and insulin release from cultured tumor cells of a malignant gastrinoma.

Inhibitory effects of 1.ALPHA., 25-dihydroxycholecalciferol on parathyroid hormone secretion in rats.

Predicting long-term glycemic control of post-educational type II diabetic patients by evaluating serum 1,5-anhydroglucitol levels.

Restoration of myo-inositol uptake by aldose reductase inhibitor in human skin fibroblasts cultured in high-glucose medium.