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.

Restoration of myo-inositol uptake by eicosapentaenoic acid in human skin fibroblasts cultured in high-glucose medium

Comparison of the absorption and biological activity of NPH human insulin (recombinant DNA) and NPH porcine insulin injected subcutaneously in type II diabetic patients.

Russo P, Lefebvre PJ: Metabolic control may influence the increased superoxide generation in diabetic serum. Diabet Med 8:540-542, 1991 4. Levine GN, Frei B, Koulouris SN, Gerhard MD, Keaney JF, Vita JA: Ascorbic acid reverses endothelial vasomotor dysfunction in patients with coronary artery disease. Circulation 93:1107-1113,1996 5. Ting HH, Timimi FK, Boles KS, Creager SJ, Ganz P, Creager MA: Vitamin C improves endothelium vasodilation in patients with non-insulin dependent diabetes mellitus. J Clin Invest 97:22-28,1996 6. Ceriello A, Giugliano D, Quatraro A, Lefebvre PJ: Anti-oxidants show an anti-hypertensive effect in diabetic and hypertensive subjects. Clin Sri 81:739-742,1991 7. Ceriello A, Quatraro A, Giugliano D: Diabetes mellitus and hypertension: the possible role of hyperglycaemia through oxidative stress. Diabetologia 36:265-266,1993

Activated protein C resistance and Japanese NIDDM patients with coronary heart disease.

A hyperprolactinemic infertile woman with a pituitary microadenoma, who was resistant to bromocriptine as a method of bringing on pregnancy, succeeded in having a normal pregnancy and delivery with Hachimi-jio-gan treatment. This paper reports that the patient did not succeed in pregnancy in spite of 16 months of bromocriptine treatment, though her prolactin level gradually decreased and continued to be between 40-60 ng/ml with Hachimi-jio-gan treatment. Although the level of prolactin of the patient did not normalize, she, nevertheless, succeeded in having a normal pregnancy and delivery.

Successful treatment of a hyperprolactinemic infertile woman with a pituitary microadenoma using hachimijiogan.

The synthesis of labile hemoglobin A1 in vivo was studied in subjects with non-insulin dependent diabetes mellitus, impaired and normal glucose tolerance. The labile hemoglobin A1 index defined as delta labile hemoglobin A1 divided by delta plasma glucose at 30 min after oral glucose load, representing the rate of labile hemoglobin A1 synthesis in vivo, was low in diabetic subjects and high in normal subjects, showing an inverse correlation with the amount of preexisting hemoglobin A1. The study on the synthesis of labile hemoglobin A1 in vitro showed a lower initial rate of synthesis and a smaller increase in labile hemoglobin A1 at saturation in red blood cells from diabetic subjects with a relatively large amount of preexisting hemoglobin A1, as opposed to red blood cells from normal subjects.Although the further study is necessary in which delta plasma glucose levels are kept relatively constant in each of 3 groups by glucose-clamp methods, our data suggest that the synthesis of labile hemoglobin A1 is limited in vivo and in vitro in diabetic subjects by the preexisting hemoglobin A1 due to the saturability of its synthesis.

Kamejiro Yamashita

Papers

Restoration of myo-inositol uptake by eicosapentaenoic acid in human skin fibroblasts cultured in high-glucose medium

Comparison of the absorption and biological activity of NPH human insulin (recombinant DNA) and NPH porcine insulin injected subcutaneously in type II diabetic patients.

Activated protein C resistance and Japanese NIDDM patients with coronary heart disease.

Successful treatment of a hyperprolactinemic infertile woman with a pituitary microadenoma using hachimijiogan.

Limited Synthesis of Labile Hemoglobin A1 In vivo and In vitro by the Preexisting Hemoglobin A1 in Diabetic Subjects