scholarly journals Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin is a Novel Risk Factor for Cardiometabolic Disorders

Diabetes ◽  
2021 ◽  
pp. db210289
Author(s):  
Prasanna K. R. Allu ◽  
Malapaka Kiranmayi ◽  
Sromona D. Mukherjee ◽  
Venkat R. Chirasani ◽  
Richa Garg ◽  
...  
Keyword(s):  
Risk Factor ◽  
Cardiometabolic Disorders

scholarly journals Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin is a Novel Risk Factor for Cardiometabolic Disorders

2021 ◽  
Author(s):  
Prasanna K. R. Allu ◽  
Malapaka Kiranmayi ◽  
Sromona D. Mukherjee ◽  
Venkat R. Chirasani ◽  
Richa Garg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Artery Disease ◽  
Risk Factor ◽  
Coronary Artery ◽  
Human Populations ◽  
Wild Type ◽  
Cardiometabolic Disorders ◽  
Artery Disease ◽  
Variant Peptide

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic diseases states in Indian populations (n≈4300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure and catecholamines in Gly/Ser subjects as compared to wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3-1.6-fold) for type-2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (<i>e.g.</i>, increased expression of gluconeogenic genes, increased catecholamine secretion, greater inhibition of insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT). Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor (IR) than PST-WT, providing a mechanistic basis for the enhanced activity of the variant peptide. <i>In vitro</i> binding assays validate these <i>in silico</i> predictions of PST peptides binding to GRP78 and IR. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type-2 diabetes/hypertension/coronary artery disease in human populations.

Abstract 26: DASH-Style Eating Pattern in Early Adolescence Reduces Cardiometabolic Risk Clustering

Circulation ◽  
2015 ◽  
Vol 131 (suppl_1) ◽  
Author(s):  
Lynn L Moore ◽  
M. Loring Bradlee ◽  
Martha R Singer ◽  
Stephen R Daniels
Keyword(s):  
Risk Factors ◽  
Blood Pressure ◽  
Risk Factor ◽  
Cardiometabolic Risk ◽  
Black Girls ◽  
Health Study ◽  
Eating Pattern ◽  
Cardiometabolic Disorders ◽  
The Impact

Cardiometabolic risk (CMR) factor clustering has its roots in childhood and the presence of multiple cardiovascular risk factors in younger populations has been linked with early vascular dysfunction. A DASH-style eating pattern has been shown to reduce blood pressure and other selected cardiometabolic outcomes, primarily in adults, but its role in the development of CMR clustering during adolescence has not been studied. Data from the National Heart, Lung, and Blood Institute’s Growth and Health Study (NGHS) will be used to evaluate the relation between early-to-mid adolescent dietary intake and CMR clustering at the end of adolescence. The NGHS began in 1987-1988 with the enrollment of 2,379 adolescent girls (with approximately equal numbers of blacks and whites), ages 9-10 years. Diet was assessed using 3-day diet records during eight of 10 years of follow up. A total of 1,369 girls had complete data on diet, all potential confounding variables, and follow-up over 10 years for all CMR factors of interest. Risk factor clustering scores were created by summing individual CMR outcomes defined as follows: waist circumference ≥88 cm, systolic and/or diastolic blood pressure ≥90th percentile for age, sex and height, LDL ≥110 mg/dL, HDL <50 mg/dL, serum TG ≥110mg/dl, and HOMA-IR ≥4. Multiple logistic regression analyses were used to estimate the impact of a DASH-style pattern on the relative risk (odds ratio) of CMR clustering at the end of adolescence, defined as having ≥ 2 or ≥ 3 of the above risk factors at 18-20 years of age. The proportion of white and black girls with CMR clustering was very similar. However, the types of risk factors differed by race with blacks being nearly twice as likely to have an increased waist size, elevated BP, or insulin resistance and white girls being much more likely to have abnormal lipid levels, particularly elevated triglyceride levels. By the end of adolescence, only 30.1% of girls had no abnormal CMR factors and 34.9% had a single risk factor; 16.6% of girls had two risk factors and 18.4% had between 3-6 prevalent risk factors. Higher intakes of fruit and non-starchy vegetables, dairy, and grains were independently associated with less CMR clustering. After adjusting for age, race, socio-economic status, height, physical activity, and television watching, girls with a DASH-style eating pattern during early-to-mid adolescence were nearly 50% less likely to have three or more CMR factors (O.R.=0.52; 95% CI: 0.30, 0.89) by late adolescence (at 18-20 years of age). These results suggest a DASH-style eating pattern during adolescence, characterized by higher intakes of fruit, non-starchy vegetables, and dairy, may lower risk for the development of subsequent cardiometabolic disorders.

scholarly journals Functional Gly297Ser Variant of the Physiological Dysglycemic Peptide Pancreastatin is a Novel Risk Factor for Cardiometabolic Disorders

2021 ◽  
Author(s):  
Prasanna K. R. Allu ◽  
Malapaka Kiranmayi ◽  
Sromona D. Mukherjee ◽  
Venkat R. Chirasani ◽  
Richa Garg ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Coronary Artery Disease ◽  
Risk Factor ◽  
Coronary Artery ◽  
Human Populations ◽  
Wild Type ◽  
Cardiometabolic Disorders ◽  
Artery Disease ◽  
Variant Peptide

Pancreastatin (PST), a chromogranin A (CHGA)-derived potent physiological dysglycemic peptide, regulates glucose/insulin homeostasis. We have identified a non-synonymous functional PST variant (p.Gly297Ser; rs9658664) that occurs in a large section of human populations. Association analysis of this single nucleotide polymorphism with cardiovascular/metabolic diseases states in Indian populations (n≈4300 subjects) displays elevated plasma glucose, glycosylated hemoglobin, diastolic blood pressure and catecholamines in Gly/Ser subjects as compared to wild-type individuals (Gly/Gly). Consistently, the 297Ser allele confers an increased risk (~1.3-1.6-fold) for type-2 diabetes/hypertension/coronary artery disease/metabolic syndrome. In corroboration, the variant peptide (PST-297S) displays gain-of-potency in several cellular events relevant for cardiometabolic disorders (<i>e.g.</i>, increased expression of gluconeogenic genes, increased catecholamine secretion, greater inhibition of insulin-stimulated glucose-uptake) than the wild-type peptide (PST-WT). Computational docking analysis and molecular dynamics simulations show higher affinity binding of PST-297S peptide with glucose-regulated protein 78 (GRP78) and insulin receptor (IR) than PST-WT, providing a mechanistic basis for the enhanced activity of the variant peptide. <i>In vitro</i> binding assays validate these <i>in silico</i> predictions of PST peptides binding to GRP78 and IR. In conclusion, the PST 297Ser allele influences cardiovascular/metabolic phenotypes and emerges as a novel risk factor for type-2 diabetes/hypertension/coronary artery disease in human populations.

Clinical aspects of reactive oxygen and nitrogen species

2004 ◽  
Vol 71 ◽  
pp. 121-133 ◽  
Author(s):  
Ascan Warnholtz ◽  
Maria Wendt ◽  
Michael August ◽  
Thomas Münzel
Keyword(s):  
Oxidative Stress ◽  
Reactive Oxygen Species ◽  
Risk Factor ◽  
Endothelial Dysfunction ◽  
Vascular Tissue ◽  
Rapid Development ◽  
Reactive Oxygen ◽  
Clinical Aspects ◽  
No Production ◽  
Oxygen Species

Endothelial dysfunction in the setting of cardiovascular risk factors, such as hypercholesterolaemia, hypertension, diabetes mellitus and chronic smoking, as well as in the setting of heart failure, has been shown to be at least partly dependent on the production of reactive oxygen species in endothelial and/or smooth muscle cells and the adventitia, and the subsequent decrease in vascular bioavailability of NO. Superoxide-producing enzymes involved in increased oxidative stress within vascular tissue include NAD(P)H-oxidase, xanthine oxidase and endothelial nitric oxide synthase in an uncoupled state. Recent studies indicate that endothelial dysfunction of peripheral and coronary resistance and conductance vessels represents a strong and independent risk factor for future cardiovascular events. Ways to reduce endothelial dysfunction include risk-factor modification and treatment with substances that have been shown to reduce oxidative stress and, simultaneously, to stimulate endothelial NO production, such as inhibitors of angiotensin-converting enzyme or the statins. In contrast, in conditions where increased production of reactive oxygen species, such as superoxide, in vascular tissue is established, treatment with NO, e.g. via administration of nitroglycerin, results in a rapid development of endothelial dysfunction, which may worsen the prognosis in patients with established coronary artery disease.

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