endothelin-1 and Prediabetic-State

The present study aimed to examine the association between big endothelin-1 (big ET-1) and long-term all-cause death in patients with coronary artery disease (CAD) and different glucose metabolism status.. We consecutively enrolled 8550 patients from January 2013 to December 2013. Patients were categorized according to both status of glucose metabolism status [Diabetes Mellitus (DM), Pre-Diabetes (Pre-DM), Normoglycemia (NG)] and big ET-1 levels. Primary endpoint was all-cause death. During a median of 5.1-year follow-up periods, 301 all-cause deaths occurred. Elevated big ET-1 was significantly associated with long-term all-cause death (adjusted HR: 2.230, 95%CI 1.629-3.051; p < 0.001). Similarly, patients with DM, but not Pre-DM, had increased risk of all-cause death compared with NG group (p < 0.05). When patients were categorized by both status of glucose metabolism and big ET-1 levels, high big ET-1 were associated with significantly higher risk of all-cause death in Pre-DM (adjusted HR: 2.442, 95% CI 1.039-5.740; p = 0.041) and DM (adjusted HR: 3.162, 95% CI 1.376-7.269; p = 0.007). The Kaplan-Meier curve indicated that DM patients with the highest big ET-1 levels were associated with the greatest risk of all-cause death (p < 0.05).. The present data indicate that baseline big ET-1 levels were independently associated with the long-term all-cause death in DM and Pre-DM patients with CAD undergoing PCI, suggesting that big ET-1 may be a valuable marker in patients with impaired glucose metabolism.

Topics: Blood Glucose; Coronary Artery Disease; Diabetes Mellitus; Endothelin-1; Humans; Percutaneous Coronary Intervention; Prediabetic State; Risk Factors; Time Factors; Treatment Outcome

Approximately 40% of patients with type 2 diabetes present with concurrent hypertension at the time of diabetes diagnosis. Increases in peripheral vascular resistance and correspondingly enhanced vasoconstrictor capacity could have profound implications for the development of hypertension and the progression of insulin resistance to overt diabetes. The purpose of this study was to determine whether skeletal muscle arteriolar vasoconstrictor dysfunction precedes or occurs concurrently with the onset of diabetes and hypertension. Male Zucker diabetic fatty (ZDF) rats were studied at 7, 13, and 20 wk of age to represent prediabetic and short-term and long-term diabetic states, respectively. Conscious mean arterial pressure (MAP), fasted plasma insulin and glucose, vasoconstrictor responses, and passive mechanical properties of isolated skeletal muscle arterioles were measured in prediabetic, diabetic, and age-matched control rats. Elevated MAP was manifest in short-term diabetes (control 117 +/- 1, diabetic 135 +/- 3 mmHg) and persisted with long-term diabetes (control 113 +/- 2, diabetic 135 +/- 3 mmHg). This higher MAP was preceded by augmented arteriolar vasoconstrictor responses to norepinephrine and endothelin-1 and followed by diminished beta-adrenergic vasodilation and enhanced myogenic constriction in long-term diabetes. Furthermore, we demonstrate that diminished nitric oxide (NO) signaling underlies the increases in vasoconstrictor responsiveness in arterioles from prediabetic and diabetic rats. Arteriolar stiffness was not different between control and prediabetic or diabetic rats at any time point studied. Collectively, these results indicate that increases in vasoconstrictor responsiveness resulting from diminished NO signaling in skeletal muscle arterioles precede the development of diabetes and hypertension in ZDF rats.

Topics: Animals; Arterioles; Blood Glucose; Blood Pressure; Diabetes Mellitus, Type 2; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Down-Regulation; Endothelin-1; Enzyme Inhibitors; Hypertension; Insulin; Isoproterenol; Male; Muscle, Skeletal; NG-Nitroarginine Methyl Ester; Nitric Oxide; Nitric Oxide Synthase Type II; Nitric Oxide Synthase Type III; Norepinephrine; Potassium Chloride; Prediabetic State; Rats; Rats, Zucker; Signal Transduction; Superoxide Dismutase; Superoxide Dismutase-1; Time Factors; Vasoconstriction; Vasoconstrictor Agents; Vasodilator Agents

In the aorta of prediabetic non-obese diabetic mice, a model of human type 1 diabetes, we investigated gene expression of the endothelin receptors and contractility to big endothelin-1 and endothelin-1 at the ages of 10 and 16 weeks. A subgroup of 10- week-old animals was treated with the endothelin ETA receptor antagonist LU461314 (30 mg/kg per day for 6 weeks). Blood glucose levels were normal in all animals. Real-time polymerase chain reaction analysis revealed that vascular ETB receptor expression was higher in 10-week-old non-obese diabetic (NOD) mice compared with controls. In 16-week-old NOD mice, but not in control mice, ETB receptor mRNA was twofold lower (P < 0.05 vs 10-week-old NOD mice). In all groups ETA receptor expression was unaffected by age or treatment. Contractions to big endothelin-1 and endothelin-1 were lower in 10-week-old NOD mice compared with controls. Treatment with LU461314 increased ETB receptor expression in 16-week-old NOD mice, but had no effect on vascular contractility. These data indicate that dysregulation of ETB receptor expression and a decreased contractile response to big endothelin-1 and endothelin-1 are present in the prediabetic state of a model of human type 1 diabetes. These alterations occur independent of glucose levels. Furthermore, ETA receptor blockade is effective in increasing ETB receptor gene expression, suggesting a potential role for endothelin ETA antagonists in the treatment of type 1 diabetes.

Topics: Age Factors; Animals; Aorta; Blood Glucose; Cardiovascular Agents; Diabetes Mellitus, Type 1; Disease Models, Animal; Dose-Response Relationship, Drug; Endothelin A Receptor Antagonists; Endothelin-1; Female; Mice; Mice, Inbred NOD; Prediabetic State; Receptor, Endothelin A; Receptor, Endothelin B; RNA, Messenger; Up-Regulation; Vasoconstriction