Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(−/−) mice: therapy for exocrine pancreatic disorders?

Reddy, Raju C.; Hao, Ya; Lee, Sae Hong; Gangireddy, Srinivasa R.; Owyang, Chung; DiMagno, Matthew

doi:10.1152/ajpgi.00442.2006

Cited by 7 publications

(2 citation statements)

References 82 publications

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“…In addition, drinking alcohol may predispose to pancreatic diseases by uncoupling NO production from the enzyme endothelial NO synthase (eNOS)21, 48. eNOS helps maintain normal endothelial function and has protective effects on acute pancreatitis49, possibly by maintaining pancreatic exocrine secretion48, augmenting pancreatic blood flow49 or indirectly inhibiting intracellular trypsinogen activation49.…”

Section: Discussionmentioning

confidence: 99%

Alcohol Use and Cigarette Smoking as Risk Factors for Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis

DeBenedet

Raghunathan

Wing

et al. 2009

Clinical Gastroenterology and Hepatology

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Background & Aims Alcohol use and cigarette smoking associate with various pancreatic diseases, but it is not known whether they associate with post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). We performed a retrospective case-control study to determine if these activities increase the risk of PEP. Methods We identified 7,638 patients that had undergone ERCP in the University of Michigan Health System and applied exclusion criteria to identify 123 with PEP. We randomly selected 308 age- and gender-stratified controls (2.5-fold case sample); after applying exclusion criteria 248 remained. In a masked fashion, we collected data for alcohol use, cigarette smoking, and 5 internal control variables: suspected sphincter of Oddi dysfunction (SOD), pancreatic sphincterotomy, moderate/difficult cannulation, ≥ 2 pancreatic injections and pancreatic stent placement. Results The univariate model showed an increased frequency of PEP in current drinkers (P<0.001), former drinkers (P<0.001) and former smokers (P<0.001), as well as patients who were suspected of having SOD (P<0.001), had undergone pancreatic sphincterotomy (P<0.001), had a moderate/difficult cannulation (P=0.001), and/or had ≥2 pancreatic injections (P=0.007). The frequency of PEP was reduced in current smokers (P<0.001). The multivariate model showed that the only independent significant predictors of PEP were current drinking (OR=4.70, 95% CI 2.60–8.50, P<0.0001), former cigarette smoking (OR=3.29, 95% CI 1.28–8.44, P<0.013), suspected SOD (OR= 3.69, 95% CI 1.94–7.02, P<0.001), and pancreatic sphincterotomy (OR=5.91, 95% CI 2.04–17.14, P=0.001). Conclusions Current alcohol use and potentially former cigarette smoking are new risk factors for PEP. It is important to consider these variables in designing PEP prevention trials.

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Section: Discussionmentioning

confidence: 99%

Alcohol Use and Cigarette Smoking as Risk Factors for Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis

DeBenedet

Raghunathan

Wing

et al. 2009

Clinical Gastroenterology and Hepatology

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“…In contrast, it has been shown that eNOS Ϫ/Ϫ mice have insulin resistance and an impaired exocrine pancreatic secretion function. Pio improves both the exocrine secretion function and insulin resistance in eNOS Ϫ/Ϫ mice (45). Using human umbilical vein endothelial cells, our laboratory has shown that Pio increases the production of PGD 2 and 15-deoxy-⌬-12,14-PGJ 2 , which is formed by the nonenzymatic conversion of PGD 2 (72).…”

Section: Role Of Cpla 2 and Cox2mentioning

confidence: 99%

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Ye¹,

Lin²,

Manickavasagam³

et al. 2008

American Journal of Physiology-Heart and Circulatory Physiology

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Ye Y, Lin Y, Manickavasagam S, Perez-Polo JR, Tieu BC, Birnbaum Y. Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice. Am J Physiol Heart Circ Physiol 295: H2436 -H2446, 2008. First published October 17, 2008 doi:10.1152/ajpheart.00690.2008.-Endothelial nitric oxide synthase (eNOS) activation with subsequent inducible NOS (iNOS), cytosolic phospholipase A2 (cPLA2), and cyclooxygenase-2 (COX2) activation is essential to statin inhibition of myocardial infarct size (IS). In the rat, the peroxisome proliferator-activated receptor-␥ agonist pioglitazone (Pio) limits IS, upregulates and activates cPLA 2 and COX2, and increases myocardial 6-keto-PGF1␣ levels without activating eNOS and iNOS. We asked whether Pio also limits IS in eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ mice. Male C57BL/6 wild-type (WT), eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice received 10 mg ⅐ kg Ϫ1 ⅐ day Ϫ1 Pio (Pioϩ) or water alone (PioϪ) for 3 days. Mice underwent 30 min coronary artery occlusion and 4 h reperfusion, or hearts were harvested and subjected to ELISA and immunoblotting. As a result, Pio reduced IS in the WT (15.4 Ϯ 1.4% vs. 39.0 Ϯ 1.1%; P Ͻ 0.001), as well as in the eNOS Ϫ/Ϫ (32.0 Ϯ 1.6% vs. 44.2 Ϯ 1.9%; P Ͻ 0.001) and iNOS Ϫ/Ϫ (18.0 Ϯ 1.2% vs. 45.5 Ϯ 2.3%; P Ͻ 0.001) mice. The protective effect of Pio in eNOS Ϫ/Ϫ mice was smaller than in the WT (P Ͻ 0.001) and iNOS Ϫ/Ϫ (P Ͻ 0.001) mice. Pio increased myocardial Ser633 and Ser1177 phosphorylated eNOS levels in the WT and iNOS Ϫ/Ϫ mice. iNOS was undetectable in all six groups. Pio increased cPLA 2, COX2, and PGI2 synthase levels in the WT, as well as in the eNOS Ϫ/Ϫ and iNOS Ϫ/Ϫ , mice. Pio increased the myocardial 6-keto-PGF 1␣ levels and cPLA2 and COX2 activity in the WT, eNOS Ϫ/Ϫ , and iNOS Ϫ/Ϫ mice. In conclusion, the myocardial protective effect of Pio is iNOS independent and may be only partially dependent on eNOS. Because eNOS activity decreases with age, diabetes, and advanced atherosclerosis, this effect may be relevant in a clinical setting and should be further characterized. endothelial nitric oxide synthase; inducible nitric oxide synthase; peroxisome proliferator-activated receptor-␥ PROTECTION AGAINST ischemia-reperfusion injury may have a potential benefit in three distinct clinical situations: 1) limiting reperfusion injury in patients presenting with ST-elevation acute myocardial infarction before undergoing reperfusion therapy; 2) short-to intermediate-term treatment before elective procedures that may pose a risk for myocardial ischemia, such as cardiac or noncardiac surgery or percutaneous coronary interventions; and 3) long-term treatment in patients with established coronary artery disease to minimize the damage from an effort-induced ischemia or a potential future myocardial infarction. In the present study we studied whether the myocardial protection effects of intermediate-term pretreatment with pioglitazone (Pio) is dependent on nitric oxide (NO) synthases (NOSs), using a model that may be relevant to the second option mentioned above....

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Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans

Jansson

Carlsson

2019

Comprehensive Physiology

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The pancreatic islets are more richly vascularized than the exocrine pancreas, and possess a 5‐ to 10‐fold higher basal and stimulated blood flow, which is separately regulated. This is reflected in the vascular anatomy of the pancreas where islets have separate arterioles. There is also an insulo‐acinar portal system, where numerous venules connect each islet to the acinar capillaries. Both islets and acini possess strong metabolic regulation of their blood perfusion. Of particular importance, especially in the islets, is adenosine and ATP/ADP. Basal and stimulated blood flow is modified by local endothelial mediators, the nervous system as well as gastrointestinal hormones. Normally the responses to the nervous system, especially the parasympathetic and sympathetic nerves, are fairly similar in endocrine and exocrine parts. The islets seem to be more sensitive to the effects of endothelial mediators, especially nitric oxide, which is a permissive factor to maintain the high basal islet blood flow. The gastrointestinal hormones with pancreatic effects mainly influence the exocrine pancreatic blood flow, whereas islets are less affected. A notable exception is incretin hormones and adipokines, which preferentially affect islet vasculature. Islet hormones can influence both exocrine and endocrine blood vessels, and these complex effects are discussed. Secondary changes in pancreatic and islet blood flow occur during several conditions. To what extent changes in blood perfusion may affect the pathogenesis of pancreatic diseases is discussed. Both type 2 diabetes mellitus and acute pancreatitis are conditions where we think there is evidence that blood flow may contribute to disease manifestations. © 2019 American Physiological Society. Compr Physiol 9:799‐837, 2019.

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Pioglitazone reverses insulin resistance and impaired CCK-stimulated pancreatic secretion in eNOS(−/−) mice: therapy for exocrine pancreatic disorders?

Cited by 7 publications

References 82 publications

Alcohol Use and Cigarette Smoking as Risk Factors for Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis

Alcohol Use and Cigarette Smoking as Risk Factors for Post–Endoscopic Retrograde Cholangiopancreatography Pancreatitis

Pioglitazone protects the myocardium against ischemia-reperfusion injury in eNOS and iNOS knockout mice

Pancreatic Blood Flow with Special Emphasis on Blood Perfusion of the Islets of Langerhans

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