Sodium, Potassium-Activated Adenosine Triphosphatase Activity Is Impaired in the Guinea Pig Pancreatic Duct System in Streptozotocin-Induced Diabetes

Hootman, S. R.; Jones, John E.; Kapoor, Ravi; Nguyen, Kaitlyn; Ondarza, José de

doi:10.1006/bbrc.1998.8195

Cited by 9 publications

(8 citation statements)

References 25 publications

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“…Several mechanisms have been proposed to contribute to the development of exocrine pancreatic insufficiency. These include derangements in calcium and magnesium homeostasis and a decrease in gene expression of amylase, 11 reduced enzyme synthesis and secretion, 8 insensitivity of receptors to CCK that usually act to stimulate amylase release, 9 and reduced amino acid and glucose uptakes and Na + /K + ATPase activities in pancreas acinar cells 16 . The results of this study for the first time, demonstrate that exocrine pancreatic insufficiency may be due to changes in signaling, which controls protein turnover and transcription.…”

Section: Discussionmentioning

confidence: 99%

Signaling Proteins Associated with Diabetic‐Induced Exocrine Pancreatic Insufficiency in Rats

Patel

Atherton

Wackerhage

et al. 2006

Annals of the New York Academy of Sciences

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Diabetes mellitus (DM) is associated with pancreatic atrophy and compromised digestion of carbohydrates as a result of exocrine pancreatic insufficiency and lower alpha-amylase synthesis and secretion. The reduced production of digestive enzymes is likely to be caused by deregulated protein metabolism. The relative concentrations and phosphorylation of signaling proteins associated with protein translation, such as PKB, p70S6K1, 4E-BP1, ERK1/2, and also some of those implicated in protein breakdown, such as ubiquitin and NF-kappaB, in the pancreas of streptozotocin (STZ)-induced type I diabetic pancreas were measured using Western blotting. There were significant decreases in the levels of total PKB, p70S6K, 4E-BP1, ERK1/2, and NF-kappaB in the diabetic pancreas compared to control. In contrast, the phosphorylation of p70S6K1, 4E-BP1, ERK1/2, and protein ubiquitination increased significantly compared to controls. Together, these results indicate that STZ-induced DM leads to reduced levels of enzymes mediating protein synthesis while their phosphorylation is actually increased, perhaps in an attempt to maintain protein homeostasis, which is further compromised by heightened ubiquitin-dependent protein breakdown. It is likely that these factors are responsible for pancreatic atrophy, enzyme synthesis, and net protein loss in DM.

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Section: Discussionmentioning

confidence: 99%

Signaling Proteins Associated with Diabetic‐Induced Exocrine Pancreatic Insufficiency in Rats

Patel

Atherton

Wackerhage

et al. 2006

Annals of the New York Academy of Sciences

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“…Previous studies have demonstrated inhibition of Na + , K + -ATPase by high intracellular glucose in pancreatic duct cells [4,9]. It is thought that the resultant elevation of intracellular Na + concentration ([Na + ] i ) attenuates the Na + gradient across the basolateral membrane, which consequently reduces the uptake of Cl − and HCO 3 − via Na + -coupled transporters, such as the Na + -HCO 3 − cotransporter, at the basolateral membrane (Fig.…”

Section: Inhibition Of Fluid Secretion and Basolateral Hcomentioning

confidence: 98%

High glucose inhibits HCO 3 − and fluid secretion in rat pancreatic ducts

Futakuchi

Ishiguro

Naruse

et al. 2009

Pflugers Arch - Eur J Physiol

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Cellular mechanisms underlying the impairment of pancreatic fluid and electrolyte secretion in diabetes were examined using interlobular ducts isolated from rat pancreas. Fluid secretion was assessed by monitoring changes in luminal volume. HCO3(-) uptake across the basolateral membrane was estimated from the recovery of intracellular pH following an acid load. Exposure to high glucose concentrations inhibited fluid secretion and reduced the rate of basolateral HCO3(-) uptake in secretin-stimulated ducts isolated from normal rats. In ducts isolated from streptozotocin-treated diabetic rats, fluid secretion and basolateral HCO3(-) uptake were also severely impaired but could be largely reversed by incubation in normal-glucose solutions. Sodium-dependent glucose cotransporter 1 (SGLT1), glucose transporter (GLUT)1, GLUT2, and GLUT8 transcripts were detected by reverse transcriptase polymerase chain reaction in isolated ducts. Raising the luminal glucose concentration in microperfused ducts caused a depolarization of the membrane potential, consistent with the presence of SGLT1 at the apical membrane. Unstimulated ducts filled with high-glucose solutions lost luminal fluid by a phlorizin-sensitive mechanism, indicating that pancreatic ducts are capable of active glucose reabsorption from the lumen via SGLT1. In ducts exposed to high glucose concentrations, continuous glucose diffusion to the lumen and active reabsorption via SGLT1 would lead to elevation of intracellular Na+ concentration and sustained depolarization of the apical membrane. These two factors would tend to inhibit the basolateral uptake and apical efflux of Cl(-) and HCO3(-) and could therefore account for the impaired fluid and electrolyte secretion that is observed in diabetes.

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“…Similar to rodent models, insulin and c-peptide were very low in STZ guinea pigs (Gorray et al, 1986; Howell et al, 1971; Junod et al, 1969; Lundquist et al, 1975). However, hyperglycemia and ketosis were milder in STZ guinea pigs (Elliott and Pogson, 1977; Gorray et al, 1986; Hootman et al, 1998; Johnson, Jr., 1978; Peterssen et al, 1970; Schlosser et al, 1984; Schlosser et al, 1987) as compared to STZ rats (Hawkins et al, 1986; Junod et al, 1969). Hence, to focus on the contribution of insulin deficiency to autonomic neuropathy and motor dysfunction, the effect of neostigmine on ileal motility was determined in STZ-treated guinea pigs.…”

Section: Introductionmentioning

confidence: 96%

Neostigmine-induced contraction and nitric oxide-induced relaxation of isolated ileum from STZ diabetic guinea pigs

Cellini

Jukic

LePard

2011

Autonomic Neuroscience

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Both delayed gastrointestinal transit and autonomic neuropathy have been documented in patients with diabetes mellitus. The mechanism of neostigmine, an agent that mimics release of acetylcholine from autonomic neurons by prokinetic agents, to contract smooth muscle, despite dysfunctional enteric neural pathways, was determined using isolated ilea from STZ-treated and control guinea pigs. Both bethanechol- and neostigmine-induced contractions were stronger in diabetic ileum. Bethanechol-induced contractions of control but not diabetic ileum were increased by low dose scopolamine suggesting reduced activation of presynaptic muscarinic autoreceptors in diabetic ileum. The muscarinic receptor antagonist 4-DAMP strongly, but the nicotinic receptor antagonist hexamethonium only weakly, reduced neostigmine-induced contractions of control and diabetic ilea. The amount of acetylcholine, inferred from tissue choline content, was increased in diabetic ileum. Nicotinic neural and noncholinergic postjunctional smooth muscle receptors contributed more strongly to neostigmine-induced contractions in diabetic than control ileum. Relaxation of diabetic ileum by exogenous nitric oxide generated from sodium nitroprusside was comparable to control ileum, but smooth muscle relaxation by L-arginine using neuronal nitric oxide synthase to generate nitric oxide was weaker in diabetic ileum with evidence for a role for inducible nitric oxide synthase. Despite autonomic neuropathy, neostigmine strongly contracted ileum from diabetic animals but by a different mechanism including stronger activation of postjunctional muscarinic receptors, greater synaptic acetylcholine, stronger activation of noncholinergic excitatory pathways, and weaker activation of inhibitory pathways. A selective medication targeting a specific neural pathway may more effectively treat disordered gastrointestinal transit in patients with diabetes mellitus.

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Sodium, Potassium-Activated Adenosine Triphosphatase Activity Is Impaired in the Guinea Pig Pancreatic Duct System in Streptozotocin-Induced Diabetes

Cited by 9 publications

References 25 publications

Signaling Proteins Associated with Diabetic‐Induced Exocrine Pancreatic Insufficiency in Rats

Signaling Proteins Associated with Diabetic‐Induced Exocrine Pancreatic Insufficiency in Rats

High glucose inhibits HCO 3 − and fluid secretion in rat pancreatic ducts

Neostigmine-induced contraction and nitric oxide-induced relaxation of isolated ileum from STZ diabetic guinea pigs

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