Virus-induced alterations in insulin release in hamster islets of Langerhans.

Abstract

A B S T R A C T After the inoculation of Golden Syrian hamsters with the TC-83 vaccine strain of Venezuelan encephalitis (VE) virus, a sustained diminution in glucose-stimulated insulin release and glucose intolerance of shorter duration develops. To understand better the mechanism of this defect in insulin release, we examined insulin secretion in response to several test agents in isolated perifused islets from control and 24-d post-VE virus-infected hamsters. 50 islets were used in all perifusion experiments, and data were expressed as total insulin released as well as peak response for each test agent during a 30-min perifusion period from control and VE-infected islets. After perifusion with 20 mM glucose, a 45% diminution of insulin release was noted in VE-infected islets in comparison with control islets, which in turn was similar to in vivo findings. However, following 1-mM tolbutamide stimulation, insulin release was similar in control and VE-infected islets. In separate studies, 1 mM tolbutamide, 10 mM theophilline, 1 mM dibutyryl cyclic (c)AMP, and 1 mM 8-bromo-cAMP resulted in statistically similar insulin-release curves in control and VE-infected islets. Additional experiments assessing [5_3H]glucose use in control and infected islets after 20 min ofperifusion with 20 mM glucose revealed virtually identical values (239±30-control; and 222 ±27-VE-infected islets). Morphological and morphometric evaluation of VE-infected islets (21 d following virus inoculation) showed no changes in islet volume density, beta cell density, and beta cell granulation. Thus, VE virus induces a defect in glucose-stimulated insulin release from hamster beta cells that can be corrected by cAMP analogues and does not alter islet glucose use.

Virus-induced alterations in cyclic adenosine monophosphate generation in hamster islets of Langerhans.

“…We developed a hamster model in which VE virus infection results in a significant diminution of glucosestimulated insulin release in vivo and vitro (6,7). Since VE virus is relatively non-lytic, no long-term morphologic nor morphometric changes are demonstrable in the islets from infected hamsters (6,7). The decrease in insulin release triggered by glucose can be corrected in vitro in isolated perifused islets treated with agents that raise cAMP levels: theophylline (a phosphodiesterase inhibitor) and cAMP analogs (7).…”

“…Specifically, there were no changes in islet volume density, volume density ofindividual islet subtypes (beta, alpha, delta, pancreatic polypeptide), or beta cell granulation in virus infected islets (7). Decreased insulin release can be corrected in vitro by 8-bromo-cyclic AMP (cAMP), dibutyryl cAMP, and by the phosphodiesterase inhibitor, theophylline (7). a-Ketoisocaproic acid, an insulin secretagogue whose action is independent of glucose, induces normal insulin release in VE-infected islets (8).…”

“…Most ofthe studies performed in animal models ofviral diabetes have used viruses highly lytic to beta cells in vivo, in which islet destruction parallels the degree of hyperglycemia (4,5 1. Abbreviations used in this paper: B, rate of cyclic AMP generation; cAMP, cyclic AMP; IBMX, 3-isobutyl-1-methylxanthine; RO 20-1724, d-4-(3-butoxy-4-methoxybenzyl)-2-imidazol-idinone; VE, Venezuelan encephalitis virus; VEsm, TC-83 vaccine strain of VE. in glucose-stimulated insulin release, in vivo (6) and in vitro in isolated, perifused pancreatic islets of Langerhans (7). After VE infection, no long-term morphologic alterations in the pancreas are observed (6,7).…”

“…Abbreviations used in this paper: B, rate of cyclic AMP generation; cAMP, cyclic AMP; IBMX, 3-isobutyl-1-methylxanthine; RO 20-1724, d-4-(3-butoxy-4-methoxybenzyl)-2-imidazol-idinone; VE, Venezuelan encephalitis virus; VEsm, TC-83 vaccine strain of VE. in glucose-stimulated insulin release, in vivo (6) and in vitro in isolated, perifused pancreatic islets of Langerhans (7). After VE infection, no long-term morphologic alterations in the pancreas are observed (6,7). Specifically, there were no changes in islet volume density, volume density ofindividual islet subtypes (beta, alpha, delta, pancreatic polypeptide), or beta cell granulation in virus infected islets (7).…”

“…After VE infection, no long-term morphologic alterations in the pancreas are observed (6,7). Specifically, there were no changes in islet volume density, volume density ofindividual islet subtypes (beta, alpha, delta, pancreatic polypeptide), or beta cell granulation in virus infected islets (7). Decreased insulin release can be corrected in vitro by 8-bromo-cyclic AMP (cAMP), dibutyryl cAMP, and by the phosphodiesterase inhibitor, theophylline (7).…”