Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes

Yamamoto, Kyohei; Hashimoto, Hitoshi; Tomimoto, Shuhei; Shintani, Norihito; Miyazaki, Jun‐ichi; Tashiro, Fumi; Aihara, Hiroyuki; Nammo, Takao; Li, Ming; Yamagata, Kazuya; Miyagawa, Jun Ichiro; Matsuzawa, Yūji; Kawabata, Yuki; Fukuyama, Yuji; Koga, Katsumi; Mori, Wakaba; Tanaka, Kazuhiro; Matsuda, Takehisa; Baba, Akemichi

doi:10.2337/diabetes.52.5.1155

Cited by 78 publications

(71 citation statements)

References 49 publications

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“…The detailed biochemical mechanism of action of PACAP27 on islet NOS isoenzymes seems to be very complex and will certainly await further studies, since regulation of NOS enzymes has been described (18) at all levels from gene transcription to covalent modifications and allosteric regulation of the enzyme itself. It should be noted that there are some potential drawbacks of PACAP as therapeutic agent in the long term, especially with regard to type 2 diabetes, since PACAP is reportedly inactivated by dipeptidyl peptidase IV and stimulates the release of glucagon and epinephrine as well as hepatic glucose production (41,50). On the other hand, PACAP has insulin-sensitizing properties and suppresses appetite (41).…”

Section: Discussionmentioning

confidence: 99%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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Qader SS, Jimenez-Feltström J, Ekelund M, Lundquist I, Salehi A. Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27. Am J Physiol Endocrinol Metab 292: E1447-E1455, 2007. First published January 30, 2007; doi:10.1152/ajpendo.00172.2006.-Chronic exposure of pancreatic islets to elevated plasma lipids (lipotoxicity) can lead to ␤-cell dysfunction, with overtime becoming irreversible. We examined, by confocal microscopy and biochemistry, whether the expression of islet inducible nitric oxide synthase (iNOS) and the concomitant inhibition of glucose-stimulated insulin release seen after lipid infusion in rats was modulated by the islet neuropeptide pituitary adenylate cyclase-activating polypeptide (PACAP)27. Lipid infusion for 8 days induced a strong expression of islet iNOS, which was mainly confined to ␤-cells and was still evident after incubating islets at 8.3 mmol/l glucose. This was accompanied by a high iNOS-derived NO generation, a decreased insulin release, and increased cyclic GMP accumulation. No iNOS expression was found in control islets. Addition of PACAP27 to incubated islets from lipid-infused rats resulted in loss of iNOS protein expression, increased cyclic AMP, decreased cyclic GMP, and suppression of the activities of neuronal constitutive (nc)NOS and iNOS and increased glucose-stimulated insulin response. These effects were reversed by the PKA inhibitor H-89. The suppression of islet iNOS expression induced by PACAP27 was not affected by the proteasome inhibitor MG-132, which by itself induced the loss of iNOS protein, making a direct proteasomal involvement less likely. Our results suggest that PACAP27 through its cyclic AMP-and PKA-stimulating capacity strongly suppresses not only ncNOS but, importantly, also the lipid-induced stimulation of iNOS expression, possibly by a nonproteasomal mechanism. Thus PACAP27 restores the impairment of glucose-stimulated insulin release and additionally might induce cytoprotection against deleterious actions of iNOS-derived NO in ␤-cells. pancreatic islets; insulin secretion; isoforms of nitric oxide synthase; pituitary adenylate cyclase-activating polypeptide 27 THE SOLUTION USED for total parenteral nutrition (TPN) contains a high amount of lipids, which results in increased plasma levels of free fatty acid (FFA), triglycerides, and cholesterol (8,31,34,36). FFA has complex effects on pancreatic ␤-cells and insulin secretion (8,9,25,31,32,34,36,45,51). Hence, FFA acutely stimulates insulin secretion from isolated pancreatic islets (9), whereas long-term incubation (24 h) of islets in the presence of FFAs negatively modulates ␤-cell function and results in a markedly decreased glucose-stimulated release of insulin (51). Indeed, it has been known for a long time that chronic elevation of plasma FFA impairs the insulin-secreting response to glucose in both humans and animals (8,31,32,34,36,45,51), and this hyperlipidemia has been suggest...

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Section: Discussionmentioning

confidence: 99%

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Qader

Jimenez-Feltström²,

Ekelund³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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“…Although transgene expression in pancreatic islets of rodents has been achieved by microinjection of fertilized embryos (24)(25)(26)(27)(28)(29)(30), safe and efficient in vivo targeting of genes to pancreatic islets has been an elusive goal. This paper describes a method for efficient gene delivery to the pancreatic islets, with detection of transgene-encoded proteins (luciferase, human insulin and Cpeptide, hexokinase I) for up to 3 weeks after transfection.…”

Section: Discussionmentioning

confidence: 99%

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology

Chen

Ding

Bekeredjian³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

182

128

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This study describes a method of gene delivery to pancreatic islets of adult, living animals by ultrasound targeted microbubble destruction (UTMD). The technique involves incorporation of plasmids into the phospholipid shell of gas-filled microbubbles, which are then infused into rats and destroyed within the pancreatic microcirculation with ultrasound. Specific delivery of genes to islet beta cells by UTMD was achieved by using a plasmid containing a rat insulin 1 promoter (RIP), and reporter gene expression was regulated appropriately by glucose in animals that received a RIP-luciferase plasmid. To demonstrate biological efficacy, we used UTMD to deliver RIP-human insulin and RIP-hexokinase I plasmids to islets of adult rats. Delivery of the former plasmid resulted in clear increases in circulating human C-peptide and decreased blood glucose levels, whereas delivery of the latter plasmid resulted in a clear increase in hexokinase I protein expression in islets, increased insulin levels in blood, and decreased circulating glucose levels. We conclude that UTMD allows relatively noninvasive delivery of genes to pancreatic islets with an efficiency sufficient to modulate beta cell function in adult animals.diabetes ͉ gene therapy ͉ ultrasound

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“…5C). Increased insulin secretion has also been documented in transgenic mice overexpressing the VIP gene (20) or the PACAP gene (21) in the islet ␤-cells. The molecular basis of their effects is still far from fully understood, although it is established that VIP and PACAP signal through cAMP.…”

Section: Parasympathetic Nervous Systemmentioning

confidence: 99%

Neuropeptides and the Regulation of Islet Function

2006

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The pancreatic islets are richly innervated by autonomic nerves. The islet parasympathetic nerves emanate from intrapancreatic ganglia, which are controlled by preganglionic vagal nerves. The islet sympathetic nerves are postganglionic with the nerve cell bodies located in ganglia outside the pancreas. The sensory nerves originate from dorsal root ganglia near the spinal cord. Inside the islets, nerve terminals run close to the endocrine cells. In addition to the classic neurotransmitters acetylcholine and norepinephrine, several neuropeptides exist in the islet nerve terminals. These neuropeptides are vasoactive intestinal polypeptide, pituitary adenylate cyclase-activating polypeptide, gastrin-releasing polypeptide, and cocaineand amphetamine-regulated transcript in parasympathetic nerves; neuropeptide Y and galanin in the sympathetic nerves; and calcitonin gene-related polypeptide in sensory nerves. Activation of the parasympathetic nerves and administration of their neurotransmitters stimulate insulin and glucagon secretion, whereas activation of the sympathetic nerves and administration of their neurotransmitters inhibit insulin but stimulate glucagon secretion. The autonomic nerves contribute to the cephalic phase of insulin secretion, to glucagon secretion during hypoglycemia, to pancreatic polypeptide secretion, and to the inhibition of insulin secretion, which is seen during stress. In rodent models of diabetes, the number of islet autonomic nerves is upregulated. This review focuses on neural regulation of islet function, with emphasis on the neuropeptides. Diabetes 55 (Suppl. 2):S98 -S107, 2006 S ince the discovery of nerves in the pancreatic islet by Paul Langerhans in his thesis from 1869, the neural-islet axis has been explored by a number of neuroanatomists, physiologists, and endocrinologists (rev. in 1-3). It is currently known that branches of the parasympathetic and sympathetic as well as the sensory nervous system innervate the islets with nerve terminals ending closely to the islet endocrine cells. It is also known that these nerves affect islet hormone secretion. The classic neurotransmitters in the islet autonomic nerves are acetylcholine and norepinephrine. During the last decades, the contribution to neural regulation of islet function also by neuropeptides has been established (rev. in 4). Several neuropeptides are localized to islet nerve terminals, are released from the pancreatic nerves upon nerve stimulation, and influence islet hormone secretion. It is also known that the islet innervation is altered in animal models of type 2 diabetes (5). The autonomic nervous system has also been suggested to be involved in the regulation of islet mass (6). The present review highlights the role of neuropeptides in islet function. PARASYMPATHETIC NERVOUS SYSTEMAnatomy and effects. The parasympathetic nerves innervating the pancreatic islets emanate from the pancreatic ganglia, which are innervated by preganglionic parasympathetic nerves originating in the dorsal motor nucleus of the vagus. Activ...

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Overexpression of PACAP in Transgenic Mouse Pancreatic β-Cells Enhances Insulin Secretion and Ameliorates Streptozotocin-induced Diabetes

Cited by 78 publications

References 49 publications

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Expression of islet inducible nitric oxide synthase and inhibition of glucose-stimulated insulin release after long-term lipid infusion in the rat is counteracted by PACAP27

Efficient gene delivery to pancreatic islets with ultrasonic microbubble destruction technology

Neuropeptides and the Regulation of Islet Function

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