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Yusuke Seino, Takashi Miki, Wakako Fujimoto, Eun Young Lee, Yoshihisa Takahashi, Kohtaro Minami, Yutaka Oiso and Susumu Seino

Glucose-induced insulin secretion from pancreatic β-cells critically depends on the activity of ATP-sensitive K+ channels (KATP channel). We previously generated mice lacking Kir6.2, the pore subunit of the β-cell KATP channel (Kir6.2 −/−), that show almost no insulin secretion in response to glucose in vitro. In this study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2 + / +) and Kir6.2 −/− mice. Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6.2 + / + and Kir6.2 −/− mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6.2 −/− mice but was markedly attenuated compared with that in Kir6.2 + / + mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6.2 −/− mice. Pretreatment with a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood–brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6.2 −/− mice. Substantial glucose-induced insulin secretion was induced in the pancreas perfusion study of Kir6.2 −/− mice only in the presence of carbamylcholine. These results suggest that a KATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo.

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Hidetada Ogata, Yusuke Seino, Norio Harada, Atsushi Iida, Kazuyo Suzuki, Takako Izumoto, Kota Ishikawa, Eita Uenishi, Nobuaki Ozaki, Yoshitaka Hayashi, Takashi Miki, Nobuya Inagaki, Shin Tsunekawa, Yoji Hamada, Susumu Seino and Yutaka Oiso

Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic β-cells are glucose-responsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K+ (KATP) channel comprising KIR6.2 and sulfonylurea receptor 1. In absorptive epithelial cells and enteroendocrine cells, sodium glucose co-transporter 1 (SGLT1) is also known to play an important role in glucose absorption and glucose-induced incretin secretion. However, the glucose-sensing mechanism in K-cells is not fully understood. In this study, we examined the involvement of SGLT1 (SLC5A1) and the KATP channels in glucose sensing in GIP secretion in both normal and streptozotocin-induced diabetic mice. Glimepiride, a sulfonylurea, did not induce GIP secretion and pretreatment with diazoxide, a KATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking KATP channels (Kir6.2 −/− mice), glucose-induced GIP secretion was enhanced compared with control (Kir6.2 + / +) mice, but was completely blocked by the SGLT1 inhibitor phlorizin. In Kir6.2 −/− mice, intestinal glucose absorption through SGLT1 was enhanced compared with that in Kir6.2 + / + mice. On the other hand, glucose-induced GIP secretion was enhanced in the diabetic state in Kir6.2 + / + mice. This GIP secretion was partially blocked by phlorizin, but was completely blocked by pretreatment with diazoxide in addition to phlorizin administration. These results demonstrate that glucose-induced GIP secretion depends primarily on SGLT1 in the normal state, whereas the KATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.

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Muhammed Yusuf Ali, Matthew Whiteman, Chian-Ming Low and Philip K Moore

474 –H480. Zhao W , Zhang J, Lum Y & Wang R 2001 The vasorelaxant effect of H 2 S as a novel endogenous gaseous KATP channel opener. EMBO Journal 20 6008 –6016. Zhong G , Chen F, Cheng Y

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Neville H McClenaghan, Peter R Flatt and Andrew J Ball

This study examined the effects of glucagon-like peptide-1 (GLP-1) on insulin secretion alone and in combination with sulphonylureas or nateglinide, with particular attention to KATP channel-independent insulin secretion. In depolarised cells, GLP-1 significantly augmented glucose-induced KATP channel-independent insulin secretion in a glucose concentration-dependent manner. GLP-1 similarly augmented the KATP channel-independent insulin-releasing effects of tolbutamide, glibenclamide or nateglinide. Downregulation of protein kinase A (PKA)- or protein kinase C (PKC)-signalling pathways in culture revealed that the KATP channel-independent effects of sulphonylureas or nateglinide were critically dependent upon intact PKA and PKC signalling. In contrast, GLP-1 exhibited a reduced but still significant insulin-releasing effect following PKA and PKC downregulation, indicating that GLP-1 can modulate KATP channel-independent insulin secretion by protein kinase-dependent and -independent mechanisms. The synergistic insulin-releasing effects of combinatorial GLP-1 and sulphonylurea/nateglinide were lost following PKA- or PKC-desensitisation, despite GLP-1 retaining an insulin-releasing effect, demonstrating that GLP-1 can induce insulin release under conditions where sulphonylureas and nateglinide are no longer effective. Our results provide new insights into the mechanisms of action of GLP-1, and further highlight the promise of GLP-1 or similarly acting analogues alone or in combination with sulphonylureas or meglitinide drugs in type 2 diabetes therapy.

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Åsa Tivesten, Anna Barlind, Kenneth Caidahl, Natalia Klintland, Antonio Cittadini, Claes Ohlsson and Jörgen Isgaard

Growth hormone (GH) deficiency is associated with abnormal vascular reactivity and development of atherosclerosis. GH treatment in GH deficient states restores systemic vascular resistance, arterial compliance, endothelium-dependent and endothelium-independent vasodilation, and may reverse markers of early atherosclerosis. However, very little is known about the molecular mechanisms underlying these effects. In the present study, male Sprague Dawley rats were hypophysectomized and treated for two weeks with GH (recombinant human GH, 2 mg/kg/day) or saline as s.c. injections twice daily. GH decreased aortic systolic blood pressure compared with saline-treated animals, while the diastolic blood pressure was not significantly changed. GH treatment increased cardiac output as determined by Doppler-echocardiography and the calculated systemic vascular resistance was markedly reduced. In order to identify GH-regulated genes of importance for vascular function, aortic mRNA levels were analyzed by the microarray technique and correlated to the systolic blood pressure levels. Using this approach, we identified 18 GH-regulated genes with possible impact on vascular tone and atherogenesis. In particular, mRNA levels of the inwardly rectifying potassium channel Kir6.1 and the sulfonylurea receptor 2B, which together form the vascular smooth muscle ATP-sensitive potassium channel, were both up-regulated by GH treatment and highly correlated to systolic blood pressure. Our findings establish a major role for GH in the regulation of vascular physiology and gene expression. Increased expression of the ATP-sensitive potassium channel, recently shown to be crucial in the regulation of vascular tone, constitutes a possible mechanism by which GH governs vascular tone.

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Yu-Feng Zhao, Jianming Pei and Chen Chen

effects of LA on K ATP channels, GW9508-induced opening of KATP channels was recovered fully and quickly, suggesting that its effect is mediated by the membrane receptor. In addition, GH3 cells with K ATP channels but without GPR40 expression did not

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T S McQuaid, M C Saleh, J W Joseph, A Gyulkhandanyan, J E Manning-Fox, J D MacLellan, M B Wheeler and C B Chan

1993 Glucokinase activity in isolated islets from obese fa/fa Zucker rats. Biochemical Journal 295 673 –677. Chan CB & MacPhail RM 1996 KATP channel-dependent and -independent pathways of insulin secretion in

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Qiong You, Zijun Wu, Bin Wu, Chang Liu, Ruina Huang, Li Yang, Runmin Guo, Keng Wu and Jingfu Chen

-κB p65 was also measured in STZ-induced diabetic rats. The expression of p65 was analyzed by Western blotting analysis. (B, C, E, G, H, K and M) Densitometric analysis of the KATP channels expression levels in (A, D, F, J and L) with ImageJ 1.47i

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Sofianos Andrikopoulos, Barbara C Fam, Anita Holdsworth, Sherley Visinoni, Zheng Ruan, Maria Stathopoulos, Anne W Thorburn, Christos N Joannides, Michael Cancilla, Lois Balmer, Joseph Proietto and Grant Morahan

-sensitive potassium (KATP) channels resulting in cell membrane depolarisation, opening of voltage-gated calcium channels, an influx of intracellular calcium and finally insulin granule exocytosis. In this cascade of events, the KATP channel, composed of the outer

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Srividya Vasu, Mary K McGahon, R Charlotte Moffett, Tim M Curtis, J Michael Conlon, Yasser H A Abdel-Wahab and Peter R Flatt

-secreting cell line, BRIN-BD11, produced by electrofusion . Diabetes 45 1132 – 1140 . ( doi:10.2337/diab.45.8.1132 ) McClenaghan NH Flatt PR Ball AJ 2006 Actions of glucagon-like peptide-1 on KATP channel-dependent and -independent effects