Cephalic phase insulin secretion is KATP channel independent

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

doi:10.1530/joe-12-0579

Cited by 15 publications

(18 citation statements)

References 33 publications

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“…For example, an increase in cytosolic ATP and closure of K ATP channels does not always correlate with insulin output in GSIS [10]. Beta cells can also secrete insulin independently of K ATP channel closure by an unclear mechanism that still requires calcium influx and membrane depolarisation [10,14]. Furthermore, K ATP channel activity can be recorded from oncell patches on beta cells exposed to glucose-free solutions, despite the fact that the intracellular ATP concentration under similar conditions would predict the channels to be closed [15].…”

Section: Introductionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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Aims/hypothesis Precise regulation of insulin secretion by the pancreatic beta cell is essential for the maintenance of glucose homeostasis. Insulin secretory activity is initiated by the stepwise breakdown of ambient glucose to increase cellular ATP via glycolysis and mitochondrial respiration. Knockout of Lkb1, the gene encoding liver kinase B1 (LKB1) from the beta cell in mice enhances insulin secretory activity by an undefined mechanism. Here, we sought to determine the molecular basis for how deletion of Lkb1 promotes insulin secretion. Methods To explore the role of LKB1 on individual steps in the insulin secretion pathway, we used mitochondrial functional analyses, electrophysiology and metabolic tracing coupled with by gas chromatography and mass spectrometry. Results Beta cells lacking LKB1 surprisingly display impaired mitochondrial metabolism and lower ATP levels following glucose stimulation, yet compensate for this by upregulating both uptake and synthesis of glutamine, leading to increased production of citrate. Furthermore, under low glucose conditions, Lkb1 −/− beta cells fail to inhibit acetyl-CoA carboxylase 1 (ACC1), the rate-limiting enzyme in lipid synthesis, and consequently accumulate NEFA and display increased membrane excitability. Conclusions/interpretation Taken together, our data show that LKB1 plays a critical role in coupling glucose metabolism to insulin secretion, and factors in addition to ATP act as coupling intermediates between feeding cues and secretion. Our data suggest that beta cells lacking LKB1 could be used as a system to identify additional molecular events that connect metabolism to cellular excitation in the insulin secretion pathway.

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Section: Introductionmentioning

confidence: 99%

LKB1 couples glucose metabolism to insulin secretion in mice

Robitaille

Faubert

et al. 2015

Diabetologia

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“…Preganglionic fibers transverse the vagus and enter the pancreas, 54 terminating in intrapancreatic ganglia from which postganglionic fibers emerge to innervate the Langerhans islets. 55 Studies performed in animals and humans demonstrated that CPIR is independent of ATP-sensitive potassium channels 56 and can be abolished by vagotomy 57 or ganglionic blockade with muscarinic antagonists, 58 which reinforces that this stimulus is mediated by cholinergic neurons of the parasympathetic nervous system. However, in humans, there is evidence that CPIR is also mediated by noncholinergic mechanisms.…”

Section: Cephalic Phase Of Insulin Response and Its Relevance To Metamentioning

confidence: 87%

New concepts in microvascular function and metabolic diseases: importance of cephalic phase of insulin response

Silva¹,

Buss²,

Wiernsperger³

et al. 2018

JDMDC

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During the process of human evolution, an enormous variety of mechanisms were selected in order to maintain metabolic homeostasis. Neurally-mediated anticipatory responses, also named as cephalic phase responses (CPR), and microcirculatory regulation are examples of these mechanisms. Beyond the already known insulin´s metabolic effects, this hormone exerts clear hemodynamic effects in the entire vascular bed. One of the most studied aspects of the CPR is the one related to insulin´s action. The cephalic phase of insulin response (CPIR) is involved in glucoregulation and seems to positively influence glucose homeostasis. While receptor and mainly post-receptor defects on insulin action are factors already well-known that regulate glucose homeostasis, actually pre-receptor defects directly related to microcirculatory dysfunction may also influence glycemia. With this view, microcirculatory dysfunction could be both cause and consequence of insulin resistance and glucose homeostasis dysregulation. In this review, we aimed to discuss an interaction hypothesis between CPIR and an early activation of microcirculation in order to maintain glucose homeostasis, as well as the possible impairment promoted by obesity and insulin resistance in this association.

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“…Standard rodent normal chow, dextrin, and high-sucrose diet were used as previously reported , Seino et al 2013. Dextrin hydrate, glimepiride, diazoxide, a-methyl-D(C)-glucoside (aMG) were purchased from Wako, Osaka, Japan.…”

Section: Methodsmentioning

confidence: 99%

“…As described previously (Seino et al 2013), both Kir6.2 C/C and Kir6.2 K/K mice were trained for the experiments of voluntary feeding with standard chow or dextrin. They were deprived of food for 16 h and then given free access to standard chow or dextrin for the voluntary feeding experiments.…”

Section: Voluntary Feedingmentioning

confidence: 99%

KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state

Ogata¹,

Seino²,

Harada³

et al. 2014

Journal of Endocrinology

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Glucose-dependent insulinotropic polypeptide (GIP), a gut hormone secreted from intestinal K-cells, potentiates insulin secretion. Both K-cells and pancreatic b-cells are glucoseresponsive and equipped with a similar glucose-sensing apparatus that includes glucokinase and an ATP-sensitive K C (K ATP ) 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 K ATP 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 K ATP channel activator, did not affect glucose-induced GIP secretion in the normal state. In mice lacking K ATP channels (Kir6.2 K/K mice), glucose-induced GIP secretion was enhanced compared with control (Kir6.2 C/C ) mice, but was completely blocked by the SGLT1 inhibitor phlorizin. In Kir6.2 K/K mice, intestinal glucose absorption through SGLT1 was enhanced compared with that in Kir6.2 C/C mice. On the other hand, glucose-induced GIP secretion was enhanced in the diabetic state in Kir6.2 C/C 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 K ATP channel as well as SGLT1 is involved in GIP secretion in the diabetic state in vivo.

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Cephalic phase insulin secretion is KATP channel independent

Cited by 15 publications

References 33 publications

LKB1 couples glucose metabolism to insulin secretion in mice

LKB1 couples glucose metabolism to insulin secretion in mice

New concepts in microvascular function and metabolic diseases: importance of cephalic phase of insulin response

KATP channel as well as SGLT1 participates in GIP secretion in the diabetic state

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