Glucose elicits cephalic-phase insulin release in mice by activating KATP channels in taste cells

The taste of sugar elicits cephalic-phase insulin release (CPIR), which limits the rise in blood glucose associated with meals. Little is known, however, about the gustatory mechanisms that trigger CPIR. We asked whether oral stimulation with any of the following taste stimuli elicited CPIR in mice: glucose, sucrose, maltose, fructose, Polycose, saccharin, sucralose, AceK, SC45647, or a nonmetabolizable sugar analog. The only taste stimuli that elicited CPIR were glucose and the glucose-containing saccharides (sucrose, maltose, Polycose). When we mixed an α-glucosidase inhibitor (acarbose) with the latter three saccharides, the mice no longer exhibited CPIR. This revealed that the carbohydrates were hydrolyzed in the mouth, and that the liberated glucose triggered CPIR. We also found that increasing the intensity or duration of oral glucose stimulation caused a corresponding increase in CPIR magnitude. To identify the components of the glucose-specific taste-signaling pathway, we examined the necessity of Calhm1, P2X2+P2X3, SGLT1, and Sur1. Among these proteins, only Sur1 was necessary for CPIR. Sur1 was not necessary, however, for taste-mediated attraction to sugars. Given that Sur1 is a subunit of the ATP-sensitive K+ channel (KATP) channel and that this channel functions as a part of a glucose-sensing pathway in pancreatic β-cells, we asked whether the KATP channel serves an analogous role in taste cells. We discovered that oral stimulation with drugs known to increase (glyburide) or decrease (diazoxide) KATP signaling produced corresponding changes in glucose-stimulated CPIR. We propose that the KATP channel is part of a novel signaling pathway in taste cells that mediates glucose-induced CPIR.

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Endocrine taste cells

British Journal Of Nutrition ◽

10.1017/s0007114513002262 ◽

2014 ◽

Vol 111 (S1) ◽

pp. S23-S29 ◽

Cited By ~ 34

Author(s):

Zaza Kokrashvili ◽

Karen K. Yee ◽

Erwin Ilegems ◽

Ken Iwatsuki ◽

Yan Li ◽

...

Keyword(s):

Endocrine Cells ◽

Gut Hormones ◽

Taste Receptors ◽

Wild Type ◽

Oral Stimulation ◽

Cephalic Phase ◽

Taste Cells ◽

Glucagon Like Peptide 1 ◽

Intestinal Endocrine Cells

In taste cells, taste receptors, their coupled G proteins and downstream signalling elements mediate the detection and transduction of sweet, bitter and umami compounds. In some intestinal endocrine cells, taste receptors and gustducin contribute to the release of glucagon-like peptide 1 (GLP-1) and other gut hormones in response to glucose and non-energetic sweeteners. Conversely, taste cells have been found to express multiple hormones typically found in intestinal endocrine cells, e.g. GLP-1, glucagon, somatostatin and ghrelin. In the present study, by immunohistochemistry, multiple subsets of taste cells were found to express GLP-1. The release of GLP-1 from ‘endocrine taste cells’ into the bloodstream was examined. In wild-type mice, even after oesophagectomy and vagotomy, oral stimulation with glucose induced an elevation of GLP-1 levels in the bloodstream within 10 min. Stimulation of taste cell explants from wild-type mice with glucose led to the release of GLP-1 into the medium. Knocking out of the Tas1r3 gene did not eliminate glucose-stimulated GLP-1 release from taste cells in vivo. The present results indicate that a portion of the cephalic-phase rise in circulating GLP-1 levels is mediated by the direct release of GLP-1 from taste cells into the bloodstream.

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Faculty Opinions recommendation of Glucose elicits cephalic-phase insulin release in mice by activating K(ATP) channels in taste cells.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727262083.793530450 ◽

2017 ◽

Author(s):

Thomas Finger

Keyword(s):

Insulin Release ◽

Cephalic Phase ◽

Taste Cells

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Insulin Secretion and Glucose Tolerance after Islet Transplantation in Rats with Noninsulin-Dependent Diabetes Induced by Neonatal Streptozotocin

Cell Transplantation ◽

10.1177/096368979700600106 ◽

1997 ◽

Vol 6 (1) ◽

pp. 23-32 ◽

Cited By ~ 1

Author(s):

Maria-Angeles Tormo ◽

Trinidad Leon-Quinto ◽

Catherine Saulnier ◽

Danielle Bailbe ◽

Patricia Serradas ◽

...

Keyword(s):

Glucose Tolerance ◽

Insulin Release ◽

Insulin Response ◽

Tolerance Test ◽

Oral Glucose ◽

Β Cells ◽

Basal Plasma

The present study was designed to identify in a model of noninsulin-dependent diabetes induced by neonatal streptozotocin (n0-STZ), the long-term consequences of an islet graft upon 1) glucose handling of the recipient and, 2) glucose response of the residual β cells in the recipient pancreas. We have examined, 4 and 8 wk after islet implantation under the kidney capsule of syngeneic diabetic n0-STZ rats, their tolerance to glucose administered in vivo, together with their insulin release in response to glucose in vivo (oral glucose tolerance test) as well as in vitro (perfused pancreas). The results in the islet-grafted n0-STZ rats, were compared to those obtained in nongrafted nondiabetic rats and nongrafted n0-STZ rats. Our study shows that transplanting a limited number (900) of adult islets under the kidney capsule reverses to normal, many parameters of the noninsulin-dependent diabetic state in the n0-STZ rat model: these include body weight, basal plasma glucose in both the nonfasted and postabsorptive states, and basal plasma insulin in the postabsorptive state. Furthermore, tolerance to oral glucose administration was greatly improved in the transplanted rats and it was correlated with restoration of a manifest glucose-induced insulin secretion in vivo as evaluated (ΔI) during an oral glucose tolerance test. Our data clearly show that the insulin response to glucose from the endogenous pancreas of n0-STZ diabetic rat was not really improved by long-term (8 wk) basal normoglycemia. More precisely, we were able to detect a slight but significant improvement of the early phase of insulin release in vitro in response to glucose; however, the overall insulin response remained 15 times lower than the normal one with no reapparance of the late phase of insulin release. After cessation of glucose stimulation in vivo, off-response of insulin, which is also a landmark of the impaired insulin release by the β cells of n0-STZ rats, was still detectable in the perfused pancreas of the transplanted n0-STZ rats. Finally, because the reactivity to glucose of the endogenous residual β cells was not regained, the insulin released in vivo during the oral glucose test in the graft-bearing n0-STZ rats can be attributed mainly to functioning of the grafted islets population. Copyright © 1997 Elsevier Science Inc.

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Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion of rat neonatal islets

Endocrinology ◽

10.1210/endocr/bqab121 ◽

2021 ◽

Author(s):

Juxiang Yang ◽

Batoul Hammoud ◽

Changhong Li ◽

Abigail Ridler ◽

Daphne Yau ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Katp Channel ◽

Cultured Cells ◽

Katp Channels ◽

Lower Threshold ◽

Β Cells ◽

Membrane Area ◽

Rat Islets ◽

Glucose Threshold

Abstract Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We found a lower threshold for glucose-stimulated insulin secretion from freshly isolated embryonic day (E)22 rat islets, which persisted into the first postnatal days. The threshold reached the adult level by postnatal day (P)14. Culturing P14 islets also decreased the glucose threshold. Freshly isolated P1 rat islets had a lower threshold for insulin secretion in response to BCH (2-aminobicyclo-(2,2,1)-heptane-2-carboxylic acid), a non-metabolizable leucine analog, and diminished insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels. These findings suggested that decreased KATP channel function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal a lower expression of KATP subunit genes in E22 compared to P14 β-cells. The investigation of electrophysiological characteristics of dispersed β-cells showed that early neonatal and cultured cells had fewer functional KATP channels per unit membrane area. Our findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

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Pharmacologic activation of the mitochondrial phosphoenolpyruvate cycle enhances islet function in vivo

10.1101/2020.02.13.947630 ◽

2020 ◽

Author(s):

Abudukadier Abulizi ◽

Romana Stark ◽

Rebecca L. Cardone ◽

Sophie L. Lewandowski ◽

Xiaojian Zhao ◽

...

Keyword(s):

Insulin Secretion ◽

Pyruvate Kinase ◽

Insulin Release ◽

Glucose Sensing ◽

Oral Glucose ◽

List Type ◽

Kinase Activation ◽

Preclinical Diabetes

SummaryThe mitochondrial GTP (mtGTP)-dependent phosphoenolpyruvate (PEP) cycle is an anaplerotic-cataplerotic mitochondrial shuttle utilizing mitochondrial PEPCK (PCK2) and pyruvate kinase (PK). PEP cycling stimulates insulin secretion via OxPhos-independent lowering of ADP by PK. We assess in vivo whether islet PCK2 is necessary for glucose sensing and if speeding the PEP cycle via pharmacological PK activators amplifies insulin secretion. Pck2-/- mice had severely impaired insulin secretion during islet perifusion, oral glucose tolerance tests and hyperglycemic clamps. Acute and chronic pharmacologic PK activator therapy improved islet insulin secretion from normal, high-fat diet (HFD) fed, or Zucker diabetic fatty (ZDF) rats, and glucolipotoxic or diabetic humans. A similar improvement in insulin secretion was observed in regular chow and HFD rats in vivo. Insulin secretion and cytosolic Ca2+ during PK activation were dependent on PCK2. These data provide a preclinical rationale for strategies, such as PK activation, that target the PEP cycle to improve glucose homeostasis.HighlightsLoss of mitochondrial phosphoenolpyruvate (PEP) impairs insulin release in vivo.Pyruvate kinase (PK) activators stimulate beta-cells in preclinical diabetes models.PEP cycling in vivo depends on PK and mitochondrial PEPCK (PCK2) for insulin release.Acute and 3-week oral PK activator amplifies insulin release during hyperglycemia.eTOC BlurbAbudukadier et al. show that small molecule pyruvate kinase activation in vivo and in vitro increases insulin secretion in rodent and human models of diabetes. The phosphoenolpyruvate (PEP) cycling mechanism and its amplification are dependent on mitochondrial PEPCK (PCK2).

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Decreased KATP channel activity contributes to the low glucose threshold for insulin secretion in the early postnatal period

10.1101/2021.03.04.433947 ◽

2021 ◽

Author(s):

Juxiang Yang ◽

Batoul Hammoud ◽

Changhong Li ◽

Abigail Ridler ◽

Daphne Yau ◽

...

Keyword(s):

Insulin Secretion ◽

Single Cell ◽

Insulin Release ◽

Katp Channel ◽

Katp Channels ◽

Postnatal Period ◽

Β Cells ◽

Lower Glucose ◽

Low Glucose ◽

Glucose Threshold

Objective: Transitional hypoglycemia in normal newborns occurs in the first 3 days of life and has clinical features consistent with hyperinsulinism. We hypothesized that this transitional hyperinsulinism is due to the persistence of a fetal lower glucose threshold for insulin release from β-cells into the first postnatal days. Methods: We tested dynamic insulin secretion from freshly isolated rat islets between late gestation and adult age and from rat islets kept in culture for 1 or 2 days. We used single-cell transcriptomic and electrophysiology approaches to investigate the mechanism for insulin secretion at low glucose concentrations. Results: We found that a lower threshold for glucose-stimulated insulin secretion (GSIS) is present in embryonic day (E)22 islets and persists into the first postnatal days. The glucose threshold increases in the postnatal period and reaches the adult level by postnatal day (P)14. We also demonstrated that culturing P14 islets for 24-48 hrs can also decrease the glucose threshold. Insulin release in response to BCH, a non-metabolizable leucine analog activating glutamate dehydrogenase, had a similar lower threshold in P1 compared to P14 islets. This showed that the low threshold for GSIS is determined at a step downstream of the glycolytic pathway. P1 islets had lower insulin release in response to tolbutamide, an inhibitor of β-cell KATP channels, compared to P14 islets, suggesting that decreased KATP channel expression and/or function could be responsible for the lower glucose threshold for insulin secretion. Single-cell transcriptomic analysis did not reveal differences in transcripts between E22 and P14 β-cells supporting the lower glucose threshold. The investigation of electrophysiological characteristics of dispersed β cells showed that early neonatal cells and cultured islet cells had fewer functional KATP channels per unit membrane area. Conclusion: These findings suggest that decreased surface density of KATP channels may contribute to the observed differences in glucose threshold for insulin release.

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PDX1LOW MAFALOW β-cells contribute to islet function and insulin release

Nature Communications ◽

10.1038/s41467-020-20632-z ◽

2021 ◽

Vol 12 (1) ◽

Cited By ~ 1

Author(s):

Daniela Nasteska ◽

Nicholas H. F. Fine ◽

Fiona B. Ashford ◽

Federica Cuozzo ◽

Katrina Viloria ◽

...

Keyword(s):

Insulin Secretion ◽

Insulin Release ◽

Metabolic Stress ◽

Human Islets ◽

Islet Function ◽

Β Cells ◽

Β Cell ◽

Ionic Fluxes ◽

Transcriptomic Level ◽

Adult Islet

AbstractTranscriptionally mature and immature β-cells co-exist within the adult islet. How such diversity contributes to insulin release remains poorly understood. Here we show that subtle differences in β-cell maturity, defined using PDX1 and MAFA expression, contribute to islet operation. Functional mapping of rodent and human islets containing proportionally more PDX1HIGH and MAFAHIGH β-cells reveals defects in metabolism, ionic fluxes and insulin secretion. At the transcriptomic level, the presence of increased numbers of PDX1HIGH and MAFAHIGH β-cells leads to dysregulation of gene pathways involved in metabolic processes. Using a chemogenetic disruption strategy, differences in PDX1 and MAFA expression are shown to depend on islet Ca2+ signaling patterns. During metabolic stress, islet function can be restored by redressing the balance between PDX1 and MAFA levels across the β-cell population. Thus, preserving heterogeneity in PDX1 and MAFA expression, and more widely in β-cell maturity, might be important for the maintenance of islet function.

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Long-Term Exposure of Pancreatic β-Cells to Palmitate Results in SREBP-1C-Dependent Decreases in GLP-1 Receptor Signaling via CREB and AKT and Insulin Secretory Response

Endocrinology ◽

10.1210/en.2015-2003 ◽

2016 ◽

Vol 157 (6) ◽

pp. 2243-2258 ◽

Cited By ~ 14

Author(s):

Annalisa Natalicchio ◽

Giuseppina Biondi ◽

Nicola Marrano ◽

Rossella Labarbuta ◽

Federica Tortosa ◽

...

Keyword(s):

Protein Expression ◽

Insulin Release ◽

Binding Protein ◽

Camp Response Element Binding ◽

Β Cells ◽

Pancreatic Β Cells ◽

Camp Response Element ◽

Element Binding Protein ◽

Viral Oncogene Homolog ◽

Erk Kinase

The effects of prolonged exposure of pancreatic β-cells to high saturated fatty acids on glucagon-like peptide-1 (GLP-1) action were investigated. Murine islets, human pancreatic 1.1B4 cells, and rat INS-1E cells were exposed to palmitate for 24 hours. mRNA and protein expression/phosphorylation were measured by real-time RT-PCR and immunoblotting, respectively. Specific short interfering RNAs were used to knockdown expression of the GLP-1 receptor (Glp1r) and Srebf1. Insulin release was assessed with a specific ELISA. Exposure of murine islets, as well as of human and INS-1E β-cells, to palmitate reduced the ability of exendin-4 to augment insulin mRNA levels, protein content, and release. In addition, palmitate blocked exendin-4-stimulated cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, whereas phosphorylation of MAPK-ERK kinase-1/2 and ERK-1/2 was not altered. Similarly, RNA interference-mediated suppression of Glp1r expression prevented exendin-4-induced cAMP-response element-binding protein and v-akt murine thymoma viral oncogene homolog phosphorylation, but did not impair exendin-4 stimulation of MAPK-ERK kinase-1/2 and ERK-1/2. Both islets from mice fed a high fat diet and human and INS-1E β-cells exposed to palmitate showed reduced GLP-1 receptor and pancreatic duodenal homeobox-1 (PDX-1) and increased sterol regulatory element-binding protein (SREBP-1C) mRNA and protein levels. Furthermore, suppression of SREBP-1C protein expression prevented the reduction of PDX-1 and GLP-1 receptor levels and restored exendin-4 signaling and action. Finally, treatment of INS-1E cells with metformin for 24 h resulted in inhibition of SREBP-1C expression, increased PDX-1 and GLP-1 receptor levels, consequently, enhancement of exendin-4-induced insulin release. Palmitate impairs exendin-4 effects on β-cells by reducing PDX-1 and GLP-1 receptor expression and signaling in a SREBP-1C-dependent manner. Metformin counteracts the impairment of GLP-1 receptor signaling induced by palmitate.

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