Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes

Albrechtsen, Nicolai J. Wewer; Kuhre, Rune Ehrenreich; Windeløv, Johanne Agerlin; Ørgaard, Anne; Deacon, Carolyn F.; Kissow, Hannelouise; Hartmann, Bolette; Holst, Jens J.

doi:10.1152/ajpendo.00119.2016

Cited by 32 publications

(24 citation statements)

References 23 publications

(31 reference statements)

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“…; Wewer Albrechtsen et al . ) had no effect on [Ca 2+ ] c in the absence of IP 3 ‐linked hormones, whereas supraphysiological concentrations of glucagon (1–50 n m ) can induce asynchronous [Ca 2+ ] c increases, although these responses are still not organized as intercellular Ca 2+ waves (Gaspers & Thomas, ). The confocal images in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…; Wewer Albrechtsen et al . ) did not induce a detectable [Ca 2+ ] c response, whereas increasing the dose a 1000‐fold (5–50 n m ) only generated asynchronous [Ca 2+ ] c increases in a limited number of individual hepatocytes, predominately in the periportal zone (Gaspers & Thomas, ). These results indicate that the picomolar concentrations of glucagon used here only activate the cAMP/PKA pathway.…”

Section: Discussionmentioning

confidence: 99%

“…Higher levels of glucagon dose-dependently increased hepatic glucose production, with a maximal response at 1-10 nM. Physiological levels of glucagon typically fall in the range 5-60 pM (Emmanouel et al 1978;Wewer Albrechtsen et al 2016). The trace in Fig.…”

Section: Hepatic Glucose Production Is Increased In Parallel With Thementioning

confidence: 92%

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Intercellular calcium waves integrate hormonal control of glucose output in the intact liver

Gaspers

Pierobon

Thomas

2019

The Journal of Physiology

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Key points Sympathetic outflow and circulating glucogenic hormones both regulate liver function by increasing cytosolic calcium, although how these calcium signals are integrated at the tissue level is currently unknown. We show that stimulation of hepatic nerve fibres or perfusing the liver with physiological concentrations of vasopressin only will evoke localized cytosolic calcium oscillations and modest increases in hepatic glucose production. The combination of these stimuli acted synergistically to convert localized and asynchronous calcium responses into co‐ordinated intercellular calcium waves that spread throughout the liver lobule and elicited a synergistic increase in hepatic glucose production. The results obtained in the present study demonstrate that subthreshold levels of one hormone can create an excitable medium across the liver lobule, which allows global propagation of calcium signals in response to local sympathetic innervation and integration of metabolic regulation by multiple hormones. This enables the liver lobules to respond as functional units to produce full‐strength metabolic output at physiological levels of hormone. Abstract Glucogenic hormones, including catecholamines and vasopressin, induce frequency‐modulated cytosolic Ca 2+ oscillations in hepatocytes, and these propagate as intercellular Ca 2+ waves via gap junctions in the intact liver. We investigated the role of co‐ordinated Ca 2+ waves as a mechanism for integrating multiple endocrine and neuroendocrine inputs to control hepatic glucose production in perfused rat liver. Sympathetic nerve stimulation elicited localized Ca 2+ increases that were restricted to hepatocytes in the periportal zone. During perfusion with subthreshold vasopressin, sympathetic stimulation converted asynchronous Ca 2+ signals in a limited number of hepatocytes into co‐ordinated intercellular Ca 2+ waves that propagated across entire lobules. A similar synergism was observed between physiological concentrations of glucagon and vasopressin, where glucagon also facilitated the recruitment of hepatocytes into a Ca 2+ wave. Hepatic glucose production was significantly higher with intralobular Ca 2+ waves. We propose that inositol 1,4,5‐trisphosphate (IP 3 )‐dependent Ca 2+ signalling gives rise to an excitable medium across the functional syncytium of the hepatic lobule, co‐ordinating and amplifying the metabolic responses to multiple hormonal inputs.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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Intercellular calcium waves integrate hormonal control of glucose output in the intact liver

Gaspers

Pierobon

Thomas

2019

The Journal of Physiology

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“…No. 10-1250-01, Mercodia, Sweden) targeting "rat insulin" with plasma recoveries of 90 AE 9% as described previously (Wewer Albrechtsen et al 2016).…”

Section: Biochemical Analysismentioning

confidence: 99%

Glucagon‐like peptide‐1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP‐1 receptors

et al. 2017

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Glucagon‐like peptide‐1 (GLP‐1) is an incretin hormone increasing postprandial insulin release. GLP‐1 also induces diuresis and natriuresis in humans and rodents. The GLP‐1 receptor is extensively expressed in the renal vascular tree in normotensive rats where acute GLP‐1 treatment leads to increased mean arterial pressure (MAP) and increased renal blood flow (RBF). In hypertensive animal models, GLP‐1 has been reported both to increase and decrease MAP. The aim of this study was to examine expression of renal GLP‐1 receptors in spontaneously hypertensive rats (SHR) and to assess the effect of acute intrarenal infusion of GLP‐1. We hypothesized that GLP‐1 would increase diuresis and natriuresis and reduce MAP in SHR. Immunohistochemical staining and in situ hybridization for the GLP‐1 receptor were used to localize GLP‐1 receptors in the kidney. Sevoflurane‐anesthetized normotensive Sprague–Dawley rats and SHR received a 20 min intrarenal infusion of GLP‐1 and changes in MAP, RBF, heart rate, dieresis, and natriuresis were measured. The vasodilatory effect of GLP‐1 was assessed in isolated interlobar arteries from normo‐ and hypertensive rats. We found no expression of GLP‐1 receptors in the kidney from SHR. However, acute intrarenal infusion of GLP‐1 increased MAP, RBF, dieresis, and natriuresis without affecting heart rate in both rat strains. These results suggest that the acute renal effects of GLP‐1 in SHR are caused either by extrarenal GLP‐1 receptors activating other mechanisms (e.g., insulin) to induce the renal changes observed or possibly by an alternative renal GLP‐1 receptor.

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“…Plasma concentrations of glucagon were measured by sandwich ELISA (catalog no. 10-1281-01; Mercodia AB, Uppsala, Sweden) (22). Plasma concentrations of insulin and C-peptide were measured using ELISAs (catalog no.…”

Section: Biochemical Measurements Of Perfusion Effluents Rat Blood Amentioning

confidence: 99%

Secretin release after Roux-en-Y Gastric Bypass reveals a population of glucose-sensitive S-cells in distal small intestine

Modvig

Andersen

Grunddal

et al. 2019

Preprint

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Objective: Gastrointestinal hormones contribute to the beneficial effects of Roux-en-Y gastric bypass surgery (RYGB) on glycemic control. Secretin is secreted from duodenal S-cells in response to low luminal pH, but it is unknown whether its secretion is altered after RYGB and if secretin contributes to the post-operative improvement in glycemic control. We hypothesized that secretin secretion increases after RYGB as a result of the diversion of nutrients to more distal parts of the small intestine, and thereby affects islet hormone release. Methods:A specific secretin radioimmunoassay was developed, evaluated biochemically, and used to quantify plasma concentrations of secretin in 13 obese individuals before, 1 week after and 3 months after RYGB. Distribution of secretin and its receptor was assessed by RNA-sequencing, massspectrometry and in situ hybridization in human and rat tissues. Isolated, perfused rat intestine and pancreas were used to explore the molecular mechanism underlying glucose-induced secretin secretion and to study direct effects of secretin on glucagon, insulin and somatostatin secretion. Secretin was administered alone or in combination with GLP-1 to non-sedated rats to evaluate effects on glucose regulation.Results: Plasma postprandial secretin was more than doubled in humans after RYGB (P<0.001). The distal small intestine harbored secretin expressing cells in both rats and humans. Glucose increased secretion of secretin in a sodium-glucose co-transporter dependent manner when administered to the distal part but not into the proximal part of the rat small intestine. Secretin stimulated somatostatin secretion (fold change: 1.59, P<0.05) from the perfused rat pancreas but affected neither insulin (P=0.2) nor glucagon (P=0.97) secretion. When administered to rats in vivo, insulin secretion was attenuated and 3 glucagon secretion increased (P=0.04), while blood glucose peak time was delayed (from 15 min to 45 min) and gastric emptying time prolonged (P=0.004). Conclusion:Glucose-sensing secretin cells located in the distal part of the small intestine may contribute to increased plasma concentrations observed after RYGB. The metabolic role of the distal S-cells warrants further studies.

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Dynamics of glucagon secretion in mice and rats revealed using a validated sandwich ELISA for small sample volumes

Cited by 32 publications

References 23 publications

Intercellular calcium waves integrate hormonal control of glucose output in the intact liver

Intercellular calcium waves integrate hormonal control of glucose output in the intact liver

Glucagon‐like peptide‐1 acutely affects renal blood flow and urinary flow rate in spontaneously hypertensive rats despite significantly reduced renal expression of GLP‐1 receptors

Secretin release after Roux-en-Y Gastric Bypass reveals a population of glucose-sensitive S-cells in distal small intestine

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