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First-pass hepatic uptake and utilization of glucose in the rat.

ABSTRACT: First-pass hepatic retention of glucose had previously been measured indirectly from the appearance of ingested labelled glucose into the systemic circulation. To determine the accuracy of the procedure, results obtained by this indirect method were compared with those of direct measurement of hepatic retention of labelled glucose given by instantaneous injection into the portal vein. In the rat, the indirect procedure gave a value of 13.7 +/- 2.3%. In the direct method, [14C]glucose was injected intraportally together with [3H]sucrose as a marker of extracellular distribution. Hepatic content of both labels was maximal immediately after administration; the content of sucrose fell to basal values by 15 s, indicating that the injected bolus had passed through the liver; the content of [14C]glucose continued to fall for 90 s. The difference in tissue retention between glucose and sucrose, representing intracellular glucose, was constant from 90 to 180 s, and indicated a first-pass retention of 13 +/- 0.7%. Thus the indirect procedure gives a reliable estimate of hepatic uptake and retention of glucose. Comparison of the time courses of hepatic content of [14C]glucose, [2-3H]glucose and [3H]sucrose indicated that 50% of portal-vein glucose enters the hepatic cells; subsequently 15% traverses the glucose/glucose 6-phosphate futile cycle, 22% is released without undergoing metabolic change and 13% is retained for metabolic purposes.

SUBMITTER: Muratoglu M

PROVIDER: S-EPMC1153010 | biostudies-other | 1986 Jan

REPOSITORIES: biostudies-other

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Project description:Aims/hypothesisRecovering functional beta cell mass is a promising approach for future diabetes therapies. The aim of the present study is to investigate the effects of adjudin, a small molecule identified in a beta cell screen using zebrafish, on pancreatic beta cells and diabetes conditions in mice and human spheroids.MethodsIn zebrafish, insulin expression was examined by bioluminescence and quantitative real-time PCR (qPCR), glucose levels were examined by direct measurements and distribution using a fluorescent glucose analogue, and calcium activity in beta cells was analysed by in vivo live imaging. Pancreatic islets of wild-type postnatal day 0 (P0) and 3-month-old (adult) mice, as well as adult db/db mice (i.e. BKS(D)-Leprdb/JOrlRj), were cultured in vitro and analysed by qPCR, glucose stimulated insulin secretion and whole mount staining. RNA-seq was performed for islets of P0 and db/db mice. For in vivo assessment, db/db mice were treated with adjudin and subjected to analysis of metabolic variables and islet cells. Glucose consumption was examined in primary human hepatocyte spheroids.ResultsAdjudin treatment increased insulin expression and calcium response to glucose in beta cells and decreased glucose levels after beta cell ablation in zebrafish. Adjudin led to improved beta cell function, decreased beta cell proliferation and glucose responsive insulin secretion by decreasing basal insulin secretion in in vitro cultured newborn mouse islets. RNA-seq of P0 islets indicated that adjudin treatment resulted in increased glucose metabolism and mitochondrial function, as well as downstream signalling pathways involved in insulin secretion. In islets from db/db mice cultured in vitro, adjudin treatment strengthened beta cell identity and insulin secretion. RNA-seq of db/db islets indicated adjudin-upregulated genes associated with insulin secretion, membrane ion channel activity and exocytosis. Moreover, adjudin promoted glucose uptake in the liver of zebrafish in an insulin-independent manner, and similarly promoted glucose consumption in primary human hepatocyte spheroids with insulin resistance. In vivo studies using db/db mice revealed reduced nonfasting blood glucose, improved glucose tolerance and strengthened beta cell identity after adjudin treatment.Conclusions/interpretationAdjudin promoted functional maturation of immature islets, improved function of dysfunctional islets, stimulated glucose uptake in liver and improved glucose homeostasis in db/db mice. Thus, the multifunctional drug adjudin, previously studied in various contexts and conditions, also shows promise in the management of diabetic states.Data availabilityRaw and processed RNA-seq data for this study have been deposited in the Gene Expression Omnibus under accession number GSE235398 ( https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE235398 ).

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First-pass hepatic uptake and utilization of glucose in the rat.

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