Efficient Analysis of Hepatic Glucose Output and Insulin Action Using a Liver Slice Culture System

Buettner, Roland; Straub, Rainer H.; Ottinger, Iris; Woenckhaus, Matthias; Schölmerich, J; Lc, Bollheimer

doi:10.1055/s-2005-861289

Cited by 11 publications

(11 citation statements)

References 17 publications

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“…To assess the substrate-selective effect of guanides/biguanides on hepatic gluconeogenesis, we prepared precision-cut liver slices from healthy overnight-fasted rats ( 34 ). Increased cytosolic redox selectively inhibits gluconeogenesis from redox-dependent substrates (lactate and glycerol), but not redox-independent substrates (alanine, dihydroxyacetone [DHA], and pyruvate) ( 20 ).…”

Section: Resultsmentioning

confidence: 99%

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

LaMoia

Butrico

Kalpage

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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Significance Metformin is the most commonly prescribed drug for the treatment of type 2 diabetes mellitus, yet the mechanism by which it lowers plasma glucose concentrations has remained elusive. Most studies to date have attributed metformin’s glucose-lowering effects to inhibition of complex I activity. Contrary to this hypothesis, we show that inhibition of complex I activity in vitro and in vivo does not reduce plasma glucose concentrations or inhibit hepatic gluconeogenesis. We go on to show that metformin, and the related guanides/biguanides, phenformin and galegine, inhibit complex IV activity at clinically relevant concentrations, which, in turn, results in inhibition of glycerol-3-phosphate dehydrogenase activity, increased cytosolic redox, and selective inhibition of glycerol-derived hepatic gluconeogenesis both in vitro and in vivo.

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Section: Resultsmentioning

confidence: 99%

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

LaMoia

Butrico

Kalpage

et al. 2022

Proc. Natl. Acad. Sci. U.S.A.

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“…PCLS show preserved liver tissue architecture and cell heterogeneity, 21 closely mimicking in vivo hepatic processing, and are therefore a widely applied model to study liver glucose metabolism and INS action. 22 The defined thickness (250 μm) is optimum to maintain liver slice function and viability in PCLS culture at least up to 24 h of incubation. 23−25 As shown in Figure 4, panel A, liver slices were able to convert ProINS−Tf and release irINS−Tf into the medium after 8 h of incubation.…”

Section: Molecular Pharmaceuticsmentioning

confidence: 99%

Proinsulin–Transferrin Fusion Protein Exhibits a Prolonged and Selective Effect on the Control of Hepatic Glucose Production in an Experimental Model of Type 1 Diabetes

2016

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An ideal basal insulin (INS) replacement therapy requires the distribution or action of exogenous INS to more closely mimic physiological INS in terms of its preferential hepatic action. In this paper, we introduce a novel strategy to exert liver-specific INS action by hepatic activation of INS's precursor, proinsulin (ProINS). We demonstrated the conversion of human ProINS-transferrin (Tf) fusion protein, ProINS-Tf, into an active and immuno-reactive form of INS-Tf in the liver via the slow Tf receptor mediated recycling pathway. ProINS-Tf displayed prolonged basal blood glucose lowering effects for up to 40 h in streptozotocin-induced type 1 diabetic mice following a single subcutaneous injection. The effect of ProINS-Tf on blood glucose levels was observed predominantly under fasting conditions, with little effect under free-feeding conditions. In addition, both the pyruvate tolerance assay in normal mice and the Akt-phosphorylation assay in H-4-II-E hepatoma cells indicated that the hepatic-activated ProINS-Tf possessed a much longer effect on the control of hepatic glucose production than INS. These results indicated that ProINS-Tf may serve as an effective and safe hepatoselective INS analog to reduce the frequency of INS injections as well as avert severe hypoglycemia episodes and other side effects frequently encountered with long-acting INS therapeutics due to their peripheral action.

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“…The described protocol demonstrates the application of murine PCLS isolation and tissue culture, with experimental procedures designed to assess both viability and utility to examine impacts of exogenous mediators of liver pathobiology, using biochemical assays, histology and qPCR. The experimental utility of PCLS tissue culture in rodents and humans has been demonstrated in a wide range of applications including experimental investigations in microRNA 12 /RNA 7 /protein expression 13 , metabolism 14 , viral infection dynamics 8,15 , infection signaling 16 , tumor invasion 10 , toxicity studies 11,12,17 , DNA damage studies 18 , cell biology 19 , and secretion studies 7 .…”

Section: Discussionmentioning

confidence: 99%

Murine Precision-Cut Liver Slices as an Ex Vivo Model of Liver Biology

Pearen

Lim

Gratte

et al. 2020

JoVE

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Efficient Analysis of Hepatic Glucose Output and Insulin Action Using a Liver Slice Culture System

Cited by 11 publications

References 17 publications

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

Metformin, phenformin, and galegine inhibit complex IV activity and reduce glycerol-derived gluconeogenesis

Proinsulin–Transferrin Fusion Protein Exhibits a Prolonged and Selective Effect on the Control of Hepatic Glucose Production in an Experimental Model of Type 1 Diabetes

Murine Precision-Cut Liver Slices as an Ex Vivo Model of Liver Biology

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