NSAID-Induced Enteropathy Affects Regulation of Hepatic Glucose Production by Decreasing GLP-1 Secretion

Background/Aim: Given their widespread use and their notorious effects on the lining of gut cells, including the enteroendocrine cells, we explored if chronic exposure to non-steroidal anti-inflammatory drugs (NSAIDs) affects metabolic balance in a mouse model of NSAID-induced enteropathy. Method: We administered variable NSAIDs to C57Blk/6J mice through intragastric gavage and measured their energy balance, glucose hemostasis, and GLP-1 levels. We treated them with Exendin-9 and Exendin-4 and ran a euglycemic-hyperinsulinemic clamp. Results: Chronic administration of multiple NSAIDs to C57Blk/6J mice induces ileal ulcerations and weight loss in animals consuming a high-fat diet. Despite losing weight, NSAID-treated mice exhibit no improvement in their glucose tolerance. Furthermore, glucose-stimulated (glucagon-like peptide -1) GLP-1 is significantly attenuated in the NSAID-treated groups. In addition, Exendin-9—a GLP-1 receptor antagonist—worsens glucose tolerance in the control group but not in the NSAID-treated group. Finally, the hyper-insulinemic euglycemic clamp study shows that endogenous glucose production, total glucose disposal, and their associated insulin levels were similar among an ibuprofen-treated group and its control. Exendin-4, a GLP-1 receptor agonist, reduces insulin levels in the ibuprofen group compared to their controls for the same glucose exchange rates. Conclusions: Chronic NSAID use can induce small intestinal ulcerations, which can affect intestinal GLP-1 production, hepatic insulin sensitivity, and consequently, hepatic glucose production.

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Absorption and disposition of a glucose load in the conscious dog

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1982.242.6.e398 ◽

1982 ◽

Vol 242 (6) ◽

pp. E398-E406 ◽

Cited By ~ 12

Author(s):

N. N. Abumrad ◽

A. D. Cherrington ◽

P. E. Williams ◽

W. W. Lacy ◽

D. Rabin

Keyword(s):

Hepatic Glucose Production ◽

Control Period ◽

Glucose Production ◽

Glucose Disposal ◽

Glucose Load ◽

Insulin Levels ◽

Glucose Ingestion ◽

Hepatic Glucose ◽

Glucose Output ◽

Arterial Glucose

The quantitative disposition of an intragastrically administered glucose load was studied in eight conscious 18-h fasted dogs using isotopic and arteriovenous (A-V) techniques. During the control period, the gut utilized 25% of the basal net hepatic glucose output (2.8 +/- 0.2 mg.kg-1.min-1). After glucose ingestion, 80% of the load was absorbed as glucose, 11% was converted across the gut to lactate and alanine, and 4% was oxidized to CO2. Two percent of the load remained in the gut 4 h after glucose administration and 3% was unaccounted for. During the absorptive period, net hepatic glucose balance (NHGB) varied considerably (mean range = output of 1.8 to uptake of 9.1 mg.kg-1.min-1), while endogenous hepatic glucose production (Ra hp) showed a consistent 80% suppression. The total net hepatic glucose uptake during the absorptive period (150 +/- 10 min) accounted for the disposal of 24 +/- 10% of the ingested load, and the amount of glucose escaping the splanchnic bed was 40 +/- 3%. Overall NHGB correlated positively with basal arterial glucose and insulin levels and negatively with basal arterial glycerol and FFA and with peak absorptive arterial glucose and insulin levels. These data suggest that the hepatic response to an ingested glucose load depends in part on the degree of metabolic fast of the animal at the time of glucose ingestion; the latter may be a major determinant of the roles played by the tissues in glucose disposal.

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The impact of obesity, sex, and diet on hepatic glucose production in cats

AJP Regulatory Integrative and Comparative Physiology ◽

10.1152/ajpregu.90771.2008 ◽

2009 ◽

Vol 296 (4) ◽

pp. R936-R943 ◽

Cited By ~ 28

Author(s):

Saskia Kley ◽

Margarethe Hoenig ◽

John Glushka ◽

Eunsook S. Jin ◽

Shawn C. Burgess ◽

...

Keyword(s):

Phosphoenolpyruvate Carboxykinase ◽

Citrate Synthase ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Endogenous Glucose Production ◽

Hepatic Glucose Metabolism ◽

Peripheral Insulin Resistance ◽

Pyruvate Cycling ◽

Hepatic Glucose ◽

The Impact

Obesity is a risk factor for type 2 diabetes in cats. The risk of developing diabetes is severalfold greater for male cats than for females, even after having been neutered early in life. The purpose of this study was to investigate the role of different metabolic pathways in the regulation of endogenous glucose production (EGP) during the fasted state considering these risk factors. A triple tracer protocol using 2H2O, [U-13C3]propionate, and [3,4-13C2]glucose was applied in overnight-fasted cats (12 lean and 12 obese; equal sex distribution) fed three different diets. Compared with lean cats, obese cats had higher insulin ( P < 0.001) but similar blood glucose concentrations. EGP was lower in obese cats ( P < 0.001) due to lower glycogenolysis and gluconeogenesis (GNG; P < 0.03). Insulin, body mass index, and girth correlated negatively with EGP ( P < 0.003). Female obese cats had ∼1.5 times higher fluxes through phosphoenolpyruvate carboxykinase ( P < 0.02) and citrate synthase ( P < 0.05) than male obese cats. However, GNG was not higher because pyruvate cycling was increased 1.5-fold ( P < 0.03). These results support the notion that fasted obese cats have lower hepatic EGP compared with lean cats and are still capable of maintaining fasting euglycemia, despite the well-documented existence of peripheral insulin resistance in obese cats. Our data further suggest that sex-related differences exist in the regulation of hepatic glucose metabolism in obese cats, suggesting that pyruvate cycling acts as a controlling mechanism to modulate EGP. Increased pyruvate cycling could therefore be an important factor in modulating the diabetes risk in female cats.

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Multiple metabolic effects of CGRP in conscious rats: role of glycogen synthase and phosphorylase

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1993.264.1.e1 ◽

1993 ◽

Vol 264 (1) ◽

pp. E1-E10 ◽

Cited By ~ 2

Author(s):

L. Rossetti ◽

S. Farrace ◽

S. B. Choi ◽

A. Giaccari ◽

L. Sloan ◽

...

Keyword(s):

Skeletal Muscle ◽

Glycogen Synthase ◽

Hepatic Glucose Production ◽

Glycogen Synthesis ◽

Plasma Concentrations ◽

Glucose Production ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Intracellular Glucose

Calcitonin gene-related peptide (CGRP) is a neuropeptide that is released at the neuromuscular junction in response to nerve excitation. To examine the relationship between plasma CGRP concentration and intracellular glucose metabolism in conscious rats, we performed insulin (22 pmol.kg-1.min-1) clamp studies combined with the infusion of 0, 20, 50, 100, 200, and 500 pmol.kg-1.min-1 CGRP (plasma concentrations ranging from 2 x 10(-11) to 5 x 10(-9) M). CGRP antagonized insulin's suppression of hepatic glucose production at plasma concentrations (approximately 10(-10) M) that are only two- to fivefold its basal portal concentration. Insulin-mediated glucose disposal was decreased by 20-32% when CGRP was infused at 50 pmol.kg-1.min-1 (plasma concentration 3 x 10(-10) M) or more. The impairment in insulin-stimulated glycogen synthesis in skeletal muscle accounted for all of the CGRP-induced decrease in glucose disposal, while whole body glycolysis was increased despite the reduction in total glucose uptake. The muscle glucose 6-phosphate concentration progressively increased during the CGRP infusions. CGRP inhibited insulin-stimulated glycogen synthase in skeletal muscle with a 50% effective dose of 1.9 +/- 0.36 x 10(-10) M. This effect on glycogen synthase was due to a reduction in enzyme affinity for UDP-glucose, with no changes in the maximal velocity. In vitro CGRP stimulated both hepatic and skeletal muscle adenylate cyclase in a dose-dependent manner. These data suggest that 1) CGRP is a potent antagonist of insulin at the level of muscle glycogen synthesis and hepatic glucose production; 2) inhibition of glycogen synthase is its major biochemical action in skeletal muscle; and 3) these effects are present at concentrations of the peptide that may be in the physiological range for portal vein and skeletal muscle. These data underscore the potential role of CGRP in the physiological modulation of intracellular glucose metabolism.

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Nasal insulin administration does not affect hepatic glucose production at systemic fasting insulin levels

Diabetes Obesity and Metabolism ◽

10.1111/dom.13615 ◽

2019 ◽

Vol 21 (4) ◽

pp. 993-1000

Author(s):

Peter Plomgaard ◽

Jakob S. Hansen ◽

Bodil Ingerslev ◽

Jens O. Clemmesen ◽

Niels H. Secher ◽

...

Keyword(s):

Hepatic Glucose Production ◽

Glucose Production ◽

Fasting Insulin ◽

Insulin Administration ◽

Insulin Levels ◽

Hepatic Glucose

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Effects of norepinephrine infusion on in vivo insulin sensitivity and responsiveness

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1990.259.2.e210 ◽

1990 ◽

Vol 259 (2) ◽

pp. E210-E215 ◽

Cited By ~ 5

Author(s):

J. R. Lupien ◽

M. F. Hirshman ◽

E. S. Horton

Keyword(s):

Insulin Sensitivity ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Disposal ◽

Glucose Turnover ◽

Adrenergic Blockade ◽

Sprague Dawley ◽

Euglycemic Hyperinsulinemic Clamp ◽

Peripheral Tissues

The effect of a continuous infusion of norepinephrine (NE) on glucose disposal in vivo was examined in conscious restrained rats using the euglycemic-hyperinsulinemic clamp technique. NE, 1,000 micrograms.kg-1.day-1 (130 nmol.kg-1.h-1) or vehicle (CO) was infused for 10 days in adult male Sprague-Dawley rats using subcutaneously implanted osmotic minipumps. Body weight and food intake were similar in both groups of animals throughout the study. Fasting basal plasma glucose and insulin concentrations were similar in both groups. However, basal hepatic glucose production (HGP) was increased by NE treatment (9.03 +/- 0.63 vs. 13.20 +/- 1.15 mg.kg-1.min-1, P less than 0.05, CO vs. NE, respectively). Insulin infusions of 2, 6, and 200 mU.kg-1.min-1 suppressed HGP to the same degree in both groups. During 2, 6, and 200 mU.kg-1.h-1 insulin infusions the glucose disposal rate was 65, 60, and 13% greater in NE-treated animals than in controls. Acute beta-adrenergic blockade with propranolol infused at 405 nmol.kg-1.h-1 during the glucose clamps did not normalize glucose disposal. These results demonstrate that chronic NE infusion is associated with increased basal glucose turnover and increased insulin sensitivity of peripheral tissues.

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Effects of acute running exercise on whole body insulin action in obese male SHHF/Mcc-facp rats

Journal of Applied Physiology ◽

10.1152/jappl.1994.77.2.534 ◽

1994 ◽

Vol 77 (2) ◽

pp. 534-541 ◽

Cited By ~ 14

Author(s):

J. Gao ◽

W. M. Sherman ◽

S. A. McCune ◽

K. Osei

Keyword(s):

Heart Failure ◽

Insulin Sensitivity ◽

Acute Exercise ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Whole Body ◽

Glucose Disposal ◽

Hepatic Glucose ◽

Insulin Responsiveness ◽

Obese Male

This study utilized the obese male spontaneously hypertensive heart failure rat (SHHF/Mcc-facp), which has metabolic features very similar to human non-insulin-dependent diabetes mellitus. The purpose of this study was to assess the insulin sensitivity and responsiveness of whole body glucose disposal and insulin suppressability of hepatic glucose production with use of the euglycemic-hyperinsulinemic clamp procedure in 12- to 15-wk-old SHHF/Mcc-facp rats at rest (OS) and 2.5 h after a single session of acute exercise (OE). Lean male SHHF/Mcc-facp rats were sedentary (LS) control animals. At least three clamps producing different insulin-stimulated responses were performed on each animal in a randomized order. At this age the obese animals are normotensive and have not developed congestive heart failure. Compared with LS, OS were significantly hyperglycemic and hyperinsulinemic and insulin sensitivity and responsiveness of whole body glucose uptake and insulin suppressability of hepatic glucose production were significantly decreased. Compared with LS and OS, acute exercise significantly decreased resting plasma glucose but did not alter plasma insulin. Compared with OS, acute exercise significantly increased the insulin responsiveness of whole body glucose disposal but did not affect the sensitivity of whole body glucose disposal or insulin suppressability of hepatic glucose production. Compared with LS, however, acute exercise did not “normalize” the insulin responsiveness of whole body glucose disposal. Thus a single acute exercise session improves but does not normalize whole body insulin resistance in the SHHF/Mcc-facp rat.

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Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight-Loss

10.2337/figshare.15070008 ◽

2021 ◽

Author(s):

Rachel Ben-Haroush Schyr ◽

Abbas Al-Kurd ◽

Botros Moalem ◽

Anna Permyakova ◽

Hadar Israeli ◽

...

Keyword(s):

Weight Loss ◽

Sleeve Gastrectomy ◽

Hepatic Steatosis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Clearance ◽

Insulin Metabolism ◽

Insulin Levels ◽

Hepatic Glucose ◽

Hepatic Insulin Clearance

Bariatric surgeries induce weight loss which is associated with an improvement in hepatic steatosis and reduction in hepatic glucose production. It is not clear whether these outcomes are entirely due to weight-loss, or whether the new anatomy imposed by the surgery contributes to the improvement in the metabolic function of the liver. We performed vertical sleeve gastrectomy (VSG) on obese mice provided with a high-fat high-sucrose diet, and compared them to diet and weight-matched sham-operated mice (WMS). 40 days after surgery, VSG-operated mice displayed lesser hepatic steatosis compared to WMS. By measuring the fasting glucose and insulin levels in the blood vessels feeding and draining the liver we showed directly that hepatic glucose production was suppressed after VSG. Insulin levels were elevated in the portal vein, and hepatic insulin clearance was elevated in VSG-operated mice. The hepatic expression of genes associated with insulin clearance was upregulated. We repeated the experiment in lean mice and observed that portal insulin and glucagon are elevated, but only insulin clearance is increased in VSG-operated mice. In conclusion, direct measurement of glucose and insulin in the blood entering and leaving the liver shows that VSG affects glucose and insulin metabolism through weight-loss and diet-independent mechanisms.

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Hepatocyte serine palmitoyl transferase 2 deficiency promotes liver C16:0-ceramide accumulation through sphingomyelin hydrolysis and leads to liver damage and dysfunction in mice

10.1101/2021.09.16.460588 ◽

2021 ◽

Author(s):

Justine Lallement ◽

Ilyès Raho ◽

Gregory Merlen ◽

Dominique Rainteau ◽

Mikael Croyal ◽

...

Keyword(s):

Bile Acid ◽

Glucose Tolerance ◽

Metabolic Disorders ◽

De Novo ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Lipid Absorption ◽

Compensatory Mechanism ◽

Hepatic Glucose

Objectives: Ceramides have been shown as lipotoxic inducers, which can trigger apoptosis, inflammation and disturb numerous cell signalling pathways leading to metabolic disorders such as type 2 diabetes (T2D). In this study, we aimed to determine the role of de novo hepatic ceramide synthesis on energy and liver homeostasis in mice. Methods: In order to investigate hepatic role of de novo ceramides synthesis, we generated mice lacking serine palmitoyltransferase 2 (Sptlc2) in hepatocytes using the cre-lox system. SPTLC2 allows condensation of serine and palmitoylCoA and is the rate limiting-enzyme necessary for ceramide de novo synthesis. Sptlc2ΔHep and their littermate controls were fed with high fat diet (HFD) to induce metabolic disorders. Liver ceramides content and metabolic parameters as glucose tolerance, insulin sensitivity, and hepatic glucose production were assessed. As ceramides may have impact on bile acids (BA), we investigated BA pool composition, synthesis and transport. Finally, inflammation and apoptosis were measured in the liver using western blot analysis, pro-inflammatory cytokines expression level and immunohistochemistry. Results: Despite lower expression of hepatic Sptlc2, we observed an increased concentration of hepatic ceramides, especially C16:0-ceramide. Hepatic deletion of Sptlc2 in mice was also associated with an increased neutral sphingomyelinase 2 (nSmase2) expression, and a decreased sphingomyelin content in the liver. We showed that Sptlc2ΔHep mice are protected against body mass gain normally induced by HFD and displayed a decreased body fat mass. BA hydrophobicity was drastically decreased in Sptlc2ΔHep mice, and was associated with a defect in lipid absorption. In addition, an important increase of tauro-murocholic acid T-MCA in BA pool composition of Sptlc2ΔHep mice was associated with a downregulation of the nuclear bile acid receptor FXR target genes in ileum and liver. Sptlc2 deficiency also enhanced glucose tolerance and attenuated hepatic glucose production in an insulin-independent manner. Finally, Sptlc2 disruption promoted progressive development of hepatic fibrosis, apoptosis and inflammation in an age-related manner. Conclusion: Our data demonstrate for the first time a potential compensatory mechanism to regulate hepatic ceramides content from sphingomyelin hydrolysis. In addition, our results highlight the role of hepatic sphingolipid modulation on hepatic glucose production through bile acid composition changes.

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Sleeve Gastrectomy Suppresses Hepatic Glucose Production and Increases Hepatic Insulin Clearance Independent of Weight-Loss

10.2337/figshare.15070008.v1 ◽

2021 ◽

Author(s):

Rachel Ben-Haroush Schyr ◽

Abbas Al-Kurd ◽

Botros Moalem ◽

Anna Permyakova ◽

Hadar Israeli ◽

...

Keyword(s):

Weight Loss ◽

Sleeve Gastrectomy ◽

Hepatic Steatosis ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Insulin Clearance ◽

Insulin Metabolism ◽

Insulin Levels ◽

Hepatic Glucose ◽

Hepatic Insulin Clearance

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Abnormal regulation of HGP by hyperglycemia in mice with a disrupted glucokinase allele

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.4.e743 ◽

1997 ◽

Vol 273 (4) ◽

pp. E743-E750 ◽

Cited By ~ 10

Author(s):

Luciano Rossetti ◽

Wei Chen ◽

Meizhu Hu ◽

Meredith Hawkins ◽

Nir Barzilai ◽

...

Keyword(s):

Insulin Secretion ◽

Hepatic Glucose Production ◽

Glucose Production ◽

Glucose Disposal ◽

Relative Role ◽

Β Cells ◽

Plasma Insulin Concentration ◽

Hyperglycemic Clamp ◽

Human Diabetes ◽

Hepatic Glucose

Glucokinase (GK) catalyzes the phosphorylation of glucose in β-cells and hepatocytes, and mutations in the GK gene have been implicated in a form of human diabetes. To investigate the relative role of partial deficiencies in the hepatic vs. pancreatic GK activity, we examined insulin secretion, glucose disposal, and hepatic glucose production (HGP) in response to hyperglycemia in transgenic mice 1) with one disrupted GK allele, which manifest decreased GK activity in both liver and β-cells (GK+/−), and 2) with decreased GK activity selectively in β-cells (RIP-GKRZ). Liver GK activity was decreased by 35–50% in the GK+/− but not in the RIP-GKRZ compared with wild type (WT) mice. Hyperglycemic clamp studies were performed in conscious mice with or without concomitant pancreatic clamp. In all studies [3-3H]glucose was infused to measure the rate of appearance of glucose and HGP during 80 min of euglycemia (Glc ∼5 mM) followed by 90 min of hyperglycemia (Glc ∼17 mM). During hyperglycemic clamp studies, steady-state plasma insulin concentration, rate of glucose infusion, and rate of glucose disappearance (Rd) were decreased in both GK+/− and RIP-GKRZ compared with WT mice. However, whereas the basal HGP (at euglycemia) averaged ∼22 mg ⋅ kg−1 ⋅ min−1in all groups, during hyperglycemia HGP was suppressed by only 48% in GK+/− compared with ∼70 and 65% in the WT and RIP-GKRZ mice, respectively. During the pancreatic clamp studies, the ability of hyperglycemia per se to increase Rd was similar in all groups. However, hyperglycemia inhibited HGP by only 12% in GK+/−, vs. 42 and 45%, respectively, in the WT and RIP-GKRZ mice. We conclude that, although impaired glucose-induced insulin secretion is common to both models of decreased pancreatic GK activity, the marked impairment in the ability of hyperglycemia to inhibit HGP is due to the specific decrease in hepatic GK activity.

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