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  • 1
    Online Resource
    Online Resource
    Redox state and altered pyruvate metabolism contribute to a dose-dependent metformin-induced lactate production of human myotubes
    American Physiological Society ; 2023
    In:  American Journal of Physiology-Cell Physiology Vol. 325, No. 4 ( 2023-10-01), p. C1131-C1143
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 325, No. 4 ( 2023-10-01), p. C1131-C1143
    Abstract: Metformin-induced glycolysis and lactate production can lead to acidosis as a life-threatening side effect, but slight increases in blood lactate levels in a physiological range were also reported in metformin-treated patients. However, how metformin increases systemic lactate concentrations is only partly understood. Because human skeletal muscle has a high capacity to produce lactate, the aim was to elucidate the dose-dependent regulation of metformin-induced lactate production and the potential contribution of skeletal muscle to blood lactate levels under metformin treatment. This was examined by using metformin treatment (16–776 μM) of primary human myotubes and by 17 days of metformin treatment in humans. As from 78 µM, metformin induced lactate production and secretion and glucose consumption. Investigating the cellular redox state by mitochondrial respirometry, we found metformin to inhibit the respiratory chain complex I (776 µM, P 〈 0.01) along with decreasing the [NAD + ]:[NADH] ratio (776 µM, P 〈 0.001). RNA sequencing and phospho-immunoblot data indicate inhibition of pyruvate oxidation mediated through phosphorylation of the pyruvate dehydrogenase (PDH) complex (39 µM, P 〈 0.01). On the other hand, in human skeletal muscle, phosphorylation of PDH was not altered by metformin. Nonetheless, blood lactate levels were increased under metformin treatment ( P 〈 0.05). In conclusion, the findings suggest that metformin-induced inhibition of pyruvate oxidation combined with altered cellular redox state shifts the equilibrium of the lactate dehydrogenase (LDH) reaction leading to a dose-dependent lactate production in primary human myotubes. NEW & NOTEWORTHY Metformin shifts the equilibrium of lactate dehydrogenase (LDH) reaction by low dose-induced phosphorylation of pyruvate dehydrogenase (PDH) resulting in inhibition of pyruvate oxidation and high dose-induced increase in NADH, which explains the dose-dependent lactate production of differentiated human skeletal muscle cells.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00186.2023
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2023
    detail.hit.zdb_id: 1477334-X
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  • 2
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    Online Resource
    Pancreatic fat cells of humans with type 2 diabetes display reduced adipogenic and lipolytic activity
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Cell Physiology Vol. 320, No. 6 ( 2021-06-01), p. C1000-C1012
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 320, No. 6 ( 2021-06-01), p. C1000-C1012
    Abstract: Obesity, especially visceral fat accumulation, increases the risk of type 2 diabetes (T2D). The purpose of this study was to investigate the impact of T2D on the pancreatic fat depot. Pancreatic fat pads from 17 partial pancreatectomized patients (PPP) were collected, pancreatic preadipocytes isolated, and in vitro differentiated. Patients were grouped using HbA1c into normal glucose tolerant (NGT), prediabetic (PD), and T2D. Transcriptome profiles of preadipocytes and adipocytes were assessed by RNAseq. Insulin sensitivity was estimated by quantifying AKT phosphorylation on Western blots. Lipogenic capacity was assessed with oil red O staining, lipolytic activity via fatty acid release. Secreted factors were measured using ELISA. Comparative transcriptome analysis of preadipocytes and adipocytes indicates defective upregulation of genes governing adipogenesis ( NR1H3), lipogenesis ( FASN, SCD, ELOVL6, and FADS1), and lipolysis ( LIPE) during differentiation of cells from T2D–PPP. In addition, the ratio of leptin/adiponectin mRNA was higher in T2D than in NGT–PPP. Preadipocytes and adipocytes of NGT–PPP were more insulin sensitive than T2D–PPP cells in regard to AKT phosphorylation. Triglyceride accumulation was similar in NGT and T2D adipocytes. Despite a high expression of the receptors NPR1 and NPR2 in NGT and T2D adipocytes, lipolysis was stimulated by ANP 1.74-fold in NGT cells only. This stimulation was further increased by the PDE5 inhibitor dipyridamole (3.09-fold). Dipyridamole and forskolin increased lipolysis receptor independently 1.88-fold and 1.48-fold, respectively, solely in NGT cells. In conclusion, the metabolic status persistently affects differentiation and lipolysis of pancreatic adipocytes. These alterations could aggravate the development of T2D.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00595.2020
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477334-X
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  • 3
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    Online Resource
    A high-fat, ketogenic diet causes hepatic insulin resistance in mice, despite increasing energy expenditure and preventing weight gain
    American Physiological Society ; 2010
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 299, No. 5 ( 2010-11), p. E808-E815
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 299, No. 5 ( 2010-11), p. E808-E815
    Abstract: Low-carbohydrate, high-fat ketogenic diets (KD) have been suggested to be more effective in promoting weight loss than conventional caloric restriction, whereas their effect on hepatic glucose and lipid metabolism and the mechanisms by which they may promote weight loss remain controversial. The aim of this study was to explore the role of KD on liver and muscle insulin sensitivity, hepatic lipid metabolism, energy expenditure, and food intake. Using hyperinsulinemic-euglycemic clamps, we studied insulin action in mice fed a KD or regular chow (RC). Body composition was assessed by 1 H magnetic resonance spectroscopy. Despite being 15% lighter ( P 〈 0.001) than RC-fed mice because of a 17% increase in energy expenditure ( P 〈 0.001), KD-fed mice manifested severe hepatic insulin resistance, as reflected by decreased suppression (0% vs. 100% in RC-fed mice, P 〈 0.01) of endogenous glucose production during the clamp. Hepatic insulin resistance could be attributed to a 350% increase in hepatic diacylglycerol content ( P 〈 0.001), resulting in increased activation of PKCε ( P 〈 0.05) and decreased insulin receptor substrate-2 tyrosine phosphorylation ( P 〈 0.01). Food intake was 56% ( P 〈 0.001) lower in KD-fed mice, despite similar caloric intake, and could partly be attributed to a more than threefold increase ( P 〈 0.05) in plasma N-acylphosphatidylethanolamine concentrations. In conclusion, despite preventing weight gain in mice, KD induces hepatic insulin resistance secondary to increased hepatic diacylglycerol content. Given the key role of nonalcoholic fatty liver disease in the development of type 2 diabetes and the widespread use of KD for the treatment of obesity, these results may have potentially important clinical implications.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00361.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2010
    detail.hit.zdb_id: 1477331-4
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  • 4
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    Online Resource
    Nutritional and metabolic regulation of the metabolite dimethylguanidino valeric acid: an early marker of cardiometabolic disease
    American Physiological Society ; 2020
    In:  American Journal of Physiology-Endocrinology and Metabolism Vol. 319, No. 3 ( 2020-09-01), p. E509-E518
    Details
    In: American Journal of Physiology-Endocrinology and Metabolism, American Physiological Society, Vol. 319, No. 3 ( 2020-09-01), p. E509-E518
    Abstract: Dimethylguanidino valeric acid (DMGV) is a marker of fatty liver disease, incident coronary artery disease, cardiovascular mortality, and incident diabetes. Recently, it was reported that circulating DMGV levels correlated positively with consumption of sugary beverages and negatively with intake of fruits and vegetables in three Swedish community-based cohorts. Here, we validate these results in the Framingham Heart Study Third Generation Cohort. Furthermore, in mice, diets rich in sucrose or fat significantly increased plasma DMGV concentrations. DMGV is the product of metabolism of asymmetric dimethylarginine (ADMA) by the hepatic enzyme AGXT2. ADMA can also be metabolized to citrulline by the cytoplasmic enzyme DDAH1. We report that a high-sucrose diet induced conversion of ADMA exclusively into DMGV (supporting the relationship with sugary beverage intake in humans), while a high-fat diet promoted conversion of ADMA to both DMGV and citrulline. On the contrary, replacing dietary native starch with high-fiber-resistant starch increased ADMA concentrations and induced its conversion to citrulline, without altering DMGV concentrations. In a cohort of obese nondiabetic adults, circulating DMGV concentrations increased and ADMA levels decreased in those with either liver or muscle insulin resistance. This was similar to changes in DMGV and ADMA concentrations found in mice fed a high-sucrose diet. Sucrose is a disaccharide of glucose and fructose. Compared with glucose, incubation of hepatocytes with fructose significantly increased DMGV production. Overall, we provide a comprehensive picture of the dietary determinants of DMGV levels and association with insulin resistance.
    Type of Medium: Online Resource
    ISSN: 0193-1849 , 1522-1555
    URL: Article
    DOI: 10.1152/ajpendo.00207.2020
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2020
    detail.hit.zdb_id: 1477331-4
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  • 5
    Online Resource
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    Experimental nephrotic syndrome leads to proteolytic activation of the epithelial Na + channel in the mouse kidney
    American Physiological Society ; 2021
    In:  American Journal of Physiology-Renal Physiology Vol. 321, No. 4 ( 2021-10-01), p. F480-F493
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 321, No. 4 ( 2021-10-01), p. F480-F493
    Abstract: Proteolytic activation of the renal epithelial Na + channel (ENaC) involves cleavage events in its α- and γ-subunits and is thought to mediate Na + retention in nephrotic syndrome (NS). However, the detection of proteolytically processed ENaC in kidney tissue from nephrotic mice has been elusive so far. We used a refined Western blot technique to reliably discriminate full-length α-ENaC and γ-ENaC and their cleavage products after proteolysis at their proximal and distal cleavage sites (designated from the NH 2 -terminus), respectively. Proteolytic ENaC activation was investigated in kidneys from mice with experimental NS induced by doxorubicin or inducible podocin deficiency with or without treatment with the serine protease inhibitor aprotinin. Nephrotic mice developed Na + retention and increased expression of fragments of α-ENaC and γ-ENaC cleaved at both the proximal cleavage site and, more prominently, the distal cleavage site, respectively. Treatment with aprotinin but not with the mineralocorticoid receptor antagonist canrenoate prevented Na + retention and upregulation of the cleavage products in nephrotic mice. Increased expression of cleavage products of α-ENaC and γ-ENaC was similarly found in healthy mice treated with a low-salt diet, sensitive to mineralocorticoid receptor blockade. In human nephrectomy specimens, γ-ENaC was found in the full-length form and predominantly cleaved at its distal cleavage site. In conclusion, murine experimental NS leads to aprotinin-sensitive proteolytic activation of ENaC at both proximal and, more prominently, distal cleavage sites of its α- and γ-subunit, most likely by urinary serine protease activity or proteasuria. NEW & NOTEWORTHY This study demonstrates that murine experimental nephrotic syndrome leads to aprotinin-sensitive proteolytic activation of the epithelial Na + channel at both the α- and γ-subunit, most likely by urinary serine protease activity or proteasuria.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00199.2021
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2021
    detail.hit.zdb_id: 1477287-5
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