Nuclear Magnetic Resonance Studies of Hepatic Glucose Metabolism in Humans

Roden, Michael

doi:10.1210/rp.56.1.219

Cited by 102 publications

(70 citation statements)

References 53 publications

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“…The latter has broad implications given that, in insulin-resistant patients and animals, decreased sensitivity to insulin-mediated suppression of hepatic glucose output is a major contributor to hyperglycemia. 50 …”

Section: Discussionmentioning

confidence: 99%

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Li¹

2003

Hepatology

831

582

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Ob/ob mice, a model for nonalcoholic fatty liver disease (NAFLD), develop intestinal bacterial overgrowth and overexpress tumor necrosis factor ␣ (TNF-␣). In animal models for alcoholic fatty liver disease (AFLD), decontaminating the intestine or inhibiting TNF-␣ improves AFLD. Because AFLD and NAFLD may have a similar pathogenesis, treatment with a probiotic (to modify the intestinal flora) or anti-TNF antibodies (to inhibit TNF-␣ activity) may improve NAFLD in ob/ob mice. To evaluate this hypothesis, 48 ob/ob mice were given either a high-fat diet alone (ob/ob controls) or the same diet ؉ VSL#3 probiotic or anti-TNF antibodies for 4 weeks. Twelve lean littermates fed a high-fat diet served as controls. Treatment with VSL#3 or anti-TNF antibodies improved liver histology, reduced hepatic total fatty acid content, and decreased serum alanine aminotransferase (ALT) levels. These benefits were associated with decreased hepatic expression of TNF-␣ messenger RNA (mRNA) in mice treated with anti-TNF antibodies but not in mice treated with VSL#3. Nevertheless, both treatments reduced activity of Jun N-terminal kinase (JNK), a TNFregulated kinase that promotes insulin resistance, and decreased the DNA binding activity of nuclear factor B (NF-B), the target of IKK␤, another TNF-regulated enzyme that causes insulin resistance. Consistent with treatment-related improvements in hepatic insulin resistance, fatty acid ␤-oxidation and uncoupling protein (UCP)-2 expression decreased after treatment with VSL#3 or anti-TNF antibodies. In conclusion, these results support the concept that intestinal bacteria induce endogenous signals that play a pathogenic role in hepatic insulin resistance and NAFLD and suggest novel therapies for these common conditions. (HEPATOLOGY 2003;37:343-350.)

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Section: Discussionmentioning

confidence: 99%

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Li¹

2003

Hepatology

831

582

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“…Note that GS associated with the intramyofibrillar glycogen particles is weakly immunodetected by the phospho-specific antibody against P-GS2ϩ2a, indicating that it is dephosphorylated at such sites and is therefore more active. This could translate into a higher glycogen re-synthesis after exhausting exercise in the intramyofibrillar particles, which are preferentially used during muscle contraction (2)(3)(4)(5). Further studies are needed to fully understand the physical binding of the different phosphorylation forms of GS to specific glycogen pools and the functional implications on muscle glycogen metabolism.…”

Section: Discussionmentioning

confidence: 99%

“…3 Defective muscle glycogen synthesis has been repeatedly reported in patients with T2DM (1)(2)(3). Several studies have shown impairments of insulin-induced glycogen synthase (GS) activation in skeletal muscle from T2DM patients and in healthy subjects at increased risk for T2DM, such as healthy obese and first-degree relatives of patients with T2DM (4 -9).…”

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confidence: 99%

Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization

Prats

Helge

Nordby

et al. 2009

Journal of Biological Chemistry

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Glycogen synthase (GS) is considered the rate-limiting enzyme in glycogenesis but still today there is a lack of understanding on its regulation. We have previously shown phosphorylation-dependent GS intracellular redistribution at the start of glycogen re-synthesis in rabbit skeletal muscle (Prats, C., Cadefau, J. A., Cussó, R., Qvortrup, K., Nielsen, J. N., Wojtaszewki, J. F., Wojtaszewki, J. F., Hardie, D. G., Stewart, G., Hansen, B. F., and Ploug, T. (2005) J. Biol. Chem. 280, 23165-23172). In the present study we investigate the regulation of human muscle GS activity by glycogen, exercise, and insulin. Using immunocytochemistry we investigate the existence and relevance of GS intracellular compartmentalization during exercise and during glycogen re-synthesis. The results show that GS intrinsic activity is strongly dependent on glycogen levels and that such regulation involves associated dephosphorylation at sites 2؉2a, 3a, and 3a ؉ 3b. Furthermore, we report the existence of several glycogen metabolism regulatory mechanisms based on GS intracellular compartmentalization. After exhausting exercise, epinephrine-induced protein kinase A activation leads to GS site 1b phosphorylation targeting the enzyme to intramyofibrillar glycogen particles, which are preferentially used during muscle contraction. On the other hand, when phosphorylated at sites 2؉2a, GS is preferentially associated with subsarcolemmal and intermyofibrillar glycogen particles. Finally, we verify the existence in human vastus lateralis muscle of the previously reported mechanism of glycogen metabolism regulation in rabbit tibialis anterior muscle. After overnight low muscle glycogen level and/or in response to exhausting exercise-induced glycogenolysis, GS is associated with spherical structures at the I-band of sarcomeres.

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“…Positron emission tomography (PET), magnetic resonance imaging (MRI), functional MRI, and advanced ultrasound techniques have emerged as useful noninvasive research methods in recent years. For example, 18 F-FDG (fluorodeoxyglucose) has been used successfully with Pet to study how insulin stimulates glucose uptake in the human liver (Bertoldo et al, 2006;Iozzo et al, 2003;Roden et al, 2001). The ability to monitor glucose and insulin real-time with advanced β-cell imaging techniques offers valuable insights into human glucose biology (Kilimnik et al, 2011;Ahlgren and Kostromina, 2011).…”

Section: Glucose Biology: Population and Environment Levelmentioning

confidence: 99%

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

Chandrasekera¹

2014

ALTEX

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Summaryonly a limited number of anti-diabetic drugs are in clinical use for humans, most of which have adverse health effects, but little impact on disease progression, and none of which cures t2DM or clearly prolongs life.the purpose of this review is to examine the underlying molecular, biological, and physiological differences -from gene regulation to whole-animal and population levels -that help explain why rodents do not serve as reliable models for studying human t2DM. this review will also address how researchers may overcome this translational barrier by employing a wide range of human-based investigational methods that will promote human-relevant discoveries while reducing -and eventually replacing -the use of animals in t2DM research.

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Nuclear Magnetic Resonance Studies of Hepatic Glucose Metabolism in Humans

Cited by 102 publications

References 53 publications

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Probiotics and antibodies to TNF inhibit inflammatory activity and improve nonalcoholic fatty liver disease

Dual Regulation of Muscle Glycogen Synthase during Exercise by Activation and Compartmentalization

Of rodents and men: Species-specific glucose regulation and type 2 diabetes research

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