Tissue-Specific Differences in the Development of Insulin Resistance in a Mouse Model for Type 1 Diabetes

Jeleník, Tomáš; Séquaris, Gilles; Kaul, Kirti; Ouwens, D. Margriet; Phielix, Esther; Kotzka, Jörg; Knebel, Birgit; Weiß, Jürgen; Reinbeck, Anna Lena; Janke, Linda; Nowotny, Peter; Partke, Hans-Joachim; Zhang, Dongyan; Shulman, Gerald I.; Szendroedi, Julia; Roden, Michael

doi:10.2337/db13-1794

Cited by 53 publications

(67 citation statements)

References 49 publications

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“…Recent studies in mouse models of type 1 diabetes described greater mitochondrial biogenesis by increased transcript levels of PGC1a and TFAM and respiratory chain complex activity as adaptation to the increased lipid and glucose flux at diabetes onset and compensation for mitochondrial energetic deficit due to enhanced gluconeogenesis (11,39). Liver biopsy samples were not available in the current study, rendering direct measurements of mitochondrial function and biogenesis impossible.…”

Section: Discussionmentioning

confidence: 87%

“…Circulating FGF21, fetuin A, selenoprotein P (SepP), and highmolecular-weight adiponectin were determined by ELISA (13,27). Peroxidation of endogenous lipids and nucleic acid oxidation were assessed from thiobarbituric acid reactive substances (TBARS) and 8-hydroxydeoxyguanosine (8-OHdG), respectively (11,13). Protein carbonyl products and oxidized LDL (oxLDL) were measured with ELISA (Biocat, Heidelberg, Germany; intra-assay coefficient of variation: 1.6 and 2.5%, respectively).…”

Section: Blood Analysesmentioning

confidence: 99%

“…However, hepatic respiratory capacity was transiently elevated and followed by augmented production of lipid peroxides in the NOD mouse, a model of human type 1 diabetes (11). Recent studies provided further evidence for enhanced hepatic energy metabolism and oxidative stress in human obesity and NAFLD (12,13).…”

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confidence: 98%

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Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes

et al. 2016

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Type 1 diabetes has been recently linked to nonalcoholic fatty liver disease (NAFLD), which is known to associate with insulin resistance, obesity, and type 2 diabetes. However, the role of insulin resistance and hyperglycemia for hepatic energy metabolism is yet unclear. To analyze early abnormalities in hepatic energy metabolism, we examined 55 patients with recently diagnosed type 1 diabetes. They underwent hyperinsulinemicnormoglycemic clamps with [6,6-2 H 2 ]glucose to assess whole-body and hepatic insulin sensitivity. Hepatic gATP, inorganic phosphate (Pi), and triglyceride concentrations (hepatocellular lipid content [HCL]) were measured with multinuclei magnetic resonance spectroscopy ( 31 P/ 1 H-MRS). Glucose-tolerant humans served as control (CON) (n = 57). Whole-body insulin sensitivity was 44% lower in patients than in age-and BMI-matched CON. Hepatic gATP was 15% reduced (2.3 6 0.6 vs. 2.7 6 0.6 mmol/L, P < 0.001), whereas hepatic Pi and HCL were similar in patients when compared with CON. Across all participants, hepatic gATP correlated negatively with glycemia and oxidized LDL. Carriers of the PPARG G allele (rs1801282) and noncarriers of PPARGC1A A allele (rs8192678) had 21 and 13% lower hepatic ATP concentrations. Variations in genes controlling oxidative metabolism contribute to a reduction in hepatic ATP in the absence of NAFLD, suggesting that alterations in hepatic mitochondrial function may precede diabetes-related liver diseases.

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Section: Discussionmentioning

confidence: 87%

Section: Blood Analysesmentioning

confidence: 99%

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Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes

et al. 2016

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“…Elevated levels of FFA contribute to increased ceramide formation (64)(65)(66). In STZ-induced diabetes, the lack of insulin releases suppression of lipolysis in adipocytes ( 67,68 ), resulting in elevated levels of FFA in plasma (69)(70)(71)(72), accompanied by expression of is not in direct equilibrium with the pool of ceramide accessible to NCDase, and that the increase in SM in mitochondrial subpopulations of diabetic hearts refl ects a suppression of SM hydrolysis rather than activation of SM synthesis. In line with this notion, there is no evidence of the SM synthase presence in mitochondria, but a novel mitochondria-associated neutral SMase has been cloned and characterized ( 12,13,83 ).…”

Section: Lactosylceramide Suppresses Mitochondrial Respiration and Dementioning

confidence: 99%

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Novgorodov

Riley

et al. 2016

Journal of Lipid Research

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This article is available online at http://www.jlr.orgCompelling epidemiological and clinical data indicate that diabetes mellitus increases the risk for cardiac dysfunction and heart failure independently of other risk factors, such as coronary disease and hypertension. Lipotoxicity is an important contributor to cardiac dysfunction in both type 1 ( 1, 2 ) and type 2 ( 3-6 ) diabetes, which are characterized by excessive accumulation of triacylglycerols, long-chain acyl-CoAs, diacylglycerols, and ceramides in myocardium. Correlation of the increased ceramide level with development of diabetic cardiomyopathy has attracted special attention in recent years because of the well-documented ability of this sphingolipid to regulate a number of cell processes, including cell proliferation, growth arrest, differentiation and apoptosis, and the mediation of responses to stress stimuli .Ceramide is a hub of sphingolipid metabolism ( 7,8 ). The balance between ceramide-producing pathways and pathways that consume it dictates ceramide level in the cell. The de novo ceramide biosynthesis pathway, one of the major ceramide producing pathways, localizes in the endoplasmic reticulum (ER) and starts with the condensation of serine and palmitoyl-CoA producing 3-ketosphingonine, which, in turn, is rapidly converted to dihydrosphingosine. Subsequent acylation of dihydrosphingosine by a set of (dihydro)ceramide synthases (CerSs) gives rise to dihydroceramide. Finally, the removal of two hydrogens from the fatty acid chain of dihydroceramide by desaturase leads to the formation of ceramide. Other possible contributors to elevated ceramide level are: hydrolysis of SM catalyzed by SMases, Abstract Sphingolipids have been implicated as key mediators of cell-stress responses and effectors of mitochondrial function. To investigate potential mechanisms underlying mitochondrial dysfunction, an important contributor to diabetic cardiomyopathy, we examined alterations of cardiac sphingolipid metabolism in a mouse with streptozotocininduced type 1 diabetes. Diabetes increased expression of desaturase 1, (dihydro)ceramide synthase (CerS)2, serine palmitoyl transferase 1, and the rate of ceramide formation by mitochondria-resident CerSs, indicating an activation of ceramide biosynthesis. However, the lack of an increase in mitochondrial ceramide suggests concomitant upregulation of ceramide-metabolizing pathways. Elevated levels of lactosylceramide, one of the initial products in the formation of glycosphingolipids were accompanied with decreased respiration and calcium retention capacity (CRC) in mitochondria from diabetic heart tissue. In baseline mitochondria, lactosylceramide potently suppressed state 3 respiration and decreased CRC, suggesting lactosylceramide as the primary sphingolipid responsible for mitochondrial defects in diabetic hearts. Moreover, knocking down the neutral ceramidase (NCDase) resulted in an increase in lactosylceramide level, suggesting a crosstalk between glucosylceramide synthase-and NCDase-mediated ceramide utiliz...

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“…As a result, the active NF-κB pathway is critical for LPS-induced resistance to hepatotoxicity (50). Additionally, a high-fat diet and obesity are associated with prolonged JNK activation and TNFinduced cell death (51,52). This alludes to an adaptation, which is lost upon repeated and/or sustained exposure to hepatotoxic stimuli leading to NAFLD and steatohepatitis.…”

Section: Figure 2 Time Courses Of Circulating Metabolites and Hormonmentioning

confidence: 99%

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

Hernández¹,

Kahl²,

Seelig³

et al. 2017

Journal of Clinical Investigation

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H and ex vivo2 H magnetic resonance spectroscopy before and during hyperinsulinemiceuglycemic clamps with isotope dilution. Mice underwent identical clamp procedures and hepatic transcriptome analyses.RESULTS. PO administration decreased whole-body, hepatic, and adipose tissue insulin sensitivity by 25%, 15%, and 34%, respectively. Hepatic triglyceride and ATP content rose by 35% and 16%, respectively. Hepatic gluconeogenesis increased by 70%, and net glycogenolysis declined by 20%. Mouse transcriptomics revealed that PO differentially regulates predicted upstream regulators and pathways, including LPS, members of the TLR and PPAR families, NF-κB, and TNF-related weak inducer of apoptosis (TWEAK). CONCLUSION.Saturated fat ingestion rapidly increases hepatic lipid storage, energy metabolism, and insulin resistance. This is accompanied by regulation of hepatic gene expression and signaling that may contribute to development of NAFLD. PO results in increased circulating TG, glucagon, and incretins. After PO administration, TG in plasma rose by 59% (area under the time curve [AUC], P < 0.001) and by 156% in chylomicrons (AUC, P = 0.009) (Figure 2A). The AUC for plasma free fatty acids (FFA) ( Figure 2B) and insulin concentrations ( Figure 2C) was unchanged, while the AUC for plasma C-peptide was 28% higher after PO ingestion versus VCL (P < 0.005, Figure 2D). Of note, FFA were increased at 300, 420, and 480 minutes. Blood glucose levels were not different between PO-and VCL-treated groups ( Figure 2E). Plasma glucagon rose by 41% (AUC, P < 0.0001) only after PO ingestion ( Figure 2F). Also, glucagon-like peptide 1 (GLP-1) and gastric inhibitory polypeptide (GIP) levels were markedly increased and remained elevated after PO ingestion (both P < 0.005) (Supplemental Figure 2; supplemental material available online with this article; https://doi.org/10.1172/ JCI89444DS1). Circulating levels of TNF-α, IL-6, fetuin-A, chemerin, omentin, and cortisol were not different between PO and VCL groups (P > 0.5 for all) (Supplemental Table 1). REGISTRATION. The Journal of Clinical Investigation C L I N I C A L M E D I C I N EPO induces insulin resistance at whole-body, liver, and adipose tissue levels. Insulin sensitivity was measured using hyperinsulinemic-euglycemic clamp tests in healthy humans. Steady state was reached (Supplemental Figure 1), and pertinent parameters were analyzed during this time. PO ingestion reduced WBIS by 25% compared with VCL treatment (P = 0.0005, Figure 3A). Furthermore, after PO, volunteers also showed a decrease of 22% (P = 0.002) in the rate of glucose disappearance (Rd), mostly due to a 33% (P = 0.01) reduction in glucose oxidation (GOX), while the rate of nonoxidative glucose disposal remained unchanged

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Tissue-Specific Differences in the Development of Insulin Resistance in a Mouse Model for Type 1 Diabetes

Cited by 53 publications

References 49 publications

Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes

Variants in Genes Controlling Oxidative Metabolism Contribute to Lower Hepatic ATP Independent of Liver Fat Content in Type 1 Diabetes

Lactosylceramide contributes to mitochondrial dysfunction in diabetes

Acute dietary fat intake initiates alterations in energy metabolism and insulin resistance

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