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1.
Undersea Hyperb Med ; 46(4): 437-445, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31509900

RESUMO

Introduction: To determine if hyperbaric oxygen (HBO2) therapy has an effect on diabetic blood glucose levels (BGL) and, if so, the extent of this effect. Also, to examine factors that exacerbate any observed effect. Methods: This was a retrospective review of prospectively collected quality data on diabetics undergoing HBO2. Pre- and post-treatment BGL were recorded. Pre-treatment BGL ⟨120 mg/dL received glucose supplementation. Hypoglycemia was defined as BGL ⟨70 mg/dL. BGL ⟨90 mg/dL was included as an elevated hypoglycemia threshold. Results: 77 patients representing 1,825 treatments were included for analysis. No patient had deleterious side effects or required emergency care. BGL decreased in 75.4% of treatments in this group, with a median decrease of 25 mg/dL (IQR=54 mg/dL; range of decreased 374 mg/dL to increased 240 mg/dL). A statistically significant greater percentage of treatments of patients with type 2 diabetes resulted in a decrease in BGL (1598 or 77.5%) compared to treatments of patients with type 1 diabetes (169 or 51.5%) (χ2(1, N=1767) =55.37, p⟨0.001). 1.1% of treatments had post-HBO2 serum glucose ⟨90 mg/dL, and 0.2% of treatments had post-HBO2 serum glucose ⟨70 mg/dL. The majority (70%) of patients with post-HBO2 BGL ⟨90 mg/dL were maintained on insulin alone (χ2(2, N=20) =12.4, p=0.002). Well-controlled diabetics (i.e., those with all BGLs within 50 mg/dL over all pre-HBO2 treatments) had no post-HBO2 BGL ⟨70 mg/dL or ⟨90 mg/dL. Conclusion: Our results suggest that HBO2 does not cause a clinically significant decrease in diabetic patient BGL. No patient in our study had deleterious side effects or required emergency care. We found that glucose level of ⟨90 mg/dL occurred more often in those who use insulin. Hyperbaric patients who exhibit consistent BGL values may represent a group who could be managed similarly to the non-diabetic population.


Assuntos
Glicemia/análise , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 2/sangue , Oxigenação Hiperbárica , Idoso , Diabetes Mellitus/induzido quimicamente , Diabetes Mellitus Tipo 1/tratamento farmacológico , Diabetes Mellitus Tipo 2/tratamento farmacológico , Feminino , Humanos , Oxigenação Hiperbárica/efeitos adversos , Oxigenação Hiperbárica/estatística & dados numéricos , Hipoglicemia/sangue , Hipoglicemia/induzido quimicamente , Hipoglicemiantes/uso terapêutico , Insulina/uso terapêutico , Masculino , Estudos Retrospectivos , Esteroides/efeitos adversos
2.
Mol Metab ; 5(10): 926-936, 2016 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-27689005

RESUMO

OBJECTIVE: Plasma levels of branched-chain amino acids (BCAA) are consistently elevated in obesity and type 2 diabetes (T2D) and can also prospectively predict T2D. However, the role of BCAA in the pathogenesis of insulin resistance and T2D remains unclear. METHODS: To identify pathways related to insulin resistance, we performed comprehensive gene expression and metabolomics analyses in skeletal muscle from 41 humans with normal glucose tolerance and 11 with T2D across a range of insulin sensitivity (SI, 0.49 to 14.28). We studied both cultured cells and mice heterozygous for the BCAA enzyme methylmalonyl-CoA mutase (Mut) and assessed the effects of altered BCAA flux on lipid and glucose homeostasis. RESULTS: Our data demonstrate perturbed BCAA metabolism and fatty acid oxidation in muscle from insulin resistant humans. Experimental alterations in BCAA flux in cultured cells similarly modulate fatty acid oxidation. Mut heterozygosity in mice alters muscle lipid metabolism in vivo, resulting in increased muscle triglyceride accumulation, increased plasma glucose, hyperinsulinemia, and increased body weight after high-fat feeding. CONCLUSIONS: Our data indicate that impaired muscle BCAA catabolism may contribute to the development of insulin resistance by perturbing both amino acid and fatty acid metabolism and suggest that targeting BCAA metabolism may hold promise for prevention or treatment of T2D.

3.
Cephalalgia ; 32(12): 924-31, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-22833613

RESUMO

BACKGROUND: The frequency of migraine headaches is higher in women than in men and in susceptible women attacks are related to changes in ovarian hormone levels. Intracranial mast cells (MCs) are likely to have a role in migraine headache genesis, and changes in the dural MC population might influence headache susceptibility. The present study thus tested the hypothesis that sex and ovarian hormones influence the density and phenotypic makeup of dural MCs. METHODS: Histochemistry combined with quantitative analyses was used to investigate sex differences, estrous cycle and ovarian hormones on dural MC density, phenotype and degranulation level in male and female rats. RESULTS: Our data show that in female rats, dural MC density fluctuates during the estrous cycle and is overall higher than in males. In ovariectomized rats, estradiol, but not progesterone, promoted an increase in dural MC density. This effect was abolished by a splenectomy, suggesting estrogen-related recruitment of MCs from the spleen. Finally, our data suggest that the phenotypic make up of dural MCs, which represents the level of cellular maturity, is also governed by changes in estrogen levels. CONCLUSIONS: Given the potential role of dural MCs in triggering headache, our data suggest that estrogen-related modulation of dural MC density and phenotypic makeup could have a role in mediating the higher frequency and severity of headaches such as migraine, in women.


Assuntos
Encéfalo/citologia , Dura-Máter/citologia , Estrogênios/fisiologia , Ciclo Estral/fisiologia , Mastócitos/citologia , Caracteres Sexuais , Animais , Encéfalo/metabolismo , Dura-Máter/metabolismo , Feminino , Masculino , Transtornos de Enxaqueca/metabolismo , Transtornos de Enxaqueca/patologia , Ovariectomia , Ratos , Ratos Sprague-Dawley , Baço/citologia
4.
Cell Metab ; 15(3): 267-269, 2012 Mar 07.
Artigo em Inglês | MEDLINE | ID: mdl-25960695

RESUMO

We would like to respond to Brosch et al. regarding our manuscript "Expression of the Splicing Factor Gene SFRS10 Is Reduced in Human Obesity and Contributes to Enhanced Lipogenesis" (Pihlajamäki et al., 2011b). Brosch performed RT-PCR in liver samples from 13 lean and 34 obese individuals, finding no differences in SFRS10 or LPIN1 expression. We wish to address points raised by Brosch, including experimental strategy and analysis of human SFRS10 expression.

5.
Cell Metab ; 14(2): 208-18, 2011 Aug 03.
Artigo em Inglês | MEDLINE | ID: mdl-21803291

RESUMO

Alternative mRNA splicing provides transcript diversity and may contribute to human disease. We demonstrate that expression of several genes regulating RNA processing is decreased in both liver and skeletal muscle of obese humans. We evaluated a representative splicing factor, SFRS10, downregulated in both obese human liver and muscle and in high-fat-fed mice, and determined metabolic impact of reduced expression. SFRS10-specific siRNA induces lipogenesis and lipid accumulation in hepatocytes. Moreover, Sfrs10 heterozygous mice have increased hepatic lipogenic gene expression, VLDL secretion, and plasma triglycerides. We demonstrate that LPIN1, a key regulator of lipid metabolism, is a splicing target of SFRS10; reduced SFRS10 favors the lipogenic ß isoform of LPIN1. Importantly, LPIN1ß-specific siRNA abolished lipogenic effects of decreased SFRS10 expression. Together, our results indicate that reduced expression of SFRS10, as observed in tissues from obese humans, alters LPIN1 splicing, induces lipogenesis, and therefore contributes to metabolic phenotypes associated with obesity.


Assuntos
Lipídeos/biossíntese , Lipogênese/genética , Proteínas do Tecido Nervoso/genética , Obesidade/genética , Fosfatidato Fosfatase/genética , Proteínas de Ligação a RNA/genética , Adulto , Idoso , Animais , Linhagem Celular Tumoral , Feminino , Regulação da Expressão Gênica , Humanos , Lipídeos/sangue , Lipídeos/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Proteínas do Tecido Nervoso/biossíntese , Obesidade/metabolismo , Processamento de RNA , Proteínas de Ligação a RNA/biossíntese , Fatores de Processamento de Serina-Arginina
6.
J Clin Invest ; 121(3): 918-29, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21393865

RESUMO

Insulin resistance in skeletal muscle is a key phenotype associated with type 2 diabetes (T2D) for which the molecular mediators remain unclear. We therefore conducted an expression analysis of human muscle biopsies from patients with T2D; normoglycemic but insulin-resistant subjects with a parental family history (FH(+)) of T2D; and family history-negative control individuals (FH(­)). Actin cytoskeleton genes regulated by serum response factor (SRF) and its coactivator megakaryoblastic leukemia 1 (MKL1) had increased expression in T2D and FH(+) groups. Furthermore, striated muscle activator of Rho signaling (STARS), an activator of SRF, was upregulated in T2D and FH(+) and was inversely correlated with insulin sensitivity. Skeletal muscle from insulin-resistant mice recapitulated this gene expression pattern and showed reduced G-actin and increased nuclear localization of MKL1, each of which regulates SRF activity. Overexpression of MKL1 or reduction in G-actin decreased insulin-stimulated Akt phosphorylation, whereas reduction of STARS expression increased insulin signaling and glucose uptake. Pharmacological SRF inhibition by CCG-1423 reduced nuclear MKL1 and improved glucose uptake and tolerance in insulin-resistant mice in vivo. Thus, SRF pathway alterations are linked to insulin resistance, may contribute to T2D pathogenesis, and could represent therapeutic targets.


Assuntos
Regulação da Expressão Gênica , Músculo Esquelético/metabolismo , Fator de Resposta Sérica/metabolismo , Actinas/metabolismo , Animais , Biópsia , Estudos de Coortes , Citoesqueleto/metabolismo , Glucose/metabolismo , Humanos , Insulina/metabolismo , Resistência à Insulina , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fosforilação , Ratos , Transdução de Sinais
7.
J Clin Endocrinol Metab ; 94(9): 3521-9, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19549744

RESUMO

CONTEXT: Fatty liver is an important complication of obesity; however, regulatory mechanisms mediating altered gene expression patterns have not been identified. OBJECTIVE: The aim of the study was to identify novel transcriptional changes in human liver that could contribute to hepatic lipid accumulation and associated insulin resistance, type 2 diabetes, and nonalcoholic steatohepatitis. DESIGN: We evaluated gene expression in surgical liver biopsies from 13 obese (nine with type 2 diabetes) and five control subjects using Affymetrix U133A microarrays. PCR validation was performed in liver biopsies using an additional 16 subjects. We also tested thyroid hormone responses in mice fed chow or high-fat diet. SETTING: Recruitment was performed in an academic medical center. PARTICIPANTS: Individuals undergoing elective surgery for obesity or gallstones participated in the study. RESULTS: The top-ranking gene set, down-regulated in obese subjects, was comprised of genes previously demonstrated to be positively regulated by T(3) in human skeletal muscle (n = 399; P < 0.001; false discovery rate = 0.07). This gene set included genes related to RNA metabolism (SNRPE, HNRPH3, TIA1, and SFRS2), protein catabolism (PSMA1, PSMD12, USP9X, IBE2B, USP16, and PCMT1), and energy metabolism (ATP5C1, COX7C, UQCRB). We verified thyroid hormone regulation of these genes in the liver after injection of C57BL/6J mice with T(3) (100 microg/100 g body weight); furthermore, T(3)-induced increases in expression of these genes were abolished by high-fat diet. In agreement, expression of these genes inversely correlated with liver fat content in humans. CONCLUSIONS: These data suggest that impaired thyroid hormone action may contribute to altered patterns of gene expression in fatty liver.


Assuntos
Fígado Gorduroso/metabolismo , Regulação da Expressão Gênica , Tri-Iodotironina/farmacologia , Adulto , Animais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Proteínas de Choque Térmico/genética , Humanos , Resistência à Insulina , Iodeto Peroxidase/genética , Fígado/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Coativador 1-alfa do Receptor gama Ativado por Proliferador de Peroxissomo , Receptores para Leptina/genética , Fatores de Transcrição/genética
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