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1.
Mol Metab ; 40: 101020, 2020 10.
Artigo em Inglês | MEDLINE | ID: mdl-32439336

RESUMO

OBJECTIVE: Insulin signalling via phosphoinositide 3-kinase (PI3K) requires PIK3R1-encoded regulatory subunits. C-terminal PIK3R1 mutations cause SHORT syndrome, as well as lipodystrophy and insulin resistance (IR), surprisingly without fatty liver or metabolic dyslipidaemia. We sought to investigate this discordance. METHODS: The human pathogenic Pik3r1 Y657∗ mutation was knocked into mice by homologous recombination. Growth, body composition, bioenergetic and metabolic profiles were investigated on chow and high-fat diet (HFD). We examined adipose and liver histology, and assessed liver responses to fasting and refeeding transcriptomically. RESULTS: Like humans with SHORT syndrome, Pik3r1WT/Y657∗ mice were small with severe IR, and adipose expansion on HFD was markedly reduced. Also as in humans, plasma lipid concentrations were low, and insulin-stimulated hepatic lipogenesis was not increased despite hyperinsulinemia. At odds with lipodystrophy, however, no adipocyte hypertrophy nor adipose inflammation was found. Liver lipogenic gene expression was not significantly altered, and unbiased transcriptomics showed only minor changes, including evidence of reduced endoplasmic reticulum stress in the fed state and diminished Rictor-dependent transcription on fasting. Increased energy expenditure, which was not explained by hyperglycaemia nor intestinal malabsorption, provided an alternative explanation for the uncoupling of IR from dyslipidaemia. CONCLUSIONS: Pik3r1 dysfunction in mice phenocopies the IR and reduced adiposity without lipotoxicity of human SHORT syndrome. Decreased adiposity may not reflect bona fide lipodystrophy, but rather, increased energy expenditure, and we suggest that further study of brown adipose tissue in both humans and mice is warranted.


Assuntos
Classe Ia de Fosfatidilinositol 3-Quinase/genética , Transtornos do Crescimento/metabolismo , Hipercalcemia/metabolismo , Resistência à Insulina/genética , Doenças Metabólicas/metabolismo , Nefrocalcinose/metabolismo , Tecido Adiposo Marrom/metabolismo , Adiposidade , Animais , Classe Ia de Fosfatidilinositol 3-Quinase/metabolismo , Dieta Hiperlipídica , Dislipidemias/genética , Metabolismo Energético/genética , Fígado Gorduroso/metabolismo , Transtornos do Crescimento/genética , Hipercalcemia/genética , Inflamação/metabolismo , Insulina/metabolismo , Lipogênese , Fígado/metabolismo , Masculino , Doenças Metabólicas/genética , Camundongos , Camundongos Endogâmicos C57BL , Nefrocalcinose/genética , Obesidade/genética , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo
2.
J Clin Endocrinol Metab ; 103(10): 3845-3855, 2018 10 01.
Artigo em Inglês | MEDLINE | ID: mdl-30085133

RESUMO

Context: Insulin autoimmune syndrome (IAS), spontaneous hyperinsulinemic hypoglycemia due to insulin-binding autoantibodies, may be difficult to distinguish from tumoral or other forms of hyperinsulinemic hypoglycemia, including surreptitious insulin administration. No standardized treatment regimen exists. Objectives: To evaluate an analytic approach to IAS and responses to different treatments. Design and Setting: Observational study in the UK Severe Insulin Resistance Service. Patients: Six patients with hyperinsulinemic hypoglycemia and detectable circulating anti-insulin antibody (IA). Main Outcome Measures: Glycemia, plasma insulin, and C-peptide concentrations by immunoassay or mass spectrometry (MS). Immunoreactive insulin was determined in the context of polyethylene glycol (PEG) precipitation and gel filtration chromatography (GFC). IA quantification using ELISA and RIA, and IA were further characterized using radioligand binding studies. Results: All patients were diagnosed with IAS (five IgG, one IgA) based on a high insulin/C-peptide ratio, low insulin recovery after PEG precipitation, and GFC evidence of antibody-bound insulin. Neither ELISA nor RIA result proved diagnostic for every case. MS provided a more robust quantification of insulin in the context of IA. One patient was managed conservatively, four were treated with diazoxide without sustained benefit, and four were treated with immunosuppression with highly variable responses. IA affinity did not appear to influence presentation or prognosis. Conclusions: IAS should be considered in patients with hyperinsulinemic hypoglycemia and a high insulin/C-peptide ratio. Low insulin recovery on PEG precipitation supports the presence of insulin-binding antibodies, with GFC providing definitive confirmation. Immunomodulatory therapy should be customized according to individual needs and clinical response.


Assuntos
Doenças Autoimunes/diagnóstico , Hiperinsulinismo Congênito/diagnóstico , Anticorpos Anti-Insulina/sangue , Adulto , Idoso , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/imunologia , Biomarcadores/sangue , Glicemia/metabolismo , Peptídeo C/sangue , Cromatografia em Gel , Hiperinsulinismo Congênito/tratamento farmacológico , Hiperinsulinismo Congênito/imunologia , Diazóxido/uso terapêutico , Feminino , Humanos , Imunossupressores/uso terapêutico , Insulina/sangue , Resistência à Insulina/fisiologia , Masculino , Pessoa de Meia-Idade , Síndrome
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