Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss

Kaminska, Dorota; Hämäläinen, Maija; Cederberg, Henna; Käkelä, Pirjo; Venesmaa, Sari; Miettinen, Pekka; Ilves, Imre; Herzig, Karl‐Heinz; Kolehmainen, Marjukka; Karhunen, Leila; Kuusisto, Johanna; Gylling, Helena; Laakso, Markku; Pihlajamäki, Jussi

doi:10.1007/s00125-013-3097-4

Cited by 41 publications

(41 citation statements)

References 10 publications

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“…In omental adipose tissue of morbidly obese patients, hnRNPA1 expression is decreased (51). Moreover, hnRNPA1 is also associated with insulin receptor gene splicing in adipose tissue of humans with body weight loss (52).…”

Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis

et al. 2018

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Mammalian genomes encode a huge number of long noncoding RNAs (lncRNAs) with unknown functions. This study determined the role and mechanism of a new lncRNA, lncRNA suppressor of hepatic gluconeogenesis and lipogenesis (lncSHGL), in regulating hepatic glucose/lipid metabolism. In the livers of obese mice and patients with nonalcoholic fatty liver disease, the expression levels of mouse lncSHGL and its human homologous lncRNA B4GALT1-AS1 were reduced. Hepatic lncSHGL restoration improved hyperglycemia, insulin resistance, and steatosis in obese diabetic mice, whereas hepatic lncSHGL inhibition promoted fasting hyperglycemia and lipid deposition in normal mice. lncSHGL overexpression increased Akt phosphorylation and repressed gluconeogenic and lipogenic gene expression in obese mouse livers, whereas lncSHGL inhibition exerted the opposite effects in normal mouse livers. Mechanistically, lncSHGL recruited heterogeneous nuclear ribonucleoprotein A1 (hnRNPA1) to enhance the translation efficiency of CALM mRNAs to increase calmodulin (CaM) protein level without affecting their transcription, leading to the activation of the phosphatidyl inositol 3-kinase (PI3K)/Akt pathway and repression of the mTOR/SREBP-1C pathway independent of insulin and calcium in hepatocytes. Hepatic hnRNPA1 overexpression also activated the CaM/Akt pathway and repressed the mTOR/SREBP-1C pathway to ameliorate hyperglycemia and steatosis in obese mice. In conclusion, lncSHGL is a novel insulin-independent suppressor of hepatic gluconeogenesis and lipogenesis. Activating the lncSHGL/hnRNPA1 axis represents a potential strategy for the treatment of type 2 diabetes and steatosis.

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Section: Discussionmentioning

confidence: 99%

Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis

et al. 2018

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“…Obesity is the most common condition associated with insulin resistance. Therefore, the improvement of insulin resistance induced by weight loss obtained by a very low-calorie diet or bariatric surgery results in an increase in IRB in adipose tissue [ 96 ]. Changes in the IRA/IRB ratio in favour of the more metabolically active IRB are often related to a reduction in circulating insulin levels and should contribute to improve insulin sensitivity [ 77 ] ( Figure 3 ).…”

Section: Role Of Insulin Receptor Isoforms In Type 2 Diabetes and mentioning

confidence: 99%

The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications

Escribano

Beneit

Rubio-Longás

et al. 2017

Journal of Diabetes Research

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The insulin receptor (IR) presents by alternative splicing two isoforms: IRA and IRB. The differential physiological and pathological role of both isoforms is not completely known, and it is determinant the different binding affinity for insulin-like growth factor. IRB is more abundant in adult tissues and it exerts mainly the metabolic actions of insulin, whereas IRA is mainly expressed in fetal and prenatal period and exerts mitogenic actions. However, the change in the expression profile of both IR isoforms and its dysregulation are associated with the development of different pathologies, such as cancer, insulin resistance, diabetes, obesity, and atherosclerosis. In some of them, there is a significant increase of IRA/IRB ratio conferring a proliferative and migratory advantage to different cell types and favouring IGF-II actions with a sustained detriment in the metabolic effects of insulin. This review discussed specifically the role of IR isoforms as well as IGF-IR in diabetes and its associated complications as obesity and atherosclerosis. Future research with new IR modulators might be considered as possible targets to improve the treatment of diabetes and its associated complications.

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“…The importance of the different isoforms for pancreatic β-cell proliferation or survival is unknown and the factors that determine which isoform will be formed in the cell are also largely unknown 16 . Alteration of INSR alternative splicing has been associated with several diseases such as myotonic dystrophy 12 17 , cancer 18 , and recovery from type 2 diabetes after bariatric surgery 19 .…”

mentioning

confidence: 99%

Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival

Malakar¹,

Chartarifsky²,

Hija³

et al. 2016

Sci Rep

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Type 2 Diabetes (T2DM) affects more than 300 million people worldwide. One of the hallmarks of T2DM is peripheral insulin resistance, in part due to unproductive insulin signaling through the insulin receptor. The insulin receptor (INSR) exists as two isoforms, INSR-A and INSR-B, which results from skipping or inclusion of exon 11 respectively. What determines the relative abundance of the different insulin receptor splice variants is unknown. Moreover, it is not yet clear what the physiological roles of each of the isoforms are in normal and diseased beta cells. In this study, we show that insulin induces INSR exon 11 inclusion in pancreatic beta cells in both human and mouse. This occurs through activation of the Ras-MAPK/ERK signaling pathway and up-regulation of the splicing factor SRSF1. Induction of exon 11 skipping by a splice-site competitive antisense oligonucleotide inhibited the MAPK-ERK signaling pathway downstream of the insulin receptor, sensitizing the pancreatic β-cell line MIN6 to stress-induced apoptosis and lipotoxicity. These results assign to insulin a regulatory role in INSR alternative splicing through the Ras-MAPK/ERK signaling pathway. We suggest that in beta cells, INSR-B has a protective role, while INSR-A expression sensitizes beta cells to programmed cell death.

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Adipose tissue INSR splicing in humans associates with fasting insulin level and is regulated by weight loss

Cited by 41 publications

References 10 publications

Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis

Long Noncoding RNA lncSHGL Recruits hnRNPA1 to Suppress Hepatic Gluconeogenesis and Lipogenesis

The Role of Insulin Receptor Isoforms in Diabetes and Its Metabolic and Vascular Complications

Insulin receptor alternative splicing is regulated by insulin signaling and modulates beta cell survival

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