GSE143319: Inhibition of Grb14, a negative modulator of insulin signaling, improves glucose homeostasis without causing cardiac dysfunction

Gene Expression Data Explorer
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GROUP CONDITION SAMPLES
Subcutaneous adipose tissue
GSM4257094 GSM4257096 GSM4257098 GSM4257100 GSM4257102 GSM4257104 GSM4257106 GSM4257108 GSM4257110 GSM4257112
GSM4257093 GSM4257095 GSM4257097 GSM4257099 GSM4257101 GSM4257103 GSM4257105 GSM4257107 GSM4257109 GSM4257111
GSM4257078 GSM4257079 GSM4257080 GSM4257081 GSM4257082 GSM4257083 GSM4257084 GSM4257085 GSM4257086 GSM4257087 GSM4257088 GSM4257089 GSM4257090 GSM4257091 GSM4257092
GSM4257063 GSM4257064 GSM4257065 GSM4257066 GSM4257067 GSM4257068 GSM4257069 GSM4257070 GSM4257071 GSM4257072 GSM4257073 GSM4257074 GSM4257075 GSM4257076 GSM4257077
Description

Submission Date: Jan 08, 2020

Summary: Insulin resistance increases patient's risk of developing type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and germline Grb14-knockout (KO) mice have improved insulin signaling in liver and muscle tissues. Here, we show that Grb14 knockdown in the liver and the heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and decreased systolic function, effects that could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in hemodynamic function as measured by echocardiography in DIO Grb14 and DIO sham mice for a period of four months. While additional studies are needed to further establish efficacy and to de-risk potential negative cardiac effects in pre-clinical heart failure models, our data support inhibiting Grb14 to treat diabetes and related conditions.

GEO Accession ID: GSE143319

PMID: 32099031

Description

Submission Date: Jan 08, 2020

Summary: Insulin resistance increases patient's risk of developing type 2 diabetes (T2D), nonalcoholic steatohepatitis (NASH) and a host of other comorbidities including cardiovascular disease and cancer. At the molecular level, insulin exerts its function through the insulin receptor (IR), a transmembrane receptor tyrosine kinase. Data from human genetic studies have shown that Grb14 functions as a negative modulator of IR activity, and germline Grb14-knockout (KO) mice have improved insulin signaling in liver and muscle tissues. Here, we show that Grb14 knockdown in the liver and the heart with an AAV-shRNA (Grb14-shRNA) improves glucose homeostasis in diet-induced obese (DIO) mice. A previous report has shown that germline deletion of Grb14 in mice results in cardiac hypertrophy and decreased systolic function, effects that could severely limit the therapeutic potential of targeting Grb14. In this report, we demonstrate that there are no significant changes in hemodynamic function as measured by echocardiography in DIO Grb14 and DIO sham mice for a period of four months. While additional studies are needed to further establish efficacy and to de-risk potential negative cardiac effects in pre-clinical heart failure models, our data support inhibiting Grb14 to treat diabetes and related conditions.

GEO Accession ID: GSE143319

PMID: 32099031

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