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

Xunshan Ding1, Rugmani Iyer1, Christopher Novotny1

  • 1Merck & Co., Inc., South San Francisco, CA, USA.

Scientific Reports
|February 27, 2020
PubMed

Insights

Inhibiting Grb14 in mice improves glucose control and insulin sensitivity, offering a potential new treatment for type 2 diabetes and related metabolic disorders. This approach avoids negative cardiac effects seen in other studies.

Area of Science:

  • Metabolic disease research
  • Molecular endocrinology
  • Pharmacological intervention strategies

Background:

  • Insulin resistance is a key factor in developing type 2 diabetes (T2D), non-alcoholic steatohepatitis (NASH), cardiovascular disease, and cancer.
  • Insulin receptor (IR) activity is crucial for insulin signaling, and Grb14 acts as a negative modulator of this receptor.
  • Previous studies indicated Grb14 knockout mice exhibit improved insulin signaling but also cardiac issues.

Purpose of the Study:

  • To investigate the therapeutic potential of Grb14 inhibition in diet-induced obesity (DIO) mouse models.
  • To assess the impact of localized Grb14 knockdown on glucose homeostasis and insulin sensitivity.
  • To evaluate the cardiac safety of Grb14 inhibition, addressing concerns from prior germline knockout studies.

Main Methods:

  • Utilized adeno-associated virus short hairpin RNA (AAV-shRNA) to achieve liver-specific and tissue-specific Grb14 knockdown (Grb14-shRNA).
  • Administered Grb14-shRNA to diet-induced obese (DIO) mice to model metabolic dysfunction.
  • Assessed glucose homeostasis and insulin sensitivity using established metabolic assays.
  • Monitored cardiac function in Grb14-shRNA treated mice using echocardiography over a four-month period.

Main Results:

  • Grb14 knockdown in the liver, white adipose tissue, and heart significantly improved glucose homeostasis in DIO mice.
  • Mice treated with Grb14-shRNA did not exhibit significant adverse changes in cardiac function, as assessed by echocardiography, despite a high-fat diet.
  • These findings contrast with previous reports of cardiac abnormalities in germline Grb14-knockout mice.

Conclusions:

  • Targeted inhibition of Grb14 presents a promising therapeutic strategy for managing insulin resistance and related metabolic conditions like T2D.
  • Localized Grb14 knockdown demonstrates efficacy in improving metabolic parameters without compromising cardiac function in preclinical models.
  • Further research is warranted to confirm these findings and fully de-risk potential cardiac side effects before clinical translation.

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