Protein Tyrosine Phosphatase 1B Deficiency Improves Glucose Homeostasis in Type 1 Diabetes Treated With Leptin.

Abstract

Leptin, a hormone secreted by adipocytes, exhibits therapeutic potential for the treatment of type 1 diabetes (T1D). Protein tyrosine phosphatase 1B (PTP1B) is a key enzyme that negatively regulates leptin receptor signaling. Here, the role of PTP1B in the treatment of T1D was investigated using PTP1B-deficient (knockout [KO]) mice and a PTP1B inhibitor. T1D wild-type (WT) mice induced by streptozotocin showed marked hyperglycemia compared with non-T1D WT mice. KO mice displayed significantly improved glucose metabolism equivalent to non-T1D WT mice, whereas peripheral or central administration of leptin partially improved glucose metabolism in T1D WT mice. Peripheral combination therapy of leptin and a PTP1B inhibitor in T1D WT mice improved glucose metabolism to the same level as non-T1D WT mice. Leptin was shown to act on the arcuate nucleus in the hypothalamus to suppress gluconeogenesis in liver and enhance glucose uptake in both brown adipose tissue and soleus muscle through the sympathetic nervous system. These effects were enhanced by PTP1B deficiency. Thus, treatment of T1D with leptin, PTP1B deficiency, or a PTP1B inhibitor was shown to enhance leptin activity in the hypothalamus to improve glucose metabolism. These findings suggest a potential alternative therapy for T1D.

• Authors: Yoshihiro Ito, Runan Sun, Hiroshi Yagimuma, Keigo Taki, Akira Mizoguchi, Tomoko Kobayashi, Mariko Sugiyama, Takeshi Onoue, Taku Tsunekawa, Hiroshi Takagi, Daisuke Hagiwara, Shintaro Iwama, Hidetaka Suga, Hiroyuki Konishi, Hiroshi Kiyama, Hiroshi Arima, Ryoichi Banno
• Journal: Diabetes (Diabetes) Vol. 71 Issue 9 Pg. 1902-1914 (09 01 2022) ISSN: 1939-327X [Electronic] United States
• PMID: 35748319 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2022 by the American Diabetes Association.

Chemical References

• Leptin
• Protein Tyrosine Phosphatase, Non-Receptor Type 1
• Glucose

Topics

• Animals
• Diabetes Mellitus, Type 1 (drug therapy)
• Glucose (metabolism)
• Homeostasis (physiology)
• Leptin (metabolism)
• Mice
• Mice, Knockout
• Protein Tyrosine Phosphatase, Non-Receptor Type 1 (genetics, metabolism)