Making insulin-deficient type 1 diabetic rodents thrive without insulin

X Yu, BH Park, MY Wang, ZV Wang… - Proceedings of the …, 2008 - National Acad Sciences
X Yu, BH Park, MY Wang, ZV Wang, RH Unger
Proceedings of the National academy of Sciences, 2008National Acad Sciences
Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or
chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the
leptin gene. Within≈ 10 days their severe hyperglycemia and ketosis were corrected.
Despite the lack of insulin, moribund animals resumed linear growth and appeared normal.
Normoglycemia persisted 10–80 days without other treatment; normal physiological
conditions lasted for≈ 175 days despite reappearance of moderate hyperglycemia …
Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of β-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within ≈10 days their severe hyperglycemia and ketosis were corrected. Despite the lack of insulin, moribund animals resumed linear growth and appeared normal. Normoglycemia persisted 10–80 days without other treatment; normal physiological conditions lasted for ≈175 days despite reappearance of moderate hyperglycemia. Inhibition of gluconeogenesis by suppression of hyperglucagonemia and reduction of hepatic cAMP response element-binding protein, phoshoenolpyruvate carboxykinase, and peroxisome proliferator-activated receptor-γ-coactivator-1α may explain the anticatabolic effect. Up-regulation of insulin-like growth factor 1 (IGF-1) expression and plasma levels and increasing IGF-1 receptor phosphorylation in muscle may explain the increased insulin receptor substrate 1, PI3K, and ERK phosphorylation in skeletal muscle. These findings suggest that leptin reverses the catabolic consequences of total lack of insulin, potentially by suppressing glucagon action on liver and enhancing the insulinomimetic actions of IGF-1 on skeletal muscle, and suggest strategies for making type 1 diabetes insulin-independent.
National Acad Sciences