Making insulin-deficient type 1 diabetic rodents thrive without insulin.
Terminally ill insulin-deficient rodents with uncontrolled diabetes due to autoimmune or chemical destruction of beta-cells were made hyperleptinemic by adenoviral transfer of the leptin gene. Within approximately 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 approximately 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-gamma-coactivator-1alpha 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.
Yu
Xinxin
X
Touchstone Center for Diabetes Research, Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, TX 75390-8854, USA.
Park
Byung-Hyun
BH
Wang
May-Yun
MY
Wang
Zhao V
ZV
Unger
Roger H
RH
D000496:Alloxan / Q000494:pharmacology; D000818:Animals; D048909:Diabetes Complications / Q000378:metabolism; D003922:Diabetes Mellitus, Type 1 / Q000139:chemically induced / Q000378:metabolism*; D015536:Down-Regulation; D005934:Glucagon / Q000378:metabolism; D007328:Insulin / Q000172:deficiency* / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D051379:Mice; D051381:Rats; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D013311:Streptozocin / Q000494:pharmacology
D007328:Insulin; D050796:STAT3 Transcription Factor; D013311:Streptozocin; D007334:Insulin-Like Growth Factor I; D000496:Alloxan; D005934:Glucagon
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