Making insulin-deficient type 1 diabetic rodents thrive without insulin
Open accessAbstract
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.
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Hyperleptinemia induced by pharmacological leptin administration or adenoviral gene therapy fully ameliorates hyperglycemia in STZ-induced diabetic rats even with extremely low plasma insulin levels.
“hyperleptinemia induced by either pharmacological leptin administration (34) or with adenoviral gene therapy (210) fully ameliorates hyperglycemia in STZ-induced diabetic rats, even in the face of extremely low plasma insulin levels.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [210]
The anti-diabetic effects of leptin in STZ-induced diabetes are accompanied by normalization of elevated glucagon levels.
“the anti-diabetic effects of leptin in STZ-induced diabetes are accompanied by normalization of elevated glucagon levels (210).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [210]
Pharmacological administration of leptin systemically can normalize blood glucose levels in rodent models of uncontrolled diabetes mellitus.
“recent evidence suggests that pharmacological administration of leptin systemically (3,4) can also normalize blood glucose levels in rodent models of uncontrolled diabetes mellitus (uDM).”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [4]
Adenovirally induced hyperleptinemia ameliorates hyperglycemia in STZ diabetes.
“A recent study demonstrated that adenovirally induced hyperleptinemia ameliorates hyperglycemia in STZ diabetes”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [4]
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- Authors
- Yu, X., Park, B.-H., Wang, M.-Y., Wang, Z. V., & Unger, R. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Jeonbuk National University (KR)
- VA North Texas Health Care System (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2008-09-16
- Volume
- 105
- Issue
- 37
- Pages
- 14070-14075
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2544580
- OpenAlex
- W2144536242
- Cited by
- 219
- References
- 28
- Citations by year
- 2026: 2 · 2025: 1 · 2024: 3 · 2022: 6 · 2021: 12 · 2020: 7 · 2019: 10 · 2018: 11 · 2017: 18 · 2016: 22 · 2015: 17 · 2014: 19 · 2013: 15 · 2012: 22
- FWCI
- 8.03
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (5-R01-DK002700, R01DK002700)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Keywords
- type 1 diabetes, insulin deficiency, leptin, hyperleptinemia, adenoviral gene transfer, beta cell destruction, hyperglycemia, ketosis, gluconeogenesis inhibition, glucagon, insulin-like growth factor I, IGF-1 receptor, skeletal muscle, IRS-1, phosphatidylinositol 3-kinase, ERK, insulin-independent diabetes
- MeSH terms
- Alloxan, Animals, Diabetes Mellitus, Type 1, Glucagon, Insulin, Insulin-Like Growth Factor I, Liver, Streptozocin, Signal Transduction, Down-Regulation, Diabetes Complications, STAT3 Transcription Factor, Mice, Rats
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