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Leptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice
- Source :
- Proceedings of the National Academy of Sciences of the United States of America. 107(40)
- Publication Year :
- 2010
-
Abstract
- Leptin monotherapy reverses the deadly consequences and improves several of the metabolic imbalances caused by insulin-deficient type 1 diabetes (T1D) in rodents. However, the mechanism(s) underlying these effects is totally unknown. Here, we report that intracerebroventricular (icv) infusion of leptin reverses lethality and greatly improves hyperglycemia, hyperglucagonemia, hyperketonemia, and polyuria caused by insulin deficiency in mice. Notably, icv leptin administration leads to increased body weight while suppressing food intake, thus correcting the catabolic consequences of T1D. Also, icv leptin delivery improves expression of the metabolically relevant hypothalamic neuropeptides proopiomelanocortin, neuropeptide Y, and agouti-related peptide in T1D mice. Furthermore, this treatment normalizes phosphoenolpyruvate carboxykinase 1 contents without affecting glycogen levels in the liver. Pancreatic β-cell regeneration does not underlie these beneficial effects of leptin, because circulating insulin levels were undetectable at basal levels and following a glucose overload. Also, pancreatic preproinsulin mRNA was completely absent in these icv leptin-treated T1D mice. Furthermore, the antidiabetic effects of icv leptin administration rapidly vanished (i.e., within 48 h) after leptin treatment was interrupted. Collectively, these results unveil a key role for the brain in mediating the antidiabetic actions of leptin in the context of T1D.
- Subjects :
- Central Nervous System
Leptin
Male
medicine.medical_specialty
Preproinsulin
medicine.medical_treatment
Diabetes Mellitus, Experimental
Placebos
chemistry.chemical_compound
Mice
Proopiomelanocortin
Internal medicine
Insulin-Secreting Cells
medicine
Animals
Humans
Insulin
Protein Precursors
Muscle, Skeletal
Pancreas
Injections, Intraventricular
Type 1 diabetes
Multidisciplinary
Leptin receptor
biology
Glycogen
digestive, oral, and skin physiology
Biological Sciences
Neuropeptide Y receptor
medicine.disease
Disease Models, Animal
Endocrinology
Diabetes Mellitus, Type 1
chemistry
biology.protein
Receptors, Leptin
hormones, hormone substitutes, and hormone antagonists
Subjects
Details
- ISSN :
- 10916490
- Volume :
- 107
- Issue :
- 40
- Database :
- OpenAIRE
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Accession number :
- edsair.doi.dedup.....105e48fd791802217e5e09628e365eaf