Leptin therapy in insulin-deficient type I diabetes
Open accessAbstract
In nonobese diabetic mice with uncontrolled type 1 diabetes, leptin therapy alone or combined with low-dose insulin reverses the catabolic state through suppression of hyperglucagonemia. Additionally, it mimics the anabolic actions of insulin monotherapy and normalizes hemoglobin A1c with far less glucose variability. We show that leptin therapy, like insulin, normalizes the levels of a wide array of hepatic intermediary metabolites in multiple chemical classes, including acylcarnitines, organic acids (tricarboxylic acid cycle intermediates), amino acids, and acyl CoAs. In contrast to insulin monotherapy, however, leptin lowers both lipogenic and cholesterologenic transcription factors and enzymes and reduces plasma and tissue lipids. The results imply that leptin administration may have multiple short- and long-term advantages over insulin monotherapy for type 1 diabetes.
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Intact glucagon signaling is required for diabetic hyperglycemia, and leptin-mediated decrease of plasma glucagon may mediate its effects on blood glucose.
“glucagon receptor-null mice remain normoglycemic following treatment with alloxan to induce uDM, suggesting that intact glucagon signaling is required for diabetic hyperglycemia and hence that the leptin-mediated decrease of plasma glucagon levels may mediate its effects on blood glucose (191).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [191]
Cites
A SIMPLE METHOD FOR THE ISOLATION AND PURIFICATION OF TOTAL LIPIDES FROM ANIMAL TISSUES
Folch, J., Lees, M., & Stanley, G. H. S. (1957) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)64849-5 · Cited by 65,189 · see citing works
Positional cloning of the mouse obese gene and its human homologue
Zhang, Y., Proenca, R., Maffei, M., Barone, M., Leopold, L., & Friedman, J. M. (1994) · Nature · doi:10.1038/372425a0 · Cited by 13,419 · see citing works
Randle, P. J., Garland, P. B., Hales, C. N., & Newsholme, E. A. (1963) · The Lancet · doi:10.1016/s0140-6736(63)91500-9 · Cited by 5,093 · see citing works
Newgard, C. B., An, J., Bain, J. R., Muehlbauer, M. J., Stevens, R. D., Lien, L. F., Haqq, A. M., Shah, S. H., Arlotto, M., Slentz, C. A., et al. (2009) · Cell Metabolism · doi:10.1016/j.cmet.2009.02.002 · Cited by 3,165 · see citing works
Self-citationCellular mechanisms of insulin resistance
Shulman, G. I. (2000) · Journal of Clinical Investigation · doi:10.1172/jci10583 · Cited by 2,714 · see citing works
Leptin stimulates fatty-acid oxidation by activating AMP-activated protein kinase
Minokoshi, Y., Kim, Y.-B., Peroni, O. D., Fryer, L. G. D., Müller, C., Carling, D., & Kahn, B. B. (2002) · Nature · doi:10.1038/415339a · Cited by 2,053 · see citing works
THE AMP-ACTIVATED/SNF1 PROTEIN KINASE SUBFAMILY: Metabolic Sensors of the Eukaryotic Cell?
Hardie, D. G., Carling, D., & Carlson, M. (1998) · Annual Review of Biochemistry · doi:10.1146/annurev.biochem.67.1.821 · Cited by 1,436 · see citing works
Boden, G., & Shulman, G. I. (2002) · European Journal of Clinical Investigation · doi:10.1046/j.1365-2362.32.s3.3.x · Cited by 1,300 · see citing works
Lipotoxic heart disease in obese rats: Implications for human obesity
Zhou, Y.-T., Grayburn, P., Karim, A., Shimabukuro, M., Higa, M., Baetens, D., Orci, L., & Unger, R. H. (2000) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.97.4.1784 · Cited by 1,265 · see citing works
Self-citationLeptin-Replacement Therapy for Lipodystrophy
Oral, E. A., Simha, V., Ruiz, E., Andewelt, A., Premkumar, A., Snell, P., Wagner, A. J., DePaoli, A. M., Reitman, M. L., Taylor, S. I., et al. (2002) · New England Journal of Medicine · doi:10.1056/nejmoa012437 · Cited by 1,247 · cited 1× · see citing works
“Since its discovery in 1994 (29), leptin therapy in humans with diabetes has been limited to patients with generalized lipodystrophy (30), including two patients with coexisting acquired generalized lipodystrophy and T1DM (31).”
BackgroundShimomura, I., Matsuda, M., Hammer, R. E., Bashmakov, Y. K., Brown, M. S., & Goldstein, J. L. (2000) · Molecular Cell · doi:10.1016/s1097-2765(05)00010-9 · Cited by 847 · see citing works
Stanley, J. C. (1981) · British Journal of Anaesthesia · doi:10.1093/bja/53.2.123 · Cited by 731 · see citing works
What if Minkowski Had Been Ageusic? An Alternative Angle on Diabetes
McGarry, J. D. (1992) · Science · doi:10.1126/science.1439783 · Cited by 657 · see citing works
Gelling, R. W., Du, X. Q., Dichmann, D. S., Rømer, J., Huang, H., Cui, L., Obici, S., Tang, B., Holst, J. J., Fledelius, C., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0237106100 · Cited by 563 · see citing works
Self-citationChen, G., Liang, G., Ou, J., Goldstein, J. L., & Brown, M. S. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0404297101 · Cited by 546 · see citing works
Dissociation of Hepatic Steatosis and Insulin Resistance in Mice Overexpressing DGAT in the Liver
Monetti, M., Levin, M. C., Watt, M. J., Sajan, M. P., Marmor, S., Hubbard, B. K., Stevens, R. D., Bain, J. R., Newgard, C. B., Farese, R. V., et al. (2007) · Cell Metabolism · doi:10.1016/j.cmet.2007.05.005 · Cited by 511 · see citing works
Self-citationOrchard, T. J., Olson, J. C., Erbey, J. R., Williams, K., Forrest, K. Y.-Z., Smithline Kinder, L., Ellis, D., & Becker, D. J. (2003) · Diabetes Care · doi:10.2337/diacare.26.5.1374 · Cited by 492 · see citing works
An, J., Muoio, D. M., Shiota, M., Fujimoto, Y., Cline, G. W., Shulman, G. I., Koves, T. R., Stevens, R., Millington, D., & Newgard, C. B. (2004) · Nature Medicine · doi:10.1038/nm995 · Cited by 450 · see citing works
Self-citationRegulation of camp-inducible genes by creb
Montminy, M., González, G., & Yamamoto, K. K. (1990) · Trends in Neurosciences · doi:10.1016/0166-2236(90)90045-c · Cited by 419 · see citing works
Briggs, M. R., Yokoyama, C., Wang, X., Brown, M. S., & Goldstein, J. L. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)85265-1 · Cited by 401 · see citing works
Antidiabetic Effects of IGFBP2, a Leptin-Regulated Gene
Hedbacker, K., Birsoy, K., Wysocki, R. W., Asilmaz, E., Ahima, R. S., Farooqi, I. S., & Friedman, J. M. (2010) · Cell Metabolism · doi:10.1016/j.cmet.2009.11.007 · Cited by 280 · see citing works
Quantitation of Endocrine Cell Content in the Pancreas of Nondiabetic and Diabetic Humans
Stefan, Y., Orci, L., MALAISSE-LAGAE, F., Perrelet, A., Patel, Y., & Unger, R. H. (1982) · Diabetes · doi:10.2337/diab.31.8.694 · Cited by 272 · see citing works
Self-citationAcute elevation of free fatty acid levels leads to hepatic insulin resistance in obese subjects
Bevilacqua, S., Bonadonna, R. C., Buzzigoli, G., Boni, C. D., Ciociaro, D., Maccari, F., Giorico, M. A., & Ferrannini, E. (1987) · Metabolism · doi:10.1016/0026-0495(87)90051-5 · Cited by 233 · see citing works
Chahil, T. J., & Ginsberg, H. N. (2006) · Endocrinology and Metabolism Clinics of North America · doi:10.1016/j.ecl.2006.06.002 · Cited by 233 · see citing works
Ronnebaum, S. M., Ilkayeva, O., Burgess, S. C., Joseph, J. W., Lu, D., Stevens, R. D., Becker, T. C., Sherry, A. D., Newgard, C. B., & Jensen, M. V. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m511908200 · Cited by 230 · see citing works
Self-citationGlucagon: Role in the Hyperglycemia of Diabetes Mellitus
Dobbs, R., Sakurai, H., Sasaki, H., Faloona, G., Valverde, I., Baetens, D., Orci, L., & Unger, R. (1975) · Science · doi:10.1126/science.1089999 · Cited by 229 · see citing works
Self-citationMaking insulin-deficient type 1 diabetic rodents thrive without insulin
Yu, X., Park, B.-H., Wang, M.-Y., Wang, Z. V., & Unger, R. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0806993105 · Cited by 219 · see citing works
Self-citationFerrara, C. T., Wang, P., Neto, E. C., Stevens, R. D., Bain, J. R., Wenner, B. R., Ilkayeva, O., Keller, M. P., Blasiole, D. A., Kendziorski, C. M., et al. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000034 · Cited by 204 · see citing works
Self-citationLeptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.
Chinookoswong, N., Wang, J. L., & Shi, Z. Q. (1999) · Diabetes · doi:10.2337/diabetes.48.7.1487 · Cited by 197 · cited 1× · see citing works
“The ability of leptin to potentiate insulin in diabetes has been previously shown (25, 26).”
BackgroundWang, M.-Y., Orci, L., Ravazzola, M., & Unger, R. H. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0509001102 · Cited by 151 · see citing works
Self-citationYu, X., McCorkle, S. K., Wang, M., Lee, Y., Li, J., Saha, A. K., Unger, R. H., & Ruderman, N. B. (2004) · Diabetologia · doi:10.1007/s00125-004-1570-9 · Cited by 149 · see citing works
Self-citationAdipogenic capacity and the susceptibility to type 2 diabetes and metabolic syndrome
Wang, M.-Y., Grayburn, P. A., Chen, S., Ravazzola, M., Orci, L., & Unger, R. H. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0801981105 · Cited by 144 · see citing works
Self-citationLarsen, J. R., Brekke, M., Sandvik, L., et al. (2002) · Diabetes · doi:10.2337/diabetes.51.8.2637 · Cited by 135 · see citing works
Jenkins, A. B., Storlien, L. H., Chisholm, D. J., & Kraegen, E. W. (1988) · Journal of Clinical Investigation · doi:10.1172/jci113586 · Cited by 119 · see citing works
Wu, J.-Y., Kao, H., Li, S., Stevens, R., Hillman, S. L., Millington, D. S., & Chen, Y.-T. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19574 · Cited by 104 · see citing works
Self-citationUnger, R. H. (2008) · JAMA · doi:10.1001/jama.299.10.1185 · Cited by 103 · see citing works
Self-citationLiu, H.-Y., Cao, S. Y., Hong, T., Han, J., Liu, Z., & Cao, W. (2009) · Journal of Biological Chemistry · doi:10.1074/jbc.m109.016675 · Cited by 90 · see citing works
Park, J. Y., Chong, A. Y., Cochran, E. K., Kleiner, D. E., Haller, M. J., Schatz, D., & Görden, P. (2007) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2007-1856 · Cited by 79 · see citing works
Inhibitory Effects of Leptin on Pancreatic α-Cell Function
Tudurí, E., Marroquí, L., Soriano, S., Ropero, A. B., Batista, T. M., Piquer, S., López-Boado, M. Á., Carneiro, E. M., Gomis, R., Nadal, Á., et al. (2009) · Diabetes · doi:10.2337/db08-1787 · Cited by 78 · see citing works
Banting, F., & BEST, C. H. (1990) · PubMed · Cited by 75 · see citing works
Ness, G. C., Zhao, Z., & Wiggins, L. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)62026-0 · Cited by 63 · see citing works
Leptin as an adjunct of insulin therapy in insulin-deficient diabetes
Miyanaga, F., Ogawa, Y., Ebihara, K., Hidaka, S., Tanaka, T., Hayashi, S., Masuzaki, H., & Nakao, K. (2003) · Diabetologia · doi:10.1007/s00125-003-1193-6 · Cited by 51 · see citing works
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Stern, J. H., Rutkowski, J. M., & Scherer, P. E. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.04.011 · Cited by 1,031 · see citing works
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Kusminski, C. M., Bickel, P. E., & Scherer, P. E. (2016) · Nature Reviews Drug Discovery · doi:10.1038/nrd.2016.75 · Cited by 678 · see citing works
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Mantzoros, C. S., Magkos, F., Brinkoetter, M., Sienkiewicz, E., Dardeno, T. A., Kim, S.-Y., Hamnvik, O.-P. R., & Koniaris, A. (2011) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00315.2011 · Cited by 593 · see citing works
The metabolic actions of glucagon revisited
Habegger, K. M., Heppner, K. M., Geary, N., Bartness, T. J., DiMarchi, R., & Tschöp, M. H. (2010) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2010.187 · Cited by 406 · see citing works
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Myers, M. G., & Olson, D. P. (2012) · Nature · doi:10.1038/nature11705 · Cited by 399 · see citing works
Sixteen years and counting: an update on leptin in energy balance
Gautron, L., & Elmquist, J. K. (2011) · Journal of Clinical Investigation · doi:10.1172/jci45888 · Cited by 367 · see citing works
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“Moreover, glucagon receptornull mice remain normoglycemic following treatment with alloxan to induce uDM, suggesting that intact glucagon signaling is required for diabetic hyperglycemia and hence that the leptin-mediated decrease of plasma glucagon levels may mediate its effects on blood glucose (191).”
BackgroundGlucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice
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- Authors
- Wang, M.-Y., Chen, L., Clark, G. O., Lee, Y., Stevens, R. D., Ilkayeva, O. R., Wenner, B. R., Bain, J. R., Charron, M. J., Newgard, C. B., & Unger, R. H.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Duke University (US)
- Albert Einstein College of Medicine (US)
- VA North Texas Health Care System (US)
- ORCID
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2010-03
- Volume
- 107
- Issue
- 11
- Pages
- 4813-4819
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC2841945
- OpenAlex
- W2155151130
- Cited by
- 327
- References
- 42
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 4 · 2023: 17 · 2022: 9 · 2021: 15 · 2020: 10 · 2019: 13 · 2018: 14 · 2017: 23 · 2016: 25 · 2015: 25 · 2014: 33 · 2013: 31 · 2012: 43
- FWCI
- 31.36
- 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)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Management and Research
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Keywords
- leptin therapy, type 1 diabetes, insulin deficiency, hyperglucagonemia, acylcarnitines, tricarboxylic acid cycle intermediates, amino acids, acyl-CoA, plasma lipids, glycemic variability, HbA1c, NOD mice
- MeSH terms
- Adenylate Kinase, Animals, Blood Glucose, Diabetes Mellitus, Type 1, Drug Implants, Gene Expression Regulation, Glucagon, Insulin, Liver, Phosphorylation, Recombinant Proteins, RNA, Messenger, Triglycerides, Mice, Inbred NOD, Leptin, Mice, Metabolome
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