Leptin restores euglycemia and normalizes glucose turnover in insulin-deficient diabetes in the rat.
Abstract
Leptin has been shown to improve insulin sensitivity and glucose metabolism in normoinsulinemic healthy or obese rodents. It has not been determined whether leptin may act independently of insulin in regulating energy metabolism in vivo. The present study was designed to examine the effects of leptin treatment alone on glucose metabolism in insulin-deficient streptozotocin (STZ)-induced diabetic rats. Four groups of STZ-induced diabetic rats were studied: 1) rats treated with recombinant methionine murine leptin subcutaneous infusion with osmotic pumps for 12-14 days (LEP; 4 mg x kg(-1) x day(-1), n = 10); 2) control rats infused with vehicle (phosphate-buffered saline) for 12-14 days (VEH; n = 10); 3) pair-fed control rats given a daily food ration matching that of LEP rats for 12-14 days (PF; n = 8); and 4) rats treated with subcutaneous phloridzin for 4 days (PLZ; 0.4 g/kg twice daily, n = 10). Phloridzin treatment normalizes blood glucose without insulin and was used as a control for the effect of leptin in correcting hyperglycemia. All animals were then studied with a hyperinsulinemic-euglycemic clamp (6 mU x kg(-1) x min(-1). Our study demonstrates that leptin treatment in the insulin-deficient diabetic rats restored euglycemia, minimized body weight loss due to food restriction, substantially improved glucose metabolic rates during the postabsorptive state, and restored insulin sensitivities at the levels of the liver and the peripheral tissues during the glucose clamp. The effects on glucose turnover are largely independent of food restriction and changes in blood glucose concentration, as evidenced by the minimal improvement of insulin action and glucose turnover parameters in the PF and PLZ groups. Our results suggest that the antidiabetic effects of leptin are achieved through both an insulin-independent and an insulin-sensitizing mechanism.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
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 [34]
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 [3]
Cited by
Sorted by citations
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
“…2001, 2004; Holland et al., 2011), coupled with the discovery of leptin just 1 year prior (Zhang et al., 1994) and its insulin-sensitizing actions (Chinookoswong et al., 1999; Pelleymounter et al., 1995; Shimomura et al., 1999), provided the diabetes and obesity fields with promising therapeutic…”
BackgroundLeptin in Human Physiology and Pathophysiology
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
Havel, P. J. (2002) · Current Opinion in Lipidology · doi:10.1097/00041433-200202000-00008 · Cited by 575 · see citing works
The Function of Leptin in Nutrition, Weight, and Physiology
Friedman, J. M. (2002) · Nutrition Reviews · doi:10.1301/002966402320634878 · Cited by 505 · see citing works
“Anti-diabetic effects have also been observed in insulindeficient rats.(74)”
BackgroundHuman leptin: from an adipocyte hormone to an endocrine mediator
Wauters, M., Considine, R. V., & Gaal, L. V. (2000) · European Journal of Endocrinology · doi:10.1530/eje.0.1430293 · Cited by 458 · see citing works
Leptin resistance and diet-induced obesity: central and peripheral actions of leptin
Sáinź, N., Barrenetxe, J., Moreno-Aliaga, M. J., & Martínez, J. A. (2014) · Metabolism · doi:10.1016/j.metabol.2014.10.015 · Cited by 423 · see citing works
“[60] Chinookoswong N, Wang JL, Shi ZQ.”
BackgroundThe adipoinsular axis: effects of leptin on pancreatic β-cells
Kieffer, T. J., & Habener, J. F. (2000) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.2000.278.1.e1 · Cited by 418 · 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
Molecular Signatures of Obstructive Sleep Apnea in Adults: A Review and Perspective
Arnardóttir, E. S., Mackiewicz, M., Gíslason, Þ., Teff, K. L., & Pack, A. I. (2009) · SLEEP · doi:10.1093/sleep/32.4.447 · Cited by 347 · see citing works
Leptin and the Central Nervous System Control of Glucose Metabolism
Morton, G. J., & Schwartz, M. W. (2011) · Physiological Reviews · doi:10.1152/physrev.00007.2010 · Cited by 338 · see citing works
“Interestingly, 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.”
BackgroundLeptin therapy in insulin-deficient type I diabetes
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., et al. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0909422107 · Cited by 327 · see citing works
“The ability of leptin to potentiate insulin in diabetes has been previously shown (25, 26).”
BackgroundDirect and indirect effects of leptin on adipocyte metabolism
Harris, R. B. S. (2013) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2013.05.009 · Cited by 316 · see citing works
Inflammatory Process in Type 2 Diabetes: The Role of Cytokines
ALEXANDRAKI, K., PIPERI, C., KALOFOUTIS, C., SINGH, J., ALAVERAS, A., & KALOFOUTIS, A. (2006) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1372.039 · Cited by 309 · see citing works
Increased insulin and leptin sensitivity in mice lacking acyl CoA:diacylglycerol acyltransferase 1
Chen, H. C., Smith, S. J., Ladha, Z., Jensen, D. R., Ferreira, L. D., Pulawa, L. K., McGuire, J. G., Pitas, R. E., Eckel, R. H., & Farese, R. V. (2002) · Journal of Clinical Investigation · doi:10.1172/jci14672 · Cited by 329 · see citing works
“Finally, leptin enhances insulin action in several murine models of diabetes (10, 22, 23), and DGAT1 deficiency appears to increase activation of the leptin pathway.”
BackgroundLeptin revisited: its mechanism of action and potential for treating diabetes
Coppari, R., & Bjørbæk, C. (2012) · Nature Reviews Drug Discovery · doi:10.1038/nrd3757 · Cited by 295 · 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
Leptin's Role in Lipodystrophic and Nonlipodystrophic Insulin-Resistant and Diabetic Individuals
Moon, H., Dalamaga, Μ., Kim, S. Y., Pοlyzos, S. A., Hamnvik, O. R., Magkos, F., Paruthi, J., & Mantzoros, C. S. (2013) · Endocrine Reviews · doi:10.1210/er.2012-1053 · Cited by 257 · see citing works
“Subcutaneous infusion of leptin restored euglycemia and normalized peripheral insulin sensitivity in streptozotocin (STZ)-induced type 1 diabetic animals (267, 272).”
BackgroundAnalysis of paradoxical observations on the association between leptin and insulin resistance
Ceddia, R. B., Koistinen, H. A., Zierath, J. R., & Sweeney, G. (2002) · The FASEB Journal · doi:10.1096/fj.02-0158rev · Cited by 256 · see citing works
Leptin Induces Insulin-like Signaling That Antagonizes cAMP Elevation by Glucagon in Hepatocytes
Zhao, A. Z., Shinohara, M. M., Huang, D., Shimizu, M., Eldar-Finkelman, H., Krebs, E. G., Beavo, J. A., & Bornfeldt, K. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.15.11348 · Cited by 238 · see citing works
Tissue-Specific Effects of Leptin on Glucose and Lipid Metabolism
Pereira, S., Cline, D. L., Glavas, M. M., Covey, S. D., & Kieffer, T. J. (2020) · Endocrine Reviews · doi:10.1210/endrev/bnaa027 · Cited by 247 · see citing works
“models of insulin-deficient diabetes (96,97).”
BackgroundThe role of leptin in the control of insulin-glucose axis
Amitani, M. S., Asakawa, A., Amitani, H., & Inui, A. (2013) · Frontiers in Neuroscience · doi:10.3389/fnins.2013.00051 · Cited by 228 · see citing works
“Leptin therapy has been found to reverse hyperglycemia and to prevent mortality in several rodent models of type 1 diabetes (Chinookoswong et al., 1999; Yu et al., 2008; Fujikawa et al., 2010; Wang et al., 2010b,c; Denroche et al., 2011).”
BackgroundCritical role of STAT3 in leptin's metabolic actions
Buettner, C., Pocai, A., Muse, E. D., Etgen, A. M., Myers, M. G., & Rossetti, L. (2006) · Cell Metabolism · doi:10.1016/j.cmet.2006.04.014 · Cited by 228 · see citing works
Serum leptin level and cognition in the elderly: Findings from the Health ABC Study
Holden, K. F., Lindquist, K. J., Tylavsky, F. A., Rosano, C., Harris, T. B., & Yaffe, K. S. (2008) · Neurobiology of Aging · doi:10.1016/j.neurobiolaging.2007.11.024 · Cited by 227 · see citing works
Leptin—Much More Than a Satiety Signal
Harris, R. B. S. (2000) · Annual Review of Nutrition · doi:10.1146/annurev.nutr.20.1.45 · Cited by 222 · see citing works
“In support of the latter concept, high-dose leptin infusions in insulin-depleted and insulin-resistant streptozotocin rats prevented weight loss, normalized fasting glucose, and increased whole body glucose utilization during a hyperinsulinemic clamp (46).”
BackgroundLeptin therapy improves insulin-deficient type 1 diabetes by CNS-dependent mechanisms in mice
Fujikawa, T., Chuang, J.-C., Sakata, I., Ramadori, G., & Coppari, R. (2010) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1008025107 · Cited by 221 · see citing works
Making 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
“Proc Natl Acad Sci USA 73(4):1338–1342.”
BackgroundThe glucoregulatory actions of leptin
D'souza, A. M., Neumann, U. H., Glavas, M. M., & Kieffer, T. J. (2017) · Molecular Metabolism · doi:10.1016/j.molmet.2017.04.011 · Cited by 214 · see citing works
“In contrast, leptin therapy in STZ diabetic rodents potently suppresses gluconeogenesis [19,65,66] and increases glycogen synthesis [63] resulting in an overall decrease in hepatic glucose output [66,203].”
BackgroundSite and mechanism of leptin action in a rodent form of congenital lipodystrophy
Asilmaz, E., Cohen, P., Miyazaki, M., Dobrzyn, P., Ueki, K., Fayzikhodjaeva, G., Soukas, A. A., Kahn, C. R., Ntambi, J. M., Socci, N. D., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci200419511 · Cited by 210 · see citing works
Relationship between serum adiponectin and leptin concentrations and body fat distribution
Park, K., Park, K. S., Kim, M., Kim, H., Suh, Y. S., Ahn, J. D., Park, K., Chang, Y., & Lee, I. (2003) · Diabetes Research and Clinical Practice · doi:10.1016/j.diabres.2003.09.010 · Cited by 203 · see citing works
Leptin reverses diabetes by suppression of the hypothalamic-pituitary-adrenal axis
Perry, R. J., Zhang, X., Zhang, D., Kumashiro, N., Camporez, J. P., Cline, G. W., Rothman, D. L., & Shulman, G. I. (2014) · Nature Medicine · doi:10.1038/nm.3579 · Cited by 193 · see citing works
Site and mechanism of leptin action in a rodent form of congenital lipodystrophy
Asilmaz, E., Cohen, P., Miyazaki, M., Dobrzyń, P., Ueki, K., Fayzikhodjaeva, G., Soukas, A. A., Kahn, C. R., Ntambi, J. M., Socci, N. D., et al. (2004) · Journal of Clinical Investigation · doi:10.1172/jci19511 · Cited by 206 · see citing works
“cipitation; PY, phospho tyrosine; PI(3)P,”
German, J. P., Thaler, J. P., Wisse, B. E., Oh-I, S., Sarruf, D. A., Matsen, M. E., Fischer, J. D., Taborsky, G. J., Schwartz, M. W., & Morton, G. J. (2011) · Endocrinology · doi:10.1210/en.2010-0890 · Cited by 169 · see citing works
“tion of leptin systemically (3, 4) can also normalize blood”
BackgroundLeptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes
German, J. P., Wisse, B. E., Thaler, J. P., Oh-I, S., Sarruf, D. A., Ogimoto, K., Kaiyala, K. J., Fischer, J. D., Matsen, M. E., Taborsky, G. J., et al. (2010) · Diabetes · doi:10.2337/db09-1918 · Cited by 159 · see citing works
“, leptin-deficient ob/ob mice), while other studies have employed pharmacological doses of leptin (1-6).”
BackgroundInfluentialCentral nervous system regulation of organismal energy and glucose homeostasis
Myers, M. G., Affinati, A. H., Richardson, N. E., & Schwartz, M. W. (2021) · Nature Metabolism · doi:10.1038/s42255-021-00408-5 · Cited by 154 · see citing works
Role of leptin in the pancreatic β-cell: effects and signaling pathways
Marroquí, L., González, A., Ñeco, P., Caballero‐Garrido, E., Vieira, E. C., Ripoll, C., Nadal, Á., & Quesada, I. (2012) · Journal of Molecular Endocrinology · doi:10.1530/jme-12-0025 · Cited by 151 · see citing works
Han, D. C., Isono, M., Chen, S., Casaretto, A., Hong, S. W., Wolf, G., & Ziyadeh, F. N. (2001) · Kidney International · doi:10.1046/j.1523-1755.2001.0590041315.x · Cited by 151 · see citing works
The role of leptin in glucose homeostasis
Denroche, H. C., Huynh, F. K., & Kieffer, T. J. (2012) · Journal of Diabetes Investigation · doi:10.1111/j.2040-1124.2012.00203.x · Cited by 147 · see citing works
Adipose tissue as an endocrine organ: impact on insulin resistance.
Im, J., Pijl, H., & Ae, M. (2003) · PubMed · Cited by 137 · see citing works
Papaetis, G. S., Papakyriakou, P., & Panagiotou, T. N. (2015) · Archives of Medical Science · doi:10.5114/aoms.2015.52350 · Cited by 135 · see citing works
“(iii) By reducing food intake and body weight [65, 66].”
BackgroundThe adipocyte–myocyte axis in insulin resistance
Sell, H., Dietze‐Schroeder, D., & Eckel, J. (2006) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2006.10.010 · Cited by 127 · see citing works
Emerging hormonal-based combination pharmacotherapies for the treatment of metabolic diseases
Clemmensen, C., Finan, B., Müller, T. D., DiMarchi, R. D., Tschöp, M. H., & Hofmann, S. M. (2018) · Nature Reviews Endocrinology · doi:10.1038/s41574-018-0118-x · Cited by 129 · see citing works
Denroche, H. C., Levi, J., Wideman, R. D., Sequeira, R. M., Huynh, F. K., Covey, S. D., & Kieffer, T. J. (2011) · Diabetes · doi:10.2337/db10-0958 · Cited by 126 · see citing works
“Exogenous leptin can improve insulin sensitivity in rats with STZ-induced diabetes (4,15,16).”
BackgroundResultInfluentialCentral leptin increases insulin sensitivity in streptozotocin-induced diabetic rats
Lin, C.-Y., Higginbotham, D. A., Judd, R. L., & White, B. D. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00489.2001 · Cited by 124 · see citing works
“In this study, as expected, diabetic rats lost weight even though they were hyperphagic, consistent with previous studies (6, 16, 17, 34, 35).”
BackgroundResultInfluentialLeptin regulation of reproductive function and fertility
Smith, G. D., Jackson, L. M., & Foster, D. L. (2002) · Theriogenology · doi:10.1016/s0093-691x(01)00658-6 · Cited by 120 · see citing works
The role of leptin in diabetes: metabolic effects
Meek, T. H., & Morton, G. J. (2016) · Diabetologia · doi:10.1007/s00125-016-3898-3 · Cited by 119 · see citing works
“Recent evidence suggests that leptin also has glucoselowering effects in uDM [16, 17], another model of acquired leptin deficiency [18].”
BackgroundMelanocortin-independent Effects of Leptin on Hepatic Glucose Fluxes
Gutiérrez-Juárez, R., Obici, S., & Rossetti, L. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408665200 · Cited by 115 · see citing works
Hidaka, S., Yoshimatsu, H., Kondou, S., Tsuruta, Y., Oka, K., Noguchi, H., Okamoto, K., Sakino, H., Teshima, Y., Okeda, T., et al. (2002) · The FASEB Journal · doi:10.1096/fj.01-0164com · Cited by 108 · see citing works
“High-dose systemic administration of leptin improves hyperglycemia in insulin-deficient streptozotocin (STZ) -induced diabetic (STZ-D) rats ( 14 ).”
BackgroundResultInfluentialMiyazaki, M., Sampath, H., Liu, X., Flowers, M. T., Chu, K., Dobrzyń, A., & Ntambi, J. M. (2009) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2009.01.183 · Cited by 105 · see citing works
“Several lines of evidence in both cell culture and animal models suggest a complex interplay between insulin and leptin signaling in the periphery [21,26,27].”
BackgroundLeptin: linking adipocyte metabolism with cardiovascular and autoimmune diseases
Peelman, F., Waelput, W., Iserentant, H., Lavens, D., Eyckerman, S., Zabeau, L., & Tavernier, J. H. (2004) · Progress in Lipid Research · doi:10.1016/j.plipres.2004.03.001 · Cited by 103 · see citing works
Jouffe, C., Weger, B. D., Martín, E., Atger, F., Weger, M., Gobet, C., Ramnath, D., Charpagne, A., Morin‐Rivron, D., Powell, E. E., et al. (2022) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.2200083119 · Cited by 107 · see citing works
Steinberg, G. R., Bonen, A., & Dyck, D. J. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00303.2001 · Cited by 102 · see citing works
Leptin Improves Insulin Resistance and Hyperglycemia in a Mouse Model of Type 2 Diabetes
Toyoshima, Y., Gavrilova, O., Yakar, S., Jou, W., Pack, S., Shyr, Z. A., Wheeler, M. B., & LeRoith, D. (2005) · Endocrinology · doi:10.1210/en.2005-0087 · Cited by 102 · see citing works
Sweeney, G., Keen, J., Somwar, R., Konrad, D., Garg, R. R., & Klip, A. (2001) · Endocrinology · doi:10.1210/endo.142.11.8496 · Cited by 106 · see citing works
Kalra, S. P. (2007) · Peptides · doi:10.1016/j.peptides.2007.10.017 · Cited by 95 · see citing works
“Hyperinsulinemia—Although it is generally held that the fat burden of obesity contributes substantially to cause hyperinsulinemia [57,64,68,69,76,89,93], acute inhibition of insulin secretion by central administration of leptin has also been reported [34,62,89,102, 131].”
BackgroundRegulatory role of leptin in glucose and lipid metabolism in skeletal muscle
Minokoshi, Y., Toda, C., & Okamoto, S. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105573 · Cited by 93 · see citing works
Overweight/obesity and cancer genesis: More than a biological link
Irigaray, P., Newby, J. A., Lacomme, S., & Belpomme, D. (2007) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2007.10.008 · Cited by 92 · see citing works
Carvalheira, J. B. C., Ribeiro, E. B., Folli, F. B., Velloso, L. A., & Saad, M. J. A. (2003) · Biological Chemistry · doi:10.1515/bc.2003.016 · Cited by 92 · see citing works
“Furthermore, recent evidence indicates that leptin treatment in insulin-deficient diabetic rats restores normoglycemia (Chinookoswong et al., 1999), and transgenic mice overexpressing leptin show increased insulin sensitivity (Ogawa et al., 1999).”
BackgroundSteinberg, G. R., Dyck, D. J., Calles-Escandon, J., Tandon, N. N., Luiken, J. J. F. P., Glatz, J. F. C., & Bonen, A. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m107683200 · Cited by 91 · see citing works
Cummings, B. P., Bettaieb, A., Graham, J. L., Stanhope, K. L., Dill, R., Morton, G. J., Haj, F. G., & Havel, P. J. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1107163108 · Cited by 87 · see citing works
“Several studies have demonstrated marked improvement of glucose homeostasis with systemic leptin administration in rodent models of type 1 diabetes, independent of changes of energy intake or circulating insulin concentrations (11, 16, 17).”
BackgroundResultLiu, S., Chang, Y.-H., & Chiang, M. (2010) · Journal of Agricultural and Food Chemistry · doi:10.1021/jf100662r · Cited by 87 · see citing works
Acute effects of brain-derived neurotrophic factor on energy expenditure in obese diabetic mice
Tsuchida, A., Nonomura, T., Ono‐Kishino, M., Nakagawa, T., Taiji, M., & Noguchi, H. (2001) · International Journal of Obesity · doi:10.1038/sj.ijo.0801678 · Cited by 86 · see citing works
Liu, Y., Nakagawa, Y., Wang, Y., Li, R., Li, X., Ohzeki, T., & Friedman, T. C. (2003) · Diabetes · doi:10.2337/diabetes.52.6.1409 · Cited by 79 · see citing works
“Such a concept is supported by data from studies in which leptin acted independently of insulin to restore euglycemia and normalize glucose turnover in insulindeficient STZ-induced diabetic rats (46,47).”
ResultIshida, E., Kim-Muller, J. Y., & Accili, D. (2017) · Diabetes · doi:10.2337/db16-1213 · Cited by 76 · see citing works
Côté, C. D., Zadeh‐Tahmasebi, M., Rasmussen, B. A., Duca, F. A., & Lam, T. K. T. (2014) · Journal of Biological Chemistry · doi:10.1074/jbc.o114.556068 · Cited by 71 · see citing works
Lumini-Oliveira, J., Magalhães, J., Pereira, C. V., Moreira, A. C., Oliveira, P. J., & Ascensão, A. (2011) · Mitochondrion · doi:10.1016/j.mito.2010.07.005 · Cited by 66 · see citing works
“The present study did not allow examining interactions of spontaneous physical activity and food intake with hyperglycemia, which has been demonstrated elegantly by others (Chinookoswong et al., 1999; Sei et al., 1999; Ramadan et al., 2006; Punithavathi et al., 2008).”
BackgroundMechanism for leptin’s acute insulin-independent effect to reverse diabetic ketoacidosis
Perry, R. J., Peng, L., Abulizi, A., Kennedy, L., Cline, G. W., & Shulman, G. I. (2017) · Journal of Clinical Investigation · doi:10.1172/jci88477 · Cited by 67 · see citing works
“Based on these results, we hypothesize that the chronic effect of leptin can be attributed at least in part to its ability to (a) decrease hyperphagia, resulting in reductions in postprandial hyperglycemia; (b) lower ectopic lipid (DAG) content in liver and skeletal muscle, resulting in reversal of insulin resistance…”
BackgroundZhao, H., Yakar, S., Gavrilova, O., Sun, H., Zhang, Y., Kim, H., Setser, J., Jou, W., & LeRoith, D. (2004) · Diabetes · doi:10.2337/diabetes.53.11.2901 · Cited by 64 · see citing works
“The levels of adipokines released from fat mass are altered in insulin-resistant states and in diabetes (35).”
BackgroundSkeletal muscle as a therapeutic target for delaying type 1 diabetic complications
Coleman, S. K. (2015) · World Journal of Diabetes · doi:10.4239/wjd.v6.i17.1323 · Cited by 64 · see citing works
Toda, C., Shiuchi, T., Kageyama, H., Okamoto, S., Coutinho, E. A., Sato, T., Okamatsu‐Ogura, Y., Yokota, S., Takagi, K., Tang, L., et al. (2013) · Diabetes · doi:10.2337/db12-1629 · Cited by 63 · see citing works
“Treatment with leptin ameliorates diabetes in lipodystrophic mice and humans (3–5) as well as type 1 (6,7) and obesity-unrelated type 2 diabetes (8) in rodents.”
BackgroundPathways leading to muscle insulin resistance – The muscle – fat connection
Sell, H., Eckel, J., & Dietze-Schroeder, D. (2006) · Archives of Physiology and Biochemistry · doi:10.1080/13813450600711540 · Cited by 61 · see citing works
Gonçalves, G. H. M., Li, W., Garcia, A. V. C.-G., Figueiredo, M. S., & Bjørbæk, C. (2014) · Cell Reports · doi:10.1016/j.celrep.2014.04.010 · Cited by 61 · see citing works
Multifaceted Leptin Network: The Molecular Connection Between Obesity and Breast Cancer
Saxena, N. K., & Sharma, D. (2013) · Journal of Mammary Gland Biology and Neoplasia · doi:10.1007/s10911-013-9308-2 · Cited by 62 · see citing works
“Circulating as a 16 kDa non-glycosylated protein partially bound to plasma proteins, leptin targets hypothalamus, and peripheral organs, including liver, skeletal muscle and pancreas [21–23].”
Nasrallah, M., & Ziyadeh, F. N. (2013) · Seminars in Nephrology · doi:10.1016/j.semnephrol.2012.12.005 · Cited by 60 · see citing works
Naito, M., Fujikura, J., Ebihara, K., Miyanaga, F., Yokoi, H., Kusakabe, T., Yamamoto, Y., Son, C., Mukoyama, M., Hosoda, K., et al. (2011) · Diabetes · doi:10.2337/db10-1795 · Cited by 58 · see citing works
In vivo leptin infusion impairs insulin and leptin signalling in liver and hypothalamus
Benomar, Y., Wetzler, S., Larue‐Achagiotis, C., Djiane, J., Tomé, D., & Taouis, M. (2005) · Molecular and Cellular Endocrinology · doi:10.1016/j.mce.2005.07.003 · Cited by 57 · see citing works
Ueno, N., Inui, A., Kalra, P. S., & Kalra, S. P. (2006) · Peptides · doi:10.1016/j.peptides.2006.03.006 · Cited by 53 · see citing works
Control of hepatic glucose metabolism by islet and brain
Rojas, J. M., & Schwartz, M. W. (2014) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12332 · Cited by 52 · see citing works
Attele, A. S., Shi, Z. Q., & Yuan, C.-S. (2002) · Biochemical Pharmacology · doi:10.1016/s0006-2952(02)00883-3 · Cited by 52 · see citing works
Self-citationLeptin 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
“There are several reports showing a marked decrease in plasma leptin concentrations in insulin-deficient diabetic rats and humans [13, 14, 15, 16, 17, 18, 19, 20], suggesting the therapeutic implication of leptin in insulin-deficient diabetes.”
BackgroundChanges in insulin sensitivity during leptin replacement therapy in leptin-deficient patients
Paz-Filho, G., Esposito, K. F., Hurwitz, B. E., Sharma, A. M., Dong, C., Andreev, V., Delibaşı, T., Erol, H. K., Ayala, A. R., Wong, M., et al. (2008) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.90450.2008 · Cited by 50 · see citing works
da Silva, A. A., Tallam, L. S., Liu, J., & Hall, J. E. (2006) · American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · doi:10.1152/ajpregu.00187.2006 · Cited by 51 · see citing works
Sáinź, N., Rodrı́guez, A., Catalán, V., Becerril, S., Ramírez, B., Gómez‐Ambrosi, J., & Frühbeck, G. (2010) · Mediators of Inflammation · doi:10.1155/2010/784343 · Cited by 51 · see citing works
“Oxidative stress is increased in diabetes [26, 27] with leptin administration reportedly improving insulin sensitivity in normal and diabetic rodents [28–30].”
Early events involved in the development of insulin resistance in Zucker fatty rat
Liu, R., Mizuta, M., Kurose, T., & Matsukura, S. (2002) · International Journal of Obesity · doi:10.1038/sj.ijo.0801924 · Cited by 49 · see citing works
Leptin signaling and leptin resistance
Liu, J., Lai, F., Hou, Y., & Zheng, R. (2022) · Medical Review · doi:10.1515/mr-2022-0017 · Cited by 55 · see citing works
Kojima, S., Asakawa, A., Amitani, H., Sakoguchi, T., Ueno, N., Inui, A., & Kalra, S. P. (2009) · Peptides · doi:10.1016/j.peptides.2009.01.007 · Cited by 48 · see citing works
“Interestingly, systemic and central administration of leptin, a product of adipocytes, has also been shown to curb hyperglycemia and hyperphagia in STZ-pretreated rodents in short-term experiments [8,20,21].”
InfluentialCentral signalling cross‐talk between insulin and leptin in glucose and energy homeostasis
Boucsein, A., Kamstra, K., & Tups, A. (2021) · Journal of Neuroendocrinology · doi:10.1111/jne.12944 · Cited by 46 · see citing works
Kalra, S. P. (2009) · Peptides · doi:10.1016/j.peptides.2009.07.021 · Cited by 46 · see citing works
“Systemic administration of leptin to either leptindeficient ob/ob [19,35,41,61,89] or leptinopenic lipodystrophic, diabetic humans and mice stimulated glucose metabolism and normalized blood glucose concentrations, benefits previously”
BackgroundLeptin, diabetes, and the brain
Morton, G. J., & Meek, T. H. (2012) · Indian Journal of Endocrinology and Metabolism · doi:10.4103/2230-8210.105568 · Cited by 45 · see citing works
“However, in contrast to physiological replacement doses of leptin, hyperleptinemia induced by either pharmacological doses of leptin[38,39] or an adenoviral gene therapy approach[40] ameliorates hyperglycemia in rodent models of uDM, despite very low insulin levels.”
BackgroundLeptin increases osteoblast-specific osteocalcin release through a hypothalamic relay
Kalra, S. P., Dube, M. G., & Iwaniec, U. T. (2009) · Peptides · doi:10.1016/j.peptides.2009.01.020 · Cited by 46 · see citing works
“Increased leptin signaling by icv injection of either leptin or rAAV-lep readily augments energy expenditure and glucose metabolism, even in the absence of increased energy intake [1,2,17,20,21,32,59,60] and these centrally generated effects participate substantially in diminishing blood glucose levels [20,21,59,60].”
BackgroundLeptin resistance following over-expression of protein tyrosine phosphatase 1B in liver
Lam, N., Covey, S. D., Lewis, J. T., Oosman, S. N., Webber, T. D., Hsu, E. C., Cheung, A. T., & Kieffer, T. J. (2005) · Journal of Molecular Endocrinology · doi:10.1677/jme.1.01937 · Cited by 45 · see citing works
Cross-talk between adipose and gastric leptins for the control of food intake and energy metabolism
Cammisotto, P., Levy, E. H., Bukowiecki, L. J., & Bendayan, M. (2010) · Progress in Histochemistry and Cytochemistry · doi:10.1016/j.proghi.2010.06.001 · Cited by 42 · see citing works
Morton, G. J., Meek, T. H., Matsen, M. E., & Schwartz, M. W. (2015) · Journal of Clinical Investigation · doi:10.1172/jci82723 · Cited by 40 · see citing works
Kalra, S. P. (2008) · Nutrition · doi:10.1016/j.nut.2008.06.023 · Cited by 40 · see citing works
“However, contrary to this established mode for the genesis of type 2 diabetes, evidence also shows that direct activation of hypothalamic leptin receptor by intraventricular injections of leptin lowers blood glucose levels and glucose intolerance [33,34].”
BackgroundSclerostin and its significance for children and adolescents with type 1 diabetes mellitus (T1D)
Wędrychowicz, A., Sztefko, K., & Starzyk, J. (2018) · Bone · doi:10.1016/j.bone.2018.08.007 · Cited by 40 · see citing works
Leptin reduces glucose transport and cellular ATP levels in INS-1 beta-cells
Lam, N., Cheung, A., Riedel, M., Light, P., Ci, C., & Kieffer, T. J. (2004) · Journal of Molecular Endocrinology · doi:10.1677/jme.0.0320415 · Cited by 40 · see citing works
“infusion of leptin to rats enhances hepatic insulin sensitivity and increases whole-body glucose utilization (Kamohara et al. 1997, Sivitz et al. 1997, Barzilai et al. 1999, Chinookoswong et al. 1999 ).”
BackgroundPleotropic effects of leptin to reverse insulin resistance and diabetic ketoacidosis
Perry, R. J., Petersen, K. F., & Shulman, G. I. (2016) · Diabetologia · doi:10.1007/s00125-016-3909-4 · Cited by 39 · see citing works
Increased plasma leptin attenuates adaptive metabolism in early lactating dairy cows
Ehrhardt, R., Foskolos, A., Giesy, S. L., Wesolowski, S. R., Krumm, C. S., Butler, W. R., Quirk, S. M., Waldron, M. R., & Boisclair, Y. R. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0031 · Cited by 36 · see citing works
Hypothalamic clamp on insulin release by leptin-transgene expression
Boghossian, S., Dube, M. G., Torto, R., Kalra, P. S., & Kalra, S. P. (2006) · Peptides · doi:10.1016/j.peptides.2006.07.022 · Cited by 36 · see citing works
Matsubara, M., Chiba, H., Maruoka, S., & Katayose, S. (2000) · Journal of Atherosclerosis and Thrombosis · doi:10.5551/jat1994.7.231 · Cited by 36 · see citing works
Jejunal Leptin-PI3K Signaling Lowers Glucose Production
Rasmussen, B. A., Breen, D. M., Duca, F. A., Côté, C. D., Zadeh‐Tahmasebi, M., Filippi, B., & Lam, T. K. T. (2013) · Cell Metabolism · doi:10.1016/j.cmet.2013.11.014 · Cited by 32 · see citing works
- Authors
- Chinookoswong, N., Wang, J. L., & Shi, Z. Q.
- Affiliations
- Amgen (United States) (US)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-07-01
- Volume
- 48
- Issue
- 7
- Pages
- 1487-1492
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2113808580
- Cited by
- 197
- References
- 0
- Citations by year
- 2022: 4 · 2021: 6 · 2020: 2 · 2019: 1 · 2018: 4 · 2017: 11 · 2016: 14 · 2015: 9 · 2014: 11 · 2013: 12 · 2012: 13
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Neuroscience › Endocrine and Autonomic Systems › Regulation of Appetite and Obesity
- Health Sciences › Medicine › Epidemiology › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Keywords
- leptin, insulin-deficient diabetes, streptozotocin-induced diabetes, glucose turnover, normoglycemia, insulin sensitivity, hyperinsulinemic-euglycemic clamp, phloridzin, dietary restriction, weight loss, peripheral insulin action
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Drug Evaluation, Preclinical, Glucose, Insulin, Male, Obesity, Phlorhizin, Proteins, Glucose Clamp Technique, Rats, Sprague-Dawley, Leptin, Rats
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
