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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.
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In the citing paper
“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]
In the citing paper
“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]
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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
“…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
Havel, P. J. (2002) · Current Opinion in Lipidology · doi:10.1097/00041433-200202000-00008 · Cited by 575
The Function of Leptin in Nutrition, Weight, and Physiology
Friedman, J. M. (2002) · Nutrition Reviews · doi:10.1301/002966402320634878 · Cited by 510
“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 462
Metadata
- 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 › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › 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
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