Leptin Deficiency Causes Insulin Resistance Induced by Uncontrolled Diabetes
Open accessAbstract
OBJECTIVE: Depletion of body fat stores during uncontrolled, insulin-deficient diabetes (uDM) results in markedly reduced plasma leptin levels. This study investigated the role of leptin deficiency in the genesis of severe insulin resistance and related metabolic and neuroendocrine derangements induced by uDM. RESEARCH DESIGN AND METHODS: Adult male Wistar rats remained nondiabetic or were injected with the β-cell toxin, streptozotocin (STZ) to induce uDM and subsequently underwent subcutaneous implantation of an osmotic minipump containing either vehicle or leptin at a dose (150 μg/kg/day) designed to replace leptin at nondiabetic plasma levels. To control for leptin effects on food intake, another group of STZ-injected animals were pair fed to the intake of those receiving leptin. Food intake, body weight, and blood glucose levels were measured daily, with body composition and indirect calorimetry performed on day 11, and an insulin tolerance test to measure insulin sensitivity performed on day 16. Plasma hormone and substrate levels, hepatic gluconeogenic gene expression, and measures of tissue insulin signal transduction were also measured. RESULTS: Physiologic leptin replacement prevented insulin resistance in uDM via a mechanism unrelated to changes in food intake or body weight. This effect was associated with reduced total body fat and hepatic triglyceride content, preservation of lean mass, and improved insulin signal transduction via the insulin receptor substrate–phosphatidylinositol-3-hydroxy kinase pathway in the liver, but not in skeletal muscle or adipose tissue. Although physiologic leptin replacement lowered blood glucose levels only slightly, it fully normalized elevated plasma glucagon and corticosterone levels and reversed the increased hepatic expression of gluconeogenic enzymes characteristic of rats with uDM. CONCLUSIONS: We conclude that leptin deficiency plays a key role in the pathogenesis of severe insulin resistance and related endocrine disorders in uDM. Treatment of diabetes in humans may benefit from correction of leptin deficiency as well as insulin deficiency.
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Systemic administration of exogenous leptin at a dose maintaining normal physiological plasma leptin levels prevents the development of severe, progressive insulin resistance in rats with uDM, an effect not explained by changes in food intake or body weight.
“Systemic administration of exogenous leptin at a dose that maintains normal physiological plasma leptin levels prevented the development of severe, progressive insulin resistance in rats with uDM, an effect that could not be explained by leptin-induced changes of food intake or body weight (68).”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [68]
Physiological leptin replacement in uDM reduces hepatic triglyceride content and gluconeogenic gene expression, restores normal insulin signal transduction in liver but not skeletal muscle or WAT, and normalizes circulating glucagon and corticosterone.
“physiological leptin replacement in uDM reduced hepatic triglyceride content and gluconeogenic gene expression, and also restored normal insulin signal transduction in liver, but not in skeletal muscle or WAT. This intervention also normalized circulating levels of glucagon and corticosterone, both of which are elevated in uDM.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [68]
Physiological leptin replacement only modestly reduces blood glucose levels in uDM, demonstrating that factors beyond leptin deficiency, elevated glucagon, and elevated corticosterone are sufficient to explain hyperglycemia in this model.
“physiological leptin replacement only modestly reduced blood glucose levels in this setting (68), demonstrating that factors beyond leptin deficiency (and elevated levels of glucagon and corticosterone) are sufficient to explain hyperglycemia in this model.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [68]
In STZ-induced uDM rats, hyperglycemia is only slightly improved by physiological leptin replacement despite normalized plasma glucagon levels, suggesting that glucagon normalization cannot fully explain the hypoglycemic effect of pharmacological leptin administration.
“the observation that in rats with STZ-induced uDM, hyperglycemia is only slightly improved by physiological leptin replacement despite normalized plasma glucagon levels (68) suggests that the latter cannot fully explain the hypoglycemic effect of pharmacological leptin administration in this setting.”
From Leptin and the Central Nervous System Control of Glucose Metabolism (2011) · cites this paper as [68]
Factors in addition to glucagon contribute to the glucose-lowering effect of CNS leptin action.
“our data suggest that factors, in addition to glucagon, contribute to the glucoselowering effect of CNS leptin action.”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [20]
Physiological leptin replacement is sufficient to normalize circulating glucagon and corticosterone levels, yet does not reverse hyperglycemia in rats with STZ diabetes.
“we recently reported that in rats with STZ diabetes, physiological leptin replacement is sufficient to normalize cir-culating glucagon and corticosterone levels, yet does not reverse hyperglycemia (20).”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [20]
Physiological leptin replacement is sufficient to normalize plasma glucagon levels but has little effect on diabetic hyperglycemia in rats with STZ diabetes.
“We recently observed that in rats with STZ diabetes, physiological leptin replacement is sufficient to normalize plasma glucagon levels but has little effect on diabetic hyperglycemia (20).”
From Leptin Activates a Novel CNS Mechanism for Insulin-Independent Normalization of Severe Diabetic Hyperglycemia (2011) · cites this paper as [20]
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References 51 · Cited by 159
- Authors
- 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., Schwartz, M. W., & Morton, G. J.
- Affiliations
- University of Washington (US)
- Diabetes and Obesity Center of Excellence, Department of Medicine, University of Washington, Seattle, Washington;
- United States Department of Veterans Affairs (US)
- Corresponding author
- Morton, Gregory J.
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2010-04-27
- Volume
- 59
- Issue
- 7
- Pages
- 1626-1634
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- PMC
- PMC2889761
- OpenAlex
- W2163021636
- Cited by
- 159
- References
- 51
- Citations by year
- 2026: 5 · 2025: 6 · 2024: 6 · 2023: 13 · 2022: 8 · 2021: 12 · 2020: 11 · 2019: 10 · 2018: 5 · 2017: 9 · 2016: 13 · 2015: 11 · 2014: 8 · 2013: 13 · 2012: 13
- FWCI
- 5.95
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Diabetes (publishedVersion, cc-by-nc-nd)
- Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
- PubMed Central (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Funders
- American Diabetes Association
- American Heart Association
- AstraZeneca
- University of Washington (DK‐035816)
- National Institutes of Health (DK-035816)
- National Institute of Diabetes and Digestive and Kidney Diseases (R01DK074758, DK-083042, DK 035816, DK052989, R01DK052989, DK-050154-13, R56DK050154, R01DK050154, P30DK035816, R01DK083042)
- 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 deficiency, insulin resistance, uncontrolled diabetes, streptozotocin-induced diabetes, leptin replacement, hepatic gluconeogenesis, insulin receptor substrate, phosphatidylinositol 3-kinase, hepatic triglycerides, glucagon, corticosterone, insulin signaling, dietary intake
- MeSH terms
- Adipose Tissue, Analysis of Variance, Animals, Blood Glucose, Diabetes Mellitus, Experimental, Eating, Homeostasis, Insulin, Insulin Resistance, Liver, Male, Rats, Wistar, Reverse Transcriptase Polymerase Chain Reaction, Leptin, Rats
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