Central nervous system nitric oxide synthase activity regulates insulin secretion and insulin action
Open accessAbstract
Systemic inhibition of nitric oxide synthase (NOS) with NG-monomethyl-L-arginine (L-NMMA) causes acute insulin resistance (IR), but the mechanism is unknown. We tested whether L-NMMA-induced IR occurs via NOS blockade in the central nervous system (CNS). Six groups of Sprague-Dawley rats were studied after chronic implantation of an intracerebroventricular (ICV) catheter into the lateral ventricle and catheters into the carotid artery and jugular vein. Animals were studied after overnight food deprivation, awake, unrestrained, and unstressed; all ICV infusion of L-NMMA or D-NMMA (control) were performed with artificial cerebrospinal fluid. ICV administration of L-NMMA resulted in a 30% rise in the basal glucose level after 2 h, while ICV D-NMMA had no effect on glucose levels. Insulin, epinephrine, and norepinephrine levels were unchanged from baseline in both groups. Tracer (3H-3-glucose)-determined glucose disposal rates during 2 h euglycemic hyperinsulinemic (300 microU/ml) clamps performed after ICV administration of L-NMMA were reduced by 22% compared with D-NMMA. Insulin secretory responses to a hyperglycemic clamp and to a superimposed arginine bolus were reduced by 28% in L-NMMA-infused rats compared with D-NMMA. In conclusion, ICV administration of L-NMMA causes hyperglycemia via the induction of defects in insulin secretion and insulin action, thus recapitulating abnormalities observed in type 2 diabetes. The data suggest the novel concept that central NOS-dependent pathways may control peripheral insulin action and secretion. This control is not likely to be mediated via adrenergic mechanisms and could occur via nonadrenergic, noncholinergic nitrergic neural and/or endocrine pathways. These data support previously published data suggesting that CNS mechanisms may be involved in the pathogenesis of some forms of insulin resistance and type 2 diabetes independent of adiposity.
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Intracerebroventricular administration of LNMMA regulates insulin secretion and peripheral insulin sensitivity.
“Interestingly, intracerebroventricular administration of NG-monomethyl-L-arginine (LNMMA) was shown also to regulate insulin secretion and peripheral insulin sensitivity [260]”
From Regulation of obesity and insulin resistance by nitric oxide (2014) · cites this paper as [260]
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“by the induction of insulin resistance in rats by intracerebroventricular administration of N-monomethyl-Larginine monoacetate (36).”
MethodMuscle metabolism and control of capillary blood flow: insulin and exercise
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“In rats, NOS inhibitors administered by an intravenous route induce acute insulin resistance (2) and intracerebroventricular administration induces both peripheral insulin resistance and defects in insulin secretion (45).”
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“One study reported that inhibition of NOS in the central nervous system could cause hyperglycemia through induction of insulin resistance and insulin secretory defects, which are less likely to be mediated through adrenergic mechanisms but rather through nonadrenergic, noncholinergic nitrergic neural and/or endocrine…”
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- Authors
- Shankar, R., Zhu, J. S., Ladd, B., Henry, D., Shen, H. Q., & Baron, A. D.
- Affiliations
- Indiana University Indianapolis (US)
- Eli Lilly (United States) (US)
- Richard L. Roudebush VA Medical Center (US)
- Corresponding author
- Baron, A D
- ORCID
- Venue
- Journal of Clinical Investigation
- Published
- 1998-10-01
- Volume
- 102
- Issue
- 7
- Pages
- 1403-1412
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC508988
- OpenAlex
- W2089022419
- Cited by
- 79
- References
- 58
- Citations by year
- 2026: 1 · 2024: 3 · 2023: 3 · 2022: 1 · 2021: 1 · 2020: 4 · 2019: 1 · 2017: 2 · 2016: 1 · 2014: 2 · 2013: 5 · 2012: 5
- FWCI
- 3.70
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- U.S. Department of Veterans Affairs
- National Institutes of Health
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 20452, DK42469)
- Topics
- Health Sciences › Medicine › Surgery › Pancreatic function and diabetes
- Health Sciences › Medicine › Physiology › Nitric Oxide and Endothelin Effects
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- nitric oxide synthase, central nervous system, insulin resistance, insulin secretion, L-NMMA, hyperglycemia, glucose disposal, type 2 diabetes, nitric oxide pathway, intracerebroventricular infusion, arginine stimulation, hyperinsulinemic-euglycemic clamp
- MeSH terms
- Insulin Secretion, Animals, Blood Glucose, Blood Pressure, Cerebral Ventricles, Enzyme Inhibitors, Epinephrine, Infusions, Intravenous, Infusions, Parenteral, Injections, Intraventricular, Insulin, Male, Norepinephrine, Stereoisomerism, Wakefulness, Glucose Clamp Technique, Rats, Sprague-Dawley, Nitric Oxide Synthase, omega-N-Methylarginine, Rats
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