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Overnight lowering of free fatty acids with Acipimox improves insulin resistance and glucose tolerance in obese diabetic and nondiabetic subjects.
Abstract
Obesity is commonly associated with elevated plasma free fatty acid (FFA) levels, as well as with insulin resistance and hyperinsulinemia, two important cardiovascular risk factors. What causes insulin resistance and hyperinsulinemia in obesity remains uncertain. Here, we have tested the hypothesis that FFAs are the link between obesity and insulin resistance/hyperinsulinemia and that, therefore, lowering of chronically elevated plasma FFA levels would improve insulin resistance/hyperinsulinemia and glucose tolerance in obese nondiabetic and diabetic subjects. Acipimox (250 mg), a long-acting antilipolytic drug, or placebo was given overnight (at 7:00 P.M., 1:00 A.M., 7:00 A.M.) to 9 lean control subjects, 13 obese nondiabetic subjects, 10 obese subjects with impaired glucose tolerance, and 11 patients with type 2 diabetes. Euglycemic-hyperinsulinemic clamps and oral glucose tolerance tests (75 g) were performed on separate mornings after overnight Acipimox or placebo treatment. In the three obese study groups, Acipimox lowered fasting levels of plasma FFAs (by 60-70%) and plasma insulin (by approximately 50%). Insulin-stimulated glucose uptake during euglycemic-hyperinsulinemic clamping was more than twofold higher after Acipimox than after placebo. Areas under the glucose and insulin curves during oral glucose tolerance testing were both approximately 30% lower after Acipimox administration than after placebo. We conclude that lowering of elevated plasma FFA levels can reduce insulin resistance/hyperinsulinemia and improve oral glucose tolerance in lean and obese nondiabetic subjects and in obese patients with type 2 diabetes.
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“Conversely, reduction of plasma FFA concentration in insulin resistant individuals, for example, type 2 diabetic subjects, augments insulin-stimulated glucose disposal in skeletal muscle [69–72], and the improvement in insulin sensitivity is closely associated with a reduction in intramyocellular FACoA concentration [69].”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [72]
In the citing paper
“Further evidence linking fatty acids to insulin sensitivity comes from clinical studies showing that pharmacological inhibition of lipolysis decreases fatty acid levels and rapidly enhances insulin sen-sitivity in diabetic and nondiabetic, lean and obese subjects (48,49).”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [48]
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“In particular, the high absolute rates of lipolysis and systemic fatty acid availability, which are a hallmark of abdominal obesity (17), have been shown to play a causative role in the insulin resistance commonly found in obesity (26, 27, 29).”
Bajaj, M., Suraamornkul, S., Kashyap, S., Cusi, K., Mandarino, L., & DeFronzo, R. A. (2004) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2004-0224 · Cited by 109
Fasting for 72 h increases intramyocellular lipid content in nondiabetic, physically fit men
Stannard, S. R., Thompson, M. W., Fairbairn, K., Huard, B., Sachinwalla, T., & Thompson, C. H. (2002) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00108.2002 · Cited by 108
“Indeed, an acute increase in plasma FFA concentration is associated with reduced insulin sensitivity and increased IMCL content (3, 4), whereas an acute reduction in FFA concentration improves insulin sensitivity (36).”
BackgroundFree fatty acids, insulin resistance, and pregnancy
Sivan, E., & Boden, G. (2003) · Current Diabetes Reports · doi:10.1007/s11892-003-0024-y · Cited by 105
Self-citationKelley, D. E., Williams, K. V., Price, J. C., McKolanis, T. M., Goodpaster, B. H., & Thaete, F. L. (2001) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jcem.86.11.8027 · Cited by 103
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InfluentialNocturnal and Postprandial Free Fatty Acid Kinetics in Normal and Type 2 Diabetic Subjects
Miles, J. M., Wooldridge, D., Grellner, W. J., Windsor, S. L., Isley, W. L., Klein, S., & Harris, W. S. (2003) · Diabetes · doi:10.2337/diabetes.52.3.675 · Cited by 103
“A recent study reported improvement in fasting hyperglycemia, glucose tolerance, and insulin sensitivity when acipimox was administered to subjects with type 2 diabetes (47).”
BackgroundMyette‐Côté, É., Neudorf, H., Rafiei, H., Clarke, K., & Little, J. P. (2018) · The Journal of Physiology · doi:10.1113/jp275709 · Cited by 103
“…circulating NEFA is associated with improved insulin sensitivity and/or glucose tolerance, it is possible that the improvement in insulin sensitivity in the Kme condition could be the result of the decrease in circulating NEFA (Saloranta et al. 1993; Santomauro et al. 1999; Cusi et al. 2007).”
BackgroundInfluentialMontagnani, M., & Quon, M. J. (2000) · Diabetes Obesity and Metabolism · doi:10.1046/j.1463-1326.2000.00092.x · Cited by 102
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Plant-Based Diets in the Reduction of Body Fat: Physiological Effects and Biochemical Insights
Najjar, R. S., & Feresin, R. G. (2019) · Nutrients · doi:10.3390/nu11112712 · Cited by 115
The metabolic syndrome: metabolic changes with vascular consequences
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Peroxisomes and cancer: The role of a metabolic specialist in a disease of aberrant metabolism
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Targeting NAD+ in Metabolic Disease: New Insights Into an Old Molecule
Elhassan, Y., Philp, A., & Lavery, G. G. (2017) · Journal of the Endocrine Society · doi:10.1210/js.2017-00092 · Cited by 93
Metadata
- Authors
- Santomauro, A. T., Boden, G., Silva, M. E., Rocha, D. M., Santos, R. F., Ursich, M. J., Strassmann, P. G., & Wajchenberg, B. L.
- Affiliations
- Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo (BR)
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 1999-09-01
- Volume
- 48
- Issue
- 9
- Pages
- 1836-1841
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2007405015
- Cited by
- 431
- References
- 0
- Citations by year
- 2026: 3 · 2025: 5 · 2024: 7 · 2023: 9 · 2022: 7 · 2021: 11 · 2020: 20 · 2019: 10 · 2018: 17 · 2017: 18 · 2016: 10 · 2015: 17 · 2014: 18 · 2013: 20 · 2012: 24
- FWCI
- 9.91
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institutes of Health (5r01ag007988-10, 5r01aa010221-03)
- National Institute on Alcohol Abuse and Alcoholism (R01-AA-10221)
- National Institute on Aging (R01-AG07988)
- National Center for Research Resources (M01RR000349, RR-00349)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Adipokines, Inflammation, and Metabolic Diseases
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Keywords
- acipimox, free fatty acids, insulin resistance, hyperinsulinemia, glucose tolerance, obesity, type 2 diabetes, impaired glucose tolerance, insulin-stimulated glucose uptake, hyperinsulinemic-euglycemic clamp, oral glucose tolerance test
- MeSH terms
- Adult, Hypolipidemic Agents, Basal Metabolism, Diabetes Mellitus, Fatty Acids, Nonesterified, Female, Glucose Tolerance Test, Humans, Insulin Resistance, Male, Obesity, Oxidation-Reduction, Pyrazines, Glucose Clamp Technique
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