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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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Dobbins, R. L., Shearn, S. P., Byerly, R., Gao, F. F., Mahar, K. M., Napolitano, A., Nachbaur, G., & de Gouville, A. L. M. (2013) · Diabetes Obesity and Metabolism · doi:10.1111/dom.12132 · Cited by 35
Kurioka, S., Murakami, Y., Nishiki, M., Sohmiya, M., Koshimura, K., & Kato, Y. (2002) · Endocrine Journal · doi:10.1507/endocrj.49.459 · Cited by 35
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“Previous studies in humans have demonstrated that lowering plasma FFA using the NA analog acipimox for a short term (hours or days) increased insulin sensitivity (13, 34).”
BackgroundInfluence of endogenous NEFA on beta cell function in humans
Rebelos, E., Seghieri, M., Natali, A., Balkau, B., Golay, A., Piatti, P. M., Lalic, N. M., Laakso, M., Mari, A., & Ferrannini, E. (2015) · Diabetologia · doi:10.1007/s00125-015-3685-6 · Cited by 34
Nutritional effects of fat on carbohydrate metabolism
Boden, G. H., & Carnell, L. H. (2003) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/s1521-690x(03)00032-0 · Cited by 34
Self-citationThe role of the gastric fundus in glycemic control
Kehagias, D., Georgopoulos, N. A., Habeos, I. G., Lampropoulos, C., Mulita, F., & Kehagias, I. (2023) · HORMONES · doi:10.1007/s42000-023-00429-7 · Cited by 34
“Free fatty acids are greatly elevated in obesity, these being the main cause of insulin resistance and b-cell function impairment [7].”
BackgroundA Novel Link Between Circadian Clocks and Adipose Tissue Energy Metabolism
Yoshino, J., & Klein, S. (2013) · Diabetes · doi:10.2337/db13-0457 · Cited by 34
“However, it is also possible that localized adipose tissue clock disruption and downregulation of lipolytic activity have beneficial metabolic effects if energy intake and adiposity are not increased because experimentally increasing circulating FFAs causes hepatic (18) and skeletal muscle (19) insulin resistance, whe…”
BackgroundNørrelund, H., Nielsen, S., Christiansen, J., Jørgensen, J. O. L., & Møller, N. (2004) · European Journal of Endocrinology · doi:10.1530/eje.0.1500779 · Cited by 33
“Suppression of circulating levels of FFA, induced by pharmacological antilipolysis, increased insulin sensitivity ( 15 , 29, 30), and lipid infusion has been observed to inhibit glucose uptake and carbohydrate oxidation (31, 32).”
BackgroundRattarasarn, C. (2006) · Acta Physiologica · doi:10.1111/j.1748-1716.2005.01521.x · Cited by 34
“Similar findings have been previously reported in nondiabetic and type 2 diabetic patients (Vaag et al. 1991, Santamauro et al. 1999).”
ResultKavitha, S. A., Zainab, S., Muthyalaiah, Y. S., John, C. M., & Arockiasamy, S. (2025) · Molecular Biology Reports · doi:10.1007/s11033-025-10632-x · Cited by 36
“In obesity, enlarged adipose tissue releases increasing amounts of free fatty acids (FFAs), and lowering FFA levels has been shown to improve insulin sensitivity [55, 56].”
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“Interestingly, in contrast to supplementing the diet with specific beneficial FAs, numerous studies have also demonstrated that lowering overall FA concentrations in the body may also be associated with improved insulin resistance, oral glucose tolerance, and basal insulin levels in humans (Santomauro et al., 1999; Le…”
BackgroundFatty acid represses insulin receptor gene expression by impairing HMGA1 through protein kinase Cε
Dey, D., Bhattacharya, A., Roy, S., & Bhattacharya, S. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.03.183 · Cited by 32
Reducing plasma free fatty acids by acipimox improves glucose tolerance in high‐fat fed mice
Åhrén, B. (2001) · Acta Physiologica Scandinavica · doi:10.1046/j.1365-201x.2001.00794.x · Cited by 32
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Can antioxidants be effective therapeutics for type 2 diabetes?
Park, S., & Park, S. (2020) · Journal of Yeungnam Medical Science · doi:10.12701/yujm.2020.00563 · Cited by 32
“However, chronically elevated levels of FFAs in the plasma are one of the key triggers leading to defects in the insulin signaling pathway [21,22].”
BackgroundPharmacologic Therapy of Non-Alcoholic Steatohepatitis
Ratziu, V., & Zelber‐Sagi, S. (2009) · Clinics in Liver Disease · doi:10.1016/j.cld.2009.07.001 · Cited by 30
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“prevent type 2 diabetes mellitus [9] and improve insulin sensitivity in patients with known diabetes [10,11] are consistent with such a mechanism, as lowering of plasma FFA is thought to improve insulin sensitivity [12].”
BackgroundYuen, K. C. J., & Dunger, D. B. (2006) · Growth Hormone & IGF Research · doi:10.1016/j.ghir.2006.03.001 · Cited by 31
Vick, L. V., Canter, R. J., Monjazeb, A. M., & Murphy, W. J. (2023) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2023.07.004 · Cited by 35
Coffey, R., Sardo, U., Kautz, L., Gabayan, V. R., Nemeth, E., & Ganz, T. (2018) · Physiological Reports · doi:10.14814/phy2.13890 · Cited by 29
“As reducing circulating levels of NEFA improves insulin sensitivity and glucose tolerance (Santomauro et al. 1999), we aimed to test the possibility that beneficial effects of EPO treatment on glucose homeostasis (Allegra et al.”
Background
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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