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Effect of a Sustained Reduction in Plasma Free Fatty Acid Concentration on Intramuscular Long-Chain Fatty Acyl-CoAs and Insulin Action in Type 2 Diabetic Patients
Abstract
To investigate the effect of a sustained (7-day) decrease in plasma free fatty acid (FFA) concentrations on insulin action and intramyocellular long-chain fatty acyl-CoAs (LCFA-CoAs), we studied the effect of acipimox, a potent inhibitor of lipolysis, in seven type 2 diabetic patients (age 53 ± 3 years, BMI 30.2 ± 2.0 kg/m2, fasting plasma glucose 8.5 ± 0.8 mmol/l, HbA1c 7.5 ± 0.4%). Subjects received an oral glucose tolerance test (OGTT) and 120-min euglycemic insulin (80 mU/m2 per min) clamp with 3-[3H]glucose/vastus lateralis muscle biopsies to quantitate rates of insulin-mediated whole-body glucose disposal (Rd) and intramyocellular LCFA-CoAs before and after acipimox (250 mg every 6 h for 7 days). Acipimox significantly reduced fasting plasma FFAs (from 563 ± 74 to 230 ± 33 μmol/l; P < 0.01) and mean plasma FFAs during the OGTT (from 409 ± 44 to 184 ± 22 μmol/l; P < 0.01). After acipimox, decreases were seen in fasting plasma insulin (from 78 ± 18 to 42 ± 6 pmol/l; P < 0.05), fasting plasma glucose (from 8.5 ± 0.8 to 7.0 ± 0.5 mmol/l; P < 0.02), and mean plasma glucose during the OGTT (from 14.5 ± 0.8 to 13.0 ± 0.8 mmol/l; P < 0.05). After acipimox, insulin-stimulated Rd increased from 3.3 ± 0.4 to 4.4 ± 0.4 mg · kg−1 · min−1 (P < 0.03), whereas suppression of endogenous glucose production (EGP) was similar and virtually complete during both insulin clamp studies (0.16 ± 0.10 vs. 0.14 ± 0.10 mg · kg−1 · min−1; P > 0.05). Basal EGP did not change after acipimox (1.9 ± 0.2 vs. 1.9 ± 0.2 mg · kg−1 · min−1). Total muscle LCFA-CoA content decreased after acipimox treatment (from 7.26 ± 0.58 to 5.64 ± 0.79 nmol/g; P < 0.05). Decreases were also seen in muscle palmityl CoA (16:0; from 1.06 ± 0.10 to 0.75 ± 0.11 nmol/g; P < 0.05), palmitoleate CoA (16:1; from 0.48 ± 0.05 to 0.33 ± 0.05 nmol/g; P = 0.07), oleate CoA (18:1; from 2.60 ± 0.11 to 1.95 ± 0.31 nmol/g; P < 0.05), linoleate CoA (18:2; from 1.81 ± 0.26 to 1.38 ± 0.18 nmol/g; P = 0.13), and linolenate CoA (18:3; from 0.27 ± 0.03 to 0.19 ± 0.02 nmol/g; P < 0.03) levels after acipimox treatment. Muscle stearate CoA (18:0) did not decrease after acipimox treatment. The increase in Rd correlated strongly with the decrease in muscle palmityl CoA (r = 0.75, P < 0.05), oleate CoA (r = 0.76, P < 0.05), and total muscle LCFA-CoA (r = 0.74, P < 0.05) levels. Plasma adiponectin did not change significantly after acipimox treatment (7.9 ± 1.8 vs. 7.5 ± 1.5 μg/ml). These data demonstrate that the reduction in intramuscular LCFA-CoA content is closely associated with enhanced insulin sensitivity in muscle after a chronic reduction in plasma FFA concentrations in type 2 diabetic patients despite the lack of an effect on plasma adiponectin concentration.
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In the citing paper
“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 [69]
In the citing paper
“(ii) the decrease in insulin resistance brought about by reducing the plasma FFA concentration with acipimox in insulin resistant individuals is associated with a reduction in intracellular FACoA content, and the magnitude of decrease in insulin resistance strongly correlates with the decrease in FACoA content [69];”
From Pathogenesis of insulin resistance in skeletal muscle (2010) · cites this paper as [69]
In the citing paper
“In contrast, decreasing fatty acid flux in humans via pharmacological inhibition of lipolysis (49) or by discontinuing a lipid-plus-heparin infusion in rats (58) decreases IMTG concentration and/or the accumulation of fatty acid intermediates.”
From Insulin sensitivity: Modulation by nutrients and inflammation (2008) · cites this paper as [49]
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 [49]
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DeFronzo, R. A. (2009) · Diabetes · doi:10.2337/db09-9028 · Cited by 3,016
Self-citationJung, U. J., & Choi, M. (2014) · International Journal of Molecular Sciences · doi:10.3390/ijms15046184 · Cited by 1,971
Pathogenesis of type 2 diabetes mellitus
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Self-citationInsulin sensitivity: Modulation by nutrients and inflammation
Schenk, S., Saberi, M., & Olefsky, J. M. (2008) · Journal of Clinical Investigation · doi:10.1172/jci34260 · Cited by 1,191
Disordered lipid metabolism and the pathogenesis of insulin resistance.
Savage, D. B., Petersen, K. F., & Shulman, G. I. (2007) · Physiological Reviews · doi:10.1152/physrev.00024.2006 · Cited by 1,107
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Metadata
- Authors
- Bajaj, M., Suraamornkul, S., Romanelli, A., Cline, G. W., Mandarino, L. J., Shulman, G. I., & DeFronzo, R. A.
- Affiliations
- The University of Texas at San Antonio Health Science Center (US)
- Howard Hughes Medical Institute (US)
- ORCID
- Venue
- Diabetes
- Publisher
- American Diabetes Association
- Published
- 2005-11-01
- Volume
- 54
- Issue
- 11
- Pages
- 3148-3153
- ISSN
- 0012-1797 (ISSN-L)
- 1939-327X
- OpenAlex
- W2160930691
- Cited by
- 181
- References
- 55
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 1 · 2023: 5 · 2022: 10 · 2021: 7 · 2020: 7 · 2019: 4 · 2018: 8 · 2017: 4 · 2016: 5 · 2015: 11 · 2014: 6 · 2013: 9 · 2012: 11
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Diabetes (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Institute of Diabetes and Digestive and Kidney Diseases (DK 45735, DK 24092, DK-068229, P30DK045735, P01DK068229)
- National Center for Research Resources (M01RR01346, M01RR001346)
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes Treatment and Management
- Keywords
- type 2 diabetes, plasma free fatty acids, acipimox, lipolysis inhibition, long-chain fatty acyl-CoA, intramyocellular lipid, insulin action, insulin sensitivity, glucose disposal, insulin-stimulated glucose uptake, endogenous glucose production, insulin resistance, hyperinsulinemic-euglycemic clamp, oral glucose tolerance test, fatty acid oxidation
- MeSH terms
- Acyl Coenzyme A, Hypolipidemic Agents, Diabetes Mellitus, Type 2, Fatty Acids, Nonesterified, Female, Glucose Tolerance Test, Humans, Hyperlipidemias, Insulin, Male, Middle Aged, Pyrazines, Muscle, Skeletal, Adiponectin
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