Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific Insulin Sensitivity - PubMed (original) (raw)
Decreases in Circulating Concentrations of Long-Chain Acylcarnitines and Free Fatty Acids During the Glucose Tolerance Test Represent Tissue-Specific Insulin Sensitivity
Elina Makarova et al. Front Endocrinol (Lausanne). 2019.
Abstract
Background: Insulin plays a pivotal role in the regulation of both carbohydrate and lipid intermediate turnover and metabolism. In the transition from a fasted to fed state, insulin action inhibits lipolysis in adipocytes, and acylcarnitine synthesis in the muscles and heart. The aim of this study was to measure free fatty acid (FFA) and acylcarnitine levels during the glucose tolerance test as indicators of tissue-specific insulin resistance. Results: Insulin release in response to glucose administration decreased both FFA and long-chain acylcarnitine levels in plasma in healthy control animals by 30% (120 min). The glucose tolerance test and [3H]-deoxy-D-glucose uptake in tissues revealed that high fat diet-induced lipid overload in C57bl/6N mice evoked only adipose tissue insulin resistance, and plasma levels of FFAs did not decrease after glucose administration. In comparison, db/db mice developed type 2 diabetes with severely impaired insulin sensitivity and up to 70% lower glucose uptake in both adipose tissues and muscles (skeletal muscle and heart), and both plasma concentrations of FFAs and long-chain acylcarnitines did not decrease in response to glucose administration. Conclusions: These results link impaired adipose tissue insulin sensitivity with continuous FFA release in the transition from a fasted to postprandial state, while a blunted decrease in long-chain acylcarnitine levels is associated with muscle and heart insulin resistance.
Keywords: free fatty acids; glucose tolerance test; insulin resistance; long-chain acylcarnitines; type 2 diabetes.
Copyright © 2019 Makarova, Makrecka-Kuka, Vilks, Volska, Sevostjanovs, Grinberga, Zarkova-Malkova, Dambrova and Liepinsh.
Figures
Figure 1
Changes in plasma acylcarnitine concentrations in db/db and HFD-fed mice during the GTT. Long-chain (A,B), short-chain (C,D), and medium-chain (E,F) acylcarnitine concentrations were determined in fasted blood plasma samples at 1 and 2 h after glucose administration in db/L and db/db, control and HFD-fed mice. Values are represented as the average ± SEM of 5–10 animals. *Significantly different from the fasted state (paired _t_-test, p < 0.05). #Significantly different from the control group (unpaired _t_-test, p < 0.05).
Figure 2
Changes in plasma FFA concentrations in db/db and HFD-fed mice during the GTT. FFA (A,B) concentrations were determined in fasted blood plasma samples at 1 and 2 h after glucose administration in db/L and db/db, control and HFD-fed mice. Values are represented as the average ± SEM of 5–10 animals. *Significantly different from the fasted state (paired _t_-test, p < 0.05). #Significantly different from the control group (unpaired _t_-test, p < 0.05).
Figure 3
Tissue glucose uptake in db/db and HFD-fed mice. The uptake of 3H-DOG in the skeletal muscle, heart and adipose tissue in db/L and db/db (A), control and HFD-fed (B) mice was measured 2 h after the GTT. Values are represented as the average ± SEM of 4–5 animals. #Significantly different from the control group (unpaired _t_-test, p < 0.05).
Figure 4
Changes in glucose concentrations during the GTT in control, HFD-fed, db/L, and db/db mice. Changes in glucose concentrations during the GTT (A,B) and the calculated AUC of the change from basal glucose levels (C,D) in db/L and db/db, control and HFD-fed mice. Values are represented as the average ± SEM of 10 animals. *Significantly different from the fasted state (paired _t_-test, p < 0.05). #Significantly different from the control group (unpaired _t_-test, p < 0.05).
Figure 5
Concentrations of blood glucose, plasma insulin and HbA1c in control, HFD-fed, db/L, and db/db mice. Glucose concentrations in fasted and fed states and at 2 h after the glucose tolerance test (GTT) (A,B); fed and fasted insulin plasma levels (C,D) and blood HbA1c levels (E,F) in db/L and db/db, control and HFD-fed mice. Values are represented as the average ± SEM of 5–10 animals. *Significantly different from fasted state (paired _t_-test, p < 0.05). #Significantly different from the control group (unpaired _t_-test, p < 0.05).
Figure 6
Insulin-induced effects on long-chain (LC) acylcarnitine synthesis in muscle/heart cells and lipolysis in adipocytes in the transition from fasted to postprandial (fed) state. Plasma levels of FFAs and LC acylcarnitines depend on acylcarnitine synthesis rate in muscles/heart and lipolysis rate in adipocytes. In muscle and heart cells activation of insulin signaling prevents ACC phosphorylation, stimulates malonyl-CoA synthesis and results in CPT-1 inhibition. In adipocytes cAMP-dependent suppression of lipolysis by insulin signaling involves activation of PDE3 (which degrades cAMP), releasing PKA from activation, and decreasing lipolysis through a reduction in the phosphorylation-mediated activation of HSL and perilipin. Green arrows—activation, red arrows—inhibited reactions. Dotted line—efflux. ACC, acetyl-CoA carboxylase; β-ox, β-oxidation; CPT, carnitine palmitoyltransferase; HSL, hormone-sensitive lipase; PKA, protein kinase A (cAMP-dependent protein kinase); PDE3, phosphodiesterase 3B.
References
- Inzucchi SE, Bergenstal RM, Buse JB, Diamant M, Ferrannini E, Nauck M, et al. Management of hyperglycemia in type 2 diabetes, 2015: a patient-centered approach: update to a position statement of the american diabetes association and the european association for the study of diabetes. Diabetes Care. (2015) 38:140–9. 10.2337/dc14-2441 - DOI - PubMed
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