Insulin release, peripheral insulin resistance and muscle function in protein malnutrition: a role of tricarboxylic acid cycle anaplerosis

Abstract

Pancreatic beta-cells and skeletal muscle act in a synergic way in the control of systemic glucose homeostasis. Several pyruvate-dependent and -independent shuttles enhance tricarboxylic acid cycle intermediate (TACI) anaplerosis and increase beta-cell ATP:ADP ratio, triggering insulin exocytotic mechanisms. In addition, mitochondrial TACI cataplerosis gives rise to the so-called metabolic coupling factors, which are also related to insulin release. Peripheral insulin resistance seems to be related to skeletal muscle fatty acid (FA) accumulation and oxidation imbalance. In this sense, exercise has been shown to enhance skeletal muscle TACI anaplerosis, increasing FA oxidation and by this manner restores insulin sensitivity. Protein malnutrition reduces beta-cell insulin synthesis, release and peripheral sensitivity. Despite little available data concerning mitochondrial metabolism under protein malnutrition, evidence points towards reduced beta-cell and skeletal muscle mitochondrial capacity. The observed decrease in insulin synthesis and release may reflect reduced anaplerotic and cataplerotic capacity. Furthermore, insulin release is tightly coupled to ATP:ADP rise which in turn is related to TACI anaplerosis. The effect of protein malnutrition upon peripheral insulin resistance is time-dependent and directly related to FA oxidation capacity. In contrast to beta-cells, TACI anaplerosis and cataplerosis pathways in skeletal muscle seem to control FA oxidation and regulate insulin resistance.

Plasma Metabolomic Profiles Reflective of Glucose Homeostasis in Non-Diabetic and Type 2 Diabetic Obese African-American Women

“…Most investigations found a reduced number or attenuated in vivo activity of muscle mitochondria in insulin resistant subjects [39]; [66]; [67] [36]–[38], but others have reported that the function of isolated muscle mitochondria is normal in T2DM [68]; [69]. This raises the possibility that factors limiting mitochondrial activity in diabetics in situ are lost in studies in isolated organelles.…”

Acylcarnitines as markers of exercise‐associated fuel partitioning, xenometabolism, and potential signals to muscle afferent neurons

“…; Zoppi et al . ); (ii) meeting muscle ATP needs through FAO can take place without full combustion of the fat in the TCA cycle: for any given ATP requirement, one may generate chain‐shortened fatty acid metabolites through β‐oxidation that do not enter the TCA cycle at all, but simply accumulate or are exported from mitochondria; and (iii) while measuring muscle fibre metabolism ex vivo is an improvement over isolated mitochondria, bioenergetics profiles comparing insulin‐resistant and insulin‐sensitive preparations will still be strongly influenced by the ATP turnover requirements of the cells, which may differ. With these concepts in mind, we set out to determine whether incomplete LCFA combustion (viz.…”

“…Yet, the assertion that mitochondrial dysfunction underlies diabetes phenotypes has been questioned, because isolated mitochondria from insulin-resistant or T2DM individuals can display normal bioenergetics, and the muscle is calculated to have oxidative capacity that far exceeds what is required for maximal ATP generation (see Holloszy, 2009). Reconciling these various perspectives must take into account several key principles, as follows: (i) studies using isolated mitochondria are provided with fuel and anaplerotic TCA substrates artificially, potentially masking intrinsic perturbations of TCA activity that occur in situ due to 'anaplerotic/cataplerotic stress' (Adams et al 2009;Fiehn et al 2010;Zoppi et al 2010); (ii) meeting muscle ATP needs through FAO can take place without full combustion of the fat in the TCA cycle: for any given ATP requirement, one may generate chain-shortened fatty acid metabolites through β-oxidation that do not enter the TCA cycle at all, but simply accumulate or are exported from mitochondria; and (iii) while measuring muscle fibre metabolism ex vivo is an improvement over isolated mitochondria, bioenergetics profiles comparing insulin-resistant and insulin-sensitive preparations will still be strongly influenced by the ATP turnover requirements of the cells, which may differ. With these concepts in mind, we set out to determine whether incomplete LCFA combustion (viz.…”

Reduced glucose‐induced insulin secretion in low‐protein‐fed rats is associated with altered pancreatic islets redox status

“…The insulin secretion values reported by our results, showed near 50% reduction in LP GIIS, which is in agreement with other reports (Ferreira et al, , ; Filiputti et al, ). In a recent review, we presented molecular and metabolic alterations induced by protein malnutrition such as: Reduced insulin mRNA, PDX‐1 and protein kinases A and C expression, calcium influx, glucose oxidation, and anaplerotic capacity, which, taken together, may partially explain the observed reduction in low‐protein‐fed state GIIS (Zoppi et al, ). However, the redox control of GIIS under protein undernourishment status remained unclear.…”