Mitochondrial plasticity in obesity and diabetes mellitus

Abstract

Significance: Insulin resistance and its related diseases, obesity and type 2 diabetes mellitus (T2DM), have been linked to changes in aerobic metabolism, pointing to a possible role of mitochondria in the development of insulin resistance.

Recent advances: Refined methodology of ex vivo high-resolution respirometry and in vivo magnetic resonance spectroscopy now allows describing several features of mitochondria in humans. In addition to measuring mitochondrial function at baseline and after exercise-induced submaximal energy depletion, the response of mitochondria to endocrine and metabolic challenges, termed mitochondrial plasticity, can be assessed using hyperinsulinemic clamp tests. While insulin resistant states do not uniformly relate to baseline and post-exercise mitochondrial function, mitochondrial plasticity is typically impaired in insulin resistant relatives of T2DM, in overt T2DM and even in type 1 diabetes mellitus (T1DM).

Critical issues: The variability of baseline mitochondrial function in the main target tissue of insulin action, skeletal muscle and liver, may be attributed to inherited and acquired changes in either mitochondrial quantity or quality. In addition to certain gene polymorphisms and aging, circulating glucose and lipid concentrations correlate with both mitochondrial function and plasticity.

Future directions: Despite the associations between features of mitochondrial function and insulin sensitivity, the question of a causal relationship between compromised mitochondrial plasticity and insulin resistance in the development of obesity and T2DM remains to be resolved.

FIG. 1.

Interaction between glucose and lipids at the level of insulin signaling and mitochondrial function in skeletal muscle. Glucose is taken up via glucose transporter 4 (glut4) into the myocyte, activated to glucose-6-phosphate (G6P), and then oxidized in the mitochondria or stored as glycogen. Free fatty acids are taken up via fatty acid transporter protein 1 (fatp1) into the myocyte, activated to fatty acyl coenzyme A (FACoA), and then transported by the carnitine palmitoyltransferase 1 (cpt1) into mitochondria for oxidation (OX), or stored as triyglycerides, or inhibit insulin signaling by serine phosphorylation of IRS-1. Both glucose and lipid OX fuel the tricarboxylic acid cycle and serve to produce ATP via ATP synthase (ATPase). To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars

FIG. 2.

Glucose uptake and ATP synthesis in skeletal muscle of humans with type 2 diabetes mellitus. Insulin-stimulated whole body glucose disposal is about 50% lower in type 2 diabetes than in humans with normal glucose tolerance, which might lead to lower myocellular concentrations of substrates for oxidation such as glucose-6-phosphate (G6P) and thereby lower rates of ATP synthesis (white columns). However, when plasma glucose levels were increased from 5.5 to 9.5 mmol/l during hyperinsulinemic-hyperglycemic clamp tests, the doubling to myocellular G6P, insulin-stimulated ATP synthesis (mitochondrial plasticity) did not improve (black columns) (76).

FIG. 3.

Glucose uptake and hepatocellular ATP content and synthesis in humans with type 2 diabetes mellitus (T2DM), in age, sex, and body mass-matched (mCON) and in young (yCON) healthy humans. Whole body glucose uptake is about 50% lower in T2DM (black column) than in mCON (gray column), and substantially lower than in yCON (white column). Myocellular ATP content is reduced in T2DM and ATP synthesis correlates inversely with hepatic insulin resistance as given by endogenous glucose production during suppression by insulin (iEGP) (69, 74).

FIG. 4.

Correlation of mitochondrial plasticity with glycemia and lipidemia. Insulin-stimulated myocellular unidirectional ATP synthase flux (mitochondrial plasticity) negatively correlates with (A) glycemic control as assessed from hemoglobin A1c (28), and with (B) plasma concentrations of free fatty acids (FFA) in the fasted state (76).

FIG. 5.

Effect of chronic hyperglycemia per se on glucose uptake and ATP synthesis in skeletal muscle of T1DM. Insulin-stimulated whole body glucose disposal is about 50% lower in T1DM (dark bars) than in humans with normal glucose tolerance (Non-DM, light bars). In Non-DM, stimulation by insulin markedly increases myocellular concentrations of substrates for oxidation such as glucose-6-phosphate (G6P) and thereby rates of ATP synthesis (mitochondrial plasticity). In T1DM, both G6P and ATP synthesis do not adequately rise during insulin stimulation (28).

FIG. 6.

Effect of hyperlipidemia on glucose uptake and myocellular ATP synthesis in healthy humans. Whole body glucose uptake increases depending on the concentration of the plasma insulin (insulin sensitivity) under control conditions (white columns), but is about 50% lower in the presence of elevated serum triglycerides and free fatty acids (insulin resistance, black columns). Myocellular ATP synthesis (mitochondrial plasticity) increases only at a high insulin concentrations (8, 9).

FIG. 7.

Diverse effects of high-fat diets differing in the degree of saturation on palmitate oxidation in hepatocytes and involvement of AMPK. Stimulation of palmitate oxidation by AMPK activator 5-aminoimidazole-4-carboxyamide ribonucleoside (AICAR) is decreased in primary hepatocytes isolated from wild-type mice fed high-fat diet (cHF, black columns) for 9 weeks compared to low-fat diet (Chow, white columns) fed mice. Addition of polyunsaturated fatty acids into diet (cHF+F, dashed columns) prevents this decrease. Beneficial effects of feeding by cHF+F diet are lost in mice lacking α2 subunit of AMPK (AMPKα2-/- mice) (27).

FIG. 8.

Potential regulators of mitochondrial biogenesis and function. In the myocyte (A), glucose is taken up via glucose transporter 4 (glut4), activated to glucose-6-phosphate (G6P), and then oxidized in the mitochondria or stored as glycogen. Free fatty acids are taken up via LPL and fatty acid transporter proteins (fatp1, CD36) and activated to fatty acyl coenzyme A (FACoA). FACoA can be oxidized in the mitochondria or stored as triglycerides or can favor the formation of diacylglycerols (DAG) and/or ceramides, thus inhibiting insulin signaling by protein kinase C-θ (PKCθ)/IRS-1 pathway and/or protein kinase B-2 (Akt2) phosphorylation, respectively. Both glucose and lipid oxidation fuel the tricarboxylic acid cycle and serve to produce ATP. Black dashed arrows represent genetic predispositions and lifestyle interventions affecting mitochondrial biogenesis/function via different mechanisms (white arrows): inherited factors associate with decreased LPL activity and PPARδ-mediated mitochondrial biogenesis; single nucleotide polymorphism of NDUFB6 gene predisposes to impaired mitochondrial plasticity in response to exercise; and resveratrol, fasting/exercise, and nutrients increase mitochondrial biogenesis/function by increasing PGC1α activity via sirtuins, AMPK, and mTORC1, respectively. ROS have been associated with decreased mitochondrial function. In hepatocytes (B), free fatty acids are taken up via fatty acid transporter protein 5 (fatp5), activated to FACoA, and undergo similar metabolic pathway as in the myocyte. Decreased activity of IRS-2 associates with lower Foxo1 and mitochondrial function. Resveratrol increases while overloading with nutrients decreases sirtuins and mitochondrial biogenesis. Finally, ROS impact negatively on the function of mitochondria. Acetyl-CoA, acetyl coenzyme A; ADP, adenosine diphosphate; GSK3, glycogen synthase kinase 3; HKII, hexokinase II; HSL, hormone sensitive lipase; PDH, pyruvate dehydrogenase; PI3K, phosphatidylinositol 3 kinase; SREBP, sterol regulatory element binding protein; TG, triglyceride. To see this illustration in color, the reader is referred to the web version of this article at www.liebertpub.com/ars