Mitochondrial Dysfunction and Type Diabetes

Bradford B. Lowell1 and Gerald I. Shulman2

Maintenance of normal blood glucose levels depends on a complex interplay between the insulin responsiveness of skeletal muscle and liver and glucose-stimulated insulin secretion by pancreatic ß cells. Defects in the former are responsible for insulin resistance, and defects in the latter are responsible for progression to hyperglycemia. Emerging evidence supports the potentially unifying hypothesis that both of these prominent features of type 2 diabetes are caused by mitochondrial dysfunction.

Type 2 diabetes is the most common metabolic disease in the world. In the United States, it is the leading cause of blindness, end-stage renal disease, and nontraumatic loss of limb, with associated health care costs estimated to exceed $130 billion per year (1). Of even greater concern, type 2 diabetes is rapidly becoming a global pandemic and is projected to afflict more than 300 million individuals worldwide by the year 2025, with most of the increase occurring in India and Asia (2). Although the primary cause of this disease is unknown, it is clear that insulin resistance plays an early role in its pathogenesis and that defects in insulin secretion by pancreatic p cells are instrumental in the progression to hyperglycemia. Here, we explore the potentially unifying hypothesis that these two prominent features of type 2 diabetes are both attributable to defects in mitochondria, the organelles that provide energy to the cell.

Role of Intracellular Fatty Acid Metabolites in Insulin Resistance

Several lines of evidence indicate that insulin resistance is an early feature of type 2 diabetes. First, virtually all patients with type 2 diabetes are insulin-resistant, and prospective studies have shown that this insulin-resistant state develops 1 to 2 decades before the onset of the disease (3-5). Second, insulin resistance in the offspring of parents with type 2 diabetes is the best predictor for later development of the disease (6). Lastly, perturbations that reduce insulin resistance prevent the development of diabetes (7).

1Department of Medicine, Beth Israel Deaconess Medical Center, 99 Brookline Avenue, Harvard Medical School, Boston, MA 02215, USA. E-mail: [email protected] bidmc.harvard.edu 2Howard Hughes Medical Institute, Department of Internal Medicine and Department of Cellular and Molecular Physiology, Yale University School of Medicine, 300 Cedar Street, New Haven, CT 06536, USA. E-mail: [email protected]

Skeletal muscle and liver are the two key insulin-responsive organs responsible for maintaining normal glucose homeostasis, and their transition to an insulin-resistant state accounts for most of the alterations in glucose metabolism seen in patients with type 2 diabetes. Before considering whether mitochondrial dysfunction contributes to the development of insulin resistance in these organs, it is first important to understand the cellular mechanisms responsible for insulin resistance. As discussed by Lazar (8), there is growing evidence that circulating cytokines secreted by fat tissue can modulate the insulin responsiveness of liver and muscle. However, fatty acids (9) and/or intracellular fatty acid metabolites such as fatty acyl coenzyme As (fatty acyl CoAs) (10, 11), diacylglycerol (10,11), or ceramides (12) are also thought to play a critical role.

Over 40 years ago, Randle et al. demonstrated that fatty acids caused insulin resistance in an in vitro rat muscle preparation, and they hypothesized that this occurred by a substrate competition mechanism (13). According to his model, increased oxidation of muscle fatty acids would produce increased levels of intracellular acetyl CoA and citrate, which in turn would inhibit, respectively, two enzymes involved in glucose utilization, pyruvate dehydrogenase and phosphofructo-kinase. Inhibition of the glycolytic pathway at these steps would increase intracellular glucose and glucose-6-phosphate concentrations, ultimately resulting in reduced insulin-stimulated glucose uptake.

More recent studies using 13C and 31P magnetic resonance spectroscopy (MRS) have shown that this mechanism for fatty acid-induced insulin resistance is untenable in human skeletal muscle (14); rather, fatty acids appear to cause insulin resistance by directly inhibiting insulin-stimulated glucose transport activity (15). This inhibition is likely because of the accumulation of intracellular fatty acyl CoAs and diacylglycerol, which then activate critical signal transduction pathways that ultimately lead to suppression of insulin signaling (Fig. 1). One might therefore predict that any metabolic perturbation that promotes the accumulation of fatty acids in liver and/or muscle and/or any defect in the ability of these organs to metabolize fatty acids might result in insulin resistance (10). Indeed, defects in adipocyte metabolism, which occur in conditions such as severe lipodystrophy

(16), can result in the former, and it has become increasingly evident that defects in mito-chondrial fatty acid oxidation can result in the latter and may be responsible for the more common forms of insulin resistance.

Mitochondrial Dysfunction, Intracellular Fatty Acids, and Insulin Resistance

It is well established that mitochondrial function is required for normal glucose-stimulated insulin secretion from pancreatic p cells. In addition, maternally inherited defects in mito-chondrial DNA that disrupt mitochondrial function are known to cause an insulin-deficient form of diabetes resembling type 1 diabetes

(17). However, recent MRS studies of humans suggest that more subtle defects in mitochondrial function might also play a role in the pathogen-esis of insulin resistance and type 2 diabetes. Petersen et al. found that in comparison with matched young controls, healthy lean elderly subjects had severe insulin resistance in muscle, as well as significantly higher levels of triglycerides in both muscle and liver (18). These changes were accompanied by decreases in both mitochondrial oxidative activity and mito-chondrial adenosine triphosphate (ATP) synthesis. These data support the hypothesis that insulin resistance in humans arises from defects in mitochondrial fatty acid oxidation, which in turn lead to increases in intracellular fatty acid metabolites (fatty acyl CoA and diacylglyerol) that disrupt insulin signaling (Fig. 1).

Alterations in mitochondrial DNA (MtDNA) have been correlated with human aging in several previous studies, and a recent study of genetically manipulated mice provided evidence that such alterations may play a causal role in aging (19). Whether the mitochondrial dysfunction detected in the elderly subjects studied by Petersen et al. (18) is related to age-associated accumulation of MtDNA mutations is not yet clear.

Other studies using the MRS technique have revealed similar decreases in mitochondrial activity and increases in intramyocellular fat content in young insulin-resistant offspring of parents with type 2 diabetes, a group that has a strong tendency to develop diabetes later in life (20). In addition, in comparison with insulinsensitive controls, the insulin-resistant subjects were found to have a lower ratio of type 1 to type 2 muscle fibers. Type 1 fibers are mostly oxidative and contain more mitochondria than type 2 muscle fibers, which are more glyco-lytic. Conceivably, these individuals may have fewer muscle mitochondria, possibly because of decreased expression of nuclear-encoded genes that regulate mitochondrial biogenesis, such as peroxisome proliferator-activated recep-torg coactivator 1a [PGC-1a (21) and PGC-1ß (22)]. Microarray studies support this idea: PGC-1a-responsive genes are down-regulated in obese Caucasians with impaired glucose tolerance and type 2 diabetes (23), and PGC-1a and PGC-1ß are themselves down-regulated in both obese diabetic and overweight nondia-betic Mexican-Americans (24).

Alternatively, the reduction in mitochondrial oxidative-phosphorylation activity in insulin-resistant individuals could be due not to mitochondrial loss but rather to a defect in mito-chondrial function. This hypothesis is supported by muscle biopsy studies. In one study, the activity of mitochondrial oxidative enzymes was found to be lower in type 2 diabetic subjects (25), and in another, the activity of mitochondrial rotenone-sensitive nicotinamide adenine dinucleotide oxidoreduc-tase [NADH:O(2)] was found to be lower (26). However, in contrast to the MRS studies, these studies were performed with isolated mitochondria obtained from diabetic subjects who were also obese. Because obese individuals have also been shown to have smaller mitochondria with reduced bioenergetic capacity compared with lean controls (26), the mitochondrial abnormalities in these subjects might be related to obesity rather than to insulin resistance. The role of the obese state in the down-regulated expression of the PGC-1a and PGC-1ß

genes discussed above (23, 24) is an important question that remains to be answered.

Mitochondrial Dysfunction and Insulin Secretion by Pancreatic p Cells

Many obese individuals with marked insulin resistance do not develop frank diabetes. In these individuals, the pancreatic p cells adapt to meet the body's markedly increased demand for insulin. This adaptation involves expansion of p cell mass, as well as maintenance of normal responsiveness of p cells to glucose. Conversely, in obese individuals destined to develop type 2 diabetes, p cells do not secrete enough insulin to compensate for the increased demand. This p cell failure is likely caused by inadequate expansion of the p cell mass and/or failure of the existing p cell mass to respond to glucose (27).

p cell mass is governed by several factors, including p cell size, the rate of p cell replication and/or differentiation, and the rate of p cell apoptotic cell death. Although difficult to quantify, p cell mass appears to be decreased in individuals with type 2 diabetes relative to matched individuals with similar degrees of insulin resistance (28, 29). Although the cause of this relative decrease in p cell mass is unknown, increased rates of apoptosis may play an important role (27, 28, 30). The signals to and from mitochondria that regulate apoptosis in p cells and the effect of the prediabetic milieu on these signals are incompletely understood (31, 32) but are likely to be a fertile area of future investigation.

Numerous studies have documented that, in individuals with type 2 diabetes, p cells do not sense glucose properly and therefore do not release appropriate amounts of insulin (33). Glucose sensing requires oxidative mito-chondrial metabolism, leading to the generation of ATP (34). This increases the ratio of ATP to adenosine diphosphate (ADP) in the p cell, which then initiates the following chain of events: inhibition of the cell's ATP/ADP-regulated potassium channel (KATP), plasma membrane depolarization, opening of a voltage-gated calcium channel, calcium

Mitochondrial Calcium Channels

Fig. 1. Potential mechanism by which mitochondrial dysfunction induces insulin resistance in skeletal muscle. In the depicted model, a decrease in mitochondrial fatty acid oxidation, caused by mitochondrial dysfunction and/or reduced mitochondrial content, produces increased levels of intracellular fatty acyl CoA and diacylglycerol. These molecules activate novel protein kinase C, which in turn activates a serine kinase cascade [possibly involving inhibitor of nuclear factor kB kinase (IKK) and c-Jun N-terminal kinase-1], leading to increased serine phosphorylation (pS) of insulin receptor substrate-1 (IRS-1). Increased serine phosphorylation of IRS-1 on critical sites (e.g., IRS-1 Ser307) blocks IRS-1 tyrosine (Y) phosphorylation by the insulin receptor, which in turn inhibits the activity of phosphatidyl inositol 3-kinase (PI 3-kinase). This inhibition results in suppression of insulin-stimulated glucose transport, the process by which glucose is removed from the blood. PIP3 indicates phosphatidylinositol 3,4,5-trisphosphate;PTB, phosphotyrosine binding domain;PH, pleckstrin homology domain;SH2, src homology domain.

Fig. 1. Potential mechanism by which mitochondrial dysfunction induces insulin resistance in skeletal muscle. In the depicted model, a decrease in mitochondrial fatty acid oxidation, caused by mitochondrial dysfunction and/or reduced mitochondrial content, produces increased levels of intracellular fatty acyl CoA and diacylglycerol. These molecules activate novel protein kinase C, which in turn activates a serine kinase cascade [possibly involving inhibitor of nuclear factor kB kinase (IKK) and c-Jun N-terminal kinase-1], leading to increased serine phosphorylation (pS) of insulin receptor substrate-1 (IRS-1). Increased serine phosphorylation of IRS-1 on critical sites (e.g., IRS-1 Ser307) blocks IRS-1 tyrosine (Y) phosphorylation by the insulin receptor, which in turn inhibits the activity of phosphatidyl inositol 3-kinase (PI 3-kinase). This inhibition results in suppression of insulin-stimulated glucose transport, the process by which glucose is removed from the blood. PIP3 indicates phosphatidylinositol 3,4,5-trisphosphate;PTB, phosphotyrosine binding domain;PH, pleckstrin homology domain;SH2, src homology domain.

influx, and secretion of insulin (Fig. 2). Although insulin secretion is also modulated by a number of stimuli that operate outside this pathway, it is clear that oxidative mito-chondrial metabolism is central to glucose-stimulated insulin secretion (34).

The critical role of mitochondria is evident from the rare hereditary disorders in which diabetes with p cell dysfunction have been traced to specific mutations in the mitochondrial genome (34, 35). Given the central role of mitochondria in glucose sensing, it is possible that decreased mitochondrial function in p cells, analogous to that observed in skeletal muscle (described above), might predispose individuals to develop p cell dysfunction and type 2 diabetes. However, because of the difficulties in obtaining p cell samples for analyses, this

Mitochondria Glucose
Obesity Hyperglycemia

f UCP2 Protein f Superoxide

f UCP2 Protein f Superoxide

UCP2 activity

ß-cell dysfunction

UCP2 activity

Insulin resistance

ß-cell dysfunction

Type 2 Diabetes

Fig. 2. Potential mechanism by which UCP2-mediated mitochondrial dysfunction disrupts insulin secretion from pancreatic p cells. (A) UCP2, superoxide, and glucose-stimulated insulin secretion. Insulin secretion is coupled to glucose metabolism by the subsequent increase in the ATP/ADP ratio arising from glucose oxidation, which closes KATP channels. This depolarizes the plasma membrane, opening voltage-gated Ca2+ channels with the influx of Ca2+ stimulating secretion of insulin. UCP2 decreases glucose-stimulated insulin secretion by increasing proton leak across the mitochondrial inner membrane, diverting energy stored within electrochemical potential gradient away from ATP synthase, thereby decreasing the yield of ATP from glucose. Superoxide generated by the electron transport chain stimulates proton leak activity of UCP2 protein, thereby decreasing glucose-stimulated insulin secretion. [Figure adapted with permission from (58). Copyright 2001, Massachusetts Medical Society. All rights reserved.] (B) The effects of obesity, hyperglycemia, and lipids on UCP2. In the obese state, hyperglycemia, and high lipid levels each induce expression of UCP2 protein in pancreatic p cells. These stimuli also increase production of superoxide by the electron transport chain. As a result, UCP2 is activated, leading to a marked increase in UCP2-mediated proton leak. This proton leak impairs glucose-stimulated insulin secretion, resulting in p cell dysfunction. p cell dysfunction and insulin resistance in muscle, liver, and fat are characteristic features of type 2 diabetes.

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