Intoduction
The association of obesity with type 2 diabetes has been recognized for decades, and the major basis for this link is the ability of obesity to engender insulin resistance. Insulin resistance is a fundamental aspect of the etiology of type 2 diabetes and is also linked to a wide array of other pathophysiologic sequelae including hypertension, hyperlipidemia, atherosclerosis (i.e., the metabolic syndrome, or syndrome X), and polycystic ovarian disease ). Although many details of the mechanisms by which the enlarged adipose tissue mass that defines obesity causes systemic insulin resistance remain unknown, the past several years have witnessed an explosive increase in our understanding of what may now be referred to as the adipo-insulin axis. There are also grounds for considering the related possibility that insulin resistance and hyperinsulinemia, in addition to being caused by obesity, can contribute to the development of obesity. In this Perspective, we will review recent progress, highlight areas of controversy or uncertainty, and suggest approaches to clarifying the unresolved issues.
Insulin action in the adipocyte.
Insulin is a critical regulator of virtually all aspects of adipocyte biology, and adipocytes are one of the most highly insulin-responsive cell types. Insulin promotes adipocyte triglyceride stores by a number of mechanisms, including fostering the differentiation of preadipocytes to adipocytes and, in mature adipocytes, stimulating glucose transport and triglyceride synthesis (lipogenesis), as well as inhibiting lipolysis . Insulin also increases the uptake of fatty acids derived from circulating lipoproteins by stimulating lipoprotein lipase activity in adipose tissue. Insulin’s metabolic effects are mediated by a broad array of tissue-specific actions that involve rapid changes in protein phosphorylation and function, as well as changes in gene expression. The fundamental biologic importance of these actions of insulin is evidenced by the fact that the insulin signaling cascade which initiates these events is largely conserved in evolution from C. elegans to humans
The initial molecular signal for insulin action involves activation of the insulin receptor tyrosine kinase, which results in phosphorylation of insulin receptor substrates (IRSs) on multiple tyrosine residues. These phosphotyrosine residues act as docking sites for many SH2 domain–containing proteins, including the p85 regulatory subunit of phosphoinositide 3′ kinase (PI3K). Binding of the p110 catalytic subunit of PI3K to p85 activates the lipid kinase that promotes glucose transport. Whereas activation of PI3K is necessary for full stimulation of glucose transport by insulin, emerging evidence suggests that it is not sufficient and another pathway may also be necessary. The signals downstream of PI3K are still unknown, and there is controversy as to whether the serine/threonine kinase Akt/protein kinase B (PKB) or the protein kinase C (PKC) isoform λ/ζ mediates insulin stimulation of glucose transport. Most likely, the pathways that mediate insulin’s metabolic effects diverge downstream of PI3K and show differential sensitivity to varying levels of insulin. For example, the antilipolytic effect of insulin requires much lower insulin concentrations than stimulation of glucose transport. Hence, even in insulin-resistant states in which glucose transport is impaired, sensitivity to insulin’s antilipolytic effect is relatively preserved, resulting in maintenance or expansion of adipose stores. Insulin also activates the ras–mitogen-activated protein kinase (ras-MAPK) signaling cascade. This pathway appears to be important for the mitogenic effects of insulin, but most data do not implicate the MAPK pathway in the well-studied metabolic actions of insulin. Insulin action in adipocytes also involves changes in gene transcription. The transcription factor ADD-1/SREBP-1c (adipocyte determination and differentiation factor-1/sterol regulatory element–binding protein-1c) may play a critical role in the actions of insulin to regulate adipocyte gene expression, by inducing genes involved in lipogenesis and repressing those involved in fatty acid oxidation. Transcription factors of the forkhead family may also play a major role in transducing insulin signals to the nucleus. The relative functions of the ADD-1/SREBP-1c and forkhead pathways should be the subject of future research.
Insulin resistance in obesity and type 2 diabetes.
The term “insulin resistance” usually connotes resistance to the effects of insulin on glucose uptake, metabolism, or storage. Insulin resistance in obesity and type 2 diabetes is manifested by decreased insulin-stimulated glucose transport and metabolism in adipocytes and skeletal muscle and by impaired suppression of hepatic glucose output. These functional defects may result, in part, from impaired insulin signaling in all three target tissues and, in adipocytes, also from downregulation of the major insulin-responsive glucose transporter, GLUT4. In both muscle and adipocytes, insulin binding to its receptor, receptor phosphorylation and tyrosine kinase activity, and phosphorylation of IRSs are reduced. There are also tissue-specific alterations: In adipocytes from obese humans with type 2 diabetes, IRS-1 expression is reduced, resulting in decreased IRS-1–associated PI3K activity, and IRS-2 becomes the main docking protein for PI3K. In contrast, in skeletal muscle of obese, type 2 diabetic subjects, IRS-1 and IRS-2 protein levels are normal but PI3K activity associated with both IRSs is impaired.
One mechanism for the signaling defects in obesity may be the increased expression and activity of several protein tyrosine phosphatases (PTPs), which dephosphorylate and thus terminate signaling propagated through tyrosyl phosphorylation events. Some data indicate that at least three PTPs, including PTP1B, leukocyte antigen–related phosphatase (LAR), and src-homology-phosphatase 2, are increased in expression and/or activity in muscle and adipose tissue of obese humans and rodents. PTP1B and LAR have been shown to dephosphorylate the insulin receptor and IRS-1 in vitro. In fact, mice in which PTP1B has been knocked out have increased insulin sensitivity and resistance to diet-induced obesity, at least in part, due to increased energy expenditure. This suggests a regulatory role for PTP1B not only in insulin action, but also in energy homeostasis. Interestingly, the insulin sensitivity is present in muscle and liver but not in adipocytes. Whether there is a causal relationship between the insulin sensitivity and leanness/energy expenditure or whether these are regulated by independent signaling pathways is a key question.
Other mechanisms also contribute to insulin resistance in obesity. In morbid obesity, the expression of various insulin signaling molecules is reduced in skeletal muscle. In all forms of obesity and diabetes, a major factor contributing to the impaired insulin-stimulated glucose transport in adipocytes is the downregulation of GLUT4. However, in skeletal muscle of obese and diabetic humans, GLUT4 expression is normal (reviewed in ref.) and defective glucose transport appears to be due to impaired translocation, docking, or fusion of GLUT4-containing vesicles with the plasma membrane.
Although insulin resistance is characteristic of obesity and type 2 diabetes, it is not established that all of insulin’s actions are impaired in individuals with both conditions. It is possible that hepatic lipogenesis and lipid storage are being driven to excess in adipose tissue, whereas other insulin effects related to glucose homeostasis are impaired. It will be important to identify the signaling pathways and transcription factors that could allow for such discordant actions of insulin.
Conclusions and implications
The relationship of obesity to insulin resistance and type 2 diabetes is a long-recognized phenomenon with fundamentally important scientific and clinical implications. The paradox that either absence or excess of adipose tissue causes insulin resistance highlights the complexity of this relationship and underscores the fact that adipose tissue undoubtedly subserves multiple functions. Advances over the last decade have expanded our understanding of the role of adipocytes in biology, and this has begun to provide mechanistic insights into the causal relationship between obesity and diabetes. It is now clear that adipocytes function as endocrine glands with wide-reaching effects on other organs including the brain. The release of a wide variety of molecules including hormones such as leptin, cytokines such as TNF-α, and substrates such as FFAs allows the adipose organ to play a major regulatory role in energy balance and glucose homeostasis. Current challenges on the horizon include (a) discovering additional adipocyte-secreted products which are central to these processes; (b) deepening our understanding of the cellular and molecular mechanisms underlying insulin sensitivity and secretion, including previously unidentified pathways such as those mediated by nuclear receptors such as PPARγ; and (c) exploring the possibility of divergence among different insulin-mediated processes, such that those driving adipogenesis and fat storage may actually be augmented, at least in some tissues, in insulin-resistant states.
Most likely, the complex orchestration of the relationship between adipose tissue, insulin action, and glucose homeostasis evolved out of survival needs to maintain fuel supplies when food was scarce. Now in times of plenty in Western society, obesity with its accompanying morbidities has reached epidemic proportions and the need for scientific advances to identify new therapeutic approaches could not be more acute. The challenge to use the increasing repertoire of adipocyte functions to shift the equation of energy intake and utilization toward reduced fat storage holds great opportunities to alter the course of human disease.
Acknowledgments
This work was supported by grants from the NIH (RO1 DK-43051, RO1 DK-28082, and PO1 DK-56116) and a grant from Eli Lilly and Co. The authors recognize many additional contributions to the field which they were unable to cite due to a limitation in the number of references. The authors thank Young-Bum Kim for expert assistance.