The Importance of Adipose Tissue in Diabetes Pathophysiology and Treatment

Once thought to be an inert energy storage depot, adipose tissue is now known to be a critical endocrine organ.

The term “adipocytokines” or “adipokines” has been used to describe the numerous adipocyte secretory products which include: leptin, adiponectin, resistin, visfatin, tumor necrosis factor alpha (TNF-α), adipsin, estrogen, angiotensin II, angiotensinogen, plasminogen activator I (PAI-1), agouti protein, acylation stimulating protein (ASP), bone morphogenic protein (BMP), prostaglandins, insulin-like growth factor-1 (IGF-1) and various IGF binding proteins, interleukins (ILs), and transforming growth factor (TGF)-B [1] [2] [3].

In human visceral adipose tissue, TNF-α has been shown to have regulatory functions on adiponectin, adiponectin receptor 1 and visfatin: in states of obesity and insulin resistance, it has been suggested that the increased TNF-α levels could be the reason for the decrease in the level of adiponectin, and the increase in the level of visfatin observed in these conditions [4]. Moreover, recent findings obtained in mice subjected to subcutaneous lipectomy with/without subsequent fat transplantation indicate that subcutaneous fat regulates systemic insulin sensitivity possibly through altering fat storage and the expression of TNF-α by adipocytes in visceral fat [5].

Adipose tissue is also the source of important substrates such as nonesterified fatty acids and glycerol [6] [7]. Nonesterified fatty acids levels have been shown to be closely related to the development of insulin resistance in subjects with metabolic disorders [8].

A vasoregulatory role for local deposits of fat around blood vessels has also been proposed. In particular, it has been proposed that the localized fat depot around the origin of skeletal muscle arterioles may play a physiological role in blood flow distribution. Isolated rat arterioles have been found to be under dual regulation by insulin, which activates both endothelin-1 mediated vasoconstriction and nitric oxide mediated vasodilatation. In obese rat arterioles insulin-stimulated nitric oxide synthesis is impaired, resulting in unopposed vasoconstriction. This may be the consequence of production of TNF-α from the fat surrounding the vessel origin [9] [10].

Tissue-specific genetic knockout of GLUT4 expression in adipose tissue or muscle of mice has provided new insights into the pathogenesis of insulin resistance [11]. Yang et al. [12] recently determined that the expression of serum retinol binding protein (RBP4) is induced in adipose tissue as a consequence of decreased GLUT4 expression. These authors found that RBP4 is elevated in the serum of insulin resistant humans and mice [12] [13]. Furthermore, they found that increasing serum RBP4 levels by transgenic over-expression or by injection of purified RBP4 protein into normal mice causes insulin resistance [12]. Therefore, RBP4 appears to play an important role in mediating adipose tissue communication with other insulin target tissues in insulin resistance [14].

Recent findings have led to evidence that the primary lymphoid tissue, the lymph nodes, is mostly present within adipose tissue depots throughout the body. There are at least 12 such depots and about 10¹² lymphocytes, 99% of which are present in lymph nodes. These lymphocytes may provide a temporary buffer for glucose in the form of lactate and aspartate and, in this way, restrict the rise in blood glucose in the blood after a meal by converting it to glycogen for storage [15].

Recent studies on adipose tissue physiology have made it clear that the processes of fat storage and mobilization are regulated in a highly coordinated manner with rapid shifts in metabolic fluxes after a meal and in the fasting state. Attention has also been focused on the role of adipose tissue and nonesterified fatty acids in the pathophysiology of hyperglycemia in various conditions, such as type 2 diabetes and obesity [16] [17] [18] [19] [20] [21]. Adipose tissue has been suggested to play a crucial part in buffering the flux of fatty acids in the circulation in the postprandial period, analogous to the roles of liver and skeletal muscle in buffering postprandial glucose fluxes [19]. Adipose tissue provides its buffering action by suppressing the release of nonesterified fatty acids into the circulation and by increasing triglyceride clearance. Adipose tissue buffering of lipid fluxes is impaired in obesity and type 2 diabetes through defects in the ability of adipose tissue to respond rapidly to the dynamic situation that occurs after meals. It is also impaired in lipodystrophy because there is simply not sufficient adipose tissue to provide the necessary buffering capacity. As a result, liver, skeletal muscle and β-cells are exposed to excessive fluxes of lipid fuels and could accumulate these in the form of triglycerides, leading to insulin resistance and impaired insulin secretion [19].

From a clinical point of view, the more recently developed therapeutic options for treatment of type 2 diabetes are increasingly targeted to adipose tissue. Thus, thiazolidinediones appear to exert their major effects by altering gene expression in adipose tissue which is associated with changes in inflammatory parameters, increases in adiponectin and alterations of lipid metabolism. The endocannabinoid antagonist rimonabant also exerts clear positive effects on adipose tissue as shown by its actions on CRP and adiponectin in addition to its favorable effects on body weight which are probably related to central mechanisms of energy balance [22].

The topic of this symposium is far-reaching and touches the crucial and complex question: is the adipose tissue the key to understand the pathophysiology of type 2 diabetes and to improve the treatment of this complicated disease?

The aim of this symposium is to provide the latest information on the role of the adipose tissue in the development of insulin resistance. We are joined by a most distinguished panel of international experts, who cover the topic both at a molecular and a clinical level.

This symposium was organized on Sunday, 11th September 2005, in the Peace & Friendship Stadium, on the occasion of the 41st Annual European Association for the Study of Diabetes (EASD) Congress in Athens. It was supported by the Hellenic National Centre for the Research, Prevention and Treatment of Diabetes Mellitus and its Complications (President of the Council, our Mentor and President of the EASD-Congress in Athens, Professor S. A. Raptis), which is a public benefit, nonprofit Institution under the supervision of the Hellenic Ministry of Health and Social Welfare.

References

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Correspondence