With the prediction that over 300 million people will develop type 2 diabetes in the next 25 years, it is important to understand the pathogenesis of this condition and develop new approaches to prevention and treatment. This series aims to provide insight into the new and rapidly changing areas of research at the heart of T2D pathogenesis.
It is now well accepted that diabetes mellitus is one of the main threats to human health in the twenty-first century. The total number of people with diabetes worldwide was estimated at between 151 million and 171 million in 2000 and is projected to increase to 221 million in 2010 and to 366 million in 2030. Needless to say, the increase in the number of people with diabetes will be accompanied by an increase in the number of those with diabetic complications such as nephropathy, retinopathy, neuropathy, and atherosclerosis. The global mortality attributable to diabetes in the year 2000 was estimated at 2.9 million deaths, a number that will also increase. Given that type 2 diabetes accounts for more than 90% of cases of diabetes worldwide, it is important that we understand the pathogenesis of this condition and develop new approaches to its prevention and treatment.
Insulin has pleiotropic biological effects in virtually all tissues. However, the relevance of insulin signaling in peripheral tissues has been studied far more extensively than its role in the brain. An evolving body of evidence indicates that in the brain, insulin is involved in multiple regulatory mechanisms including neuronal survival, learning, and memory, as well as in regulation of energy homeostasis and reproductive endocrinology. Here we review insulin’s role as a central homeostatic signal with regard to energy and glucose homeostasis and discuss the mechanisms by which insulin communicates information about the body’s energy status to the brain. Particular emphasis is placed on the controversial current debate about the similarities and differences between hypothalamic insulin and leptin signaling at the molecular level.
Leona Plum, Bengt F. Belgardt, Jens C. Brüning
Recent data underscore the importance of intertissue communication in the maintenance of normal glucose homeostasis. Important signals are conveyed by hormones, cytokines, and fuel substrates and are sensed through a variety of cellular mechanisms. The ability of tissues to sense and adapt to changes in metabolic status and fuel availability is altered in insulin-resistant states including type 2 diabetes. Here we review the roles of glucose and its metabolites as signaling molecules and the diverse physiologic mechanisms for glucose sensing.
Mark A. Herman, Barbara B. Kahn
AMP-activated protein kinase (AMPK) is an energy sensor that regulates cellular metabolism. When activated by a deficit in nutrient status, AMPK stimulates glucose uptake and lipid oxidation to produce energy, while turning off energy-consuming processes including glucose and lipid production to restore energy balance. AMPK controls whole-body glucose homeostasis by regulating metabolism in multiple peripheral tissues, such as skeletal muscle, liver, adipose tissues, and pancreatic β cells — key tissues in the pathogenesis of type 2 diabetes. By responding to diverse hormonal signals including leptin and adiponectin, AMPK serves as an intertissue signal integrator among peripheral tissues, as well as the hypothalamus, in the control of whole-body energy balance.
Yun Chau Long, Juleen R. Zierath
Adiponectin is an adipokine that is specifically and abundantly expressed in adipose tissue and directly sensitizes the body to insulin. Hypoadiponectinemia, caused by interactions of genetic factors such as SNPs in the Adiponectin gene and environmental factors causing obesity, appears to play an important causal role in insulin resistance, type 2 diabetes, and the metabolic syndrome, which are linked to obesity. The adiponectin receptors, AdipoR1 and AdipoR2, which mediate the antidiabetic metabolic actions of adiponectin, have been cloned and are downregulated in obesity-linked insulin resistance. Upregulation of adiponectin is a partial cause of the insulin-sensitizing and antidiabetic actions of thiazolidinediones. Therefore, adiponectin and adiponectin receptors represent potential versatile therapeutic targets to combat obesity-linked diseases characterized by insulin resistance. This Review describes the pathophysiology of adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome.
Takashi Kadowaki, Toshimasa Yamauchi, Naoto Kubota, Kazuo Hara, Kohjiro Ueki, Kazuyuki Tobe
Over a hundred years ago, high doses of salicylates were shown to lower glucose levels in diabetic patients. This should have been an important clue to link inflammation to the pathogenesis of type 2 diabetes (T2D), but the antihyperglycemic and antiinflammatory effects of salicylates were not connected to the pathogenesis of insulin resistance until recently. Together with the discovery of an important role for tissue macrophages, these new findings are helping to reshape thinking about how obesity increases the risk for developing T2D and the metabolic syndrome. The evolving concept of insulin resistance and T2D as having immunological components and an improving picture of how inflammation modulates metabolism provide new opportunities for using antiinflammatory strategies to correct the metabolic consequences of excess adiposity.
Steven E. Shoelson, Jongsoon Lee, Allison B. Goldfine
The major focus of this Review is on the mechanisms of islet β cell failure in the pathogenesis of obesity-associated type 2 diabetes (T2D). As this demise occurs within the context of β cell compensation for insulin resistance, consideration is also given to the mechanisms involved in the compensation process, including mechanisms for expansion of β cell mass and for enhanced β cell performance. The importance of genetic, intrauterine, and environmental factors in the determination of “susceptible” islets and overall risk for T2D is reviewed. The likely mechanisms of β cell failure are discussed within the two broad categories: those with initiation and those with progression roles.
Marc Prentki, Christopher J. Nolan
Considerable evidence supports the association between insulin resistance and vascular disease, and this has led to wide acceptance of the clustering of hyperlipidemia, glucose intolerance, hypertension, and obesity as a clinical entity, the metabolic syndrome. While insulin resistance, by promoting dyslipidemia and other metabolic abnormalities, is part of the proatherogenic milieu, it is possible that insulin resistance itself in the vascular wall does not promote atherosclerosis. Recent findings suggest that insulin resistance and atherosclerosis could represent independent and ultimately maladaptive responses to the disruption of cellular homeostasis caused by the excess delivery of fuel.
Clay F. Semenkovich