Adipokines as novel biomarkers and regulators of the metabolic syndromeDeng, Yingfeng; Scherer, Philipp E.
doi: 10.1111/j.1749-6632.2010.05875.xpmid: 21276002
Over the past two decades our view of adipose tissue has undergone a dramatic change from an inert energy storage tissue to an active endocrine organ. Adipose tissue communicates with other central and peripheral organs by synthesis and secretion of a host of molecules that we generally refer to as adipokines. The levels of some adipokines correlate with specific metabolic states and have the potential to impact directly upon the metabolic homeostasis of the system. A dysregulation of adipokines has been implicated in obesity, type 2 diabetes, hypertension, cardiovascular disease, and an ever‐growing larger list of pathological changes in a number of organs. Here, we review the recent progress regarding the synthesis, secretion, and physiological function of adipokines with perspectives on future directions and potential therapeutic goals.
Three years with adult human brown adipose tissueNedergaard, Jan; Bengtsson, Tore; Cannon, Barbara
doi: 10.1111/j.1749-6632.2010.05905.xpmid: 21375707
The presence of active brown adipose tissue in adult humans has been recognized in general physiology only since 2007. The intervening three years established that the depots originally observed by 18F‐fluoro‐deoxy‐glucose positron emission tomography (FDG PET) scanning techniques really are brown adipose tissue depots because they are enriched for uncoupling protein 1 (UCP1). Reports of low apparent prevalence of brown adipose tissue based on retrospective studies of hospital records of FDG PET scans markedly underestimate true prevalence because such studies only reflect acute activity state; consequently, such retrospective studies cannot be conclusively analysed for factors influencing activity and amount of brown adipose tissue. Dedicated studies show that the true prevalence is 30–100%, depending on cohort. Warm temperature during the investigation—as well as adrenergic antagonists—inhibit tissue activity. There is probably no sexual dimorphism in the prevalence of brown adipose tissue. Outdoor temperature may affect the amount of brown adipose tissue, and the amount is negatively correlated with age and obesity. The presence of brown adipose tissue is associated with cold‐induced nonshivering thermogenesis, and the tissue may be a major organ for glucose disposal. The decline in brown adipose tissue amount with increasing age may account for or aggravate middle‐age obesity. Maintained activation of brown adipose tissue throughout life may thus protect against obesity and diabetes.
Metabolic surgery for type 2 diabetesAhn, Soo Min; Pomp, Alfons; Rubino, Francesco
doi: 10.1111/j.1749-6632.2011.05984.xpmid: 21732953
Conventional bariatric operations, including Roux‐en‐Y gastric bypass (RYGB), laparoscopic adjustable gastric banding, and biliopancreatic diversion (BPD) appear to be a safe and effective treatment for many severely obese patients with type 2 diabetes mellitus (T2DM). These operations improve glucose homeostasis through a variety of mechanisms, however, not only due to reduced food intake and body weight. Research to elucidate the weight‐independent antidiabetic mechanisms of gastrointestinal (GI) surgery and to clarify the molecular mechanisms responsible for the benefits of GI surgery on glucose homeostasis is a compelling research objective. We review the existing knowledge regarding the clinical outcomes and of the mechanisms of GI surgery to treat T2DM.
Management of hyperglycemia in hospitalized patientsSmiley, Dawn; Umpierrez, Guillermo E.
doi: 10.1111/j.1749-6632.2010.05805.xpmid: 21039589
Hyperglycemia is a common occurrence in hospitalized patients, and several studies have shown a strong association between hyperglycemia and the risk of complications, prolonged hospitalization, and death for patients with and without diabetes. Past studies have shown that glucose management in the intensive care setting improves clinical outcomes by reducing the risk of multiorgan failure, systemic infection, and mortality, and that the importance of hyperglycemia also applies to noncritically ill patients. Based on several past observational and interventional studies, aggressive control of blood glucose had been recommended for most adult patients with critical illness. Recent randomized controlled trials, however, have shown that aggressive glycemic control compared to conventional control with higher blood glucose targets is associated with an increased risk of hypoglycemia and may not result in the improvement in clinical outcomes. This review aims to give an overview of the evidence for tight glycemic control (blood glucose targets <140 mg/dL), the evidence against tight glycemic control, and the updated recommendations for the inpatient management of diabetes in the critical care setting and in the general wards.
Neuroendocrine responses to hypoglycemiaTesfaye, Nolawit; Seaquist, Elizabeth R.
doi: 10.1111/j.1749-6632.2010.05820.xpmid: 21039590
The counterregulatory response to hypoglycemia is a complex and well‐coordinated process. As blood glucose concentration declines, peripheral and central glucose sensors relay this information to central integrative centers to coordinate neuroendocrine, autonomic, and behavioral responses and avert the progression of hypoglycemia. Diabetes, both type 1 and type 2, can perturb these counterregulatory responses. Moreover, defective counterregulation in the setting of diabetes can progress to hypoglycemia unawareness. While the mechanisms that underlie the development of hypoglycemia unawareness are not completely known, possible causes include altered sensing of hypoglycemia by the brain and/or impaired coordination of responses to hypoglycemia. Further study is needed to better understand the intricacies of the counterregulatory response and the mechanisms contributing to the development of hypoglycemia unawareness.
Cardiovascular outcomes in type 2 diabetes: the impact of preventative therapiesZoungas, Sophia; Patel, Anushka
doi: 10.1111/j.1749-6632.2010.05837.xpmid: 21091713
The world is facing an unprecedented increase in type 2 diabetes. Most disability and premature mortality experienced by people with diabetes is related to cardiovascular disease. This review summarizes recent evidence about approaches for managing cardiovascular risk in patients with type 2 diabetes. While optimal blood pressure targets in people with diabetes remain uncertain, new data have demonstrated the benefits of routine blood pressure lowering in these patients, when administered without regard to initial blood pressure level. Other recent data indicate that blood pressure lowering treatment in patients with diabetes needs to be continued for ongoing benefit. The effects of intensive blood glucose lowering have been evaluated recently in a number of large trials, and individually these have failed to provide evidence of cardioprotection over a 4–5 year period. However, longer‐term follow‐up data suggest that there may be a delay in any such benefits becoming apparent. The benefits of statin therapy in preventing cardiovascular events in diabetic patients have been recently confirmed in a systematic overview of relevant trials; however, effects of fibrate therapy appear more limited. The role of antiplatelet agents remains unknown, as adequately powered trials of aspirin for the primary prevention of cardiovascular events in patients with diabetes have not yet been completed.
Gastrointestinal hormones and the regulation of β‐cell massLavine, Jeremy A.; Attie, Alan D.
doi: 10.1111/j.1749-6632.2010.05802.xpmid: 21039588
Type 2 diabetes occurs due to a relative deficit in β‐cell mass or function. Glucagon‐like peptide 1 (GLP‐1), glucose‐dependent insulinotropic polypeptide (GIP), cholecystokinin (CCK), and gastrin are gastrointestinal hormones that are secreted in response to nutrient intake, regulating digestion, insulin secretion, satiety, and β‐cell mass. In this review, we focus upon β‐cell mass regulation. β‐cell mass expands through β‐cell proliferation and islet neogenesis; β‐cell mass is lost via apoptosis. GLP‐1 and GIP are well‐studied gastrointestinal hormones and influence β‐cell proliferation, apoptosis, and islet neogenesis. CCK regulates β‐cell apoptosis and mitogenesis, and gastrin stimulates islet neogenesis. GLP‐1 and GIP bind to G protein‐coupled receptors and regulate β‐cell mass via multiple signaling pathways. The protein kinase A pathway is central to this process because it directly regulates proliferative and anti‐apoptotic genes and transactivates several signaling cascades, including Akt and mitogen‐activated protein kinases. However, the signaling pathways downstream of G protein‐coupled CCK receptors that influence β‐cell mass remain unidentified. Gastrointestinal hormones integrate nutrient signals from the gut to the β‐cell, regulating insulin secretion and β‐cell mass adaptation.
The genetics of type 2 diabetes: what have we learned from GWAS?Billings, Liana K.; Florez, Jose C.
doi: 10.1111/j.1749-6632.2010.05838.xpmid: 21091714
Type 2 diabetes mellitus has been at the forefront of human diseases and phenotypes studied by new genetic analyses. Thanks to genome‐wide association studies, we have made substantial progress in elucidating the genetic basis of type 2 diabetes. This review summarizes the concept, history, and recent discoveries produced by genome‐wide association studies for type 2 diabetes and glycemic traits, with a focus on the key notions we have gleaned from these efforts. Genome‐wide association findings have illustrated novel pathways, pointed toward fundamental biology, confirmed prior epidemiological observations, drawn attention to the role of β‐cell dysfunction in type 2 diabetes, explained ∼10% of disease heritability, tempered our expectations with regard to their use in clinical prediction, and provided possible targets for pharmacotherapy and pharmacogenetic clinical trials. We can apply these lessons to future investigation so as to improve our understanding of the genetic basis of type 2 diabetes.
Early life nutrition and metabolic programmingFernandez‐Twinn, Denise S.; Ozanne, Susan E.
doi: 10.1111/j.1749-6632.2010.05798.xpmid: 21070247
Research investigating the early programming of adult metabolic disease has in recent years provided much mechanistic insight into how the early environment impacts on long‐term health. It includes studies addressing the roles of intrauterine nutrient availability, which is determined by maternal nutrition, maternal exposure to oxygen, toxic events, and infection; the placental interface; and also the early postnatal environment. This review will explore the epidemiological evidence for programming of metabolic disease and provide an overview of the various studies using animals to model metabolic phenotypic outcome. It will also discuss evidence for the proposed molecular mechanisms and the potential for intervention.
CNS leptin and insulin action in the control of energy homeostasisBelgardt, Bengt F.; Brüning, Jens C.
doi: 10.1111/j.1749-6632.2010.05799.xpmid: 21070248
The obesity and diabetes pandemics have made it an urgent necessity to define the central nervous system (CNS) pathways controlling body weight, energy expenditure, and fuel metabolism. The pancreatic hormone insulin and the adipose tissue–derived leptin are known to act on diverse neuronal circuits in the CNS to maintain body weight and metabolism in a variety of species, including humans. Because these homeostatic circuits are disrupted during the development of obesity, the pathomechanisms leading to CNS leptin and insulin resistance are a focal point of research. In this review, we summarize the recent findings concerning the mechanisms and novel neuronal mediators of both insulin and leptin action in the CNS.