Volume 26, Issue 1 - Special issue: Hormones and Diabetes / Editors: Leandro Fernandez Pérez and Gérard S. Chetrite

Ghrelin is a 28-amino acid (aa) stomach-derived peptide discovered in 1999 as the endogenous ligand for growth hormone secretagogue-receptor (GHS-R). Ghrelin-producing cells constitute a distinct group of endocrine cells dispersed throughout the gastric mucosa and to a lesser extent in the small intestine and the endocrine pancreas. Ghrelin plasma levels rise during fasting and chronic caloric restriction to stimulate food intake and fat storage and to prevent life-threatening falls in blood glucose. Plasma ghrelin levels decrease after a meal is consumed and in conditions of energy surplus (such as obesity). Ghrelin has emerged as a key player in the regulation of appetite and energy homeostasis. Ghrelin achieves these functions through binding the ghrelin receptor GHS-R in appetite-regulating neurons and in peripheral metabolic organs including the endocrine pancreas. Ghrelin levels are negatively correlated with body mass index (BMI) and insulin resistance. In addition, ghrelin secretion is impaired in obesity and insulin resistance. Several studies highlight an important role for ghrelin in glucose homeostasis. Genetic, immunological, and pharmacological blockade of ghrelin signaling resulted in improved glucose tolerance and insulin sensitivity. Furthermore, exogenous ghrelin administration was shown to decrease glucose-induced insulin release and increase glucose level in both humans and rodents. GHS-R was shown to be expressed in pancreatic β-cells and ghrelin suppressed insulin release via a Ca 2+ -mediated pathway. In this review, we provide a detailed summary of recent advances in the field that focuses on the role of insulin and insulin resistance in the regulation of ghrelin secretion and on the role of ghrelin in glucose-stimulated insulin secretion (GSIS).

Skeletal muscle is the largest tissues in the human body and is considered the primary target for insulin-stimulated glucose disposal. In skeletal muscle, binding of the insulin to insulin receptor (IR) initiates a signaling cascade that results in the translocation of the insulin-sensitive glucose transporter protein 4 (GLUT4) to the plasma membrane which leads to facilitated diffusion of glucose into the cell. Understanding the precise signaling events guiding insulin-stimulated glucose uptake is pivotal, because impairment in these signaling events leads to development of insulin resistance and type 2 diabetes. This review summarizes current understanding of insulin signaling pathways mediating glucose uptake in healthy and insulin-resistant skeletal muscle.

Adipose tissue is a complex endocrine organ with an intricate role in whole body homeostasis. Beyond storing energy, adipose tissue is fundamental in numerous processes including, but not limited to, metabolism, food intake and immune cell function. Adipokines and cytokines are the signaling factors from adipose tissue. These factors play a role in maintaining health, but are also candidates for pathologies associated with obesity. Indeed excessive adiposity causes dysregulation of these factors which negatively affect health and contribute to numerous obesity-induced co-morbidities. In particular, adipokines are fundamental in regulation of glucose homeostasis and insulin signaling, thus aberrant production of these adipose derived hormones correlates with the development and progression of type 2 diabetes. Therefore, elucidation of adipose regulation is crucial for understanding the pathophysiological basis of obesity and metabolic diseases such as type 2 diabetes. In the present review, we summarize current data on the relation between adipokines and adipose depot derived cytokines in the maintenance of glucose homeostasis. Specifically, physiological and molecular functions of several adipokines are defined with particular focus on interactions within the insulin-signaling pathway and subsequent regulation of glucose uptake in both standard and obesity-induced dysregulated conditions. This same relation will be discussed for cytokines and inflammation as well.

Over the past decades, obesity and its metabolic co-morbidities such as type 2 diabetes (T2D) developed to reach an endemic scale. However, the mechanisms leading to the development of T2D are still poorly understood. One main predictor for T2D seems to be lipid accumulation in “non-adipose” tissues, best known as ectopic lipid storage. A growing body of data suggests that these lipids may play a role in impairing insulin action in metabolic tissues, such as liver and skeletal muscle. This review aims to discuss recent literature linking ectopic lipid storage and insulin resistance, with emphasis on lipid deposition in skeletal muscle. The link between skeletal muscle lipid content and insulin sensitivity, as well as the mechanisms of lipid-induced insulin resistance and potential therapeutic strategies to alleviate lipotoxic lipid pressure in skeletal muscle will be discussed.

Primary hyperaldosteronism (PA) has recently been demonstrated to be strictly associated to metabolic syndrome as compared with essential hypertension (EH). Besides, the characteristics of metabolic syndrome are different in PA compared to EH, as high fasting glucose is more frequent in the former condition. The adverse effect of excess aldosterone on insulin metabolic signaling has generated increasing interest in the role of hyperaldosteronism in the pathogenesis of insulin resistance and resistant hypertension. Moreover, aldosterone receptor antagonist therapy in diabetic and cardiopathic patients improved coronary flow. The aim of this review is to present recent knowledge about the relationship between aldosterone, insulin resistance and diabetes.

The hormone 1,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] induces cellular Ca 2+ signals which regulate insulin secretion, while low vitamin D status may be a risk factor for type 2 diabetes (T2D). In pancreatic β-cells in vitro, 1,25(OH) 2 D 3 induces, via multiple Ca 2+ signaling pathways, synchronous Ca 2+ oscillations, which quantitatively, temporally, and spatially pattern pulsatile insulin secretion from these cells. In animal studies employing a high fat diet-induced obesity model of pre-T2D, an increased intake of vitamin D delayed development of T2D and adiposity and was associated with the improved blood markers of diabetes and the vitamin D nutritional and hormonal status [plasma concentrations of glucose, insulin, adiponectin, 25-hydroxyvitamin D, and 1,25(OH) 2 D 3 ]. Observational studies demonstrated associations between vitamin D status, insulin secretion and resistance to T2D, however, randomized controlled trials did not provide conclusive insights into the potential role of vitamin D in prevention of T2D. The 1,25(OH) 2 D 3 -dependent cellular Ca 2+ signaling can be important for maintaining the normal level of insulin secretion from pancreatic β-cells, and an increased intake of vitamin D may contribute to the prevention of T2D and metabolic disorders associated with this disease.

Background: Diabetes type 1 is characterized by the failure of beta cells to produce insulin. Suppressor of cytokine signaling (SOCS) proteins are important regulators of the Janus kinase/signal transducer and activator of transcription (JAK-STAT) pathway. Previous studies have shown that GH can prevent the development of type I diabetes in mice and that SOCS2 deficiency mimics a state of increased GH sensitivity. Methodology: The elevated sensitivity of SOCS2 –/– mice to GH and possibly to PRL was the rationale to analyze the effects of multiple low dose streptozotocin (MLDSTZ)-induced diabetes in SOCS2 –/– mice. Results: We show that 6-month-old SOCS2 –/– mice, but not 2-month-old mice, were less sensitive to MLDSTZ-induced diabetes, compared to controls. MLDSTZ treatment induced glucose intolerance in both SOCS2 +/+ and SOCS2 –/– mice, as shown by glucose tolerance tests, with SOCS2 +/+ mice showing a more marked intolerance, compared to SOCS2 –/– mice. Furthermore, insulin tolerance tests showed that the SOCS2 –/– mice have an improved hypoglycemic response to exogenous insulin, compared to SOCS2 +/+ mice. Moreover, in isolated islets, lipotoxic effects on insulin release could partly be overcome by ligands, which bind to GH or PRL receptors. Conclusion: Knockdown of SOCS2 makes mice less sensitive to MLDSTZ. These results are consistent with the proposal that elimination of SOCS2 in pancreatic islets creates a state of β-cell hypersensitivity to GH/PRL that mimics events in pregnancy, and which is protective against MLDSTZ-induced type I diabetes in mice. SOCS2-dependent control of β-cell survival may be of relevance to islet regeneration and survival in transplantation.