Cholesterol is a critical component of cell membranes, and cellular cholesterol levels and distribution are tightly regulated in mammals. Recent evidence has revealed a critical role for pancreatic β cell-specific cholesterol homeostasis in insulin secretion as well as in β cell dysfunction in diabetes and the metabolic response to thiazolidinediones (TZDs), which are antidiabetic drugs. The ATP-binding cassette transporter G1 (ABCG1) has been shown to play a role in cholesterol efflux, but its role in β cells is currently unknown. In other cell types, ABCG1 expression is downregulated in diabetes and upregulated by TZDs. Here we have demonstrated an intracellular role for ABCG1 in β cells. Loss of ABCG1 expression impaired insulin secretion both in vivo and in vitro, but it had no effect on cellular cholesterol content or efflux. Subcellular localization studies showed the bulk of ABCG1 protein to be present in insulin granules. Loss of ABCG1 led to altered granule morphology and reduced granule cholesterol levels. Administration of exogenous cholesterol restored granule morphology and cholesterol content and rescued insulin secretion in ABCG1-deficient islets. These findings suggest that ABCG1 acts primarily to regulate subcellular cholesterol distribution in mouse β cells. Furthermore, islet ABCG1 expression was reduced in diabetic mice and restored by TZDs, implicating a role for regulation of islet ABCG1 expression in diabetes pathogenesis and treatment.
Background The diagnosis of hypoglycemia and the use of diazoxide have risen in the last decade. Diazoxide is the only FDA-approved pharmacologic treatment for neonatal hypoglycemia caused by hyperinsulinism (HI). Recent publications have highlighted that diazoxide has serious adverse effects (AEs) such as pulmonary hypertension (2-3%) and neutropenia (15%). Despite its increasing use, there is little information regarding dosing of diazoxide and/or monitoring for AEs. Methods We convened a working group of pediatric endocrinologists who were members of the Drug and Therapeutics Committee of the Pediatric Endocrine Society (PES) to review the available literature. Our Committee sent a survey to its PES members regarding the use of diazoxide in their endocrine practices. Our review of the results concluded that there was substantial heterogeneity in usage and monitoring for AEs for diazoxide among pediatric endocrinologists. Conclusions Based on our extensive literature review and on the lack of consensus regarding use of diazoxide noted in our PES survey, our group graded the evidence using the framework of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group, and has proposed expert consensus practice guidelines for the appropriate use of diazoxide in infants and children with HI. We summarized information on AEs reported to date and have provided practical ideas for dosing and monitoring for AEs in infants treated with diazoxide.
| INTRODUC TI ONSubsequent to its discovery in 1999, 1 ghrelin has been increasingly recognised for its role in diverse biological functions. Ghrelin stimulates growth hormone and adrenocorticotrophic hormone secretion, increases appetite and nutrient intake, decreases mean arterial blood pressure and augments cardiac output, enhances gut motility and gastric acid secretion, influences energy expenditure, affects learning and memory, and contributes to the hedonic aspects of food. 2,3 Ghrelin also impacts glucose metabolism both during typical fasting and fed states and at times of stress. For example, during starvation, ghrelin is essential for maintaining glucose homeostasis. 4-7 Although the ability of ghrelin to regulate glucose metabolism is widely accepted, the mechanisms by which it achieves these effects remain to be fully clarified. Ghrelin-induced lipolysis and counter regulatory hormone release is well recognised, 8-10 although only recently has its modulation of insulin release via pancreatic islet δ-cells 11,12 and a role in stimulating the secretion of other gastrointestinal hormones been identified. 10,13 This review focuses on the effects of ghrelin on glucose metabolism by summarising in vitro, rodent and human studies, at the same time as highlighting recent discoveries (Figure 1). Throughout the review, we use "acyl ghrelin" and "ghrelin" interchangeably and explicitly state studies reporting desacyl ghrelin or total ghrelin findings. Funding informationNational Institute of Diabetes and Digestive and Kidney Diseases: T32DK007012 to S.M.G., R01DK097550 to J.T Ghrelin and its receptor, the growth hormone secretagogue receptor 1a (GHSR1a), are implicated in the regulation of glucose metabolism via direct actions in the pancreatic islet, as well as peripheral insulin-sensitive tissues and the brain. Although many studies have explored the role of ghrelin in glucose tolerance and insulin secretion, a complete mechanistic understanding remains to be clarified. This review highlights the local expression and function of ghrelin and GHSR1a in pancreatic islets and how this axis may modulate insulin secretion from pancreatic β-cells. Additionally, we discuss the effect of ghrelin on in vivo glucose metabolism in rodents and humans, as well as the metabolic circumstances under which the action of ghrelin may predominate. K E Y W O R D Sghrelin, glucose tolerance, insulin, insulin secretion
The prevalence of pediatric obesity in the United States is nearly 17%. Most cases are “exogenous”, resulting from excess energy intake relative to energy expenditure over a prolonged period of time. However, some cases of obesity are “endogenous”, associated with hormonal, genetic, or syndromic disorders such as hypothyroidism, Cushing’s syndrome, growth hormone deficiency, defective leptin signaling, mutations in the melanocortin 4 receptor, and Prader-Willi and Bardet-Biedl syndromes. This article reviews the hormonal, monogenic, and syndromic causes of childhood obesity and identifies critical features that distinguish “endogenous” obesity disorders from the more common exogenous obesity. Findings that raise suspicion for endogenous obesity include onset in infancy, lack of satiety, poor linear growth, dysmorphic features, and cognitive dysfunction. Selection and interpretation of appropriate laboratory tests and indications for subspecialist referral are also discussed.
Emerging evidence supports the importance of ghrelin to defend against starvation-induced hypoglycemia. This effect may be mediated by inhibition of glucose-stimulated insulin secretion as well as reduced insulin sensitivity. However, administration of ghrelin during meal consumption also stimulates the release of glucagon-like peptide 1 (GLP-1), an incretin important in nutrient disposition. The objective of this study was to evaluate the interaction between ghrelin and GLP-1 on parameters of glucose tolerance following a mixed-nutrient meal. Fifteen healthy men and women completed the study. Each consumed a standard meal on four separate occasions with a superimposed infusion of ) saline,) ghrelin, ) the GLP-1 receptor antagonist exendin(9-39) (Ex9), or) combined ghrelin and Ex9. Similar to previous studies, infusion of ghrelin caused glucose intolerance, whereas Ex9 had a minimal effect. However, combined ghrelin and Ex9 resulted in greater postprandial glycemia than either alone, and this effect was associated with impaired β-cell function and decreased glucose clearance. These findings suggest that in the fed state, stimulation of GLP-1 mitigates some of the effect of ghrelin on glucose tolerance. This novel interaction between gastrointestinal hormones suggests a system that balances insulin secretion and glucose disposal in the fed and fasting states.
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