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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Identification of genes and pathways that alter lifespan has allowed for new insights into factors that control the aging process as well as disease. While strong molecular links exist between aging and metabolism, we hypothesize that targeting the mechanisms involved in aging will also give rise to therapeutics that treat other devastating age-related diseases, such as neurodegeneration, cancer, inflammation and cardiovascular disease. Insulin sensitivity, glycemic control and adiposity are not only hallmarks of the major metabolic diseases, type 2 diabetes and obesity, but they also represent significant risk factors for the development of Alzheimer's Disease and cognitive impairment. Insulin/IGF-1 signaling is an important pathway regulating aging and disease in a variety of species, including mammals. Here we describe an important role for the gut-derived peptide ghrelin in upstream signaling through the insulin/IGF-1 pathway and exemplify modulation of ghrelin signaling as an approach to mechanistic treatment of multiple age-related diseases by virtue of its ability to regulate key metabolic functions.
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PMID:Insulin resistance, glycemic control and adiposity: key determinants of healthy lifespan. 1743 Feb 40

Type 2 diabetes is a chronic, debilitating disease characterized by insulin resistance, impaired insulin secretion, and hyperglycaemia, and afflicting at least 171 million people worldwide (31.7 million in India). This chronic disease is not benign and patients with diabetes suffer from numerous microvascular and macrovascular complications which cause a lot of morbidity and mortality. Results from the UKPDS (United Kingdom Prospective Diabetes Study) clearly demonstrate that tight glucose and blood pressure control in patients with type 2 diabetes prevents the development of and delays the progression of microvascular complications and possibly macrovascular disease. In addition, results from the UKPDS and other studies like the Heart Protection Study (HPS) have also shown that treatment of concomitant risk factors like lipids and blood pressure and the use of aspirin have favourable effects on cardiovascular complications and mortality in patients with type 2 diabetes. In order to achieve glycaemic goals, we have several anti-hyperglycaemic agents in our therapeutic armamentarium today. However, despite their availability, we have not been able to achieve glycaemic goals in our patients with diabetes due to a variety of reasons. However, there appears to be hope for the future. The progress of research in all fields of diabetes therapeutics from diabetes treatment to continuous glucose monitoring systems to novel insulin delivery systems has been spectacular. These advances have resulted in newer pharmacologic agents, implantable glucose sensors and inhaled insulin. There is also hope that large scale implementation of intensive lifestyle programmes and education efforts may help to prevent diabetes in high risk individuals. Indeed, the repertoire of options and strategies currently available (and in the pipeline) to treat and prevent/delay diabetes and its complications is impressive. In this review, we will discuss the evolving cardiovascular benefits of the thiazolidinediones (TZDs); describe in detail the newer glucose lowering gut hormones with novel mechanisms of action; delineate the recent advances in non invasive insulin delivery systems (including inhaled insulin); review the ongoing developments in continuous glucose measuring devices and finally present an update on the prevention of diabetes.
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PMID:New frontiers in the management of type 2 diabetes. 1749 56

Glucagon-like peptide-1 (GLP-1) is a gut hormone secreted in response to the ingestion of a meal. It exerts various favourable metabolic effects among which a glucose-dependent stimulation of insulin secretion, an inhibition of glucagon secretion, a slow down of gastric emptying, and a central anorectic effect. In rodents, a protective effect, or even a trophic effect, on B cell has also been reported. Interestingly, GLP-1 secretion is decreased in patients with type 2 diabetes. This observation stimulated the pharmaceutical research with the aim of restoring appropriate GLP-1 circulating levels able to exert the numerous positive effects of the hormone. One of the main objectives was to solve the problem due to the very short half-life of GLP-1. We here briefly describe the main two proposed approaches : ether to subcutaneously inject an incretinomimetic agent closed to GLP-1 (exenatide) or a long-acting GLP-1 analogue (liraglutide), both being partially resistant to the action of dipeptidylpeptidase-IV (DPP-IV), either to orally administer a selective DPP-IV inhibitor, an enzyme metabolising endogenous GLP-1 (sitagliptin, vildagliptin, .... These new drugs offer the advantage of improving blood glucose control of type 2 diabetic patients, without inducing severe hypoglycaemia and without promoting weight gain (instead a weight reduction is generally observed). These agents should occupy a key place in the overall pharmacological strategy of type 2 diabetes in a near future, especially if the additional favourable effects on B cells are confirmed in clinical practice.
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PMID:[Glucagon-like peptide-1 (GLP-1), new target for the treatment of type 2 diabetes]. 1756 92

Recognition of the interplay between genes and diet in development of disease and for maintenance of optimal metabolism has led to nutrigenomic or nutrigenetic approaches to personalising or individualising nutrition, with the potential of preventing, delaying, or reducing the symptoms of chronic diseases. Some of the development work has focussed on cardiovascular disease or type II diabetes mellitus, where various groups have identified potential diet-gene interactions. However, the available studies also emphasise the exponential increase in numbers of subjects necessary to recruit for clinical evaluation if we are to successfully provide informative high-dimensional datasets of genetic, nutrient, metabolomic (clinical), and other variables. There is also a significant bioinformatics challenge to analyze these. To add to the complexity, many of the pioneering studies had assumed that single nucleotide polymorphisms (SNPs) were the main source of human variability, but an increasing evidence base suggests the importance of more subtle gene regulatory mechanisms, including copy number variants. As an example, the risk of Inflammatory Bowel Disease (IBD) is associated with the inheritance of a number of contributory SNPs as well as with copy number variants of certain other genes. The variant forms of genes often result in disruptions to bacterial homeostasis mechanisms or to signal transduction of the intestinal epithelial cell of the host, and thereby to altered intestinal barrier function, and/or adaptive immune responses. The human gut microbiota is altered in individuals suffering from disorders such as IBD, and probiotic or prebiotic therapies or elemental diets may be beneficial to a high proportion of individuals through modifying the gut microbiota, and also modulating immune responses. New putative foods or dietary therapies may be identified through novel tissue culture screens, followed by further testing with in vivo animal models of human disease. A scientifically based rationale for developing novel foods related to genotype might use a combination of food fractionation, testing in tissue culture models and validation through animal models, before moving into human populations. However, the field of nutrigenomics raises ethical, legal and social issues, and will be of genuine benefit to human health only if developed in linkage with adequately trained health professionals. Such training will widen public understanding, and permit dialogue with regulatory officials to responsibly develop, apply and progress this new field.
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PMID:Nutrigenomics and gut health. 1756 28

Because of its growing prevalence in Western countries, the metabolic syndrome, a common metabolic disorder that clusters a constellation of abnormalities, including central obesity, hypertension, dyslipidemia and insulin resistance, is emerging as one of the most important public health problems in the world, taking into account that it is a major risk factor mainly for type 2 diabetes and cardiovascular diseases, and also for many types of cancer. Although the pathogenesis of this syndrome is complex and not fully understood, obesity and insulin resistance, accompanied by an altered profile of number of hormones and cytokines produced by the adipose tissue, seem to be the main causative agents. A prime therapeutic approach to the prevention and treatment of this syndrome involves lifestyle changes. Among dietary modifications, dietary fiber intake could play an interesting role in the management of metabolic syndrome through different mechanisms related to its dietary sources, specific chemical structure and physical properties, or fermentability in the gut. According to all of these variables, the different types of dietary fibers have been reported to take part in the control of body weight, glucose and lipid homeostasis, insulin sensitivity and in the regulation of many inflammation markers involved in the pathogenesis of metabolic syndrome, and which are also considered to be among its features.
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PMID:Effects of dietary fibers on disturbances clustered in the metabolic syndrome. 1761 8

Delayed gastric emptying is frequently observed in patients with long-standing type 1 and type 2 diabetes mellitus, and potentially impacts on upper gastrointestinal symptoms, glycaemic control, nutrition and oral drug absorption. The pathogenesis remains unclear and management strategies are currently suboptimal. Therapeutic strategies focus on accelerating gastric emptying, controlling symptoms and improving glycaemic control. The potential adverse effects of hyperglycaemia on gastric emptying and upper gut symptoms indicate the importance of normalising blood glucose if possible. Nutritional and psychological supports are also important, but often neglected. A number of recent pharmacological and non-pharmacological therapies show promise, including gastric electrical stimulation. As with all chronic illnesses, a multidisciplinary approach to management is recommended, but there are few data regarding long-term outcomes.
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PMID:Pathophysiology and management of diabetic gastropathy: a guide for endocrinologists. 1768 69

GLP-1 receptor agonists such as exenatide are a group of new therapeutic agents that mimic the gut-derived incretin hormone GLP-1. These drugs stimulate insulin secretion while suppressing glucagon secretion, inhibit gastric motility, reduce appetite and hence, food intake. This group of drugs also induce reduction in fasting and postprandial glucose concentrations, HbA1c and ultimately lead to weight loss. The drugs are administered subcutaneously (exenatide twice daily). The most common side effect is mild nausea. Although short-term studies are promising, long-term clinical studies are needed to determine the benefits of this approach for the treatment of type 2 diabetes.
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PMID:[Glucagon-like peptide 1 (GLP-1)]. 1771 50

Incretins are gut peptides that potentiate nutrient-stimulated insulin secretion following meal ingestion. Activities of the dominant incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide, include glucose-dependent stimulation of insulin secretion and, in preclinical models, improvement in islet beta-cell mass. GLP-1 additionally reduces glucagon secretion, inhibits gastric emptying and promotes satiety. Patients with type 2 diabetes mellitus (T2DM) exhibit reduced total and intact GLP-1 levels, and exogenous administration of the hormone via continuous infusion results in glucose profiles similar to those in non-diabetic subjects. Incretins are rapidly degraded by dipeptidyl peptidase-4 (DPP-4). Thus, strategies to enhance incretin activity have included development of GLP-1 receptor agonists resistant to the action of DPP-4 (e.g. exenatide and liraglutide) and DPP-4 inhibitors that act to increase concentrations of endogenous intact incretins (e.g. sitagliptin and vildagliptin). Clinical trials of these incretin-based therapies have shown them to be effective in improving glycaemic control in patients with T2DM.
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PMID:Incretin-based treatment of type 2 diabetes: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors. 1787 44

Glucagon-like peptide 1 (GLP-1) is a 30-amino acid peptide hormone produced in the intestinal epithelial endocrine L-cells by differential processing of proglucagon, the gene which is expressed in these cells. The current knowledge regarding regulation of proglucagon gene expression in the gut and in the brain and mechanisms responsible for the posttranslational processing are reviewed. GLP-1 is released in response to meal intake, and the stimuli and molecular mechanisms involved are discussed. GLP-1 is extremely rapidly metabolized and inactivated by the enzyme dipeptidyl peptidase IV even before the hormone has left the gut, raising the possibility that the actions of GLP-1 are transmitted via sensory neurons in the intestine and the liver expressing the GLP-1 receptor. Because of this, it is important to distinguish between measurements of the intact hormone (responsible for endocrine actions) or the sum of the intact hormone and its metabolites, reflecting the total L-cell secretion and therefore also the possible neural actions. The main actions of GLP-1 are to stimulate insulin secretion (i.e., to act as an incretin hormone) and to inhibit glucagon secretion, thereby contributing to limit postprandial glucose excursions. It also inhibits gastrointestinal motility and secretion and thus acts as an enterogastrone and part of the "ileal brake" mechanism. GLP-1 also appears to be a physiological regulator of appetite and food intake. Because of these actions, GLP-1 or GLP-1 receptor agonists are currently being evaluated for the therapy of type 2 diabetes. Decreased secretion of GLP-1 may contribute to the development of obesity, and exaggerated secretion may be responsible for postprandial reactive hypoglycemia.
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PMID:The physiology of glucagon-like peptide 1. 1792 88

Inulin-type fructans have been tested for their capacity to modulate lipid and glucose metabolism in several animal models. Oligofructose (OFS) decreases food intake, fat mass development, and hepatic steatosis in normal and in obese rats; moreover, it exerts an antidiabetic effect in streptozotocin-treated rats and high-fat-fed mice. In most cases, the beneficial effects of OFS are linked to an increase of glucagon-like peptide-1 (GLP-1) level in the portal vein and of GLP-1 and proglucagon mRNA, its precursor, in the proximal colon. In this organ, OFS increases the number of GLP-1-positive L cells by promoting factors (Neurogenin 3 and NeuroD) involved in the differentiation of stem cells into L cells. The chronic administration of GLP-1 receptor antagonist exendin 9-39 totally prevents the beneficial effects of OFS (improved glucose tolerance, fasting blood glucose, glucose-stimulated insulin secretion, insulin-sensitive hepatic glucose production, and reduced body weight gain). Furthermore GLP-1 receptor knockout mice are completely insensitive to the antidiabetic actions of OFS. These findings highlight the potential interest of enhancing endogenous GLP-1 secretion by inulin-type fructans for the prevention/treatment of obesity and type 2 diabetes. Moreover, OFS is also able to modulate other gastrointestinal peptides (such as PYY and ghrelin) that could be involved in the control of food intake. Several studies in humans already support interest in OFS in the control of satiety, triglyceridemia, or steatohepatitis. The link with gut peptides production in humans remains to be proven.
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PMID:Modulation of glucagon-like peptide 1 and energy metabolism by inulin and oligofructose: experimental data. 1795


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