Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Incretins such as glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide 1 (GLP-1) are intestinal hormones that are released in response to ingestion of nutrients, especially carbohydrate. They have a number of important biological effects, which include release of insulin, inhibition of glucagon and somatostatin, maintenance of beta-cell mass, delay of gastric emptying, and inhibition of feeding. These properties allow them to be potentially suitable agents for the treatment of type 2 diabetes (T2D). Incretin receptors are also present in other parts of the body including the brain, where their effects are beginning to be understood and their relevance to disorders of nutrition and ageing are being explored. There is currently a pandemic of obesity and diabetes, and existing treatments are largely inadequate in regard to efficacy as well as their ability to tackle important factors in the pathogenesis of T2D. There is increasing evidence that current treatments do not address the issue of progressive beta-cell failure in T2D. As obesity is the engine that is driving the epidemic of diabetes, it is disappointing that most treatments that succeed in lowering plasma glucose are also associated with weight gain. It is now well established that intensively treated T2D has a better outcome than standard treatment. Consequently, achieving better control of diabetes with lower HbA1c is the goal of optimal treatment. Despite the use of usual therapeutic agents in T2D, often in high doses and as combinations, such as metformin, sulphonylurea, alpha-glycosidase inhibitors, thiazolidinediones and a number of animal and human insulin preparations, optimal control of glycaemia is not achieved. The use of incretins as therapeutic agents offers a new approach to the treatment of T2D. Incretin metabolism is abnormal in T2D, evidenced by a decreased incretin effect, reduction in nutrient-mediated secretion of GIP and GLP-1 in T2D, and resistance to GIP. GLP-1, on the other hand, when administered intravenously in T2D is able to increase insulin secretion and improve glucose homeostasis. As GLP-1 has a very short half-life, due to rapid degradation by the enzyme dipeptidyl peptidase IV (DPPIV), analogues of GIP and GLP-1 that are resistant to the action of DPPIV have been developed and clinical trials have shown their effectiveness. Another novel agent, naturally resistant to DPPIV that is given by subcutaneous injection is a synthetic peptide called exenatide, has recently been approved for treatment of T2D in the USA. Efforts are underway to develop agents that can be given orally and include a DPPIV inhibitor that has been licensed for the treatment of T2D in the USA, and several other agents are undergoing clinical trials. Strategies to augment the biological actions of GIP and/or GLP-1 in T2D are expected to minimise weight gain, reduce hypoglycaemic episodes and prevent progressive beta-cell failure by increasing beta-cell mass. The optimal agent(s) that may mimic and replace the endogenous incretin effect is not fully known and awaits the outcome of clinical trials that are still ongoing. The potential therapeutic role in non-diabetic states, including obesity and neurodegenerative disease, is intriguing and depends upon results from ongoing research.
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PMID:The entero-insular axis: implications for human metabolism. 1802 Sep 66

A relative decrease in beta-cell mass is key in the pathogenesis of type 1 diabetes, type 2 diabetes, and in the failure of transplanted islet grafts. It is now clear that beta-cell duplication plays a dominant role in the regulation of adult beta-cell mass. Therefore, knowledge of the endogenous regulators of beta-cell replication is critical for understanding the physiological control of beta-cell mass and for harnessing this process therapeutically. We have shown that concentrations of insulin known to exist in vivo act directly on beta-cells to promote survival. Whether insulin stimulates adult beta-cell proliferation remains unclear. We tested this hypothesis using dispersed primary mouse islet cells double labeled with 5-bromo-2-deoxyuridine and insulin antisera. Treating cells with 200-pm insulin significantly increased proliferation from a baseline rate of 0.15% per day. Elevating glucose from 5-15 mm did not significantly increase beta-cell replication. beta-Cell proliferation was inhibited by somatostatin as well as inhibitors of insulin signaling. Interestingly, inhibiting Raf-1 kinase blocked proliferation stimulated by low, but not high (superphysiological), insulin doses. Insulin-stimulated mouse insulinoma cell proliferation was dependent on both phosphatidylinositol 3-kinase/Akt and Raf-1/MAPK kinase pathways. Overexpression of Raf-1 was sufficient to increase proliferation in the absence of insulin, whereas a dominant-negative Raf-1 reduced proliferation in the presence of 200-pm insulin. Together, these results demonstrate for the first time that insulin, at levels that have been measured in vivo, can directly stimulate beta-cell proliferation and that Raf-1 kinase is involved in this process. These findings have significant implications for the understanding of the regulation of beta-cell mass in both the hyperinsulinemic and insulin-deficient states that occur in the various forms of diabetes.
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PMID:Insulin stimulates primary beta-cell proliferation via Raf-1 kinase. 1820 27

Diabetic retinopathy continues to be the leading cause of legal blindness among working-age individuals. The earliest histological features of diabetic retinopathy include neuroretinal damage, capillary basement membrane thickening, loss of pericytes and loss of endothelial cells. At advanced stages, neovascularization, the hallmark of proliferative diabetic retinopathy (PDR) occurs, and blindness can result from relentless abnormal fibrovascular proliferation with subsequent bleeding and retinal detachment. Macular oedema is another retinal complication of diabetes that is responsible for a major part of vision loss, particularly in type 2 diabetes. The breakdown of the blood retinal barrier and the consequent vascular leakage and thickening of retina are the main events involved in its pathogenesis. Although a tight control of both blood glucose levels and hypertension are essential to prevent or arrest progression of the disease, the recommended goals are difficult to achieve in many patients. Laser photocoagulation treatment soon after the onset of PDR significantly reduces the incidence of severe vision loss. However, the optimal timing for laser treatment is frequently passed and, in addition, it is not uniformly successful in halting visual decline. For all these reasons, new pharmacological treatments based on the understanding of the pathophysiological mechanisms of diabetic retinopathy have been developed in recent years. There is mounting evidence to suggest that angiogenic factors play a crucial role in PDR development, vascular endothelial growth factor (VEGF) being the most relevant. Other growth factors or cytokines such as insulin-like growth factor I (IGF-1), hepatocyte growth factor (HGF), basic fibroblast growth factor (b-FGF), platelet derived growth factor (PDGF), pro-inflammatory cytokines and angiopoetins, are also involved in the pathogenesis of PDR. However, the intraocular synthesis of angiogenic factors is counterbalanced by the synthesis of antiangiogenic factors. Therefore, the balance between the angiogenic and antiangiogenic factors rather than angiogenic factors themselves will be crucial in determining the progression of PDR. The main antiangiogenic factor is the pigment epithelium derived factor (PEDF) but the transforming growth factor beta (TGF-beta), thrombospondin (TSP) and somatostatin are also among the intraocullary synthesized antiangiogenic factors.
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PMID:Angiogenic and antiangiogenic factors in proliferative diabetic retinopathy. 1822 Jun 19

Antagonists of cannabinoid CB1 receptor (CB1, CNR1) promote weight loss and decrease hyperglycemia in patients with type 2 diabetes. While the endocannabinoid system may modulate islet hormone secretion, the cell-type expressing CB1 receptor in islets has not been fully resolved. In this study, we verified receptor gene expression in rodent islets and cell lines and examined the distribution of CB1 receptor in mouse, rat, and human islets by confocal immunofluorescence (IF) microscopy. IF demonstrated CB1 receptor was present in beta-cell lines, but co-localized solely with somatostatin in the islet delta-cells of Zucker rats, C57BL/6 mice, and humans; no CB1 receptor expression was observed in alpha-, beta-, or pp-cells. Similarly, a rat somatostatinoma cell line, MSL-G2-Tu6, was found to express CB1 receptor. We also found monoacylglycerol lipase (MAGL) to be expressed in delta-cells and fatty acid amide hydrolase (FAAH) to be expressed in alpha-cells. The specific expression of CB1 in delta-cells suggests that the ECS may play a role in modulating islet hormone secretion. As there are some differences between our findings and previous reports, further studies, including detailed physiological studies of the effects of the ECS on islet function, are warranted.
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PMID:The cannabinoid CB1 receptor is expressed in pancreatic delta-cells. 1850 78

Insulin is released in a pulsatile manner, which results in oscillatory concentrations in blood. The oscillatory secretion improves release control and enhances the hormonal action. Insulin oscillates with a slow ultradian periodicity (approximately 140 min) and a high-frequency periodicity (approximately 6-10 min). Only the latter is reviewed in this article. At least 75% of the insulin secretion is released in a pulsatile manner. Individuals prone to developing diabetes or with overt type 2 diabetes are characterized by irregular oscillations of plasma insulin. Many factors have impact on insulin pulsatility such as age, insulin resistance and glycemic level. In addition, tiny glucose oscillations are capable of entraining insulin oscillations in healthy people in contrast to type 2 diabetic individuals emphasizing a profound disruption of the beta-cells in type 2 diabetes to sense or respond to physiological glucose excursions. A crucial question is how approximately 1,000,000 islets, each containing from a few to several thousand beta-cells, can be coordinated to secrete insulin in a pulsatile manner. This is blatantly a very complex operation to control involving an intra-pancreatic neural network, an intra-islet communication and metabolic oscillations in the beta-cell itself. Overnight beta-cell rest, e.g. during somatostatin administration, improves the disordered pulsatile insulin secretion in type 2 diabetes. Acute as well as long-term administration of sulphonylureas (SU) leads to substantial amplification (approximately 50%) of the pulsatile insulin secretion in type 2 diabetes. This is probably cardinal in terms of governing the hepatic glucose release in type 2 diabetes. Whether sulfonylureas also improve the ability of the beta-cells to sense glucose fluctuations remains to be explored. Thiazolidinediones reduce the pulsatile insulin secretion without affecting regularity, but appear to improve the ability of the beta-cell to be entrained by small glucose excursions. Finally, similar to SUs, the incretin hormone GLP-1 also results in an augmented pulsatile burst mass in both healthy and diabetic individuals, in the latter group, however, without influencing the disorderliness of pulses. This review will briefly describe the high-frequency insulin pulsatility during physiologic and pathophysiologic conditions as well as the influence of some hypoglycemic compounds on the insulin oscillations.
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PMID:On high-frequency insulin oscillations. 1858 99

Visfatin is a newly discovered adipocyte hormone with a direct relationship between plasma visfatin level and type 2 diabetes mellitus. Visfatin binds to the insulin receptor at a site distinct from that of insulin and causes hypoglycaemia by reducing glucose release from liver cells and stimulating glucose utilization in adipocytes and myocytes. Visfatin is upregulated by hypoxia, inflammation and hyperglycaemia and downregulated by insulin, somatostatin and statins. This hormone is found in the cytoplasm as well as the nucleus of cells and has been identified in many tissues and organs including the brain, kidney, lung, spleen and testis but preferentially expressed in visceral adipose tissue and upregulated in some animal models of obesity. Visceral adipose tissue is regarded to be more pernicious than subcutaneous adipose tissue. Visfatin is an endocrine, autocrine as well as paracrine peptide with many functions including enhancement of cell proliferation, biosynthesis of nicotinamide mono- and dinucleotide and hypoglycaemic effect. Visfatin, also known as a pre-B cell colony-enhancing factor, consists of 491 amino acids (aa) in human, chimpanzee, cattle, pig, rat and mouse, 490 aa in rhesus monkey, 285 aa in sheep, 587 in opossum and 588 aa in canines. Visfatin gene is well preserved during evolution. For example, the canine visfatin protein sequence is 96% and 94% identical to human and rodent visfatin, respectively. Since evidence of a direct link between visfatin genotype and human type 2 diabetes mellitus is still weak, more molecular, physiological and clinical studies are needed to determine the role of visfatin in the etiology and pathogenesis of type 2 diabetes mellitus.
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PMID:Visfatin: structure, function and relation to diabetes mellitus and other dysfunctions. 1869 Oct 43

The secondary occurrence of type 2 diabetes with various hormonal diseases (e.g. pituitary, adrenal and/or thyroid diseases) is a recurrent observation. Indeed, impaired glucose tolerance (IGT) and overt diabetes mellitus are frequently associated with acromegaly and hypercortisolism (Cushing syndrome). The increased cardiovascular morbidity and mortality associated with acromegaly and Cushing syndrome may partly be a consequence of increased insulin resistance that normally accompanies hormone excess. Acromegalic patients are insulin resistant, both in the liver and in the periphery, displaying hyperinsulinemia and increased glucose turnover in the basal post-absorptive states. The prevalence of diabetes mellitus and that of IGT in acromegaly is reported to range 16-56%, whereas the degree of glucose tolerance seems correlated with circulating growth hormone (GH) levels, age, and disease duration. Moreover, a family history of diabetes and concomitant presence of arterial hypertension have been found to predispose to diabetes as well. GH has physiological effects on glucose metabolism, stimulating gluconeogenesis and lipolysis, which results in increased blood glucose and free fatty acid levels. Conversely, insulin-like growth factor 1 (IGF-I) enhances insulin sensitivity primarily on skeletal muscles. However, in acromegaly, increased IGF-I levels are unable to counteract the insulin-resistance status determined by GH excess. Therapy with somatostatin analogues (SSAs) induce control of GH and IGF-I excess in the majority of patients, but their inhibitory effect on pancreatic insulin secretion might complicate the overall effect of this treatment on glucose tolerance. Hypercortisolism produces visceral obesity, insulin resistance, and dyslipidemia that together with hypertension, hypercoagulability, and ventricular morphologic and functional abnormalities increase cardiovascular risk, and persist up to 5 years after resolution of hypercortisolism. Hypercortisolism leads to hyperglycaemia and reduced glucose tolerance, determines insulin resistance, stimulates hepatic gluconeogenesis and glicogenolisis. In Cushing syndrome the prevalence of diabetes varies between 20 and 50%, but probably this prevalence is underestimated, as not always an oral glucose tolerance test is performed in the presence of an apparently normal fasting glycaemia. Again, disease duration, rather than hormone levels, seems to be the major determinant in the occurrence of systemic complications in Cushing syndrome. Due to the impact they have on mortality and morbidity in both acromegaly and Cushing syndrome, these complications should be treated aggressively. In patients with neuroendocrine tumours (NETs) the occurrence of altered glucose tolerance may be due to a decreased insulin secretion, like it happens in patients who underwent pancreatic surgery and in those with pheochromocytoma, or to an altered counterbalance between hormones, such as in patients with glucagonoma and somatostatinoma. Moreover, SSAs represent a valid therapeutic choice in the symptomatic treatment of NETs, and also in this case the medical therapy of the primary disease, may have a significant impact on the prevalence of glucose metabolism imbalance. In thyroid disorders, an abnormal glucose tolerance may be principally encountered in hyperthyroidism. The pathogenesis is complex and scant data on prevalence and severity are found in the literature. Adequate treatment for glucose imbalance is mandatory in these peculiar patients in line with the American Diabetes Association and the European Association for the Study of Diabetes consensus statement. In particular, since traditional insulins have two features that may complicate therapy (absorption profiles, delayed onset of action and peak activity), the new insulin analogues could be of particular interest in the management of the secondary diabetes associated with endocrinopathies, considering the frailty of these patients. Indeed, it has been demonstrated that insulin glargine, given once daily, reduces the risk of hypoglycaemia compared with other formulations, and can facilitate a more aggressive insulin treatment in this class of patients.
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PMID:Secondary diabetes associated with principal endocrinopathies: the impact of new treatment modalities. 1932 13

Fasting hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is attributed to increased hepatic gluconeogenesis, which has been ascribed to increased transcriptional expression of phosphoenolpyruvate carboxykinase (PEPCK) and glucose-6-phosphatase, catalytic (G6Pc). To test this hypothesis, we examined hepatic expression of these 2 key gluconeogenic enzymes in 2 rodent models of fasting hyperglycemia and in patients with T2DM. In rats, high-fat feeding (HFF) induces insulin resistance but a robust beta-cell response prevents hyperglycemia. Fasting hyperglycemia was induced in the first rat model by using nicotinamide and streptozotocin to prevent beta-cell compensation, in combination with HFF (STZ/HFF). In a second model, control and HFF rats were infused with somatostatin, followed by portal vein infusion of insulin and glucagon. Finally, the expression of these enzymes was measured in liver biopsy samples obtained from insulin sensitive, insulin resistant, and untreated T2DM patients undergoing bariatric surgery. Rats treated with STZ/HFF developed modest fasting hyperglycemia (119 +/- 4 vs. 153 +/- 6 mg/dL, P < 0.001) and increased rates of endogenous glucose production (EGP) (4.6 +/- 0.6 vs. 6.9 +/- 0.6 mg/kg/min, P = 0.02). Surprisingly, the expression of PEPCK or G6Pc was not increased. Matching plasma insulin and glucagon with portal infusions led to higher plasma glucoses in the HFF rats (147 +/- 4 vs. 161 +/- 4 mg/dL, P = 0.05) with higher rates of EGP and gluconeogenesis. However, PEPCK and G6Pc expression remained unchanged. Finally, in patients with T2DM, hepatic expression of PEPCK or G6Pc was not increased. Thus, in contrast to current dogma, these data demonstrate that increased transcriptional expression of PEPCK1 and G6Pc does not account for increased gluconeogenesis and fasting hyperglycemia in patients with T2DM.
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PMID:Fasting hyperglycemia is not associated with increased expression of PEPCK or G6Pc in patients with Type 2 Diabetes. 1958 43

The role of the newly discovered estrogen receptor GPR30 in islet physiology and pathophysiology is unclear. We examined GPR30 expression in relation to hormone secretion and possible anti-apoptotic effects in isolated mouse islets using the synthetic GPR30 ligand G-1. The mRNA and protein expression of GPR30 was analyzed by qPCR, Western blot and confocal microscopy. Hormone secretion and cAMP content were determined with RIA and apoptosis in islet cells with the Annexin-V method. GPR30 mRNA and protein expression was markedly higher in islets from females compared to male. This gender difference was not found for the genomic estrogen receptors ER alpha and ER beta, the ER alpha expression being 10-fold higher than ER beta in both genders. Confocal microscopy revealed abounden GPR30 expression in insulin, glucagon and somatostatin cells. Dose-response studies of G-1 vs 17beta-estradiol in isolated islets at 1 or 12 mM glucose showed an almost identical pattern in that both compounds increased insulin and inhibited glucagon and somatostatin secretion. ICI-182,780 and EM-652, potent antagonists of the 17beta-estradiol receptors (ER alpha and ER beta) did not influence the amplifying effect of G-1 or 17beta-estradiol on cAMP content or insulin secretion from isolated islets. Cytokine-induced (IL-1 beta+TNFalpha+INF gamma) apoptosis in islets, cultured for 24h at 5mM glucose, was almost abolished by G-1 or 17beta-estradiol treatment. Addition of ICI-182,780 or EM-652 did not affect this beneficial effect of G-1 or 17beta-estradiol. Taken together, our findings show that GPR30 is expressed in most islet endocrine cells. The synthetic GPR30 ligand G-1 mimics the non-genomic effects of 17beta-estradiol on islet hormone secretion, cAMP content in islets and its anti-apoptotic effects. G-1 or analogs thereof might be new potential candidates in the therapeutic strategy for type 2 diabetes in women.
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PMID:Activation of G protein-coupled receptor 30 modulates hormone secretion and counteracts cytokine-induced apoptosis in pancreatic islets of female mice. 2012 88

Inactive cortisone is converted to active cortisol within the liver by 11 beta-hydroxysteroid dehydrogenase-1 (11 beta-HSD1), and impaired regulation of this process may be related to increased hepatic glucose production (HGP) in individuals with type 2 diabetes. The primary aim of this study was to investigate the effect of acute 11 beta-HSD1 inhibition on HGP and fat metabolism during insulin deficiency. Sixteen conscious, 42-h-fasted, lean, healthy dogs were studied. Somatostatin was infused to create insulin deficiency, and the animals were treated with a specific 11 beta-HSD1 inhibitor (compound 531) or placebo for 5 h. 11 beta-HSD1 inhibition completely suppressed hepatic cortisol production, and this attenuated the increase in HGP that occurred during insulin deficiency. PEPCK and glucose-6-phosphatase expression were decreased when 11 beta-HSD1 was inhibited, but gluconeogenic flux was unchanged, implying an effect on glycogenolysis. Since inhibition of hepatic cortisol production reduces HGP during insulin deficiency, 11 beta-HSD1 is a potential therapeutic target for the treatment of excess glucose production that occurs in diabetes.
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PMID:Effect of 11 beta-hydroxysteroid dehydrogenase-1 inhibition on hepatic glucose metabolism in the conscious dog. 2015 54


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