Recent Progress In Hormone Research[JOURNAL]
Sun
200 papers
Glucagon-like peptide-1.
Doyle ME, Egan JM
Recent Prog Horm Res · 2001 · PMID 11237222 · Publisher ↗
There is a progressive impairment in beta-cell function with age. As a result, 19 percent of the U.S. population over the age of 65 is diagnosed with type 2 diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is a po...
There is a progressive impairment in beta-cell function with age. As a result, 19 percent of the U.S. population over the age of 65 is diagnosed with type 2 diabetes mellitus (DM). Glucagon-like peptide-1 (GLP-1) is a potent insulin secretagogue that has multiple synergetic effects on the glucose-dependent insulin secretion pathways of the beta-cell. This peptide and its longer-acting analog exendin-4 are currently under review as treatments for type 2 DM. In our work on the rodent model of glucose intolerance in aging, we found that GLP-1 is capable of rescuing the age-related decline in beta-cell function. We have shown that this is due to the ability of GLP-1 to 1) recruit beta-cells into a secretory mode; 2) upregulate the genes of the beta-cell glucose-sensing machinery; and 3) cause beta-cell differentiation and neogenesis. Our investigations into the mechanisms of action of GLP-1 began by using the reverse hemolytic plaque assay to quantify insulin secretion from individual cells of the RIN 1046-38 insulinoma cell line in response to acute treatment with the peptide. GLP-1 increases both the number of cells secreting insulin and the amount secreted per cell. This response to GLP-1 is retained even in the beta cell of the old (i.e., 22-month), glucose-intolerant Wistar rat, which exhibits a normal, first-phase insulin response to glucose following an acute bolus of GLP-1. Preincubation with GLP-1 (24 hours) potentiates glucose- and GLP-1-dependent insulin secretion and increases insulin content in the insulinoma cells. Treatment of old Wistar rats for 48 hours with GLP-1 leads to normalization of the insulin response and an increase in islet insulin content and mRNA levels of GLUT 2 and glucokinase. PDX-1, a transcriptional factor activator of these three genes, also is upregulated in the insulinoma cell line in aged rats and diabetic mice following treatment with GLP-1. Administration of GLP-1 to old rats leads to pancreatic cell proliferation, insulin-positive clusters, and an increase in beta-cell mass. This evidence led us to believe that GLP-1 is an endocrinotrophic factor. We used an acinar cell line to show that GLP-1 can directly cause the conversion of a putative pro-endocrine cell into an endocrine one. Thus, the actions of GLP-1 on the beta-cell are complex, with possible benefits to the diabetic patient that extend beyond a simple glucose-dependent increase in insulin secretion. The major limitation to GLP-1 as a clinical treatment is its short biological half-life. We have shown that the peptide exendin-4, originating in the saliva of the Gila monster, exhibits the same insulinotropic and endocrinotrophic properties as GLP-1 but is more potent and longer acting in rodents and humans.
Central melanocortins and the regulation of weight during acute and chronic disease.
Marks DL, Cone RD
Recent Prog Horm Res · 2001 · PMID 11237221 · Publisher ↗
Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these proc...
Recent advances in our understanding of the regulation of body weight, appetite, and metabolic rate have highlighted the role of the adipose-derived hormone leptin and its receptor as fundamental modulators of these processes. Investigations of the neural targets for leptin action--as well as characterization of the agouti obesity syndrome--have, in turn, led to the discovery of fundamental neural pathways involved in the central regulation of energy homeostasis. In particular, the central melanocortin system has been shown to regulate appetite and metabolic rate in rodents; mutations in this system have been demonstrated to result in obesity in humans. Overall, the melanocortin system appears to function as a bidirectional rheostat in the regulation of energy intake and expenditure in rodents and potentially in humans. The first section of this chapter will focus on the development of our understanding of melanocortin physiology in the context of obesity. In particular, recent data regarding the interplay between melanocortin and neuropeptide Y (NPY) signaling at a cellular level will be discussed. The following section will discuss the hypothesis that melanocortin signaling plays a role in pathological weight loss and hypermetabolism observed in murine cachexia models. The potential role of this system in integrating a variety of anorexic and cachexic signals, as well as the potential for its pharmacological manipulation in the treatment of human cachexia, will be discussed.
The adipocyte as a secretory organ: mechanisms of vesicle transport and secretory pathways.
Bradley RL, Cleveland KA, Cheatham B
Recent Prog Horm Res · 2001 · PMID 11237220 · Publisher ↗
Obesity is a common problem in western society that is directly linked to several disease processes and is associated with significant morbidity and mortality. Adipocytes--the primary site for energy storage (as triglyce...
Obesity is a common problem in western society that is directly linked to several disease processes and is associated with significant morbidity and mortality. Adipocytes--the primary site for energy storage (as triglycerides) and release--were long suspected to have an active role in regulating body weight homeostasis and energy balance. As a result, many studies have focused on finding abnormalities in adipocyte physiology and metabolism. An ever-increasing body of evidence indicates that, in addition to serving as a repository for energy reserves, adipocytes secrete a myriad of factors that comprise a complex network of endocrine, autocrine, and paracrine signals. Very little is known regarding the molecular mechanisms utilized by the adipocyte in regulating the biosynthesis and exocytosis of these secreted products. In order to gain a better understanding of these processes, we have examined the two classical secretory pathways: regulated and constitutive. Using leptin as a model adipocyte-secretory protein, this review focuses primarily on the latter pathway. This includes regulation of leptin synthesis and secretion by insulin and glucocorticoids and, more recently, the finding that the orexigenic neuropeptide, melanin-concentrating hormone (MCH), can stimulate leptin synthesis and secretion. This chapter also incorporates new data describing the partial purification and effect of insulin on leptin-containing vesicles in rat adipocytes. These data indicate that the majority of leptin trafficking occurs via a constitutive secretory pathway and that the primary acute insulin effect on leptin secretion is to increase leptin protein content. In addition, we describe the identification and characterization of the vesicle-associated protein, pantophysin, which may play a multifunctional role in vesicle biogenesis and transport.
The beta-adrenergic receptors and the control of adipose tissue metabolism and thermogenesis.
Collins S, Surwit RS
Recent Prog Horm Res · 2001 · PMID 11237219 · Publisher ↗
The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation...
The beta-adrenergic receptors (betaARs) are members of the large family of G protein-coupled receptors. There are three betaAR subtypes (beta1AR, beta2AR beta3AR), each of which is coupled to Galphas and the stimulation of intracellular cAMP levels. While beta1AR and beta2AR are broadly expressed throughout tissues of the body, beta3AR is found predominantly in adipocytes. Stimulation of the betaARs leads to lipolysis in white adipocytes and nonshivering thermogenesis in brown fat. However, in essentially all animal models of obesity, the betaAR system is dysfunctional and the ability to stimulate lipolysis and thermogenesis is impaired. Nevertheless, we and others have shown that selective beta3AR agonists are able to prevent or reverse obesity and the loss of betaAR expression and to stimulate thermogenesis. This chapter will review the current understanding of the role of the sympathetic nervous system and the adipocyte betaARs in models of obesity; the physiologic impact of changes in betaAR expression on body composition and thermogenesis; and the regulation and unique properties of betaAR subtypes in brown and white adipocytes. The latter includes our recent discovery of novel signal transduction mechanisms utilized by beta3AR to activate simultaneously the protein kinase A and MAP kinase pathways. The impact of understanding these pathways and their potential role in modulating adaptive thermogenesis is discussed.
Insulin resistance in polycystic ovary syndrome: progress and paradoxes.
Venkatesan AM, Dunaif A, Corbould A
Recent Prog Horm Res · 2001 · PMID 11237218 · Publisher ↗
Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogen...
Over the past 20 years, it has been clearly documented that 1) polycystic ovary syndrome (PCOS) has major metabolic sequelae related to insulin resistance and 2) insulin resistance plays an important role in the pathogenesis of the reproductive abnormalities of the disorder. Women with PCOS are at significantly increased risk of developing type 2 diabetes mellitus (DM). Studies in isolated adipocytes and in cultured skin fibroblasts from PCOS women have demonstrated intrinsic postbinding defects in insulin-mediated glucose metabolism. In fibroblasts, the mitogenic pathway of insulin action is intact, consistent with a selective defect in insulin signaling. While PCOS skeletal muscle is resistant to insulin in vivo, cultured muscle cells have normal insulin sensitivity, consistent with a major role of extrinsic factors in producing insulin resistance in this tissue. Excessive serine phosphorylation of the insulin receptor or downstream signaling proteins may be involved in the pathogenesis of insulin resistance in PCOS. The putative serine kinase is extrinsic to the insulin receptor but its identity is unknown. The explanations for tissue-specific and signaling pathway-specific differences in insulin action in PCOS are unknown but may involve differential roles of insulin receptor substrate (IRS)-1 and IRS-2 in insulin signal transduction.
Insulin resistance and its treatment by thiazolidinediones.
Lebovitz HE, Banerji MA
Recent Prog Horm Res · 2001 · PMID 11237217 · Publisher ↗
Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin res...
Insulin resistance is a change in physiologic regulation such that a fixed dose of insulin causes less of an effect on glucose metabolism than occurs in normal individuals. The normal compensatory response to insulin resistance is an increase in insulin secretion that results in hyperinsulinemia. If the hyperinsulinemia is sufficient to overcome the insulin resistance, glucose regulation remains normal; if not, type 2 diabetes ensues. Associated with insulin resistance, however, is a cluster of other metabolic abnormalities involving body fat distribution, lipid metabolism, thrombosis and fibrinolysis, blood pressure regulation, and endothelial cell function. This cluster of abnormalities is referred to as the insulin resistance syndrome or the metabolic syndrome. It is causally related not only to the development of type 2 diabetes but also to cardiovascular disease. A major unresolved issue is whether there is a single underlying cause of this syndrome and, if so, what might it be? Several promising hypotheses have been proposed. There are some data to support the hypothesis that fetal malnutrition imprints on metabolic regulatory processes that, in later adult life, predispose to the development of the insulin resistance syndrome. Visceral obesity also has been a candidate for the cause of the syndrome. Whatever mechanism is ultimately found to be responsible, it will undoubtedly have both genetic and environmental components. Among the biochemical mediators that are likely to be responsible for the interference with insulin's effects on intermediary metabolism are free fatty acids and other products from adipose tissue. Recent data suggest that the substances stimulate serine phosphorylation of molecules involved in the initial steps of insulin action, thereby blocking the ability of these molecules to be tyrosine phosphorylated and initiate the subsequent steps of the insulin action cascade. The thiazolidinediones are a new class of agents that have been developed to treat type 2 diabetic patients. These drugs act as peroxisome proliferator-activated receptor gamma (PPARgamma) agonists. Following their binding to the receptor, the heterodimer molecule that contains the binding site is activated. The activated complex binds to the response elements of specific genes that regulate molecules that effect insulin action and lipid metabolism. These genes are either activated or inhibited. Specifically, the thiazolidinediones improve insulin action and decrease insulin resistance. The exact mechanism by which these agents decrease insulin resistance is not clear but they do decrease the elevated free fatty acid levels present in insulin-resistant patients and they appear to change the body distribution of adipose tissue. Treatment of insulin-resistant type 2 diabetic patients with thiazolidinediones not only improves glycemic control and decreases insulin resistance, it also improves many of the abnormalities that are part of the insulin resistance syndrome.
Peroxisome proliferator-activated receptors: from genes to physiology.
Kliewer SA, Xu HE, Lambert MH … +1 more , Willson TM
Recent Prog Horm Res · 2001 · PMID 11237216 · Publisher ↗
The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of...
The peroxisome proliferator-activated receptors (PPARalpha, gamma, delta) are members of the nuclear receptor superfamily of ligand-activated transcription factors that have central roles in the storage and catabolism of fatty acids. Although the three PPAR subtypes are closely related and bind to similar DNA response elements as heterodimers with the 9-cis retinoic acid receptor RXR, each subserves a distinct physiology. PPARalpha (NR1C1) is the receptor for the fibrate drugs, which are widely used to lower triglycerides and raise high-density lipoprotein cholesterol levels in the treatment and prevention of coronary artery disease. In rodents, PPARalpha agonists induce hepatomegaly and stimulate a dramatic proliferation of peroxisomes as part of a coordinated physiological response to lipid overload. PPARgamma (NR1C3) plays a critical role in adipocyte differentiation and serves as the receptor for the glitazone class of insulin-sensitizing drugs used in the treatment of type 2 diabetes. In contrast to PPARalpha and PPARgamma, relatively little is known about the biology of PPARdelta (NR1C2), although recent findings suggest that this subtype also has a role in lipid homeostasis. All three PPARs are activated by naturally occurring fatty acids and fatty acid metabolites, indicating that they function as the body's fatty acid sensors. Three-dimensional crystal structures reveal that the ligand-binding pockets of the PPARs are much larger and more accessible than those of other nuclear receptors, providing a molecular basis for the promiscuous ligand-binding properties of these receptors. Given the fundamental roles that the PPARs play in energy balance, drugs that modulate PPAR activity are likely to be useful for treating a wide range of metabolic disorders, including atherosclerosis, dyslipidemia, obesity, and type 2 diabetes.
BETA2 and pancreatic islet development.
Chu K, Nemoz-Gaillard E, Tsai MJ
Recent Prog Horm Res · 2001 · PMID 11237215 · Publisher ↗
The pancreas is essential for digestion and glucose homeostasis. Diseases associated with the pancreas (e.g., pancreatitis, pancreatic cancer, diabetes) are generally debilitating for the patient. Diabetes is particularl...
The pancreas is essential for digestion and glucose homeostasis. Diseases associated with the pancreas (e.g., pancreatitis, pancreatic cancer, diabetes) are generally debilitating for the patient. Diabetes is particularly prominent in the United States, affecting nearly 6 percent of the population, with associated annual health costs in the billions of dollars. Pancreas development is a complex process that requires the timely expression of numerous factors. Among them, a basic Helix-Loop-Helix factor, BETA2, was shown to be important for terminal differentiation of islet cells including insulin- and glucagon-producing cells. Expression studies demonstrated the presence of BETA2 in islet cells and specific neurons. Targeted deletion of the BETA2 gene in mice revealed its significance in pancreas development. In addition, BETA2 is important in granule cell development of the hippocampus and cerebellum. This chapter will focus on the role of BETA2 in pancreas physiology, neuronal development, and its molecular biology.
Nuclear magnetic resonance studies of hepatic glucose metabolism in humans.
Roden M, Petersen KF, Shulman GI
Recent Prog Horm Res · 2001 · PMID 11237214 · Publisher ↗
Nuclear magnetic resonance (NMR) spectroscopy has made noninvasive and repetitive measurements of human hepatic glycogen concentrations possible. Monitoring of liver glycogen in real-time mode has demonstrated that glyco...
Nuclear magnetic resonance (NMR) spectroscopy has made noninvasive and repetitive measurements of human hepatic glycogen concentrations possible. Monitoring of liver glycogen in real-time mode has demonstrated that glycogen concentrations decrease linearly and that net hepatic glycogenolysis contributes only about 50 percent to glucose production during the early period of a fast. Following a mixed meal, hepatic glycogen represents approximately 20 percent of the ingested carbohydrates, while only about 10 percent of an intravenous glucose load is retained by the liver as glycogen. During mixed-meal ingestion, poorly controlled type 1 diabetic patients synthesize only about 30 percent of the glycogen stored in livers of nondiabetic humans studied under similar conditions. Reduced net glycogen synthesis can be improved but not normalized by short-term, intensified insulin treatment. A decreased increment in liver glycogen content following meals was also found in patients with maturity-onset diabetes of the young due to glucokinase mutations (MODY-2). In patients with poorly controlled type 2 diabetes, fasting hyperglycemia can be attributed mainly to increased rates of endogenous glucose production, which was found by 13C NMR to be due to increased rates of gluconeogenesis. Metformin treatment improved fasting hyperglycemia in these patients through a reduction in hepatic glucose production, which could be attributed to a decrease in gluconeogenesis. In conclusion, NMR spectroscopy has provided new insights into the pathogenesis of hyperglycemia in type 1, type 2, and MODY diabetes and offers the potential of providing new insights into the mechanism of action of novel antidabetic therapies.
Cell-specific roles of glucokinase in glucose homeostasis.
Postic C, Shiota M, Magnuson MA
Recent Prog Horm Res · 2001 · PMID 11237213 · Publisher ↗
Mutations in the glucokinase (GK) gene cause two different diseases of blood glucose regulation: maturity onset diabetes of the young, type 2 (MODY-2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). To ga...
Mutations in the glucokinase (GK) gene cause two different diseases of blood glucose regulation: maturity onset diabetes of the young, type 2 (MODY-2) and persistent hyperinsulinemic hypoglycemia of infancy (PHHI). To gain further understanding of the pathophysiology of these disorders, we have used both transgenic and gene-targeting strategies to explore the relationship between GK gene expression in specific tissues and the blood glucose concentration. These studies, which have included the use of aCre/loxP gene-targeting strategy to perform both pancreatic beta-cell- and hepatocyte-specific knockouts of GK, clearly demonstrate multiple, cell-specific roles for this hexokinase that, together, contribute to the maintainance of euglycemia. In the pancreatic beta cell, GK functions as the glucose sensor, determining the threshold for insulin secretion. Mice lacking GK in the pancreatic beta cell die within 3 days of birth of profound hyperglycemia. In the liver, GK facilitates hepatic glucose uptake during hyperglycemia and is essential for the appropriate regulation of a network of glucose-responsive genes. While mice lacking hepatic GK are viable, and are only mildly hyperglycemic when fasted, they also have impaired insulin secretion in response to hyperglycemia. The mechanisms that enable hepatic GK to affect beta-cell function are not yet understood. Thus, the hyperglycemia that occurs in MODY-2 is due to impaired GK function in both the liver and pancreatic beta cell, although the defect in beta-cell function is clearly more dominant. Whether defects in GK gene expression also impair glucose sensing by neurons in the brain or enteroendocrine cells in gut, two other sites known to express GK, remains to be determined. Moreover, whether the pathophysiology of PHHI also involves multitissue dysfunction remains to be explored.
Intracellular organization of insulin signaling and GLUT4 translocation.
Watson RT, Pessin JE
Recent Prog Horm Res · 2001 · PMID 11237212 · Publisher ↗
Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscl...
Glucose is cleared from the bloodstream by a family of facilitative transporters (GLUTs), which catalyze the transport of glucose down its concentration gradient and into cells of target tissues, primarily striated muscle and adipose. Currently, there are five established functional facilitative glucose transporter isoforms (GLUT1-4 and GLUTX1), with GLUT5 being a fructose transporter. GLUT1 is ubiquitously expressed with particularly high levels in human erythrocytes and in the endothelial cells lining the blood vessels of the brain. GLUT3 is expressed primarily in neurons and, together, GLUT1 and GLUT3 allow glucose to cross the blood-brain barrier and enter neurons. GLUT2 is a low-affinity (high Km) glucose transporter present in liver, intestine, kidney, and pancreatic beta cells. This transporter functions as part of the glucose sensor system in beta cells and in the basolateral transport of intestinal epithelial cells that absorb glucose from the diet. A new facilitative glucose transporter protein, GLUTX1, has been identified and appears to be important in early blastocyst development. The GLUT4 isoform is the major insulin-responsive transporter that is predominantly restricted to striated muscle and adipose tissue. In contrast to the other GLUT isoforms, which are primarily localized to the cell surface membrane, GLUT4 transporter proteins are sequestered into specialized storage vesicles that remain within the cell's interior under basal conditions. As postprandial glucose levels rise, the subsequent increase in circulating insulin activates intracellular signaling cascades that ultimately result in the translocation of the GLUT4 storage compartments to the plasma membrane. Importantly, this process is readily reversible such that when circulating insulin levels decline, GLUT4 transporters are removed from the plasma membrane by endocytosis and are recycled back to their intracellular storage compartments. Therefore, by establishing an internal membrane compartment as the default localization for the GLUT4 transporters, insulin-responsive tissues are poised to respond rapidly and efficiently to fluctuations in circulating insulin levels. Unfortunately, the complexity of these regulatory processes provides numerous potential targets that may be defective and eventually result in peripheral tissue insulin resistance and possibly diabetes. As such, understanding the molecular details of GLUT4 expression, GLUT4 vesicle compartment biogenesis, GLUT4 sequestration, vesicle trafficking, and fusion with the plasma membrane has become a major focus for many laboratories. This chapter will focus on recently elucidated insulin signal transduction pathways and GLUT4 vesicle trafficking components that are necessary for insulin-stimulated glucose uptake and GLUT4 translocation in adipocytes.
The role of protein phosphatase-1 in insulin action.
Brady MJ, Saltiel AR
Recent Prog Horm Res · 2001 · PMID 11237211 · Publisher ↗
Insulin is the most-potent physiological anabolic agent known, promoting the synthesis and storage of carbohydrates and lipids and inhibiting their degradation and release into the circulation. This action of the hormone...
Insulin is the most-potent physiological anabolic agent known, promoting the synthesis and storage of carbohydrates and lipids and inhibiting their degradation and release into the circulation. This action of the hormone is due in part to the acute regulation of metabolic enzymes through changes in their phosphorylation state. In fat, liver, and muscle, insulin stimulates the dephosphorylation of a number of enzymes involved in glycogen and lipid metabolism via activation of protein phosphatases. Numerous studies have indicated that protein phosphatase-1 (PP1) is the primary phosphatase involved in insulin action. Although PP1 is a cytosolic protein, the phosphatase is compartmentalized in cells by discrete targeting subunits. These proteins confer substrate specificity to PP1 and mediate the specific regulation of intracellular pools of PP1 by a variety of extracellular signals. Four proteins have been described that target the phosphatase to the glycogen particle. G(M) and GL are expressed exclusively in striated muscle and liver, while protein targeting to glycogen (PTG) and R6 are more widely expressed. Despite a common targeting function, these four proteins are not highly conserved, suggesting profound differences in the mechanisms by which they contribute to the hormonal regulation of PP1 activity. Overexpression studies in cell lines or animals have revealed major differences among these proteins regarding basal glycogen levels and hormonal responsiveness. Furthermore, alterations in the expression or function of PP1 glycogen-targeting subunits may contribute to the onset of insulin resistance and type 2 diabetes.
Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade.
Avruch J, Khokhlatchev A, Kyriakis JM … +4 more , Luo Z, Tzivion G, Vavvas D, Zhang XF
Recent Prog Horm Res · 2001 · PMID 11237210 · Publisher ↗
A continuing focus of our work has been an effort to understand the signal transduction pathways through which insulin achieves its cellular actions. In the mid-1970s, we and others observed that insulin promoted an incr...
A continuing focus of our work has been an effort to understand the signal transduction pathways through which insulin achieves its cellular actions. In the mid-1970s, we and others observed that insulin promoted an increase in Ser/Thr phosphorylation of a subset of cellular proteins. This finding was unanticipated, inasmuch as nearly all of the actions of insulin then known appeared to result from protein dephosphorylation. In fact, nearly 15 years elapsed before any physiologic response to insulin attributable to stimulated (Ser/Thr) phosphorylation was established. Nevertheless, based on the hypothesis that insulin-stimulated Ser/Thr phosphorylation reflected the activation of protein (Ser/Thr) kinases downstream of the insulin receptor, we sought to detect and purify these putative, insulin-responsive protein (Ser/Thr) kinases. Our effort was based on the presumption that an understanding of the mechanism for their activation would provide an entry into the biochemical reactions through which the insulin receptor activated its downstream effectors. To a degree that, in retrospect, is surprising, this goal was accomplished, much in the way originally envisioned. It is now well known that receptor tyrosine kinases (RTKs) recruit a large network of protein (Ser/Thr) kinases to execute their cellular programs. The first of these insulin-activated protein kinase networks to be fully elucidated was the Ras-Raf-mitogen-activated protein kinase (MAPK) cascade. This pathway is a central effector of cellular differentiation in development; moreover, its inappropriate and continuous activation provides a potent promitogenic force and is a very common occurrence in human cancers. Conversely, this pathway contributes minimally, if at all, to insulin's program of metabolic regulation. Nevertheless, the importance of the Ras-MAPK pathway in metazoan biology and human malignancies has impelled us to an ongoing analysis of the functions and regulation of Ras and Raf. This chapter will summarize briefly the way in which work from this and other laboratories on insulin signaling led to the discovery of the mammalian MAP kinase cascade and, in turn, to the identification of unique role of the Raf kinases in RTK activation of this protein (Ser/Thr) kinase cascade. We will then review in more detail current understanding of the biochemical mechanism through which the Ras proto-oncogene, in collaboration with the 14-3-3 protein and other protein kinases, initiates activation of the Raf kinase.
Discovery of a small molecule insulin receptor activator.
Salituro GM, Pelaez F, Zhang BB
Recent Prog Horm Res · 2001 · PMID 11237209 · Publisher ↗
Insulin elicits diverse biological responses in many tissues and cell types by binding to its specific receptor. The insulin receptor (IR) is a tetramer consisting of two extracellular alpha subunits and two membrane-spa...
Insulin elicits diverse biological responses in many tissues and cell types by binding to its specific receptor. The insulin receptor (IR) is a tetramer consisting of two extracellular alpha subunits and two membrane-spanning beta subunits. The binding of insulin to the receptor causes conformational changes that lead to autophosphorylation and activation of the tyrosine kinase intrinsic to the beta subunits. Insulin receptor transphosphorylates several immediate substrates, resulting in modulation of a cascade of downstream signal transduction molecules. In order to discover small molecules that activate the human insulin receptor tyrosine kinase (IRTK), a cell-based assay was established and utilized to screen a collection of synthetic chemicals and natural product extracts. This effort led to the identification of a nonpeptidyl, small molecule, insulin-mimetic compound (demethylasterriquinone B-1, DMAQ-B1) that was isolated from a mixture of metabolites produced by a tropical endophytic fungus, Pseudomassaria sp. This compound induced human IRTK activation and increased tyrosine phosphorylation of IR beta subunit. It mediated insulin-like effects, including insulin receptor substrate-1 (IRS-1) phosphorylation and activation of phosphotidylinositide 3-kinase and Akt kinase. DMAQ-B1 also exhibited an insulin-like effect on glucose uptake in adipocytes and skeletal muscle tissue. Furthermore, the compound was relatively selective for IR vs. insulin-like growth factor-I (IGF-I) receptor and other homologous receptor tyrosine kinases. In addition, it activated partially purified native IR or recombinant IR kinase, demonstrating the direct interaction of the small molecule with the IR. Oral administration of DMAQ-B1 resulted in significant glucose lowering in two mouse models of diabetes. Thus, DMAQ-B1 represents the first orally active insulin-mimetic agent. Pharmaceutical intervention aimed at augmenting IR function ultimately may prove beneficial as a novel therapeutic option in patients with diabetes.
Protein glycation, diabetes, and aging.
Ulrich P, Cerami A
Recent Prog Horm Res · 2001 · PMID 11237208 · Publisher ↗
Biological amines react with reducing sugars to form a complex family of rearranged and dehydrated covalent adducts that are often yellow-brown and/or fluorescent and include many cross-linked structures. Food chemists h...
Biological amines react with reducing sugars to form a complex family of rearranged and dehydrated covalent adducts that are often yellow-brown and/or fluorescent and include many cross-linked structures. Food chemists have long studied this process as a source of flavor, color, and texture changes in cooked, processed, and stored foods. During the 1970s and 1980s, it was realized that this process, called the Maillard reaction or advanced glycation, also occurs slowly in vivo. Advanced glycation endproducts (AGEs) that form are implicated, causing the complications of diabetes and aging, primarily via adventitious and crosslinking of proteins. Long-lived proteins such as structural collagen and lens crystallins particularly are implicated as pathogenic targets of AGE processes. AGE formation in vascular wall collagen appears to be an especially deleterious event, causing crosslinking of collagen molecules to each other and to circulating proteins. This leads to plaque formation, basement membrane thickening, and loss of vascular elasticity. The chemistry of these later-stage, glycation-derived crosslinks is still incompletely understood but, based on the hypothesis that AGE formation involves reactive carbonyl groups, the authors introduced the carbonyl reagent aminoguanidine hydrochloride as an inhibitor of AGE formation in vivo in the mid 1980s. Subsequent studies by many researchers have shown the effectiveness of aminoguanidine in slowing or preventing a wide range of complications of diabetes and aging in animals and, recently, in humans. Since, the authors have developed a new class of agents, exemplified by 4,5-dimethyl-3-phenacylthiazolium chloride (DPTC), which can chemically break already-formed AGE protein-protein crosslinks. These agents are based on a new theory of AGE crosslinking that postulates that alpha-dicarbonyl structures are present in AGE protein-protein crosslinks. In studies in aged animals, DPTC has been shown to be capable of reverting indices of vascular compliance to levels seen in younger animals. Human clinical trials are underway.
SH2-B and SIRP: JAK2 binding proteins that modulate the actions of growth hormone.
Carter-Su C, Rui L, Stofega MR
Recent Prog Horm Res · 2000 · PMID 11036942
Growth hormone (GH) has long been known to be a primary determinant of body height and an important regulator of body metabolism, yet the cellular and molecular bases for these effects of GH are only beginning to be unde...
Growth hormone (GH) has long been known to be a primary determinant of body height and an important regulator of body metabolism, yet the cellular and molecular bases for these effects of GH are only beginning to be understood. In 1993, GH receptor (GHR) was first observed to bind to the tyrosine kinase JAK2. GH increased JAK2's affinity for GHR, potently activated JAK2, and stimulated the phosphorylation of tyrosines within JAK2 and the cytoplasmic domain of GHR. In the intervening six years, a variety of signaling molecules have been identified that are tyrosyl phosphorylated in response to GH, presumably by the activated JAK2. These signaling molecules include 1) the latent cytoplasmic transcription factors--designated signal transducers and activators of transcription (Stats)--that have been implicated in the regulation of a variety of GH-dependent genes; 2) Shc proteins that lead to activation of the Ras-MAP kinase pathway: and 3) insulin receptor substrate (IRS) proteins that bind and thereby activate phosphatidylinositol 3' kinase and presumably other proteins. Recently, we have identified two additional signaling molecules for GH that bind to JAK2 and are phosphorylated on tyrosines in response to GH: SH2-B and signal regulated protein (SIRP). Based upon amino acid sequence analysis, SH2-B is presumed to be a cytoplasmic adapter protein. It binds with high affinity via its SH2 domain to phosphorylated tyrosines within JAK2. GH-induced binding of SH2-B to JAK2 via this site potently activates JAK2, leading to enhanced tyrosyl phosphorylation of Stat proteins and other cellular proteins. Because of its other potential protein-protein interaction domains and its recruitment and phosphorylation by kinases that are not activated by SH2-B, SH2-B is thought likely to mediate other, more-specific actions of GH, as yet to be determined. SIRP is a transmembrane protein that is now known to bind to integrin-associated protein. It appears to bind directly to JAK2 by a process that does not require tyrosyl phosphorylation, although is itself highly phosphorylated on tyrosines in response to GH. The phosphorylated SIRP recruits one or more molecules of the tyrosine phosphatase SHP2 that, in turn, de-phosphorylates SIRP and most likely JAK2. Thus, SIRP is predicted to be a negative regulator of GH action. It seems likely that the diverse actions of GH will be found to require coordinated interaction of all of these signaling proteins with each other as well as with other signaling molecules that are activated by GH and the numerous other ligands that are present at cells during a response to GH.
Secretagogues and the somatotrope: signaling and proliferation.
Frohman LA, Kineman RD, Kamegai J … +4 more , Park S, Teixeira LT, Coschigano KT, Kopchic JJ
Recent Prog Horm Res · 2000 · PMID 11036941
Somatotrope function requires consideration of both growth hormone (GH) secretion and cellular proliferation. The regulation of these processes is, to a large extent, controlled by three hypothalamic hormones: GH-releasi...
Somatotrope function requires consideration of both growth hormone (GH) secretion and cellular proliferation. The regulation of these processes is, to a large extent, controlled by three hypothalamic hormones: GH-releasing hormone (GHRH), somatostatin (SRIF), and an as-yet-unidentified GH secretagogue (GHS). Each binds to G protein-linked membrane receptors through which signaling occurs. Our laboratory has used a series of genetic and transgenic models with perturbations of individual components of the GH regulatory system to study both somatotrope signaling and proliferation. Impaired GHRH signaling is present in the lit mouse, which has a GHRH receptor (R) mutation, and the dw rat, which has a post-receptor signaling defect. Both models also have impaired responses to a GHS, implying an interaction between the two signaling systems. The spontaneous dwarf rat (SDR), in which a mutation of the GH gene results in total absence of the hormone, shows characteristic changes in the hypothalamic regulatory hormones due to an absence of GH feedback and alterations in the expression of each of their pituitary receptors. Treatment of SDRs with GHRH and a GHS has allowed demonstration of a stimulatory effect of GHRH on GHRH-R, GHS-R, and SRIF type 2 receptor (SSTR-2) expression and an inhibitory effect on SSTR-5 expression. GH also modifies the expression of these receptors, though its effects are seen at later time periods and appear to be indirect. Overall, the results indicate a complex regulation of GH secretion in which somatotrope receptor, as well as ligand expression, exerts an important physiological role. Both the SDR and the GH-R knockout (ko) mouse have small pituitaries and decreased somatotropes, despite elevated GHRH secretion and intact GHRH-R signaling. Introduction of the hGHRH transgene into GH-R ko mice confirmed that the proliferative effects of GHRH require GH/insulin-like growth factor-I (IGF-I) action. The results offer new insights into factors participating in somatotrope proliferation.
Regulation of the pituitary somatotroph cell by GHRH and its receptor.
Mayo KE, Miller T, DeAlmeida V … +3 more , Godfrey P, Zheng J, Cunha SR
Recent Prog Horm Res · 2000 · PMID 11036940
Hormones from the hypothalamus mediate interactions between the nervous and endocrine systems by controlling the activity of specific target cells in the anterior pituitary gland. The hypothalamic peptide, growth hormone...
Hormones from the hypothalamus mediate interactions between the nervous and endocrine systems by controlling the activity of specific target cells in the anterior pituitary gland. The hypothalamic peptide, growth hormone-releasing hormone (GHRH), acts on pituitary somatotroph cells to stimulate their proliferation during development and to regulate their ability to produce and secrete growth hormone (GH). These actions are mediated by a recently identified receptor for GHRH that belongs to family B-III of the G protein-coupled receptor superfamily. The rat GHRH receptor is expressed predominantly in the pituitary gland and in somatotroph cells. To investigate this tissue- and cell-specific expression, the receptor gene has been cloned and characterized. The receptor gene promoter is selectively expressed in pituitary cells and is regulated by the pituitary-specific transcription factor Pit-1. There is a sexual dimorphism in GHRH receptor expression in the rat pituitary, suggesting regulation by gonadal steroids. In addition, glucocorticoids are potent positive regulators of GHRH receptor gene expression. Substantial evidence points to an important role for GHRH in regulating the proliferation and functional activity of the somatotroph cell. This is best observed in the dwarf little mouse, which harbors a mutation in the extracellular domain of the GHRH receptor that abolishes the receptor's hormone-binding and signaling properties, resulting in severe somatotroph hypoplasia. Complementary studies in transgenic mice overexpressing the ligand GHRH reveal corresponding somatotroph hyperplasia. Consistent with these observations, GHRH potently activates the MAP kinase pathway in pituitary somatotroph cells. To better understand the hormone-binding and signaling properties of the GHRH receptor, mutant and chimeric receptors have been analyzed to define domains important for GHRH interaction. The GHRH receptor signals predominantly through cAMP-dependent pathways; however, a variant form of the GHRH receptor with an insertion into the third intracellular domain, generated through alternative RNA processing, binds GHRH but fails to signal, suggesting potential modulation of receptor function at a post-transcriptional level. This chapter will integrate these basic investigations of GHRH and its receptor with current information on the involvement of the GHRH signaling system in human diseases of GH secretion and growth.
New steps in the Wnt/beta-catenin signal transduction pathway.
Sakanaka C, Sun TQ, Williams LT
Recent Prog Horm Res · 2000 · PMID 11036939
Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. Wnt family genes encode secreted gl...
Wnt regulates developmental and oncogenic processes through its downstream effector, beta-catenin, and a set of other intracellular regulators that are largely conserved among species. Wnt family genes encode secreted glycoproteins that act as ligands for membrane receptors belonging to the Frizzled family of proteins. Wnt-1 originally was found as a proto-oncogene that was upregulated in tumors caused by the mouse mammary tumor virus. The Drosophila homologue of Wnt-1, wingless, is a segment polarity gene that regulates body patterning of the fly embryo. In Xenopus, the Wnt pathway regulates formation of the ventral-dorsal axis. Although Wnt proteins are expressed widely in mammals, the function of the Wnt signaling pathway in normal adult mammalian tissues is not understood. Downstream components of the Wnt pathway, APC (adenomatous polyposis coli) and beta-catenin, clearly are involved in human cancer. There are also several reports that Wnt ligands are highly expressed in tumors. Wnt stabilizes cytoplasmic beta-catenin and activates beta-catenin/Lef-1 (lymphoid enhancer factor), Tcf (T-cell factor)-dependent gene transcription. This regulation of cytosolic beta-catenin is mediated by glycogen synthase kinase-3 (GSK-3) activity but in neither case is the mechanism known. The mechanism by which Wnt inhibits GSK-3 is unknown. Recent studies have shown that some of the intracellular signaling molecules that mediate the Wnt pathway are in complexes, including Dishevelled (Dsh or Dvl), GSK-3beta, and APC protein. However, little is known about how Wnt or other upstream stimuli regulate these complexes to stabilize beta-catenin. We took a variety of approaches to identify new components of the Wnt pathway. Using an expression-cloning technique, we isolated casein kinase I (CKI)epsilon as a positive regulator of beta-catenin in the Wnt pathway. Overexpression of CKIepsilon mimics Wnt by stabilizing beta-catenin, thereby increasing expression of beta-catenin-dependent genes. Inhibition of endogenous CKIepsilon attenuated gene transcription stimulated by Wnt or by Dsh. CKIepsilon forms a complex with Axin and the other downstream components of the Wnt pathway. CKIepsilon is a positive regulator of the Wnt pathway and a possible functional link between upstream signals and the intracellular Axin signaling complex that regulates beta-catenin. In separate experiments, we have identified a Dishevelled-associated kinase (DAK) that binds to Dsh and regulates its functions. Dsh is required for two different pathways, the Wnt pathway and planar polarity pathway in Drosophila. DAK dramatically enhances the function of Dsh in the Wnt pathway and inhibits its function in the planar polarity pathway. This chapter will discuss these newly identified components of the Wnt pathway.
Glia-to-neuron signaling and the neuroendocrine control of female puberty.
Ojeda SR, Ma YJ, Lee BJ … +1 more , Prevot V
Recent Prog Horm Res · 2000 · PMID 11036938
It is becoming increasingly clear that astroglial cells are active participants in the process by which information is generated and disseminated within the central nervous system (CNS). In the hypothalamus, astrocytes r...
It is becoming increasingly clear that astroglial cells are active participants in the process by which information is generated and disseminated within the central nervous system (CNS). In the hypothalamus, astrocytes regulate the secretory activity of neuroendocrine neurons. They contribute to facilitating sexual development by stimulating the release of luteinizing hormone-releasing hormone (LHRH), the neuropeptide that controls sexual development, from LHRH neurons. Astrocytes secrete several growth factors able to stimulate LHRH secretion. Two members of the epidermal growth factor (EGF) family--transforming growth factor alpha (TGFalpha) and the neuregulins (NRGs)-are produced in hypothalamic astrocytes and elicit LHRH secretion indirectly, via activation of receptor complexes formed by three members of the EGF receptor family, also located on astrocytes. Activation of these receptors results in the production of at least one neuroactive substance, prostaglandin E2 (PGE2), which stimulates LHRH secretion upon binding to specific receptors on LHRH neurons. Overexpression of TGFalpha in the hypothalamus accelerates puberty, whereas blockade of either TGFalpha or NRG actions delays the process, indicating that both peptides are physiological components of the neuroendocrine mechanism that controls sexual maturation. An increase in hypothalamic expression of at least two of the erbB receptors is initiated before the pubertal augmentation of gonadal steroid secretion and is completed on the day of the first preovulatory surge of gonadotropins. This secondary increase is brought about by gonadal steroids. Estrogen and progesterone facilitate erbB-mediated glia-to-LHRH neuron communication by enhancing astrocytic gene expression of at least one of the EGF-related ligands (TGFalpha) and two of the receptors (erbB-2 and erbB-4). They also facilitate the LHRH response to PGE2 via induction of PGE2 receptors in LHRH neurons. A search for genes that may act as upstream regulators of the pubertal process resulted in the identification of two potential candidates: Oct-2, a POU domain gene originally described in cells of the immune system, and TTF-1, a member of the Nkx family of homeodomain transcriptional regulators required for diencephalic morphogenesis. The hypothalamic expression of both genes increases during juvenile development before the first hormonal manifestations of puberty take place. Their mRNA transcripts are localized to specific hypothalamic cellular subsets, where they appear to regulate different, but interactive, components of the neuronal-glial complex controlling LHRH secretion. While Oct-2 transactivates the TGFalpha promoter, TTF-1 does so to the erbB-2 and LHRH genes but inhibits preproenkephalin promoter activity, suggesting that both transcriptional regulators may act coordinately in the normal hypothalamus to activate genes involved in facilitating the advent of puberty and repress those restraining sexual development. Altogether, these observations indicate that the central activation of the pubertal process involves the participation of both neuronal and astroglial networks and the contribution of upstream transcriptional regulators acting on both the neuronal and glial components of the system.
About
- Frequency
- Sun
- Papers found
- 200
- RSS feed
- Subscribe