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What Inhibits The Production Of Insulin?

The Role Of Hepatic Insulin Receptors In The Regulation Of Glucose Production

The Role Of Hepatic Insulin Receptors In The Regulation Of Glucose Production

The inability of insulin to suppress hepatic glucose production (HGP) is a key defect found in type 2 diabetes. Insulin inhibits HGP through both direct and indirect means, the latter of which include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid level, decrease in the load of gluconeogenic substrates reaching the liver, and change in neural signaling to the liver. Two studies in this issue of the JCI demonstrate that selective changes in the expression of insulin receptors in mouse liver do not have a detectable effect on the ability of insulin to inhibit HGP (see the related articles beginning on pages 1306 and 1314). These provocative data suggest that the indirect effects of insulin on the liver are the primary determinant of HGP in mice. Until late 1987, it was believed that insulin’s ability to reduce hepatic glucose production (HGP) resulted from the direct interaction of the hormone with its receptor in the hepatocyte plasma membrane. This belief was called into question when Prager et al. (1) noted that in obese, nondiabetic humans, suppression of glucose production could occur in response to insulin infusion, even when the estimated portal vein insulin concentration did not rise. These results suggested that insulin also reduces hepatic glucose output by indirect mechanisms. Subsequent work by others supported this concept (2–5), and it is now recognized that insulin can inhibit HGP by both direct and indirect means (Figure 1). Figure 1 Mechanisms by which insulin can inhibit HGP in vivo. The indirect actions of insulin on HGP are diverse. Glucagon secretion from the α cell of the pancreas is diminished by insulin, which in turn causes a reduction in HGP (6). Likewise, nonesterified fatty acid (NEFA) release from the adipo Continue reading >>

Insulin And Insulin Resistance

Insulin And Insulin Resistance

Go to: Abstract As obesity and diabetes reach epidemic proportions in the developed world, the role of insulin resistance and its consequences are gaining prominence. Understanding the role of insulin in wide-ranging physiological processes and the influences on its synthesis and secretion, alongside its actions from the molecular to the whole body level, has significant implications for much chronic disease seen in Westernised populations today. This review provides an overview of insulin, its history, structure, synthesis, secretion, actions and interactions followed by a discussion of insulin resistance and its associated clinical manifestations. Specific areas of focus include the actions of insulin and manifestations of insulin resistance in specific organs and tissues, physiological, environmental and pharmacological influences on insulin action and insulin resistance as well as clinical syndromes associated with insulin resistance. Clinical and functional measures of insulin resistance are also covered. Despite our incomplete understanding of the compl Continue reading >>

You And Your Hormones

You And Your Hormones

Alternative names for somatostatin SS, SST or SOM; growth hormone inhibitory hormone (GHIH); somatotropin release inhibiting factor (SRIF); somatotropin release inhibiting hormone (SRIH) What is somatostatin? Somatostatin is a hormone produced by many tissues in the body, principally in the nervous and digestive systems. It regulates a wide variety of physiological functions and inhibits the secretion of other hormones, the activity of the gastrointestinal tract and the rapid reproduction of normal and tumour cells. Somatostatin may also act as a neurotransmitter in the nervous system. The hypothalamus is a region of the brain that regulates secretion of hormones from the pituitary gland located below it. Somatostatin from the hypothalamus inhibits the pituitary gland’s secretion of growth hormone and thyroid stimulating hormone. In addition, somatostatin is produced in the pancreas and inhibits the secretion of other pancreatic hormones such as insulin and glucagon. Somatostatin is also produced in the gastrointestinal tract where it acts locally to reduce gastric secretion, gastrointestinal motility and to inhibit the secretion of gastrointestinal hormones, including gastrin and secretin. Chemically altered equivalents of somatostatin are used as a medical therapy to control too much hormone secretion in patients with acromegaly and other endocrine conditions, and to treat some gastrointestinal diseases and a variety of tumours. How is somatostatin controlled? In the same way that somatostatin controls the production of several hormones, these hormones feed back to control the production of somatostatin. This is increased by raised levels of these other hormones and reduced by low levels. Somatostatin is also secreted by the pancreas in response to many factors rela Continue reading >>

Regulation Of Insulin Synthesis And Secretion And Pancreatic Beta-cell Dysfunction In Diabetes

Regulation Of Insulin Synthesis And Secretion And Pancreatic Beta-cell Dysfunction In Diabetes

Go to: INSULIN Insulin structure The crystal structure of insulin is well documented as well as the structural features that confer receptor binding affinity and activity. This has been extensively reviewed and readers are encouraged to visit [1] and [2] for excellent discussions on insulin structure and structure-activity relationships. As discussed in this review, insulin receptor downstream signaling intersects with the signaling pathways of other growth factors, including IGF1 and IGF2 [3]. This demonstrates the importance of identifying receptor ligand agonists as potential insulin-mimetic therapeutic agents in diabetes. This section of the review will focus on the native structure of insulin. For an excellent review on the insulin receptor structure and binding domains, readers are encouraged to visit several references [2, 3]. The 3-D structure of monomeric insulin was first discovered by x-ray crystallography and reported in 1926 [4]. More than 40 years later, the structure of the zinc-containing hexameric insulin was solved [5–8]. 2D NMR studies have also contributed to knowledge on the monomeric, dimeric and hexameric conformations of insulin, all revealing information on the native structure of insulin and the amino acids that confer binding specificity to the insulin receptor [1]. Insulin concentration and surrounding pH influence the conformational state of insulin. The monomers tend to form dimers as the concentration of insulin rises, and in the presence of zinc and favorable pH (10 mM Zn++, pH ~6.0) the monomers assemble into higher order conformations called hexamers [9]. As discussed below, interactions among hydrophobic amino acids in insulin dimer structures favor aggregation as concentrations rise. Once the hexamers are secreted from the β-cell a Continue reading >>

How The Liver Affects Insulin And Vice Versa: Part 1 Carbohydrate Metabolism

How The Liver Affects Insulin And Vice Versa: Part 1 Carbohydrate Metabolism

The human body is able to maintain tight control of blood glucose despite varying glucose consumption, production, and utilization. Two key players involved in maintaining glucose homeostasis are the liver and the hormone insulin which affect each other through various direct and indirect mechanisms…. Insulin Physiology and Metabolism by the Liver Insulin is produced by the β-cells of the pancreas in response to elevated blood glucose concentrations. The GLUT2 transporter on the β-cellplasma membrane allows free movement of glucose.1 Once inside the cell, glucose becomes phosphorylated by glucokinase to glucose-6-phosphate, which effectively traps the glucose within the cell. Then the process of glycolysis produces an increase in adenosine triphosphate (ATP), which blocks ATP-dependent K+ channels in the β-cell membrane. The resulting cell depolarization allows Ca2+ to enter the cell which triggers exocytosis of the insulin-containing granules.2 Insulin then makes its way to target tissues to affect anabolic and catabolic processes before it undergoes metabolism. The two main organs that predominantly clear insulin from circulation are the liver and kidney. In a non-diabetic patient the liver clears about 60% of endogenous insulin via the hepatic portal vein while the kidney removes about 35-40%. In diabetic patients who rely on subcutaneous insulin injections this ratio is flipped; the kidney clears as much as 60% of exogenous insulin and the liver removes no more than 30-40%.3 Insulin Stimulates Glycogen Storage in the Liver The major glucose transporter in the muscle, adipose and other target tissues is the GLUT4 transporter. When insulin binds to the insulin receptors on the surface of target cells, it stimulates translocation of GLUT4 transporters from storage Continue reading >>

Acetic Acid Inhibits Insulin Secretion

Acetic Acid Inhibits Insulin Secretion

Acetate receptor inhibitors could improve diabetes therapy In type 2 diabetes, the level of sugar in the blood rises because the cells of the body are no longer sensitive enough to insulin, or because the pancreas produces insufficient insulin. Scientists from the Max Planck Institute for Heart and Lung Research in Bad Nauheim have now discovered that FFA2 and FFA3 receptors inhibit insulin secretion. These receptors are activated by acetic acid, which is formed by the insulin-producing cells of the pancreas, among others. This enables the pancreas to prevent the production of too much insulin, and the corresponding excessive drop in blood sugar levels. As acetate is primarily formed in the presence of normal or high blood sugar, acetate receptor inhibitors do not boost insulin production when blood sugar is low. This fact may help prevent dangerous hypoglycaemia in the treatment of diabetes. The primary cause of type 2 diabetes was long held to be a reduced sensitivity of the body cells to insulin. In recent years, however, it has become clear that already in the early stages of type 2 diabetes insulin secretion is also impaired. Insulin is produced in pancreatic cells and ensures that body cells can absorb glucose from the blood, thereby reducing blood sugar levels. One trigger for the secretion of insulin is the increase in blood glucose after a meal. Other substances apart from glucose can also function as inhibitors or boosters by acting on the receptors responsible for regulating insulin secretion. The scientists have now identified receptors in the insulin-producing cells of mice and humans, which can inhibit the secretion of insulin. "When a cell absorbs glucose, it produces acetic acid. This activates the FFA2 and FFA3 receptors and thus inhibits insulin produc Continue reading >>

Insulin-inducible Smile Inhibits Hepatic Gluconeogenesis

Insulin-inducible Smile Inhibits Hepatic Gluconeogenesis

The role of a glucagon/cAMP-dependent protein kinase–inducible coactivator PGC-1α signaling pathway is well characterized in hepatic gluconeogenesis. However, an opposing protein kinase B (PKB)/Akt-inducible corepressor signaling pathway is unknown. A previous report has demonstrated that small heterodimer partner–interacting leucine zipper protein (SMILE) regulates the nuclear receptors and transcriptional factors that control hepatic gluconeogenesis. Here, we show that hepatic SMILE expression was induced by feeding in normal mice but not in db/db and high-fat diet (HFD)-fed mice. Interestingly, SMILE expression was induced by insulin in mouse primary hepatocyte and liver. Hepatic SMILE expression was not altered by refeeding in liver-specific insulin receptor knockout (LIRKO) or PKB β-deficient (PKBβ−/−) mice. At the molecular level, SMILE inhibited hepatocyte nuclear factor 4–mediated transcriptional activity via direct competition with PGC-1α. Moreover, ablation of SMILE augmented gluconeogenesis and increased blood glucose levels in mice. Conversely, overexpression of SMILE reduced hepatic gluconeogenic gene expression and ameliorated hyperglycemia and glucose intolerance in db/db and HFD-fed mice. Therefore, SMILE is an insulin-inducible corepressor that suppresses hepatic gluconeogenesis. Small molecules that enhance SMILE expression would have potential for treating hyperglycemia in diabetes. Insulin induces the insulin receptor tyrosine kinase–mediated activation of the phosphatidylinositol 3-kinase pathway that controls hepatic glucose production. Ablation of insulin signaling leads to the increased gluconeogenesis in type 2 diabetes (1–3). In the fed condition, insulin inhibits hepatic gluconeogenesis by downregulating the expression of PEP Continue reading >>

What Is Insulin?

What Is Insulin?

Insulin is a hormone; a chemical messenger produced in one part of the body to have an action on another. It is a protein responsible for regulating blood glucose levels as part of metabolism.1 The body manufactures insulin in the pancreas, and the hormone is secreted by its beta cells, primarily in response to glucose.1 The beta cells of the pancreas are perfectly designed "fuel sensors" stimulated by glucose.2 As glucose levels rise in the plasma of the blood, uptake and metabolism by the pancreas beta cells are enhanced, leading to insulin secretion.1 Insulin has two modes of action on the body - an excitatory one and an inhibitory one:3 Insulin stimulates glucose uptake and lipid synthesis It inhibits the breakdown of lipids, proteins and glycogen, and inhibits the glucose pathway (gluconeogenesis) and production of ketone bodies (ketogenesis). What is the pancreas? The pancreas is the organ responsible for controlling sugar levels. It is part of the digestive system and located in the abdomen, behind the stomach and next to the duodenum - the first part of the small intestine.4 The pancreas has two main functional components:4,5 Exocrine cells - cells that release digestive enzymes into the gut via the pancreatic duct The endocrine pancreas - islands of cells known as the islets of Langerhans within the "sea" of exocrine tissue; islets release hormones such as insulin and glucagon into the blood to control blood sugar levels. Islets are highly vascularized (supplied by blood vessels) and specialized to monitor nutrients in the blood.2 The alpha cells of the islets secrete glucagon while the beta cells - the most abundant of the islet cells - release insulin.5 The release of insulin in response to elevated glucose has two phases - a first around 5-10 minutes after g Continue reading >>

Article Suppression Of Insulin Production And Secretion By A Decretin Hormone

Article Suppression Of Insulin Production And Secretion By A Decretin Hormone

Highlights • Lst hormone is induced in gut-associated CC cells by carbohydrate restriction • Lst suppresses insulin output by fly insulin-producing cells (IPCs) • • NMU inhibits human islet insulin secretion and is a candidate mammalian decretin Decretins, hormones induced by fasting that suppress insulin production and secretion, have been postulated from classical human metabolic studies. From genetic screens, we identified Drosophila Limostatin (Lst), a peptide hormone that suppresses insulin secretion. Lst is induced by nutrient restriction in gut-associated endocrine cells. limostatin deficiency led to hyperinsulinemia, hypoglycemia, and excess adiposity. A conserved 15-residue polypeptide encoded by limostatin suppressed secretion by insulin-producing cells. Targeted knockdown of CG9918, a Drosophila ortholog of Neuromedin U receptors (NMURs), in insulin-producing cells phenocopied limostatin deficiency and attenuated insulin suppression by purified Lst, suggesting CG9918 encodes an Lst receptor. NMUR1 is expressed in islet β cells, and purified NMU suppresses insulin secretion from human islets. A human mutant NMU variant that co-segregates with familial early-onset obesity and hyperinsulinemia fails to suppress insulin secretion. We propose Lst as an index member of an ancient hormone class called decretins, which suppress insulin output. Graphical Abstract Figure 2. Obesity in lst Mutants (A) Triglyceride content of control Ilp2-GAL4 and Ilp2-GAL4>NaChBac flies. (B and C) Whole-fly triglyceride content and nile red staining of abdominal lipid droplets in adult lst1 flies and controls. (D) Triglyceride content after silencing of IPCs using Ilp2-GAL4 to drive UAS-Kir2.1 in yw; lstctrl and yw; lst1 background, normalized to yw; lstctrl; Ilp2-GAL4 > UAS-Ki Continue reading >>

Insulin

Insulin

Insulin, hormone that regulates the level of sugar (glucose) in the blood and that is produced by the beta cells of the islets of Langerhans in the pancreas. Insulin is secreted when the level of blood glucose rises—as after a meal. When the level of blood glucose falls, secretion of insulin stops, and the liver releases glucose into the blood. Insulin was first reported in pancreatic extracts in 1921, having been identified by Canadian scientists Frederick G. Banting and Charles H. Best and by Romanian physiologist Nicolas C. Paulescu, who was working independently and called the substance “pancrein.” After Banting and Best isolated insulin, they began work to obtain a purified extract, which they accomplished with the help of Scottish physiologist J.J.R. Macleod and Canadian chemist James B. Collip. Banting and Macleod shared the 1923 Nobel Prize for Physiology or Medicine for their work. Insulin is a protein composed of two chains, an A chain (with 21 amino acids) and a B chain (with 30 amino acids), which are linked together by sulfur atoms. Insulin is derived from a 74-amino-acid prohormone molecule called proinsulin. Proinsulin is relatively inactive, and under normal conditions only a small amount of it is secreted. In the endoplasmic reticulum of beta cells the proinsulin molecule is cleaved in two places, yielding the A and B chains of insulin and an intervening, biologically inactive C peptide. The A and B chains become linked together by two sulfur-sulfur (disulfide) bonds. Proinsulin, insulin, and C peptide are stored in granules in the beta cells, from which they are released into the capillaries of the islets in response to appropriate stimuli. These capillaries empty into the portal vein, which carries blood from the stomach, intestines, and pancrea Continue reading >>

Insulin Acutely Inhibits Intestinal Lipoprotein Secretion In Humans In Part By Suppressing Plasma Free Fatty Acids

Insulin Acutely Inhibits Intestinal Lipoprotein Secretion In Humans In Part By Suppressing Plasma Free Fatty Acids

OBJECTIVE Intestinal lipoprotein production has recently been shown to be increased in insulin resistance, but it is not known whether it is regulated by insulin in humans. Here, we investigated the effect of acute hyperinsulinemia on intestinal (and hepatic) lipoprotein production in six healthy men in the presence and absence of concomitant suppression of plasma free fatty acids (FFAs). RESEARCH DESIGN AND METHODS Each subject underwent the following three lipoprotein turnover studies, in random order, 4–6 weeks apart: 1) insulin and glucose infusion (euglycemic-hyperinsulinemic clamp) to induce hyperinsulinemia, 2) insulin and glucose infusion plus Intralipid and heparin infusion to prevent the insulin-induced suppression of plasma FFAs, and 3) saline control. RESULTS VLDL1 and VLDL2-apoB48 and -apoB100 production rates were suppressed by 47–62% by insulin, with no change in clearance. When the decline in FFAs was prevented by concomitant infusion of Intralipid and heparin, the production rates of VLDL1 and VLDL2-apoB48 and -apoB100 were intermediate between insulin and glucose infusion and saline control. CONCLUSIONS This is the first demonstration in humans that intestinal apoB48-containing lipoprotein production is acutely suppressed by insulin, which may involve insulin's direct effects and insulin-mediated suppression of circulating FFAs. Dyslipidemia is a well-recognized feature of insulin resistance and type 2 diabetes and is a common risk factor for atherosclerotic cardiovascular disease. Hypertriglyceridemia, low plasma concentrations of HDL, and qualitative changes in LDL comprise the typical dyslipidemia, which is felt to play an important but not exclusive role in accelerated atherosclerosis of affected individuals (1,2). Overproduction of large, trig Continue reading >>

High Glucose Inhibits Insulin-stimulated Nitric Oxide Production Without Reducing Endothelial Nitric-oxide Synthase Ser1177 Phosphorylation In Human Aortic Endothelial Cells*

High Glucose Inhibits Insulin-stimulated Nitric Oxide Production Without Reducing Endothelial Nitric-oxide Synthase Ser1177 Phosphorylation In Human Aortic Endothelial Cells*

Abstract Recent studies have indicated that insulin activates endothelial nitric-oxide synthase (eNOS) by protein kinase B (PKB)-mediated phosphorylation at Ser1177 in endothelial cells. Because hyperglycemia contributes to endothelial dysfunction and decreased NO availability in types 1 and 2 diabetes mellitus, we have studied the effects of high glucose (25 mm, 48 h) on insulin signaling pathways that regulate NO production in human aortic endothelial cells. High glucose inhibited insulin-stimulated NO synthesis but was without effect on NO synthesis stimulated by increasing intracellular Ca2+ concentration. This was accompanied by reduced expression of IRS-2 and attenuated insulin-stimulated recruitment of PI3K to IRS-1 and IRS-2, yet insulin-stimulated PKB activity and phosphorylation of eNOS at Ser1177 were unaffected. Inhibition of insulin-stimulated NO synthesis by high glucose was unaffected by an inhibitor of PKC. Furthermore, high glucose down-regulated the expression of CAP and Cbl, and insulin-stimulated Cbl phosphorylation, components of an insulin signaling cascade previously characterized in adipocytes. These data suggest that high glucose specifically inhibits insulin-stimulated NO synthesis and down-regulates some aspects of insulin signaling, including the CAP-Cbl signaling pathway, yet this is not a result of reduced PKB-mediated eNOS phosphorylation at Ser1177. Therefore, we propose that phosphorylation of eNOS at Ser1177 is not sufficient to stimulate NO production in cells cultured at 25 mm glucose. Abstract The question remains open whether the signaling pathways shown to be important for growth and transformation in adherent cultures proceed similarly and play similar roles for cells grown under anchorage-independent conditions. Chicken embryo fi Continue reading >>

The Inhibitory Effects Of Insulin On Hepatic Glucose Production Are Both Direct And Indirect

The Inhibitory Effects Of Insulin On Hepatic Glucose Production Are Both Direct And Indirect

Previous studies suggest that insulin can inhibit hepatic glucose production by both direct and indirect actions. The indirect effects include inhibition of glucagon secretion, reduction in plasma nonesterified fatty acid levels, reduction of the amount of gluconeogenic precursor supplied to the liver, and change in neural input to the liver. There is a controversy concerning the fact that the dominant action of insulin on hepatic glucose production is direct, as suggested by studies in fed dogs, or indirect, via the hypothalamus, as suggested by studies in rodents. A possible explanation for this discrepancy will be proposed involving the relative importance of glycogenolysis and gluconeogenesis in hepatic glucose production in dogs and rodents. Finally, the relative importance of direct and/or indirect effects of insulin on hepatic glucose production for the treatment of diabetes will be discussed. For a long time, it was believed that the inhibition of hepatic glucose production (HGP) by insulin resulted only from a direct effect of the hormone on the liver. This was logical since insulin is secreted in the portal vein and the liver is the first organ encountered by insulin. In addition, the liver is exposed to the highest insulin concentration among the insulin-sensitive organs. Finally, the liver capillaries are fenestrated (no endothelial barrier) and thus insulin can reach the liver immediately. However, several observations have challenged this view: 1) whereas insulin is a potent inhibitor of HGP in vivo, the hormone is relatively ineffective in vitro in rodent liver (1,2) suggesting that insulin primarily acts on extrahepatic tissue; 2) insulin infused peripherally in human and dogs is as effective in suppressing HGP as insulin infused intraportally (3–6), s Continue reading >>

Secretion Of Insulin In Response To Diet And Hormones

Secretion Of Insulin In Response To Diet And Hormones

1. The Dual Nature of the Pancreas The pancreas is a complex gland active in digestion and metabolism through secretion of digestive enzymes from the exocrine portion and hormones from the endocrine portion. The exocrine pancreas, which accounts for more than 95% of the pancreas mass, is structurally comprised of lobules, with acinar cells surrounding a duct system. The endocrine pancreas makes up only 2% of the pancreatic mass and is organized into the islets of Langerhans— small semi-spherical clusters of about 1500 cells (55) dispersed throughout the pancreatic parenchyme— which produce and secrete hormones critical for glucose homeostasis. The existence of islets was first described by Paul Langerhans in the 1890s, and the functional role of islets in glucose homeostasis was first demonstrated in 1890 when Joseph von Mering and colleagues showed that dogs developed diabetes mellitus following pancreatectomy (17). Though islet mass may vary between individuals—an example is the increase in the setting of adult obesity (64)— the average adult human pancreas is estimated to contain one to two million islets (24, 73). In the human pancreas, the concentration of islets is up to two times higher in the tail compared to the head and neck. However, the cellular composition and architectural organization of cell types within the islets is preserved throughout the pancreas (82). Each pancreatic islet is composed of α, β, δ, ε and PP cells; these are primarily endocrine (hormone-secreting) cells, containing numerous secretory granules with stored hormone molecules, ready for release upon receipt of the appropriate stimulus. Insulin-producing b cells are the most common cell type, making up 50-70% of islet mass, with small islets containing a greater percentage of b Continue reading >>

Insulin And Glucagon

Insulin And Glucagon

Acrobat PDF file can be downloaded here. The islets of Langerhans The pancreatic Islets of Langerhans are the sites of production of insulin, glucagon and somatostatin. The figure below shows an immunofluorescence image in which antibodies specific for these hormones have been coupled to differing fluorescence markers. We can therefore identify those cells that produce each of these three peptide hormones. You can see that most of the tissue, around 80 %, is comprised of the insulin-secreting red-colored beta cells (ß-cells). The green cells are the α-cells (alpha cells) which produce glucagon. We see also some blue cells; these are the somatostatin secreting γ-cells (gamma cells). Note that all of these differing cells are in close proximity with one another. While they primarily produce hormones to be circulated in blood (endocrine effects), they also have marked paracrine effects. That is, the secretion products of each cell type exert actions on adjacent cells within the Islet. An Introduction to secretion of insulin and glucagon The nutrient-regulated control of the release of these hormones manages tissue metabolism and the blood levels of glucose, fatty acids, triglycerides and amino acids. They are responsible for homeostasis; the minute-to-minute regulation of the body's integrated metabolism and, thereby, stabilize our inner milieu. The mechanisms involved are extremely complex. Modern medical treatment of diabetes (rapidly becoming "public enemy number one") is based on insight into these mechanisms, some of which are not completely understood. I will attempt to give an introduction to this complicated biological picture in the following section. Somewhat deeper insight will come later. The Basics: secretion Let us begin with two extremely simplified figur Continue reading >>

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