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What Regulates Insulin Secretion?

Insulin Synthesis And Secretion

Insulin Synthesis And Secretion

Insulin is a small protein, with a molecular weight of about 6000 Daltons. It is composed of two chains held together by disulfide bonds. The figure to the right shows a molecular model of bovine insulin, with the A chain colored blue and the larger B chain green. You can get a better appreciation for the structure of insulin by manipulating such a model yourself. The amino acid sequence is highly conserved among vertebrates, and insulin from one mammal almost certainly is biologically active in another. Even today, many diabetic patients are treated with insulin extracted from pig pancreas. Biosynthesis of Insulin Insulin is synthesized in significant quantities only in beta cells in the pancreas. The insulin mRNA is translated as a single chain precursor called preproinsulin, and removal of its signal peptide during insertion into the endoplasmic reticulum generates proinsulin. Proinsulin consists of three domains: an amino-terminal B chain, a carboxy-terminal A chain and a connecting peptide in the middle known as the C peptide. Within the endoplasmic reticulum, proinsulin is exposed to several specific endopeptidases which excise the C peptide, thereby generating the mature form of insulin. Insulin and free C peptide are packaged in the Golgi into secretory granules which accumulate in the cytoplasm. When the beta cell is appropriately stimulated, insulin is secreted from the cell by exocytosis and diffuses into islet capillary blood. C peptide is also secreted into blood, but has no known biological activity. Control of Insulin Secretion Insulin is secreted in primarily in response to elevated blood concentrations of glucose. This makes sense because insulin is "in charge" of facilitating glucose entry into cells. Some neural stimuli (e.g. sight and taste of food) 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 >>

Microtubules Negatively Regulate Insulin Secretion In Pancreatic Cells - Sciencedirect

Microtubules Negatively Regulate Insulin Secretion In Pancreatic Cells - Sciencedirect

Volume 34, Issue 6 , 28 September 2015, Pages 656-668 Microtubule disruption enhances glucose-stimulated insulin secretion Microtubules withdraw insulin granules from the cell periphery Glucose induces remodeling of Golgi-derived microtubules in cells Microtubule meshwork is overly dense in cells from diabetic mice For glucose-stimulated insulin secretion (GSIS), insulin granules have to be localized close to the plasma membrane. The role of microtubule-dependent transport in granule positioning and GSIS has been debated. Here, we report that microtubules, counterintuitively, restrict granule availability for secretion. In cells, microtubules originate at the Golgi and form a dense non-radial meshwork. Non-directional transport along these microtubules limits granule dwelling at the cell periphery, restricting granule availability for secretion. High glucose destabilizes microtubules, decreasing their density; such local microtubule depolymerization is necessary for GSIS, likely because granule withdrawal from the cell periphery becomes inefficient. Consistently, microtubule depolymerization by nocodazole blocks granule withdrawal, increases their concentration atexocytic sites, and dramatically enhances GSIS invitro and in mice. Furthermore, glucose-driven MT destabilization is balanced by new microtubule formation, which likely prevents over-secretion. Importantly, microtubule density is greater in dysfunctional cells of diabetic mice. Continue reading >>

Regulation Of Insulin Secretion In Human Pancreatic Islets

Regulation Of Insulin Secretion In Human Pancreatic Islets

Regulation of Insulin Secretion in Human Pancreatic Islets Vol. 75:155-179 (Volume publication date February 2013) First published online as a Review in Advance on September 4, 2012 1Oxford Center for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LJ, United Kingdom; email: [emailprotected] 2Alberta Diabetes Institute, University of Alberta, Edmonton T6G 2E1, Canada Pancreatic cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human cells. These studies have revealed numerous and important differences between human and rodent cells. Here we discuss the properties of human pancreatic cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic. Continue reading >>

Circulating Glucagon 1-61 Regulates Blood Glucose By Increasing Insulin Secretion And Hepatic Glucose Production

Circulating Glucagon 1-61 Regulates Blood Glucose By Increasing Insulin Secretion And Hepatic Glucose Production

View all Images/DataFigure 1 (A) Overview of the processing of proglucagon (1-160). In the pancreas, proglucagon is processed by prohormone convertase 2 (PC2), resulting in the formation of glicentin-related pancreatic polypeptide (GRPP), glucagon, and the major proglucagon fragment. In the intestine, the actions of prohormone convertase 1/3 (PC1/3) lead to the formation of glicentin, glucagon-like peptide 1 (GLP-1), and glucagon-like peptide 2 (GLP-2). Below, potential (denoted as X and Y) N-terminally elongated and C-terminally truncated forms of glucagon are depicted. (B) A mass-spectrometry-based platform for identification of low-abundant peptides such as glucagon. In short, blood is taken from a subject, and the plasma is subjected to ultra-pressure liquid chromatography (UPLC), and the peptides are sprayed into an Orbitrap-based mass spectrometer, using an electrospray technique (ESI). The identified spectra are deconvoluted into amino acid sequences using the MaxQuant software package. (C) Separate plasma pools, obtained from subjects with kidney failure (n = 8) and from healthy subjects (n = 8), were subjected to the platform shown in (B), and the corresponding amino acid intensities are depicted as red (kidney failure) and green (healthy subjects). Synthesized PG 1-61 (positive control) is depicted in blue. (D) By comparing plasma levels of immunoreactive total glucagon (i.e., PG 1-61 + PG 33-61 [glucagon]), using a C-terminal assay (blue), to plasma levels of PG 1-61 (black) and glucagon 33-61 (red) using two sandwich ELISAs, we were able to verify immunoreactive PG 1-61 in plasma in response to an oral glucose load (E) in the same kidney failure individuals used in our mass-spectrometry-based platform (C). (F) Size-exclusion chromatography identified two maj 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 >>

Triggering And Amplifying Pathways Of Regulation Of Insulin Secretion By Glucose.

Triggering And Amplifying Pathways Of Regulation Of Insulin Secretion By Glucose.

Glucose stimulates insulin secretion by generating triggering and amplifying signals in beta-cells. The triggering pathway is well characterized. It involves the following sequence of events: entry of glucose by facilitated diffusion, metabolism of glucose by oxidative glycolysis, rise in the ATP-to-ADP ratio, closure of ATP-sensitive K+ (KATP) channels, membrane depolarization, opening of voltage-operated Ca2+ channels, Ca2+ influx, rise in cytoplasmic free Ca2+ concentration ([Ca2+]i), and activation of the exocytotic machinery. The amplifying pathway can be studied when beta-cell [Ca2+]i is elevated and clamped by a depolarization with either a high concentration of sulfonylurea or a high concentration of K+ in the presence of diazoxide (K(ATP) channels are then respectively blocked or held open). Under these conditions, glucose still increases insulin secretion in a concentration-dependent manner. This increase in secretion is highly sensitive to glucose (produced by as little as 1-6 mmol/l glucose), requires glucose metabolism, is independent of activation of protein kinases A and C, and does not seem to implicate long-chain acyl-CoAs. Changes in adenine nucleotides may be involved. The amplification consists of an increase in efficacy of Ca2+ on exocytosis of insulin granules. There exists a clear hierarchy between both pathways. The triggering pathway predominates over the amplifying pathway, which remains functionally silent as long as [Ca2+]i has not been raised by the first pathway; i.e., as long as glucose has not reached its threshold concentration. The alteration of this hierarchy by long-acting sulfonylureas or genetic inactivation of K(ATP) channels may lead to inappropriate insulin secretion at low glucose. The amplifying pathway serves to optimize the s Continue reading >>

Nutrient Regulation Of Insulin Secretion And Action

Nutrient Regulation Of Insulin Secretion And Action

Introduction Homoeostatic regulation of fuel metabolism in the body is a tightly controlled process and dysregulation can lead to pathological conditions such as diabetes mellitus (DM), cardiovascular disease, stroke, renal disease and other manifestations of the metabolic syndrome. Glucose, the body's primary metabolic fuel source, is ingested usually in polymeric form following the consumption of a mixed meal, and the subsequent postprandial elevation in blood glucose level is stringently modulated by the release of the pancreatic hormones insulin and glucagon. These hormones target metabolically active tissues such as muscle, adipose tissue and liver in order to maintain blood glucose concentration within narrow limits (∼4.0–6.0 mmol/l). However, dysregulation of metabolic processes may result in chronic hyperglycaemic, dyslipidaemic or glucolipotoxic conditions that may negatively impact a wide variety of tissues and organs including pancreatic islets, skeletal muscle, adipose tissue and the liver and are frequently observed in DM. According to the International Diabetes Federation (IDF), in 2011, 336 million of the world's population (∼6.4%) had either type 1 (T1DM) or type 2 DM (T2DM), yet the prevalence is continuing to rise at rapid rates and is projected to exceed 550 million by 2030 (Whiting et al. 2011). Furthermore, T2DM is by far the most common form of the disease, representing about 90–95% of DM cases. Pancreatic islets are specialised and highly vascularised structures that monitor the nutrient contents of the blood stream and consist of mainly five cell types; α-cells, β-cells, δ-cells, ghrelin cells (γ-cells) and pancreatic peptide (PP)-secreting cells (Wierup et al. 2014). Islets continually sample blood from the branches of the splenic an Continue reading >>

Somatostatin Receptor Subtype 5 Regulates Insulin Secretion And Glucose Homeostasis

Somatostatin Receptor Subtype 5 Regulates Insulin Secretion And Glucose Homeostasis

Somatostatin Receptor Subtype 5 Regulates Insulin Secretion and Glucose Homeostasis Departments of Molecular Endocrinology (M.Z.S., Z.L., D.S., B.B.Z.), Rahway, New Jersey 07065 Address all correspondence and requests for reprints to: Dr. Hilary A. Wilkinson, Department of Atherosclerosis & Endocrinology, Merck Research Laboratories, RY80Y-305, Rahway, New Jersey 07065.; or Dr. Mathias Z. Strowski, Medizinische Klinik M. S. Hepatologie und Gastroenterologie, Charite, Campus Virchow-Klinikum, Humboldt University, 13353 Berlin, Germany. Search for other works by this author on: Ion Channels (M.K.), Rahway, New Jersey 07065 Search for other works by this author on: Metabolic Disorders (H.Y.C., M.E.T.), Rahway, New Jersey 07065 Search for other works by this author on: Metabolic Disorders (H.Y.C., M.E.T.), Rahway, New Jersey 07065 Search for other works by this author on: Departments of Molecular Endocrinology (M.Z.S., Z.L., D.S., B.B.Z.), Rahway, New Jersey 07065 Search for other works by this author on: Departments of Molecular Endocrinology (M.Z.S., Z.L., D.S., B.B.Z.), Rahway, New Jersey 07065 Search for other works by this author on: Comparative Medicine (S.G.-T., J.K.F.), Merck Research Laboratories, Rahway, New Jersey 07065 Search for other works by this author on: Comparative Medicine (S.G.-T., J.K.F.), Merck Research Laboratories, Rahway, New Jersey 07065 Search for other works by this author on: Atherosclerosis & Endocrinology (J.M.S., H.A.W.), Rahway, New Jersey 07065 Search for other works by this author on: Department of Biology (A.D.B.), Seton Hall University, South Orange, New Jersey 07079 Search for other works by this author on: Departments of Molecular Endocrinology (M.Z.S., Z.L., D.S., B.B.Z.), Rahway, New Jersey 07065 Search for other works by this auth Continue reading >>

Normal Regulation Of Blood Glucose

Normal Regulation Of Blood Glucose

The human body wants blood glucose (blood sugar) maintained in a very narrow range. Insulin and glucagon are the hormones which make this happen. Both insulin and glucagon are secreted from the pancreas, and thus are referred to as pancreatic endocrine hormones. The picture on the left shows the intimate relationship both insulin and glucagon have to each other. Note that the pancreas serves as the central player in this scheme. It is the production of insulin and glucagon by the pancreas which ultimately determines if a patient has diabetes, hypoglycemia, or some other sugar problem. In this Article Insulin Basics: How Insulin Helps Control Blood Glucose Levels Insulin and glucagon are hormones secreted by islet cells within the pancreas. They are both secreted in response to blood sugar levels, but in opposite fashion! Insulin is normally secreted by the beta cells (a type of islet cell) of the pancreas. The stimulus for insulin secretion is a HIGH blood glucose...it's as simple as that! Although there is always a low level of insulin secreted by the pancreas, the amount secreted into the blood increases as the blood glucose rises. Similarly, as blood glucose falls, the amount of insulin secreted by the pancreatic islets goes down. As can be seen in the picture, insulin has an effect on a number of cells, including muscle, red blood cells, and fat cells. In response to insulin, these cells absorb glucose out of the blood, having the net effect of lowering the high blood glucose levels into the normal range. Glucagon is secreted by the alpha cells of the pancreatic islets in much the same manner as insulin...except in the opposite direction. If blood glucose is high, then no glucagon is secreted. When blood glucose goes LOW, however, (such as between meals, and during Continue reading >>

Regulation Of Insulin Secretion

Regulation Of Insulin Secretion

This activity is intended for endocrinologists, diabetologists, family physicians, and primary care physicians. The goal of the conference coverage from the 62nd Scientific Sessions of the American Diabetes Association is to provide clinicians with the most current information on the basic science of diabetes and how this science informs the treatment of the disease. By presenting cutting-edge advances in the study of diabetes, conferences summaries aim to encourage the evaluation of current practice methods and to support clinicians who treat patients with diabetes and its ensuing complications. Upon completion of this activity, participants should be able to: Discuss new findings on the hormonal, metabolic, and neural aspects of insulin and leptin signaling in the hypothalamus. Discuss the progress that has been made in the understanding of the molecular mechanisms of insulin secretion and the therapeutic strategies that these findings suggest. Assistant Professor and Deputy Chief, Section of Endocrinology, Department of Medicine, Baylor College of Medicine, Houston, Texas. Disclosure: Arun S. Rajan, MD, has no significant financial interests to disclose. Medical Education Collaborative, a nonprofit education organization, is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Medical Education Collaborative designates this educational activityfor a maximum of 1 category 1 credits toward the AMA Physician'sRecognition Award. Each physician should claim only those credits thathe/she actually spent in the activity. This CME activity is cosponsored by Medical EducationCollaborative and Medscape, also an ACCME-accredited provider. For questions regarding the content of this activity, con Continue reading >>

Optogenetic Regulation Of Insulin Secretion In Pancreatic Β-cells

Optogenetic Regulation Of Insulin Secretion In Pancreatic Β-cells

Pancreatic β-cell insulin production is orchestrated by a complex circuitry involving intracellular elements including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of β-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in β-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from Beggiatoa (bPAC) was delivered to β-cells. A cAMP increase was noted within 5 minutes of photostimulation and a significant drop at 12 minutes post-illumination. The concomitant augmented insulin secretion was comparable to that from β-cells treated with secretagogues. Greater insulin release was also observed over repeated cycles of photoinduction without adverse effects on viability and proliferation. Furthermore, the expression and activation of bPAC increased cAMP and insulin secretion in murine islets and in β-cell pseudoislets, which displayed a more pronounced light-triggered hormone secretion compared to that of β-cell monolayers. Calcium channel blocking curtailed the enhanced insulin response due to bPAC activity. This optogenetic system with modulation of cAMP and insulin release can be employed for the study of β-cell function and for enabling new therapeutic modalities for diabetes. Precise control of complex cellular functions with external stimuli is essential for engineering effective cell therapeutics. Pharmacological manipulations typically exhibit poor cellular specificity and temporal control that is not harmonized with the timescale of relevant physiological processes. One such function is the glucose-stimulated insulin secretion (GSIS) Continue reading >>

Reactome | Regulation Of Insulin Secretion

Reactome | Regulation Of Insulin Secretion

Regulation of insulin secretion (Homo sapiens) Pancreatic beta cells integrate signals from several metabolites and hormones to control the secretion of insulin. In general, glucose triggers insulin secretion while other factors can amplify or inhibit the amount of insulin secreted in response to glucose. Factors which increase insulin secretion include the incretin hormones Glucose-dependent insulinotropic polypeptide (GIP and glucagon-like peptide-1 (GLP-1), acetylcholine, and fatty acids. Factors which inhibit insulin secretion include adrenaline and noradrenaline. Increased blood glucose levels from dietary carbohydrate play a dominant role in insulin release from the beta cells of the pancreas. Glucose catabolism in the beta cell is the transducer that links increased glucose levels to insulin release. Glucose uptake and glycolysis generate cytosolic pyruvate; pyruvate is transported to mitochondria and converted both to oxaloacetate which increases levels of TCA cycle intermediates, and to acetyl-CoA which is oxidized to CO2 via the TCA cycle. The rates of ATP synthesis and transport to the cytosol increase, plasma membrane ATP-sensitive inward rectifying potassium channels (KATP channels) close, the membrane depolarizes, and voltage-gated calcium channels in the membrane open (Muoio and Newgard 2008; Wiederkehr and Wollheim 2006). Elevated calcium concentrations near the plasma membrane cause insulin secretion in two phases: an initial high rate within minutes of glucose stimulation and a slow, sustained release lasting longer than 30 minutes. In the initial phase, 50-100 insulin granules already docked at the membrane are exocytosed. Exocytosis is rendered calcium-dependent by Synaptotagmin V/IX, a calcium-binding membrane protein located in the membrane of the Continue reading >>

Regulation Of Insulin Secretion In Human Pancreatic Islets.

Regulation Of Insulin Secretion In Human Pancreatic Islets.

Abstract Pancreatic β cells secrete insulin, the body's only hormone capable of lowering plasma glucose levels. Impaired or insufficient insulin secretion results in diabetes mellitus. The β cell is electrically excitable; in response to an elevation of glucose, it depolarizes and starts generating action potentials. The electrophysiology of mouse β cells and the cell's role in insulin secretion have been extensively investigated. More recently, similar studies have been performed on human β cells. These studies have revealed numerous and important differences between human and rodent β cells. Here we discuss the properties of human pancreatic β cells: their glucose sensing, the ion channel complement underlying glucose-induced electrical activity that culminates in exocytotic release of insulin, the cellular control of exocytosis, and the modulation of insulin secretion by circulating hormones and locally released neurotransmitters. Finally, we consider the pathophysiology of insulin secretion and the interactions between genetics and environmental factors that may explain the current diabetes epidemic. Continue reading >>

Insulin

Insulin

This article is about the insulin protein. For uses of insulin in treating diabetes, see insulin (medication). Not to be confused with Inulin. Insulin (from Latin insula, island) is a peptide hormone produced by beta cells of the pancreatic islets, and it is considered to be the main anabolic hormone of the body.[5] It regulates the metabolism of carbohydrates, fats and protein by promoting the absorption of, especially, glucose from the blood into fat, liver and skeletal muscle cells.[6] In these tissues the absorbed glucose is converted into either glycogen via glycogenesis or fats (triglycerides) via lipogenesis, or, in the case of the liver, into both.[6] Glucose production and secretion by the liver is strongly inhibited by high concentrations of insulin in the blood.[7] Circulating insulin also affects the synthesis of proteins in a wide variety of tissues. It is therefore an anabolic hormone, promoting the conversion of small molecules in the blood into large molecules inside the cells. Low insulin levels in the blood have the opposite effect by promoting widespread catabolism, especially of reserve body fat. Beta cells are sensitive to glucose concentrations, also known as blood sugar levels. When the glucose level is high, the beta cells secrete insulin into the blood; when glucose levels are low, secretion of insulin is inhibited.[8] Their neighboring alpha cells, by taking their cues from the beta cells,[8] secrete glucagon into the blood in the opposite manner: increased secretion when blood glucose is low, and decreased secretion when glucose concentrations are high.[6][8] Glucagon, through stimulating the liver to release glucose by glycogenolysis and gluconeogenesis, has the opposite effect of insulin.[6][8] The secretion of insulin and glucagon into the Continue reading >>

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