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 >>
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- Antidepressant Medication as a Risk Factor for Type 2 Diabetes and Impaired Glucose Regulation
A Role For Glutamate Transporters In The Regulation Of Insulin Secretion
Abstract In the brain, glutamate is an extracellular transmitter that mediates cell-to-cell communication. Prior to synaptic release it is pumped into vesicles by vesicular glutamate transporters (VGLUTs). To inactivate glutamate receptor responses after release, glutamate is taken up into glial cells or neurons by excitatory amino acid transporters (EAATs). In the pancreatic islets of Langerhans, glutamate is proposed to act as an intracellular messenger, regulating insulin secretion from β-cells, but the mechanisms involved are unknown. By immunogold cytochemistry we show that insulin containing secretory granules express VGLUT3. Despite the fact that they have a VGLUT, the levels of glutamate in these granules are low, indicating the presence of a protein that can transport glutamate out of the granules. Surprisingly, in β-cells the glutamate transporter EAAT2 is located, not in the plasma membrane as it is in brain cells, but exclusively in insulin-containing secretory granules, together with VGLUT3. In EAAT2 knock out mice, the content of glutamate in secretory granules is higher than in wild type mice. These data imply a glutamate cycle in which glutamate is carried into the granules by VGLUT3 and carried out by EAAT2. Perturbing this cycle by knocking down EAAT2 expression with a small interfering RNA, or by over-expressing EAAT2 or a VGLUT in insulin granules, significantly reduced the rate of granule exocytosis. Simulations of granule energetics suggest that VGLUT3 and EAAT2 may regulate the pH and membrane potential of the granules and thereby regulate insulin secretion. These data suggest that insulin secretion from β-cells is modulated by the flux of glutamate through the secretory granules. Figures Citation: Gammelsaeter R, Coppola T, Marcaggi P, Storm-M Continue reading >>
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 >>
Pathway: Map04911
Description Pancreatic beta cells are specialised endocrine cells that continuously sense the levels of blood sugar and other fuels and, in response, secrete insulin to maintain normal fuel homeostasis. Glucose-induced insulin secretion and its potentiation constitute the principal mechanism of insulin release. Glucose is transported by the glucose transporter (GLUT) into the pancreatic beta-cell. Metabolism of glucose generates ATP, which inhibits ATP-sensitive K+ channels and causes voltage-dependent Ca2+ influx. Elevation of [Ca2+]i triggers exocytotic release of insulin granules. Insulin secretion is further regulated by several hormones and neurotransmitters. Peptide hormones, such as glucagon-like peptide 1 (GLP-1), increase cAMP levels and thereby potentiate insulin secretion via the combined action of PKA and Epac2. Achetylcholine (ACh), a major parasympathetic neurotransmitter, binds to Gq-coupled receptors and activates phospholipase C- (PLC-), and the stimulatory effects involve activation of protein kinase C (PKC), which stimulates exocytosis. In addition, ACh mobilizes intracellular Ca2+ by activation of IP3 receptors. Pathway map Continue reading >>
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 >>
Fractalkine Signaling In Regulation Of Insulin Secretion
Fractalkine is a chemokine, which has been shown to play important roles in metabolic disease in both animal models and humans. Fractalkine is a key player in the accumulation of atherosclerotic plaques, and fractalkine receptor (CX3CR1) mutations have been implicated in obesity. Serum fractalkine levels have been found to be elevated in type 2 diabetic patients, but the role of fractalkine signaling on the pancreatic β cell was unclear. Recently published findings in April 2013 issue of the journal Cell by Lee and Olefsky et al. have implicated fractalkine in β-cell insulin secretion. They demonstrate that Cx3cr1 knockout mice have impaired glucose tolerance resulting from decreased insulin secretion. In addition, fractalkine administration improved glucose tolerance and induced insulin secretion. This modulation of insulin secretion was proposed to result from an increase in intracellular calcium and potentiation of insulin secretion, which occurs in a Gαi and MEK-dependent manner. They also found that Cx3cr1 knockout animals had transcriptional repression of genes important for β-cell function, specifically NeuroD, via induction of ICER-1. One important issue that remains unresolved is how CX3CR1 signaling regulates the potentiation of calcium influx and the distal events in insulin exocytosis. Finally, testing the effects of fractalkine treatment on proliferation and survival in vivo during regenerative conditions would be critical to determine the potential use of this chemokine in diabetes. While these exciting results open the possibility for new therapeutics, there are some concerns about a potential risk for exacerbation of atherosclerosis. Continue reading >>
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 >>
Regulation Of Pancreatic Β-cell Insulin Secretion By Actin Cytoskeleton Remodelling: Role Of Gelsolin And Cooperation With The Mapk Signalling Pathway
We have previously isolated two MIN6 β-cell sublines, B1, highly responsive to glucose-stimulated insulin secretion, and C3, markedly refractory (Lilla, V., Webb, G., Rickenbach, K., Maturana, A., Steiner, D. F., Halban, P. A. and Irminger, J. C. (2003) Endocrinology 144, 1368-1379). We now demonstrate that C3 cells have substantially increased amounts of F-actin stress fibres whereas B1 cells have shorter cortical F-actin. Consistent with these data, B1 cells display glucose-dependent actin remodelling whereas, in C3 cells, F-actin is refractory to this secretagogue. Furthermore, F-actin depolymerisation with latrunculin B restores glucose-stimulated insulin secretion in C3 cells. In parallel, glucose-stimulated ERK1/2 activation is greater in B1 than in C3 cells, and is potentiated in both sublines following F-actin depolymerisation. Glucose-activated phosphoERK1/2 accumulates at actin filament tips adjacent to the plasma membrane, indicating that these are the main sites of action for this kinase during insulin secretion. In addition, B1 cell expression of the calcium-dependent F-actin severing protein gelsolin is >100-fold higher than that of C3 cells. Knock-down of gelsolin reduced glucose-stimulated insulin secretion, whereas gelsolin over-expression potentiated secretion from B1 cells. Gelsolin localised along depolymerised actin fibres after glucose stimulation. Taken together, these data demonstrate that F-actin reorganization prior to insulin secretion requires gelsolin and plays a role in the glucose-dependent MAPK signal transduction that regulates β-cell insulin secretion. The actin cytoskeleton is a highly dynamic structure that is remodelled in response to a variety of signals. It plays essential roles in the regulation of numerous cellular processes, s Continue reading >>
(316d) Optogenetic Regulation Of Insulin Secretion In Pancreatic Beta-cells
Proper insulin production by pancreatic beta-cells, which is central to blood glucose homeostasis, is orchestrated by a complex circuitry involving intracellular molecules including cyclic AMP (cAMP). Tackling aberrations in glucose-stimulated insulin release such as in diabetes with pharmacological agents, which boost the secretory capacity of beta-cells, is linked to adverse side effects. We hypothesized that a photoactivatable adenylyl cyclase (PAC) can be employed to modulate cAMP in beta-cells with light thereby enhancing insulin secretion. To that end, the PAC gene from the bacterium Beggiatoa (bPAC) was delivered to beta-cells. Upon illumination a cAMP increase was noted within 5 minutes and a significant drop at 12 minutes post-irradiation. The concomitant augmented insulin secretion was comparable to that from beta-cells treated with secretagogues. Greater insulin release was also observed over repeated cycles of photoinduction without adverse effects on viability and proliferation. PAC-expressing beta-cells cultured as pseudoislets displayed a more pronounced light-triggered increase in insulin secretion versus that from monolayers. The enhanced hormone release was curtailed upon Ca channel blocking. This optogenetic system for modulating cAMP and insulin release can be employed for the study of beta-cell function and for enabling new therapeutic modalities for diabetes. Continue reading >>
Sympathetic Regulation Of Insulin Secretionits Relation To Diabetes Mellitus
This review summarizes evidence showing inhibition of insulin release by epinephrine and norepinephrine. The receptor theory for catecholamine action is discussed and the inhibition shown to be mediated by α-adrenergic receptor stimulation; β-adrenergic receptors are also described which stimulate insulin release, indicating a unique dual receptor system in the pancreatic islet. The possible physiologic importance of these findings is suggested in a discussion of the carbohydrate intolerance found in patients with pheochromocytoma and during severe hypothermia in children. A possible relation of the inhibition of insulin release and the increased fatty acid mobilization caused by catecholamines to exacerbations of the diabetic syndrome is examined. It is postulated that the catecholamine release which is stimulated by volume depletion, infection, or stress may be an important "reversible" factor in some patients with diabetic ketoacidosis. Continue reading >>
- Relation of total sugars, fructose and sucrose with incident type 2 diabetes: a systematic review and meta-analysis of prospective cohort studies
- Women in India with Gestational Diabetes Mellitus Strategy (WINGS): Methodology and development of model of care for gestational diabetes mellitus (WINGS 4)
- Body temperature regulation in diabetes
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 >>
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 >>
Dispatch Insulin Secretion: Feed-forward Control Of Insulin Biosynthesis?
Introduction Insulin, the body's chief anabolic hormone, is synthesised in pancreatic islets, and released when the blood glucose level rises. Defective insulin release contributes to non-insulin-dependent diabetes mellitus (NIDDM). A new study has now shown that targeted inactivation of insulin receptors in pancreatic β cells, by genetic manipulation of mice using the Cre–loxP system, produces animals which suffer insulin secretory defects akin to those found in human patients with NIDDM [1]. Furthermore, in vitro studies have shown that exogenous insulin added directly to normal islets causes transcriptional up-regulation of the preproinsulin gene [2], activation of protein translational machinery [3] and insulin secretion [4]. The important implication is that insulin acts back on the β cells to promote its own production. Insulin biosynthesis In mammals, an increase in the blood glucose level enhances transcription of the preproinsulin gene [5] and translation of preproinsulin mRNA [6], and stimulates the release of insulin by regulated exocytosis of the mature hormone. The latter process, which resembles the regulated release of neurotransmitters from neurons, involves Ca2+ influx through L-type channels, an increase in intracellular Ca2+ concentration and exocytosis from dense-core secretory vesicles (Figure 1) [7]. Figure 1. The possible interplay between the action of glucose (top left) and secreted insulin (red squares) one preproinsulin gene expression in this islet β cell. (See text for details.) Is secreted insulin involved in stimulating insulin gene expression? Certainly, the order of events in response to glucose is compatible with this idea. Insulin secretion is activated seconds to minutes after an elevation in the glucose level, preproinsulin mRNA Continue reading >>
Multicellular Regulation Of Insulin Secretion From Pancreatic Islets
Objective Type 2 diabetes mellitus, one of the major healthcare challenges of our time, is characterized by failure of beta cells to functionally adapt to increased peripheral insulin resistance. The resulting chronic elevations in blood glucose concentration are associated with heart, kidney, liver, nerve and retinal disease, as well as cancer. Here, by combining novel optogenetic, photopharmacological and innovative imaging approaches, we aim to unravel the complexity underlying the… (+) Host Institution Expand all Continue reading >>
Autocrine Regulation Of Insulin Secretion
Abstract Impaired insulin secretion from pancreatic β-cells is a major factor in the pathogenesis of type 2 diabetes. The main regulator of insulin secretion is the plasma glucose concentration. Insulin secretion is modified by other nutrients, circulating hormones and the autonomic nervous system, as well as local paracrine and autocrine signals. Autocrine signalling involves diffusible molecules that bind to receptors on the same cell from which they have been released. The first transmitter to be implicated in the autocrine regulation of β-cell function was insulin itself. The importance of autocrine insulin signalling is underscored by the finding that mice lacking insulin receptors in β-cells are glucose intolerant. In addition to insulin, β-cells secrete a variety of additional substances, including peptides (e.g. amylin, chromogranin A and B and their cleavage products), neurotransmitters (ATP and γ-aminobutyric acid) and ions (e.g. zinc). Here we review the autocrine effects of substances secreted from β-cells, with a focus on acute effects in stimulus–secretion coupling, present some novel data and discuss the general significance of autocrine signals for the regulation of insulin secretion. Continue reading >>
