What cells are target cells for insulin?
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What is the target organ for insulin?
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What is the target cell of insulin?
Liver cells are the target cells for insulin and glucagon. Insulin and glucagon are instrumental in the regulation of blood glucose levels, allowing cells to receive proper nutrients. The liver contains glucagon receptors. When stimulated by glucagon, these receptors enable glucose release through the activation of glycogenolysis and gluconeogenesis.
How do insulin and glucagon reach their target cells?
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What are the two target cells for insulin?
Bundles of cells in the pancreas, called the islets of Langerhans, contain two kinds of cells: alpha cells and beta cells. These cells control blood glucose concentration by producing the antagonistic hormones insulin and glucagon. Beta cells secrete insulin.
What tissues does insulin affect?
Cells of the muscle tissue, vascular endothelium, heart, and liver carry out the insulin-dependent cascade. The response generated by insulin's effects in these cells is tissue-specific. In adipose tissue, skeletal muscle, and the heart, the result is glucose metabolism via glucose uptake into cells.
Which tissues are responsive to insulin?
In mammals, insulin regulates lipid and glucose metabolism and energy homeostasis by initiating its signaling events in target tissues such as liver, skeletal muscle, adipose tissues, and the brain.
How does insulin bind to target tissues?
Insulin receptors (comprising 2 α and 2 β subunits) are present on the surface of target cells such as liver, muscle and fat. Insulin binding results in tyrosine autophosphorylation of the β subunit. This then phosphorylates other substrates so that a signalling cascade is initiated and biological responses ensue.
How does insulin affect target cells?
Abstract. Insulin is a key hormone regulating glucose homeostasis. Its major target tissues are the liver, the skeletal muscle and the adipose tissue. At the cellular level, insulin activates glucose and amino acids transport, lipid and glycogen metabolism, protein synthesis, and transcription of specific genes.
What is the target tissue of glucagon?
Glucagon promotes energy storage in different types of tissues in response to feeding. The liver represents the major target organ for glucagon.
Does adipose tissue have insulin receptors?
Adipose-derived stem cells (ASCs) are the principal components of AT involved in homeostatic maintenance and tissue development, and they are highly responsive to insulin.
Why is it important that specific tissues respond to insulin in different ways?
Why is it important that specific tissues respond to insulin in different ways? The purpose of feedback inhibition is to shut down a pathway after it is no longer needed. The best examples are in metabolism where the final product of a pathway inhibits one of the enzymes at the beginning of the pathway.
Which cell is the target of insulin?
Insulin: target cells include adipose tissue, skeletal muscle, and the liver; insulin binds to receptors on target cells, a cascade of phosphorylation leads to premade glucose channels being inserted into the membrane; glucose enters through the channels; indirectly stimulates live and skeletal muscles to store sugar; ...
What are the targets of insulin?
The primary targets for insulin are liver, skeletal muscle, and fat. Insulin has multiple actions in each of these tissues, the net result of which is fuel storage (glycogen or fat). Glucose enters the circulation either from the diet or from synthesis in the liver. Click to see full answer. Correspondingly, what is the target tissue of insulin?
What is the role of insulin in fuel?
Insulin facilitates entry of glucose into muscle, adipose and several other tissues. Binding of insulin to receptors on such cells leads rapidly to fusion of those vesicles with the plasma membrane and insertion of the glucose transporters, thereby giving the cell an ability to efficiently take up glucose. What is the normal role of insulin in fuel ...
How does insulin affect glucose?
Insulin promotes storage of metabolic fuels within cells. Insulin increases the movement of glucose into many peripheral tissues (West & Passey, 1967. (1967).
Where is insulin secreted?
Insulin from the endocrine pancreas is secreted into the portal vein, so the liver is exposed to insulin concentrations two- to threefold higher than those in the general circulation ( 136 ). Portal venous insulin measurements, especially in rodents, are difficult and infrequently performed, but investigators studying hepatic insulin action by infusing insulin peripherally must keep in mind that the increment in plasma insulin concentration measured from a peripheral site is not equal to the increment in portal vein insulin concentration “seen” by the liver.
What is the function of insulin in skeletal muscle?
The principal function of insulin in the skeletal muscle is to promote cellular glucose uptake, a process controlled by GLUT4 translocation. Insulin-stimulated muscle glucose uptake is highly susceptible to insulin resistance and is indeed a principal component of typical obesity-associated insulin resistance and T2D ( 182, 767 ). Because skeletal muscle is a major site of insulin-stimulated glucose disposal (70–80% during a hyperinsulinemic euglycemic clamp, although only 25–30% in the postprandial state where glucose appearance site, glucose concentrations, and tissue glucose demand all differ from the clamped state), muscle insulin resistance has a large effect on whole body glucose turnover ( 182, 428 ). Insulin stimulation of glycogen synthesis and glycolysis both require intact insulin-stimulated glucose uptake to furnish substrate, so these effects also become resistant to insulin action ( 152, 768 ).
What is the energy stored in skeletal muscle?
Skeletal muscle is an energy-consuming tissue; any energy the myocyte stores is mostly for its own later use with the exception of 3-carbon units (lactate, alanine) generated by glycolysis that are released by skeletal muscle and mostly cycled to the liver. Insulin signals to skeletal muscle that glucose is abundant; accordingly, the myocyte insulin signaling cascade is specialized to promote glucose uptake and net glycogen synthesis. The absolute requirement of the myocellular insulin receptor for these processes was demonstrated by hyperinsulinemic-euglycemic clamp studies of muscle-specific INSR knockout (MIRKO) mice, which displayed impairments in insulin-stimulated muscle glucose uptake and muscle glycogen synthesis ( 407 ). Muscle-specific knockout of Grb10 in mice, which results in loss of its feedback inhibition on INSR as discussed previously, enhances myocellular insulin sensitivity and increases muscle size ( 329 ). Although both IRS1 and IRS2 are expressed in skeletal muscle, the primary INSR substrate in muscle appears to be IRS1. IRS1 knockdown, but not IRS2 knockdown, causes defective insulin-stimulated glucose transport in L6 rat myotubes and human primary myotubes ( 87, 340, 837 ). Additionally, isolated soleus muscles from Irs2−/− mice have normal dose-dependent insulin stimulation of glucose uptake ( 316 ). Irs2 may be important for insulin control of lipid metabolism in the myocyte ( 87 ). Both of the major isoforms of the PI3K catalytic subunit, p110α and p110β, are expressed in skeletal muscle. Of the five PI3K regulatory subunit splice isoforms, p85α, p85β, and p55α are thought to be most relevant in skeletal muscle ( 826 ), as mice with muscle-specific deletion of these isoforms have impaired (although not abolished) insulin-stimulated glucose uptake and glycogen synthesis ( 505 ). Increases in membrane PIP 3 content cause the membrane recruitment of the PH domain-containing kinases PDK1 and AKT ( 471 ). Both AKT1 and AKT2 are present in skeletal muscle, but AKT2 appears to be more important for insulin-stimulated glucose metabolism. RNA interference of Akt2 in primary human myotubes abrogated insulin stimulation of glucose uptake and glycogen synthesis, while Akt1 knockdown had no effect on these parameters ( 87 ). In support of this paradigm, Akt2−/− mice are severely glucose intolerant ( 141 ), while Akt1−/− mice display normal glucose tolerance, although a severe growth defect complicates metabolic phenotyping in Akt1−/− mice ( 142 ).
How many serine sites does IRS1 phosphorylate?
IRS1 can be phosphorylated on more than 50 serine/threonine sites, most of which are dynamically regulated by insulin and other metabolic stimuli; the structural basis by which a given serine/threonine phosphorylation event may impair IRS1 tyrosine phosphorylation is largely unknown ( 169, 300 ).
What is T2D in medical terms?
Type 2 diabetes mellitus (T2D) is one of the defining medical challenges of the 21st century ( 960 ). Overconsumption of relatively inexpensive, calorically dense, inadequately satiating, highly palatable food in industrialized nations has led to unprecedented increases in obesity. In the United States, the combined prevalence of diabetes and prediabetes is over 50% ( 538 ). Although only a subset of obese people develops T2D, obesity is a major risk factor for T2D, and rates of T2D prevalence have paralleled those of obesity ( 381 ). The fasting hyperglycemia that defines T2D is largely secondary to inadequate action of the major glucose-lowering hormone: insulin. Understanding the mechanisms of insulin action is therefore essential for the continued development of effective therapeutic strategies to combat T2D.
What is lipid induced insulin resistance?
The phenomenon of lipid-induced insulin resistance was perhaps first described in a 1941 report describing insensitivity to insulin-induced hypoglycemia after intravenous lipid infusion in rabbits ( 940 ). In the early 1960s, a series of reports linked elevated NEFA or ketone body levels to impaired insulin-stimulated glucose uptake ( 257, 677, 765, 904 ). These findings were synthesized by Randle and co-workers ( 677 – 679 ), who proposed a glucose-fatty acid cycle controlling oxidative substrate selection in skeletal and cardiac muscle. The glucose-fatty acid cycle hypothesis posited that oxidative substrate selection followed a reciprocal relationship controlled by substrate supply: fatty acid availability promotes fat oxidation while inhibiting glucose oxidation, and vice versa ( 676 ). The proposed mechanisms were allosteric in nature: increased fat oxidation drives accumulation of mitochondrial acetyl CoA and NADH, which inhibit PDH to limit entry of pyruvate into the mitochondrion for oxidation. Increased cytoplasmic citrate would also slow glycolytic flux through allosteric feedback inhibition of phosphofructokinase-1. The resultant increase in glucose-6-phosphate would in turn allosterically inhibit hexokinase and lead to an increase in intramyocellular glucose concentration.
When was INSR used in insulin?
In the 1970s and early 1980s, when INSR was the only known molecular effector of insulin action, several groups used insulin dose-response curves and 125 I-insulin binding studies to relate surface INSR content to physiological insulin action and resistance ( 26, 272, 378, 417, 420, 595, 787 ).
Which organ secretes insulin?
Insulin is an anabolic peptide hormone secreted by the b-cells of the pancreas that plays a critical role in the regulation of human metabolism (Fig. 1) (1). Its biosynthesis, secretion, structure and structure-activity relationships are thoroughly reviewed by Michel Weiss and colleagues in Endotext (2).
Where is insulin secreted?
ABSTRACT. Insulin is an anabolic peptide hormone secreted by the b cells of the pancreas acting through a receptor located in the membrane of target cells - major ones being liver (where it promotes glucose storage into glycogen and decreases glucose output), as well as skeletal muscle and fat ...
How many exons are in the insulin receptor?
The insulin receptor has a modular structure (for review see ref. 25) encoded by a gene (located on chromosome 19) with 22 exons and 21 introns (26, Fig. 3). The short exon 11 that encodes a 12-amino acid sequence is alternatively spliced, resulting in two receptor isoforms (A and B) that differ slightly in affinity for insulin (27-29). The B isoform binds the IGFs with at least 100 times lower affinity than insulin, while the A isoform has significantly higher affinity than the B isoform for IGF-I and especially IGF-II (30) and may play a role in tumorigenesis. The IGF-I receptor binds IGF-II with a lower affinity than IGF-I and insulin with a 500-fold lower affinity. The receptors are synthesized as single chain preproreceptors that are processed by a furin-like proteolytic enzyme, glycosylated, folded and dimerized to yield the mature a 2 b 2 receptor. In cells expressing both insulin and IGF-I receptors, hybrid receptors are formed consisting of one half of each (31). Their physiological role is unknown. Comparative sequence analysis of the insulin/IGF-I receptors and the related EGF receptor (32) had led Bajaj et al. to suggest (Fig. 3) that the N-terminal half consists of two large homologous globular domains, L1 and L2, separated by a cysteine-rich region later predicted to consist of a series of disulfide-linked modules similar to those found in the tumor-necrosis factor (TNF) receptor and laminin. The C-terminal half of the receptors was predicted to consist of three fibronectin type III (FnIII) domains. The second FnIII domain contains a large insert domain (120 residues) of unknown structure containing the site of cleavage between a- and b-subunits. The disulfide bond between each a- and b- subunit involves the cysteins C647 and C860. In addition there are a-a disulfide bonds at C524 in the FnIII-1 domains and between the triplet C682-C683 and C685 in the insert domain (Fig. 3). The intracellular portion of the a-subunit contains the kinase domain flanked by two regulatory regions, a juxtamembrane region involved in docking insulin receptor substrates (IRS) 1-4 and Shc as well as in receptor internalization, and a C-terminal tail. The IGF-I receptor has a similar modular organization (33). The recent progress in the X-ray crystallographic structures of whole ectodomains or fragments of the insulin and IGF-I receptors (see below) has largely validated the structural predictions shown in Fig. 3.
How are insulin receptors synthesized?
The receptors are synthesized as single chain preproreceptors that are processed by a furin-like proteolytic enzyme, glycosylated, folded and dimerized to yield the mature a2b2receptor. In cells expressing both insulin and IGF-I receptors, hybrid receptors are formed consisting of one half of each (31).
What is the metabolic effect of insulin?
The prototypical metabolic effect of insulin is the stimulation of glucose transport in adipose tissue and skeletal and cardiac muscle (1, 8, 83). Glucose disposal into muscle is the major component of insulin action that prevents postprandial hyperglycemia. This is accomplished through the translocation by exocytosis of the insulin-sensitive glucose transporter GLUT4 from intracellular vesicles to the plasma membrane, by a mechanism that is still far from completely understood (for review see 95, 96).
What is the prototypical metabolic effect of insulin?
The prototypical metabolic effect of insulin is the stimulation of glucose transport in adipose tissue and skeletal and cardiac muscle (1, 8, 83). Glucose disposal into muscle is the major component of insulin action that prevents postprandial hyperglycemia.
Which protein phosphorylates the insulin receptor?
The major and most studied protein tyrosine phosphatase acting on the insulin receptor is PTP1B. It resides in the endoplasmic reticulum and dephosphorylates the insulin receptor during internalization and recycling to the plasma membrane (107, 108).
