Browsing Pathways

Insulin is a peptide hormone secreted in the body by beta cells of islets of Langerhans of the pancreas and regulates blood glucose levels. Medical treatment with insulin is indicated when there is inadequate production or increased insulin demands in the body. Insulin is responsible for the regulation of glucose levels in the body. It stimulates the storage of energy and inhibits the breakdown of high energy metabolites. Insulin acts by directly binding to its receptors on the plasma membranes of the cells. These receptors are present on all the cells, but their density depends on the type of cells, with the maximum density being on the hepatic cells and adipocytes. The insulin receptor is a heterotetrameric glycoprotein consisting of two subunits, the alpha and the beta subunits. The extracellular alpha subunits have insulin binding sites. The beta subunits, which are transmembranous, have tyrosine kinase activity. When insulin binds to the alpha subunits, it activates the tyrosine kinase activity in the beta subunit, which causes the translocation of glucose transporters from the cytoplasm to the cell's surface. Insulin promotes glycogen synthesis, lipid synthesis, protein synthesis, DNA synthesis, and cellular growth and differentiation. Once glucose gets absorbed from a meal, it enters the blood, and then the pancreas releases insulin. Insulin synthesis occurs in the beta cells of the pancreas initially as preproinsulin. Preproinsulin then converts to proinsulin, which then transforms into a single peptide with A, B, and C peptide units. The A and B peptides are joined by disulfide bonds to make insulin and are secreted into the bloodstream. Insulin binds to its cellular receptor. The insulin receptor is composed of alpha subunits, beta subunits, and a tyrosine kinase enzyme. When insulin binds to the alpha subunit, this triggers phosphorylation and activation of the target proteins intracellularly by the tyrosine kinase leading to many effects on cellular metabolism. Activation of the insulin receptor also leads to increased expression of GLUT (a glucose transporter) to the membrane surface and promotes the entry of glucose to the intracellular compartment and then undergoes cellular metabolism. Insulin signals glucose conversion to glycogen for storage and the formation of acetyl coenzyme A and triacylglycerol, which get stored in adipose tissue. Also, insulin directs amino acids for protein synthesis. Pancreatic β-cell dysfunction plays an important role in the pathogenesis of both type 1 and type 2 diabetes. Insulin, which is produced in β-cells, is a critical regulator of metabolism. Insulin is synthesized as preproinsulin and processed to proinsulin. Proinsulin is then converted to insulin and C-peptide and stored in secretary granules awaiting release on demand. Insulin synthesis is regulated at both the transcriptional and translational level. The cis-acting sequences within the 5′ flanking region and trans-activators including paired box gene 6 (PAX6), pancreatic and duodenal homeobox-1(PDX-1), MafA, and B-2/Neurogenic differentiation 1 (NeuroD1) regulate insulin transcription, while the stability of preproinsulin mRNA and its untranslated regions control protein translation. Insulin secretion involves a sequence of events in β-cells that lead to fusion of secretory granules with the plasma membrane. Insulin is secreted primarily in response to glucose, while other nutrients such as free fatty acids and amino acids can augment glucose-induced insulin secretion. In addition, various hormones, such as melatonin, estrogen, leptin, growth hormone, and glucagon like peptide-1 also regulate insulin secretion. Thus, the β-cell is a metabolic hub in the body, connecting nutrient metabolism and the endocrine system. Although an increase in intracellular [Ca2+] is the primary insulin secretary signal, cAMP signaling-dependent mechanisms are also critical in the regulation of insulin secretion.

Endogenous incretins such as such as glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP) are hormones regulating insulin secretion and glucose metabolism in mammals. Incretin acts by stimulating β cells of the pancreas to release more insulin in the blood. GIP is secreted by the enteroendocrine K-cells that are present in high density in the duodenum and upper jejunum but are present throughout the small intestine. Oral ingestion and subsequent absorption of nutrients such as glucose, high amounts of amino acids, and long-chain fatty acids trigger the secretion of GIP. Glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide (GIP), both incretin hormones inactivated by dipeptidyl peptidase-4 (DPP-4), stimulate insulin secretion after an oral glucose load via the incretin effect. In type 2 diabetes, this process can become blunted or even be absent; however, the utilization of pharmacological levels of GLP-1 can revive insulin excretion. The benefits of this form of therapy to treat type 2 diabetes include delayed gastric emptying and inhibiting the production of glucagon from pancreatic alpha cells if blood sugar levels are high. Furthermore, GLP-1 receptor agonists can decrease pancreatic beta-cell apoptosis while promoting their proliferation. GIP acts on class-II G-protein coupled receptors. The signaling mechanism for these receptors primarily involves the activation of adenylate cyclase/protein kinase A as well as phospholipase C/protein C cascades. High levels of GIP receptors get expressed in the beta cells of the pancreatic islets. Binding of GIP to its receptor increases the intracellular cAMP levels with a downstream increase in calcium ion concentration and exocytosis of insulin. GIP is rapidly inactivated by the ubiquitous enzyme dipeptidyl peptidase 4 (DPP-4), which is the same enzyme that cleaves GLP-1. However, the inactivation of GIP occurs at a slower rate than GLP-1, giving GIP a half-life of 5 to 7 minutes. DPP-4 cleaves alanine and proline residues in position 2 of the N-terminus in peptide chains. Thus, the substitution of L-alanine for D-alanine residue at position 2 of GIP makes it resistant to the action of DPP-4 and enhances its incretin effect. Incretins binds to the ATP-sensitive potassium channels on the pancreatic cell surface. This binding causes the reduction of the potassium conductance and, in consequence, the depolarization of the membrane. This depolarization stimulates calcium ion influx through voltage-sensitive calcium channels, raising intracellular concentrations of calcium ions, which results in the secretion (exocytosis) of insulin. These incretins are released in response to food intake and regulate both basal insulin secretion and meal-stimulated insulin release.

The hypothalamic–pituitary-gonadal axis (HPG axis) is an integrated pathway that examines the brains regulation over the reproductive system in males and females. Kisspeptin neurons in the hypothalamus activate gonadotropin-releasing hormone (GnRH) neurons to secrete GnRH. GnRH acts in the anterior pituitary to secrete follicle-stimulating hormone (FSH) and luteinizing hormone (LH). These two hormones act on different gonadal cells. In the testes, FSH acts on Sertoli cells to stimulate spermatogenesis and LH acts on Leydig cells to secrete testosterone. In the ovaries, LH acts on Theca cells to secrete androgens and FSH acts on Granulosa cells to convert those androgens to estrogen. FSH also influences oocyte development.

Hypothalamic-pituitary-adrenal (HPA) axis is a response to stressors that can be both internal and external in nature. The HPA axis is activated when a stressor transmit a signal to the hypothalamus that causes the release of corticotropin-releasing hormone (CRH). CRH then goes to act upon the anterior pituitary gland that triggers the release of adrenocorticotropic hormone (ACTH). ACTH travels to the adrenal cortex to elicit the release of cortisol a glucocorticoid known commonly as the stress hormone. Cortisol goes on to produce multiple downstream effects such as increasing cardiac output through increasing blood pressure and heart rate. Another effect is the inhibition of the hypothalamic-pituitary-gonadal axis (HPG axis) through inhibition of gonadotropin releasing hormone (GnRH), luteinizing hormone (LH), follicle stimulating hormone (FSH), teststerone and estrogen. The inhibition of the HPG axis causes dysfunction in reproductive function that can negatively impact both male and female.

The transcription of DNA is aided in large part by something called "homeodomain transcription factors". They are a diverse group of DNA binding factors. In fact, genes which are created with the aid of homeodomain factors tend to conglomerate and are responsible for anterior-posterior patterning. There is much to be said as well regarding the development and growth of cardiac myocytes and homedomain transcription factors. Indeed, at the early stages of the cell differentiation of cardiac myoctes a delicate balance of joint expression of several factors is needed for correct development (namely: serum response factor (SRF), and GATA4) and a homeodomain factor known as Nkx2-5! The joint expression of the aforementioned factors is the critical in the development of myocytes as well as gene expression in the cardiac region. To underline the importance of the homeodomain transcription factors, note that an error in the Nkx2-5 gene has severe consequences, which include, though are not necessarily limited to, embryonic lethality, as well as severe problems in general heart development. To put all this in context of the pathway in question, Hop actually stands for (Homeodomain Only Protein). The Hop gene plays an important role in the cardiac development we have been describing, as it too encodes a homedomain factor which plays an important role at the onset stages of cardiac development. The Hop gene is downstream of the Mkx2-5 factor we discussed earlier, and similar to it, improper activation of Hop can lead to severe cardiac development issues. In mice for example, not have the Hop gene results in alterations to the cell cycle. In particular, cardiac cells are unable to exit the cycle at the correct stage and continue grow after normal developmental stage has finished. There exists an interesting symbiosis between Hop and SRF. First, Hop regulates gene expression by either binding to SRF or by preventing SRF binding to DNA. This occurs because Hop does not have anything to bind to DNA with, and as such must have different methods to regulate gene expression. Second, when Hop blocks normal SRF binding, the results is that the activation of genes in the heart is affected and normal development does not occur. In a nutshell, what can be said about this tango action of SRF and Hop is this: during the first stages of development, what is observed is that the Hop interaction is one which results in a cessation of the differentiation processes which are induced by SRF. In the later stages, it appears that Hop reduces cell proliferation which is normally caused by SRF.

H1-antihistamines interfere with the agonist action of histamine at the H1 receptor and are administered to attenuate inflammatory process in order to treat conditions such as allergic rhinitis, allergic conjunctivitis, and urticaria. Wakefulness is regulated by histamine in the tuberomammillary nucleus, a part of the hypothalamus. Histidine is decarboxylated into histamine in the neuron. Histamine is transported into synaptic vesicles by a monoamine transporter then released into the synapse. Normally histamine would activate the H1 histamine receptor on the post-synaptic neuron in the tuberomammillary nucleus. Doxylamine inhibits the H1 histamine receptor, preventing the depolarization of the post-synaptic neuron. This prevents the wakefulness signal from being sent to the major areas of the brain, causing sleepiness.