Insulin is a major metabolism regulating hormone secreted by β-cells of the islets of Langerhans of the pancreas. The major function of insulin is to counter the concerted actions of a number of hyperglycemia-generating hormones and to maintain low blood glucose levels. In addition to its role in regulating glucose metabolism, insulin stimulates lipogenesis, diminishes lipolysis, and increases amino acid transport into cells. Because there are numerous hyperglycemic hormones, untreated disorders associated with insulin generally lead to severe hyperglycemia and shortened life span.
Insulin also exerts activities typically associated with growth factors. Insulin is a member of a family of structurally and functionally similar molecules that includes the insulin-like growth factors (IGF-1 and IGF-2), and relaxin. The tertiary structure of all four molecules is similar, and all have growth-promoting activities. Insulin modulates transcription and stimulates protein translocation, cell growth, DNA synthesis, and cell replication, effects that it holds in common with the insulin-like growth factors and relaxin.back to the top
Insulin is synthesized, from the INS gene, as a preprohormone in the β-cells of the islets of Langerhans. The INS gene is located on chromosome 11p15.5 and is composed of 3 exons that generate four alternatively spliced mRNAs, all of which encode the same 110 amino acid preproprotein. The signal peptide of preproinsulin is removed in the cisternae of the endoplasmic reticulum. The insulin proprotein is packaged into secretory vesicles in the Golgi, folded into its native structure, and locked in this conformation by the formation of two disulfide bonds. Specific protease activity cleaves the center third of the molecule, which dissociates as C peptide, leaving the amino terminal B peptide disulfide bonded to the carboxy terminal A peptide.
Insulin secretion from β-cells is principally regulated by plasma glucose levels. Increased uptake of glucose by pancreatic β-cells leads to a concomitant increase in metabolism. The increase in metabolism leads to an elevation in the ATP/ADP ratio. This in turn leads to the inhibition of an ATP-sensitive potassium channel (KATP channel). The net result is a depolarization of the cell leading to Ca2+ influx and insulin secretion.
Although glucose is the major fuel whose oxidation leads to energy-coupled insulin secretion there are other means for stimulated insulin secretion. One important process is referred to as the pyruvate cycle and involves coupling of amino acid metabolism to insulin secretion. The insulin secreting β-cells, in contrast to the liver, do not express the gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) but do express robust levels of the gluconeogenic enzyme pyruvate carboxylase (PC). Coupled with the activity of PC is the activity of malic enzyme which together, is the only means for pyruvate cycling in β-cells. Cytoplasmic malic enzyme plays an important role in acetyl-CoA transport from the mitochondria to the cytosol for its use in lipid biosynthesis. Human cells express both cytoplasmic and mitochondrial versions of malic enzyme. The role of the mitochondrial malic enzyme is principally to provide the cell with an alternate source of pyruvate under conditions where glycolytic flux in reduced. In these circumstances, the pyruvate generated by the actions of mitochondrial malic enzyme comes from fumarate precursors such as glutamine. When glutamine is de-aminated by glutaminase the resulting glutamate can also be de-aminated by glutamate dehydrogenase yielding 2-oxoglutarate (α-ketoglutarate) which can then be shunted to malate synthesis in the TCA cycle. The malate can then be decarboxylated to pyruvate via mitochondrial malic enzyme. The pyruvate can then be decarboxylated by the PDHc and the resulting acetyl-CoA can enter the TCA cycle ultimately allowing for glutamine carbons to be oxidized for ATP synthesis. Within β-cells of the pancreas, this process, driven by mitochondrial malic enzyme serves as an important means for the use of amino acid carbon oxidation for the stimulated secretion of insulin. Indeed, this process is energetically equal to glucose-stimulated insulin secretion (GSIS).
The KATP channel is a complex of 8 polypeptides comprising four copies of the protein encoded by the ABCC8 (ATP-binding cassette, sub-family C, member 8) gene and four copies of the protein encoded by the KCNJ11 (potassium inwardly-rectifying channel, subfamily J, member 11) gene. The ABCC8 encoded protein is also known as the sulfonylurea receptor (SUR). The KCNJ11 encoded protein forms the core of the KATP channel and is called Kir6.2. The KCNJ11 gene is located on chromosome 11p15.1 and is composed of 3 exons that generate two alternatively spliced mRNAs encoding two protein isoforms (isoform 1 is 390 amino acids and isoform 2 is 303 amino acids). Mutations in the KCNJ11 gene are associated with transient neonatal diabetes mellitus type 3 (TNDM3), permanent neonatal diabetes mellitus (PNDM) familial persistent hyperinsulinemic hypoglycemia of infancy (PHHI), and also contributes to an autosomal dominant form of diabetes termed non-insulin-dependent diabetes mellitus type II. The ABCC8 gene is also located on chromosome 11p15.1 and is composed of 39 exons that generate two alternatively spliced mRNAs encoding two protein isoforms (isoform 1 is 1582 amino acids and isoform 2 is 1581 amino acids). Mutations in the ABCC8 gene are also associated with the autosomal dominant form of diabetes termed non-insulin-dependent diabetes mellitus type II and with an autosomal recessive disorder termed hyperinsulinemic hypoglycemia of infancy. As might be expected, the role of KATP channels in insulin secretion presents a viable therapeutic target for treating hyperglycemia due to insulin insufficiency as is typical in type 2 diabetes.
Chronic increases in numerous other hormones, such as growth hormone, placental lactogen, estrogens, and progestins, up-regulate insulin secretion, probably by increasing the preproinsulin mRNA and enzymes involved in processing the increased preprohormone.
Mechanism of glucose-stimulated insulin secretion, GSIS. Increased blood glucose results in uptake by pancreatic β-cells through GLUT2. The glucose is oxidized to pyruvate via glycolysis. The pyruvate is oxidized by the PDHc and the resulting acetyl-CoA is oxidized in the TCA cycle. The resulting NADH and FADH2 are oxidized via the oxidative phosphorylation machinery resulting in increased ATP levels. The increased ATP inhibits the KATP channel resulting in membrane depolarization leading to an influx of Ca2+ ions triggering migration of insulin-containing vesicle to the plasma membrane releasing the insulin to the blood.