Insulin Biosynthesis,
Secretion, and Action
Biosynthesis
Insulin is produced in the beta ce ls
of the pancreatic islets. It is
initia ly synthesized as a single-chain 86-amino-acid precursor polypeptide, preproinsulin. Subsequent Proteolytic processing removes the amino terminal signal peptide, giving rise to proinsulin. Proinsulin is structura ly related to insulin-like growth factors I and II, which bind weakly to the insulin receptor. Cleavage of an internal 31-residue fragment from proinsulin generates the C peptide and the A (21 amino acids) and B (30 amino acids) chains of insulin, which are connected by disulfide bonds (Figure-1)The mature
insulin molecule and C peptide are stored together and co secreted from secretory granules in the beta ce ls. Because the C peptide is
cleared more slowly than insulin, it is a useful marker of insulin secretion and a lows discrimination of endogenous and exogenous sources of insulin in the evaluation of hypoglycemia.
Figure-1-showing the synthesis of Insulin
Secretion
Glucose is the key regulator of insulin secretion by the pancreatic beta ce l, although amino acids, ketones, various nutrients, gastrointestinal peptides, and neurotransmitters also influence insulin secretion. Glucose levels > 3.9 mmol/L (70 mg/dL) stimulate insulin synthesis, primarily by enhancing protein translation and processing. Glucose stimulation of insulin secretion begins with its transport into the beta ce l by the GLUT2 glucose transporter. Glucose phosphorylation by glucokinase is
the rate-limiting step that controls glucose-regulated insulin secretion. Further metabolism of glucose-
6-phosphate via Glycolysis generates ATP, which inhibits the activity of an ATP-sensitive K+ channel. This channel consists of two separate proteins: one is the binding site for certain oral hypoglycemic (e.g., sulfonylureas, meglitinides);
the other is an inwardly rectifying K+ channel protein Inhibition of this K+ channel induces beta ce l membrane depolarization, which opens voltage-dependent calcium channels (leading to an influx of calcium), and stimulates insulin secretion. (See figure-2)
Figure-2- showing mechanism of secretion of insulin
Insulin secretory profiles reveal a pulsatile pattern of hormone release, with sma l secretory bursts occurring about every
10 min, superimposed upon greater amplitude osci lations of about 80–150 min. Incretins are released from neuroendocrine ce ls
of the gastrointestinal tract fo lowing food ingestion and amplify glucose-stimulated insulin secretion and suppress glucagon secretion (Figure-3). Glucagon-like peptide 1 (GLP-1), the most potent incretin, is released
from L ce ls
in
the sma l intestine and that stimulates insulin secretion only when the blood glucose is above the fasting
level. Incretin analogues, such as exena-tide, are being used to enhance endogenous insulin secretion.
Figure-3- showing Insulin release. The release is more marked after oral glucose load due to the release of
Incretins from GIT.
Action
Once insulin is
secreted into the portal venous system, ~50% is degraded by the liver. Unextracted insulin enters the systemic circulation where it binds to receptors in target sites.
Figure-4 -showing the structure of Insulin receptor.The receptor is composed of two extracellular α-subunits that are each linked to a ß-subunit and to each other by disulfide bonds.
Insulin binding to its receptor stimulates intrinsic tyrosine kinase activity (See figure -5) leading to receptor autophosphorylation and the recruitment of intrace lular signaling molecules, such as insulin receptor substrates (IRS). IRS and other adaptor proteins initiate a complex cascade of phosphorylation and dephosphorylation reactions, resulting in the widespread metabolic and mitogenic effects of insulin. As an example, activation of the phosphatidylinositol-3′-kinase (PI-3-kinase) pathway stimulates translocation of glucose transporters (e.g., GLUT4) to
the ce l surface, an event that is crucial for glucose uptake by skeletal muscle and fat. Activation of
other insulin receptor signaling pathways induces glycogen synthesis, protein synthesis, lipogenesis, and regulation of various genes in insulin- responsive ce ls.
Figure-5- showing the
mechanism of action of Insulin
Glucose homeostasis reflects a balance between hepatic glucose production and peripheral glucose uptake and utilization. Insulin is
the most important regulator of this metabolic equilibrium, but neural input, metabolic signals, and other hormones (e.g., glucagon) result in integrated control of glucose supply and utilization.
In the fasting state, low insulin levels increase glucose production by promoting hepatic Gluconeogenesis and glycogenolysis and reduce glucose uptake in insulin-sensitive tissues (skeletal muscle and fat), thereby promoting mobilization of stored precursors such as amino acids and free fatty acids (lipolysis). Glucagon, secreted by pancreatic alpha ce ls
when blood glucose or insulin levels are low, stimulates glycogenolysis and gluconeogenesis by the liver and renal medu la.
Figure-6- showing glucose homeostasis mediated by Insulin
Postprandia ly, the glucose load elicits a rise in insulin and fa l in glucagon, leading to a reversal of these processes( Figure-6). Insulin, an anabolic hormone, promotes the storage of carbohydrate and fat and protein synthesis. The major portion of postprandial glucose is utilized by skeletal muscle, an effect of insulin-stimulated glucose uptake. Other tissues, most
notably the brain, utilize glucose in an insulin-independent fashion.
Insulin and Lipid Metabolism
The metabolic pathways for utilization of fats and carbohydrates are deeply and intricately intertwined. Considering insulin’s profound effects on carbohydrate metabolism, it stands to reason that insulin also has important effects on lipid metabolism, including the fo lowing:
Fatty acid synthesis-Insulin promotes synthesis of fatty acids in the liver. insulin is stimulatory to synthesis of glycogen in the liver. However, as glycogen accumulates to high levels (roughly 5% of liver mass), further synthesis is strongly suppressed.
When the liver is
saturated with glycogen, any additional glucose taken up by hepatocytes is
shunted into pathways leading to synthesis of fatty acids, which are exported from the liver as lipoproteins. The lipoproteins are ripped apart in the circulation, providing free fatty acids for use in other tissues, including adipocytes, which use them to synthesize triglyceride.
Fatty acid oxidation-Insulin inhibits breakdown of fat in adipose tissue by inhibiting the intrace lular lipase that hydrolyzes triglycerides to release fatty acids.
Synthesis
of Glycerol-Insulin facilitates entry of glucose into adipocytes, and within those ce ls, glucose can be used to synthesize glycerol. This glycerol, along with the fatty acids delivered from the liver, are used to synthesize triglyceride
within the adipocyte. By these mechanisms, insulin is
involved in further accumulation of triglyceride in fat ce ls.
From a whole body perspective, insulin has a fat-sparing effect. Not only does it drive most
ce
ls to preferentia ly oxidize carbohydrates instead of fatty acids for energy, insulin indirectly stimulates accumulation of fat in adipose tissue.
Figure-7 -showing the effect of Insulin of fatty acid synthesis and oxidation. Insulin inhibits hormone sensitive
lipase and hence inhibits adipolysis.
Other Notable
Effects of Insulin
Amino acid metabolism-In addition to insulin’s effect on entry of glucose into ce ls, it also stimulates the uptake of amino acids, again contributing to its overa l anabolic effect. When insulin levels are low, as in the fasting state, the balance is
pushed toward intrace lular protein degradation.
Electrolyte balance-Insulin also increases the permeability of many ce ls to potassium, magnesium and phosphate ions.
The effect on potassium is
clinica ly important. Insulin activates sodium-potassium ATPases in many ce ls, causing a flux of potassium into ce ls. Under certain circumstances, injection of insulin can ki l patients because of its ability to acutely suppress plasma potassium concentrations.
Insulin Deficiency and Excess Diseases
Diabetes me litus, the most
important metabolic disease ,is an insulin deficiency state. Two principal forms of this disease are recognized:
Type I or insulin-dependent diabetes
mellitus is
the result of a frank deficiency of insulin. The onset of this disease typica ly is in childhood. It is due to destruction pancreatic beta ce ls, most likely the result of autoimmunity to one or more components of those ce ls. Many of the acute effects of this disease can be contro led by insulin replacement therapy. Maintaining tight control of blood glucose concentrations by monitoring, treatment with insulin and dietary management wi l minimize the long-term adverse effects of this disorder on blood vessels, nerves and other organ systems, a lowing a healthy life.
Type II or non-insulin-dependent diabetes
mellitus begins as a syndrome of insulin resistance. That is, target tissues fail to respond appropriately to insulin. Typica ly, the onset of this disease is
in
adulthood. Despite monumental research efforts, the precise nature of the defects leading to type II diabetes have been difficult to ascertain, and the pathogenesis of this condition is plainly multifactorial. Obesity is clearly a major risk factor, but in some cases of extreme obesity in humans and animals, insulin sensitivity is
normal. Because there is not, at least initia ly, an inability to secrete adequate amounts of insulin, insulin injections are not useful for therapy. Rather the disease is contro led through dietary therapy and hypoglycemic agents.
Hyperinsulinemia or excessive insulin secretion is
most
commonly a consequence of insulin resistance, associated with type 2 diabetes or the metabolic syndrome. More rarely, hyperinsulinemia results from an insulin-secreting tumor (insulinoma) in the pancreas. Hyperinsulinemia due to accidental or deliberate injection of excessive insulin is dangerous and can be acutely life-threatening because blood levels of glucose drop rapidly and the brain becomes starved for
energy (insulin shock).
