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Insulin Regulation

  • The primary physiological variable which controls insulin release from beta cells is the concentration of blood glucose. However, a variety of hormones can modulate beta cell-mediated release of insulin allowing fine-tuning of insulin levels to physiological demands.
Glucose Regulation
  • Overview
    • The molecular mechanism by which beta cells sense and respond to changes in blood glucose concentration is complex and involves multiple steps. However, a comprehensive understanding of this process is critical for appreciating the mechanism of action of several pharmaceuticals used to treat diabetic patients.
  • Glucose Entry
    • Glucose enters beta cells passively via facilitate diffusion through the membrane protein GLUT2. Because entry of glucose occurs passively, changes in blood glucose concentration will result in proportional changes to intracellular beta cell glucose concentrations. Consequently, intracellular glucose concentration can act as a proxy value for blood glucose concentration.
  • ATP Generation
    • Intracellular glucose within the beta cells undergoes glycolysis and results in production of ATP. Importantly, intracellular glucose levels appear to be proprotional to intracellular ATP levels, allowing ATP concentration to act as a proxy for intracellular glucose concentration.
  • ATP-gated Potassium Channels
    • The beta cell membrane displays some low permeability to positive ions such as Na+ at baseline. Therefore, in the absence of other factors the beta cell membrane will slowly depolarize as positive ions leak into the cell. Beta cells also possess K+ channels whose conductance is sensitive to changes in intracellular ATP levels. At high intracellular ATP concentrations the potassium channels display minimal K+ permeability and thus the low sodium permeability is unopposed and the beta cell slowly depolarizes.
    • However, at low intracellular ATP concentrations the potassium channels display high permeability, allowing positive ions to efflux from the cell, resulting in beta cell hyperpolarization. Given this relationship between ATP concentration and membrane polarization, the membrane potential of the beta cell acts as a proxy for intracellular ATP concentration. It should be pointed out that the relationship between ATP concentration and beta cell membrane potential is relatively smooth and does not result in action potential-like spikes in membrane potential as observed in muscles or neurons.
  • Voltage-gated Calcium Channels
    • The beta cell membrane possess voltage-gated calcium channels whose conductance is modulated by the membrane potential. When beta cells are depolarized the calcium channels open and thus allow influx of calcium into the beta cell, raising intracellular Ca++ concentration. In contrast, when beta cells are hyperpolarized the calcium channels remain closed and thus little intracellular calcium concentration is observed. Given this relationship, the intracellular calcium concentration acts as a proxy for beta cell membrane potential.
  • Calcium-dependent Insulin Secretion
    • The final link which completes the connection between blood glucose concentration and insulin secretion is calcium-dependent exocytosis of insulin-containing secretory vesicles. The rate at which this exocytic process occurs is proportion to intracellular calcium concentration. Therefore, higher intracellular calcium levels result in enhanced beta cell insulin release and lower intracellular calcium concentrations result in reduced beta cell insulin release.
  • Net Effect
    • As can be observed from the above discussion, the connection between blood glucose concentration and beta cell insulin release involves a set of proxy molecules whose concentrations proportionally rise and fall with that of blood glucose. The net effect of this mechanism is that increased levels of blood glucose result in increased levels of insulin secretion by beta cells whereas reduced levels of blood glucose result in lower levels of insulin secretion.
Hormonal Modulation
  • Although blood glucose concentration is by far the most important factor determining insulin release by beta cells a variety of physiological hormones can modulate the responsiveness of beta cells to blood glucose. he most important hormonal modulator is Gastric Inhibitory Peptide (GIP) which is released from cells in the small intestine in response to the presence of nutrients and enhances insulin release from beta cells. GIP-mediated boosting of insulin secretion is likely designed to produce a rise in insulin levels to accommodate the anticipated influx of glucose from the ingested meal.