Glucose enters beta cells through the GLUT2 transporter, facilitated by step 1. Once inside the cell, glucose is converted to G6P by glucokinase, also known as the "glucose sensor" of the beta cell, in step 2. This conversion rate is directly related to insulin secretion. The metabolism of G6P through glycolysis, the TCA cycle, and oxidative phosphorylation by beta cells increases the ATP:ADP ratio, leading to the closure of an ATP-sensitive K+ channel in step 4. This causes the beta cell membrane to depolarize, opening voltage-gated Ca++ channels in step 6. The increase in intracellular Ca++ activates the exocytosis of insulin/proinsulin-containing secretory granules through microtubule-mediated mechanisms in step 7.

When glucose is ingested, it has a greater impact on insulin secretion compared to injected glucose due to the incretin effect. This effect is caused by incretin hormones released from the gastrointestinal tract in response to glucose. One important incretin hormone is glucagon-like peptide 1 (GLP-1), which is released by L cells of the ileum when glucose is present in the ileal lumen. GLP-1 circulates and binds to the Gs-coupled GLP1 receptor (GLP1R) on beta cells. This binding activates the GLP1R/Gs/adenylyl cyclase/protein kinase A (PKA) signaling pathway, enhancing the intracellular effects of Ca++ on insulin secretion. However, GLP-1 is rapidly degraded in the circulation by dipeptidyl peptidase 4 (DPP-4).

Insulin secretion is primarily regulated by sympathetic autonomic control through α2-adrenergic receptors, which dampens its secretion. Norepinephrine or epinephrine binding to these receptors decreases cyclic adenosine monophosphate (cAMP), potentially by closing Ca++ channels. This adrenergic inhibition of insulin secretion helps protect against hypoglycemia, particularly during exercise. Beta cells also express Gs-coupled β2-adrenergic receptors, which play a minor role in promoting insulin secretion. However, it is important to note that β-adrenergic receptor agonists oppose the actions of insulin on overall metabolism and may antagonize the effects of administered insulin in diabetic individuals. Conversely, β-blockers (β-adrenergic receptor antagonists) may increase the severity of hypoglycemic episodes in patients receiving exogenous insulin.
Fig. 39.8 ). Entry of glucose into beta cells is facilitated by the GLUT2 transporter (step 1). Once glucose enters the beta cell, it is phosphorylated to G6P by the low-affinity hexokinase glucokinase (step 2). Glucokinase is referred to as the “glucose sensor” of the beta cell because the rate of glucose entry is correlated to the rate of glucose phosphorylation, which in turn is directly related to insulin secretion. Metabolism of G6P through glycolysis, the TCA cycle, and oxidative phosphorylation by beta cells increases the intracellular ATP : ADP ratio (step 3) and closes an ATP-sensitive K+ channel (step 4). This results in depolarization of the beta cell membrane (step 5), which opens voltage-gated Ca++ channels (step 6). Increased intracellular [Ca++] activates microtubule-mediated exocytosis of insulin/proinsulincontaining secretory granules (step 7).
Ingested glucose has a greater effect on insulin secretion than injected glucose. This phenomenon, called the incretin effect, is due to stimulation by glucose of incretin hormones from the gastrointestinal tract. One clinically relevant incretin hormone is glucagon-like peptide 1 (GLP-1), which is released by L cells of the ileum in response to glucose in the ileal lumen (
Fig. 39.9 ). As a hormone, GLP-1 enters the circulation and ultimately binds to the Gs-coupled GLP1 receptor (GLP1R) on beta cells. This GLP1R/Gs/adenylyl cyclase/protein kinase A (PKA) signaling pathway amplifies the intracellular effects of Ca++ on insulin secretion. GLP-1 is rapidly degraded in the circulation by dipeptidyl peptidase 4 (DPP-4).
706 SECTION8Berne & Levy Physiology •Fig. 39.8 Secondaryregulatorsofinsulinsecretion.Seetextforexplanationofabbreviations.Specific amino acids (Eating a meal) AA transporter ATP ˜CA2+ °cAMP ˛ CELL ˜cAMP M3R (Gq)ACh Parasympathetic innervation (Anticipating & ingesting a meal) Norepinephrine, epinephrine Sympathetic innervation adrenal medulla (Exercise, Hypoglycemia) ? ˛2AR (Gs) ˛2AR Agonists ˙2AR (Gi) ˙2AR Agonists Insulin
Fig. 39.10 ). Insulin secretion is primarily dampened by sympathetic autonomic regulation through α2-adrenergic receptors. Binding of norepinephrine or epinephrine to α2-adrenergic receptors decreases cyclic adenosine mono-phosphate (cAMP), possibly by closing Ca++ channels (see
Fig. 39.6 ). Adrenergic inhibition of insulin serves to protect against hypoglycemia, especially during exercise. Beta cells also express Gs-coupled β2-adrenergic receptors that normally play a minor role in promoting insulin secretion. Note, however, that β-adrenergic receptor agonists oppose the actions of insulin on overall metabolism and may antagonize the actions of administered insulin in diabetics. Conversely, β-blockers (i.e., β-adrenergic receptor antagonists) may increase the severity of hypoglycemic episodes in patients receiving exogenous insulin.