Glucose Stimulates Ca2+ Influx and Insulin Secretion in 2-Week-old β-Cells Lacking ATP-sensitive K+ Channels

Abstract

Fine control of insulin secretion by pancreatic ␤-cells is critical for glucose homeostasis: excessive release causes hypoglycemia, whereas insufficient insulin leads to diabetes. Glucose exerts its control on ␤-cells via two major, hierarchical signaling pathways (1). The triggering pathway requires functional ATP-sensitive K ϩ channels (K ATP channels) 2 to produce the essential rise in cytosolic Ca 2ϩ concentration ([Ca 2ϩ ] c ) through the following sequence of events. When the glucose concentration increases, oxidative glycolysis in ␤-cells accelerates, leading to changes in cytosolic adenine nucleotides, which close K ATP channels in the plasma membrane. The resulting depolarization opens voltage-dependent Ca 2ϩ channels, permitting Ca 2ϩ influx and a rise in [Ca 2ϩ ] c that triggers exocytosis of insulin granules (2-8). Simultaneously, glucose activates an amplifying pathway, also termed the augmentation or K ATP channel-independent pathway, which does not increase [Ca 2ϩ ] c further but augments the secretory response to the triggering Ca 2ϩ signal. The mechanisms for this metabolic amplification have not been fully identified but are distinct from neuro-hormonal amplification (1, 9 -13).K ATP channels in ␤-cells are composed of the high affinity sulfonylurea receptor (SUR1-ABCC8) and the pore-forming K IR 6.2 (KCNJ11) subunit (14). Mice lacking K ATP channels in their ␤-cells (Sur1KO or Kir6.2KO mice) are valuable models to investigate the regulation of insulin secretion without using pharmacological agents. They were originally developed (15-17) with the aim of understanding the pathology of congenital hyperinsulinism, a disease due, in 50% of cases, to inactivating mutations of K ATP channels (2, 18 -20). However, unlike the infants who suffer from severe hypoglycemia during the neonatal period, Sur1KO or Kir6.2KO mice are not hypoglycemic except for the first 48 -72 h (15, 16). In vitro islet studies done in these mice have yielded controversial results. Whereas, several groups reported that these islets are poorly sensitive to glucose stimulation, at least in the absence of simultaneous activation of protein kinases A or C (15-17, 21), we observed acute stimulation of insulin secretion by glucose in Sur1KO islets, which we attributed to both triggering and amplifying pathways (22). Smaller but distinct effects of glucose in the same model were also demonstrated by others (23,24).Previous in vitro studies of islets lacking K ATP channels have been restricted to adult animals. Because ␤-cells undergo functional maturation during the postnatal period (25,26), it is unclear whether the behavior of adult Sur1KO islets is similar to that of young Sur1KO islets or has been altered by adaptative processes, thereby invalidating all extrapolations to a human pathology of infancy. In the present study we investigated the * This work was supported by the Fonds National de la Recherche Scientifique (Grant 3.4552.04), the Belgian Science Policy (Grant PAI 5/17), the Direction de la Recherche Scientifique of...

Mapping of long-range INS promoter interactions reveals a role for calcium-activated chloride channel ANO1 in insulin secretion

“…K ATP channels are not the sole mechanism for the regulation of these complex processes, however. Glucose still induces electrical activity and insulin secretion even when K ATP channels are inactivated (24,25,35,36). Chloride levels in β cells are known to be important for insulin secretion, and chloride channel(s) have been proposed as part of the background channels contributing to the regulation of electrical activity and insulin secretion in β cells, although the identity of such a channel remains elusive (24,25).…”

Oscillatory control of insulin secretion

“…It is this depolarization that raises [Ca 2+ ] i and triggers secretion by opening voltage-dependent Ca 2+ channels (see below). However, there may be additional mechanisms contributing to depolarization, since glucose can still stimulate some voltagedependent Ca 2+ entry in β-cells lacking functional K ATP channels (Szollosi et al, 2007).…”

“…The situation is further complicated by the fact that Ca 2+ stimulates metabolism by activating mitochondrial dehydrogenases (McCormack et al, 1990;Civelek et al, 1996;Pitter et al, 2002) and that Ca 2+ may regulate glycolytic enzymes (Jung et al, 2000). Metabolic oscillations may indeed reflect intrinsic oscillatory mechanisms in glucose metabolism, but the oscillations are modified both by stimulatory and inhibitory feedback effects of Ca 2+ (Luciani et al, 2006;Bertram et al, 2007b (Henquin, 2000) or after knocking out functional K ATP channels (Nenquin et al, 2004;Szollosi et al, 2007). This K ATP channel-independent process is mostly considered as an amplification mechanism, which remains functionally silent unless [Ca 2+ ] i is elevated.…”

Molecular mechanisms triggered by low-calcium diets

“…Regarding molecular mechanisms, it has been shown that dietary Ca 2þ may lower the activity of the reninangiotensin system (94) and inhibit vascular smooth muscle cell constriction (95) . Besides, Ca 2þ facilitates weight loss (96) and stimulates insulin sensitivity (97) , which contribute to decreases in blood pressure. It remains unclear whether the Ca 2þ content alone or in combination with several components such as other minerals or proteins, peptides or amino acids are responsible for the anti-hypertensive effects of dairy products (96) .…”