Channeling β-cell Maturity: KATP Surface Localization Imparts Glucose Sensing.

Neonatal β-cells exhibit reduced glucose control of insulin secretion resulting in hyperinsulinemia during the first 24 to 72 hours following birth. Neonatal β-cells mature over several days, leading to glucose-stimulated insulin secretion (GSIS), which is required to maintain glucose homeostasis. During maturation β-cell protein/messenger RNA expression changes, and as a result Ca2+ handling, metabolism, and insulin granule exocytosis are also altered (1-4). Adenosine 5′-triphosphate (ATP)-sensitive K+ (KATP) channels are the primary ion channels required for mature β-cell glucose-mediated Ca2+ entry and GSIS, and thus altered KATP activity due to ATP availability and/or sensitivity contributes to β-cell glucose sensitivity (5, 6). In a recent issue of Endocrinology, Yang et al (2) identified increasing β-cell KATP surface localization as another important component of KATP regulation during maturation. Thus, multiple distinct mechanisms converge to promote glucose control of β-cell KATP function and facilitate GSIS during maturation.

KATP is active at low glucose in mature β cells, holding membrane potential (Vm) in a hyperpolarized state, and thus preventing Ca2+ influx and insulin secretion (1, 2, 5-7). Neonatal β-cells display reduced KATP activity during hypoglycemia, resulting in greater Vm depolarization, which triggers Ca2+ influx through voltage-dependent Ca2+ channels leading to increased insulin secretion (1, 2). Yang and colleagues (2) determined that while KATP subunit gene expression is unchanged during maturation, reduced KATP surface localization contributes to the left-shift in neonatal β-cell GSIS. Therefore, Yang et al (2, 5) suggest that altered KATP activity during maturation does not result exclusively from increased ATP availability and/or sensitivity, but also from trafficking changes. While the mechanism remains to be elucidated, many factors including adenosine monophosphate–activated protein kinase (AMPK) and 3′,5′-cyclic adenosine monophosphate (cAMP)-dependent protein kinase A (PKA) signaling as well as actin remodeling influence β-cell KATP plasma membrane trafficking (2, 6). As β-cells display enhanced AMPK expression/activity during maturation, Yang et al (2, 4) proposed this as a possible mechanism. Moreover, because neonatal β cells do not generate cAMP in a glucose-dependent manner, increasing PKA activity during maturation could also affect KATP trafficking (2). The importance of cAMP during β-cell maturation was noted by Yang and colleagues (2), who used a phosphodiesterase inhibitor to amplify neonatal β-cell cAMP and augment insulin secretion. Furthermore, alterations in glucose metabolism during maturation would be predicted to affect β-cell actin remodeling, and thus could influence KATP surface localization (7). Therefore, future studies are important for determining the mechanism(s) controlling KATP surface localization during β-cell maturation.

Metabolic changes during β-cell maturation also influence GSIS. Neonatal β-cells display elevated ATP levels at low glucose concentrations and diminished glucose-stimulated ATP production (5). This is due in part to enhanced amino acid metabolism and reduced expression of glycolytic enzymes and NADH shuttles (3, 4). As glycolysis is decreased and decoupled from oxidative phosphorylation in neonatal β-cells (3), Yang et al (2) activated mitochondrial glutamate dehydrogenase and observed a left-shift in BCH-mediated insulin secretion similar to the left-shift in glucose sensitivity. The authors also found that KATP currents are reduced in neonatal β-cells, and, based on these data, concluded that increased ATP sensitivity is due to decreased KATP surface localization (2). However, if diminished plasma membrane KATP accounts for enhanced ATP sensitivity, neonatal β-cells would also be predicted to be more responsive to tolbutamide, but instead they exhibited reduced tolbutamide sensitivity (2). The authors propose that this recapitulates previous experiments in KATP subunit knockout (KO) islets that also show reduced tolbutamide sensitivity (2), but the apparent disconnect in neonatal β-cell GSIS following KATP closure with ATP or sulfonylureas remains an interesting area of exploration. While Yang et al (2) suggest that both BCH and glucose left-shift insulin secretion because of steps downstream of metabolism (eg, decreased KATP activity and/or surface localization), they also indicated that proximal factors may play a role. As amino acid metabolism is augmented in neonatal β-cells (4), BCH-mediated ATP production could be altered. Basal intracellular Ca2+ is also elevated in neonatal β-cells (1), which would increase mitochondrial Ca2+ and potentially metabolism. Moreover, the authors make an important point that KATP KO alters β-cell metabolism (ie, elevated glutaminolysis) thus, decreased surface expression of KATP could have a similar impact (2). Further experiments are necessary to determine the contributions of metabolism as well as KATP ATP sensitivity and surface localization to β-cell glucose sensitivity during maturation.

β-cells sense and respond to environmental signals, which affect maturation and glucose sensitivity (4, 8). This is exemplified by Yang and colleagues (2), who found that culture of adult islets left-shifts glucose sensitivity in part by decreasing KATP surface localization; this indicates that external stimuli are required to maintain plasma membrane KATP. However, culture of neonatal islets increased glucose responsiveness (2), which suggests that β-cell glucose sensitivity is regulated both by positive and negative microenvironmental signaling modalities. Many aspects of islet microenvironment change during development including cell-cell junctional coupling, intraislet vascularization, and islet paracrine factor secretion (4, 8). β-cell gap junctional coupling is required for islet Ca2+ oscillation synchronization, and their disruption alters both basal insulin secretion and GSIS (4). Importantly, gap junctional formation has been linked to β-cell maturation and indeed Yang et al (2) suggest this may contribute to increased glucose responsiveness in adult β cells (4, 8). Mature islets are also characterized by a dense and highly specialized capillary network, which enables rapid glucose sensing and access to sufficient oxygen to meet the metabolic load of GSIS (8). Neonatal intraislet vascularization increases quickly post partum, and thus enhanced supplies of oxygen and/or nutrients could contribute to β-cell maturation (2, 4, 8). Finally, insulin secretion is tightly regulated by secretion of other islet hormones. For example, glucagon signaling augments GSIS; however, neonatal α-cell glucagon secretion is not stimulated by low glucose, and thus could contribute to decreased neonatal β-cell glucose sensitivity (4, 8). These are only a few of the many factors that could alter β-cell glucose sensitivity, and thus future studies are essential to elucidate how microenvironmental control of KATP surface localization affects glucose sensitivity.

The manuscript by Yang et al (2) illuminates increasing KATP surface localization as an important mechanistic underpinning β-cell maturation and GSIS. An incomplete understanding of the mechanisms guiding β-cell maturation is a barrier to the production of functional β cells from human embryonic stem cells/induced pluripotent stem cells. Therefore, uncovering the intrinsic and extrinsic factors that regulate KATP surface expression is expected to lead to novel strategies for improving β-cell function and enhancing the utility of stem-cell–derived β cells.