TY - JOUR
T1 - ATP-Sensitive Potassium Channels in Hyperinsulinism and Type 2 Diabetes
T2 - Inconvenient Paradox or New Paradigm?
AU - Nichols, Colin G.
AU - York, Nathaniel W.
AU - Remedi, Maria S.
N1 - Funding Information:
Human capital and tastes will certainly affect research productivity. Those most able and those who like to perform research will, all things being equal, be more productive. Human capital is proxied with four dummy variables. The first measures whether a faculty member had received a fellowship, scholarship, or grant during graduate school. Because these financial supports are usually awarded based on merit, this variable proxies raw ability. In addition to ability, research training will also affect productivity (Buchmueller et al., 1999; Wanner et al., 1981). The second dummy variable measures whether the faculty member had a research assistantship in graduate school, while two other variables indicate the highest degree earned, either a Ph.D. or a professional degree.
Publisher Copyright:
© 2022 by the American Diabetes Association.
PY - 2022/3/1
Y1 - 2022/3/1
N2 - Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
AB - Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
UR - http://www.scopus.com/inward/record.url?scp=85125214811&partnerID=8YFLogxK
U2 - 10.2337/db21-0755
DO - 10.2337/db21-0755
M3 - Article
C2 - 35196393
AN - SCOPUS:85125214811
SN - 0012-1797
VL - 71
SP - 367
EP - 375
JO - Diabetes
JF - Diabetes
IS - 3
ER -