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Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance.

Villareal DT, Koster JC, Robertson H, Akrouh A, Miyake K, Bell GI, Patterson BW, Nichols CG, Polonsky KS - Diabetes (2009)

Bottom Line: Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity.The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT

Objective: The E23K variant in the Kir6.2 subunit of the ATP-sensitive K(+) channel (K(ATP) channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance.

Research design and methods: Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted.

Results: Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.

Conclusions: The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes.

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Related in: MedlinePlus

Hepatic insulin sensitivity and peripheral insulin sensitivity from the hyperinsulinenimic-euglycemic clamp with stable-isotope–tracer infusion (A) and whole-body insulin sensitivity from the OGTT (B) in the K/K (□) and E/E (■) groups. Values are means ± SE. *P < 0.05 for the differences between groups.
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Figure 6: Hepatic insulin sensitivity and peripheral insulin sensitivity from the hyperinsulinenimic-euglycemic clamp with stable-isotope–tracer infusion (A) and whole-body insulin sensitivity from the OGTT (B) in the K/K (□) and E/E (■) groups. Values are means ± SE. *P < 0.05 for the differences between groups.

Mentions: The clinical findings described above (of reduced insulin secretion with normal glucose concentrations) suggest a simultaneous change in insulin sensitivity. Hyperinsulinemic-euglycemic clamp experiments revealed that hepatic insulin sensitivity was significantly greater (2.4 ± 0.4 vs. 1.5 ± 0.2 [1,000/μmol · kg fat-free mass−1 · min−1 · pmol−1 · l−1]; P < 0.05) in subjects with the K/K genotype (Fig. 6A). There was also a strong trend (0.19 ± 0.03 vs. 0.14 ± 0.2 μmol · kg fat-free mass−1 · min−1 · pmol−1 · l−1; P < 0.10) for an increase in peripheral insulin sensitivity, although the differences were not statistically significant. Similar trends were observed for whole-body insulin sensitivity as assessed from the OGTT (Fig. 6B). Glucose infusion rate, plasma glucose, insulin, glucagon, and tracer-to-tracee ratio are presented in the online appendix (available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0025/DC1).


Kir6.2 variant E23K increases ATP-sensitive K+ channel activity and is associated with impaired insulin release and enhanced insulin sensitivity in adults with normal glucose tolerance.

Villareal DT, Koster JC, Robertson H, Akrouh A, Miyake K, Bell GI, Patterson BW, Nichols CG, Polonsky KS - Diabetes (2009)

Hepatic insulin sensitivity and peripheral insulin sensitivity from the hyperinsulinenimic-euglycemic clamp with stable-isotope–tracer infusion (A) and whole-body insulin sensitivity from the OGTT (B) in the K/K (□) and E/E (■) groups. Values are means ± SE. *P < 0.05 for the differences between groups.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2712777&req=5

Figure 6: Hepatic insulin sensitivity and peripheral insulin sensitivity from the hyperinsulinenimic-euglycemic clamp with stable-isotope–tracer infusion (A) and whole-body insulin sensitivity from the OGTT (B) in the K/K (□) and E/E (■) groups. Values are means ± SE. *P < 0.05 for the differences between groups.
Mentions: The clinical findings described above (of reduced insulin secretion with normal glucose concentrations) suggest a simultaneous change in insulin sensitivity. Hyperinsulinemic-euglycemic clamp experiments revealed that hepatic insulin sensitivity was significantly greater (2.4 ± 0.4 vs. 1.5 ± 0.2 [1,000/μmol · kg fat-free mass−1 · min−1 · pmol−1 · l−1]; P < 0.05) in subjects with the K/K genotype (Fig. 6A). There was also a strong trend (0.19 ± 0.03 vs. 0.14 ± 0.2 μmol · kg fat-free mass−1 · min−1 · pmol−1 · l−1; P < 0.10) for an increase in peripheral insulin sensitivity, although the differences were not statistically significant. Similar trends were observed for whole-body insulin sensitivity as assessed from the OGTT (Fig. 6B). Glucose infusion rate, plasma glucose, insulin, glucagon, and tracer-to-tracee ratio are presented in the online appendix (available at http://diabetes.diabetesjournals.org/cgi/content/full/db09-0025/DC1).

Bottom Line: Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity.The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion.

View Article: PubMed Central - PubMed

Affiliation: Department of Medicine, Washington University School of Medicine, St. Louis, Missouri, USA.

ABSTRACT

Objective: The E23K variant in the Kir6.2 subunit of the ATP-sensitive K(+) channel (K(ATP) channel) is associated with increased risk of type 2 diabetes. The present study was undertaken to increase our understanding of the mechanisms responsible. To avoid confounding effects of hyperglycemia, insulin secretion and action were studied in subjects with the variant who had normal glucose tolerance.

Research design and methods: Nine subjects with the E23K genotype K/K and nine matched subjects with the E/E genotype underwent 5-h oral glucose tolerance tests (OGTTs), graded glucose infusion, and hyperinsulinemic-euglycemic clamp with stable-isotope-labeled tracer infusions to assess insulin secretion, action, and clearance. A total of 461 volunteers consecutively genotyped for the E23K variant also underwent OGTTs. Functional studies of the wild-type and E23K variant potassium channels were conducted.

Results: Insulin secretory responses to oral and intravenous glucose were reduced by approximately 40% in glucose-tolerant subjects homozygous for E23K. Normal glucose tolerance with reduced insulin secretion suggests a change in insulin sensitivity. The hyperinsulinemic-euglycemic clamp revealed that hepatic insulin sensitivity is approximately 40% greater in subjects with the E23K variant, and these subjects demonstrate increased insulin sensitivity after oral glucose. The reconstituted E23K channels confirm reduced sensitivity to inhibitory ATP and increase in open probability, a direct molecular explanation for reduced insulin secretion.

Conclusions: The E23K variant leads to overactivity of the K(ATP) channel, resulting in reduced insulin secretion. Initially, insulin sensitivity is enhanced, thereby maintaining normal glucose tolerance. Presumably, over time, as insulin secretion falls further or insulin resistance develops, glucose levels rise resulting in type 2 diabetes.

Show MeSH
Related in: MedlinePlus