ABCMdb

PMID: 11772909

Huopio H, Vauhkonen I, Komulainen J, Niskanen L, Otonkoski T, Laakso M
Carriers of an inactivating beta-cell ATP-sensitive K(+) channel mutation have normal glucose tolerance and insulin sensitivity and appropriate insulin secretion.
Diabetes Care. 2002 Jan;25(1):101-6., [PubMed]

Sentences

No. Mutations Sentence Comment

5 ABCC8 p.Val187Asp RESEARCH DESIGN AND METHODS - We studied 8 parents of CHI patients, all 8 of whom were heterozygous for the inactivating SUR1 mutation V187D, and 10 matched control subjects. Login to comment 7 ABCC8 p.Val187Asp RESULTS - Carriers of the V187D substitution had normal glucose tolerance, normal tissue sensitivity to insulin, and no signs of inappropriate insulin secretion. Login to comment 8 ABCC8 p.Val187Asp The normal insulin response to tolbutamide indicated that heterozygosity for the V187D mutation did not impair KATP channel function. Login to comment 31 ABCC8 p.Val187Asp We have identified a missense mutation, V187D, in the SUR1 gene that is responsible for the majority of severe CHI cases in Finland. Login to comment 35 ABCC8 p.Val187Asp To determine in vivo the effects of the heterozygous state of this mutation on the regulation of beta-cell secretion, whole-body glucose metabolism, and glucose homeostasis, including the counterregulatory system against hypoglycemia, we studied eight parents of CHI patients, all eight of whom are carriers of the V187D substitution. Login to comment 37 ABCC8 p.Val187Asp The subjects for the present study were the parents of five patients with diffuse CHI caused by the homozygous SUR1 mutation V187D. Login to comment 39 ABCC8 p.Val187Asp Genetic analysis confirmed that all eight parents were heterozygous carriers of the V187D mutation. Login to comment 49 ABCC8 p.Val187Asp Several weeks after the other tests, four carriers of the V187D mutation and six control subjects participated in the tolbutamide test. Login to comment 73 ABCC8 p.Val187Asp The tolbutamide test was performed in four V187D heterozygotes and six control subjects to investigate the beta-cell response to the KATP channel antagonist tolbutamide. Login to comment 75 ABCC8 p.Val187Asp It was thus hypothesized that the increment in insulin secretion would be lower in the V187D carriers if their KATP channels are defective. Login to comment 98 ABCC8 p.Val187Asp Altogether, 7 of 8 V187D carriers and 4 of 10 control subjects had suffered from hypoglycemic symptoms. Login to comment 99 ABCC8 p.Val187Asp ABCC8 p.Val187Asp OGTT All individuals in both study groups had normal glucose tolerance according to World Health Organization criteria (16), as determined by OGTT (fasting blood glucose: V187D heterozygotes 4.2-5.5 mmol/l, control subjects 2.8-6.2 mmol/l; 2-h blood glucose: V187D heterozygotes 2.8-6.2 mmol/l, control subjects 3.46.4 mmol/l). Login to comment 101 ABCC8 p.Val187Asp The blood glucose levels were similar in both groups (V187D heterozygotes and control subjects) at all time points measured after the oral glucose load. Login to comment 104 ABCC8 p.Val187Asp Moreover, the plasma insulin response, expressed as the incremental insulin area under the curve, was similar in the two groups (V187D heterozygotes 519 Ϯ 98 pmol/l ⅐ h, control subjects 553 Ϯ 89 pmol/l ⅐ h). Login to comment 106 ABCC8 p.Val187Asp Similarly, the incremental C-peptide area under the curve was comparable between the study groups (V187D hetrozygotes 3,125 Ϯ Figure 1-Blood glucose (A), plasma insulin (B), and plasma C-peptide (C) concentrations during the OGTT. Login to comment 107 ABCC8 p.Val187Asp E, Control subjects; f, SUR1 V187D heterozygotes. Login to comment 108 ABCC8 p.Val187Asp Table 1-Clinical and biochemical characteristics of the study groups Control subjects V187D carriers P n 10 8 Age (years) 35.6 Ϯ 1.1 35.3 Ϯ 0.9 NS Sex (M/F) 5/5 4/4 NS BMI (kg/m2 ) 23.2 Ϯ 0.6 24.0 Ϯ 1.2 NS Fasting blood glucose (mmol/l) 4.3 Ϯ 0.2 4.7 Ϯ 0.2 NS Fasting insulin (pmol/l) 49.2 Ϯ 6.6 42.0 Ϯ 5.4 NS Fasting C-peptide (pmol/l) 530 Ϯ 35 450 Ϯ 51 NS Systolic blood pressure (mmHg) 128 Ϯ 4 129 Ϯ 3 NS Diastolic blood pressure (mmHg) 84 Ϯ 2 76 Ϯ 2 NS HbA1c (%) 5.4 Ϯ 0.1 5.4 Ϯ 0.1 NS Fasting hepatic insulin extraction (pmol C-peptide/pmol P-insulin) 10.7 Ϯ 0.3 10.7 Ϯ 0.4 NS Data are means Ϯ SEM or n. Login to comment 113 ABCC8 p.Val187Asp Furthermore, the incremental glucose area under the curve was similar in both study groups (71.1 Ϯ 3.9 and 70.2 Ϯ 2.7 mmol/l ⅐ min for the V187D heterozygote group and control subjects, respectively). Login to comment 117 ABCC8 p.Val187Asp ABCC8 p.Val187Asp Finally, neither the counterregulatory hormone responses in normoglycemia (serum glucagon 84.3 Ϯ 5.5 vs. 81.0 Ϯ 9.9 pmol/l, serum epinephrine 0.14 Ϯ 0.03 vs. 0.24 Ϯ 0.05 nmol/l, serum norepinephrine 1.5 Ϯ 0.2 vs. 1.8 Ϯ 0.3 nmol/l, serum cortisol 213.3 Ϯ 37.4 vs. 253.8 Ϯ 30.7 nmol/l, and serum growth hormone 0.88 Ϯ 0.13 vs. 0.46 Ϯ 0.15 ␮g/l in the V187D heterozygote group and in the control group, respectively) and in hypoglycemia (serum glucagon 95.1 Ϯ 4.2 vs. 120.7 Ϯ 18.9 pmol/l, serum epinephrine 1.3 Ϯ 0.4 vs. 1.6 Ϯ 0.3 nmol/l, serum norepinephrine 1.9 Ϯ 0.3 vs. 2.1 Ϯ 0.3 nmol/l, serum cortisol 355.9 Ϯ 85.4 vs. 493.4 Ϯ 59.3 nmol/l, and serum growth hormone 11.4 Ϯ 2.9 vs. 14.7 Ϯ 3.9 ␮g/l in the V187D heterozygote group and control subjects, respectively) nor the symptoms of hypoglycemia evaluated during the hypoglycemic clamp differed significantly between the groups. Login to comment 118 ABCC8 p.Val187Asp Tolbutamide test Figure 4 shows that plasma insulin and C-peptide responses to the tolbutamide injection were similar in V187D heterozygotes and control subjects when expressed as the difference between the hormone levels measured at 0 and 3 min after the tolbutamide bolus. Login to comment 119 ABCC8 p.Val187Asp The incremental areas under the curve (0-10 min) did not differ, either (P-insulin 1,744 Ϯ 338 vs. 2,226 Ϯ 491 pmol/l ⅐ min and C-peptide 5,950 Ϯ 1,266 vs. 6,607 Ϯ 870 pmol/l ⅐ min for V187D carriers and control subjects, respectively). Login to comment 124 ABCC8 p.Val187Asp In this study, we investigated in detail the glucose metabolism of such individuals, who carried the previously described SUR1 loss of function mutation V187D (9). Login to comment 131 ABCC8 p.Val187Asp E, Control subjects; f, SUR1 V187D heterozygotes. Login to comment 133 ABCC8 p.Val187Asp E And Ⅺ, control subjects; f, SUR1 V187D heterozygotes. Login to comment 136 ABCC8 p.Val187Asp Our present findings, demonstrating normal insulin and C-peptide responses after tolbutamide injection, indicate that normal KATP channel function is maintained in the beta-cells of the SUR1 V187D heterozygotes. Login to comment 144 ABCC8 p.Val187Asp In our study, only one of the mothers of V187D homozygous patients had transiently elevated blood glucose levels during pregnancy. Login to comment 145 ABCC8 p.Val187Asp All V187D mutation carriers had normal glucose tolerance and normal rates of whole-body glucose uptake. Login to comment 146 ABCC8 p.Val187Asp In addition, first-phase insulin secretion, which is known to be impaired in individuals at high risk for type 1 (24) and type 2 (25,26) diabetes, was not impaired in subjects with the V187D substitution. Login to comment 147 ABCC8 p.Val187Asp Our results indicate that the carriers of the V187D substitution do not have any features of type 2 diabetes. Login to comment 150 ABCC8 p.Val187Asp In our study, 7 of the 8 V187D carriers but only 4 of the 10 control individuals had suffered from such symptoms. Login to comment 151 ABCC8 p.Val187Asp Therefore, we determined whether insulin levels of the V187D carriers were higher after overnight fasting and during hypoglycemia. Login to comment 160 ABCC8 p.Val187Asp In the present study, carriers of the V187D substitution had quite normal counterregulatory system function. Login to comment 163 ABCC8 p.Val187Asp Some mutations impair the function of KATP channels only slightly, whereas the V187D mutation leads to total inactivation of pancreatic beta-cell KATP channels. Login to comment