Study On The Mutation Of ATP-sensitive Potassium Channel In A Type 2 Diabetes Mellitus Family

Diabetes mellitus (DM) is a group of chronic metabolic diseases characterized by high blood glucose levels, which result from defects in insulin secretion, or action, or both. It can also result in abnormal metabolism of carbohydrates, fats, and proteins and cause chronic damage to eye, kidneys, nerves and cadiovascular system. It can be divided physiopathologically into type1 diabetes mellitus (T1DM), type 2 diabetes mellitus (T2DM), gestational diabetes mellitus (GDM) and other special types of diabetes mellitus. Type 2 diabetes mellitus — the main form of diabetes mellitus that typically appears first in adulthood composes nealy 90% of all the diabetes. Developed economy and inactive life style have led to increased incidence of diabetes which has ranked top 3 in life-threatening diseases.Type 2 diabetes, with significant genetic heterogeneity and multiple environment risk factors, is well known for its complex etiology. More and more evidence showed type 2 diabetes mellitus is related to multiple factors such as heredity, life style and environment, among these, heredity has played a critical role. Recent studies have indicated that many gene regions of different races are related to diabetes mellitus. Genetic mutations and gene polymorphism lead to abnormality in differet phases of glucose metabolism. The genetic epidemiologic study in type 2 diabetes families, especially study of hereditary mode and single nucleotide polymorphisms (SNPs) of predisposing genes, have a profound meaning in primary prevention and high risk population screening.This study discussed the possible molecular mechanism of family-onset type2 diabetes mellitus by singling out five predisposing genes including ATP-sensitive potassium channel (KATP) in a type 2 diabetes mellitus family. First PCR amplification and DNA determination were used for screening, thenPCR-Single strand conformational polymorphism (PCR-SSCP) combined with DNA determination were employed to detect and analyze gene mutation of KATP.PART I Screening for predisposing genes of type 2 diabetes mellitusOBJECTIVE: To study the association between the mutations of sulfonylureareceptor (SUR1), inwardly rectifying potassium channel (Kir6.2), insulin (INS),insulin receptor substrate-1 (IRS-1), type 2 glucose transporter (GLUT2), isletamyloid polypeptide (IAPP) and type 2 diabetes mellitus in the proband and hisfather.METHODS: PCR amplification and DNA determination were used to detect themutation of the target gene.RESULTS: The change of the exon 16 -3C→T in SUR1 and Kir6.2 E23Koccurred in the proband and his father. The exon 18 ACC→ACT and the exon 31AGG→AGA in SUR1, Arg 65 His in INS, Gly 971 Arg in IRS-1, Thr 110 Ile inGLUT2, Ser 20 Gly in IAPP were not found.CONCLUSIONS: (1) The exon 16 -3C→T in SUR1 and Kir6.2 E23K werecorrelated with the proband and his father; (2) The exon 18 ACC→ACT and theexon 31 AGG→AGA in SUR1, Arg 65 His in INS, Gly 971 Arg in IRS-1, Thr 110He in GLUT2, Ser 20 Gly in IAPP were not correlated with the proband and hisfather.PART II Study on the mutation of ATP-sensitive potassium channel in a type 2 diabetes mellitus familyOBJECTIVE: In the pancreas, the ATP-sensitive potassium channel (KATP) is compsed of SUR1 and Kir6.2, which controlled the glucose-induced insulin secretion, participates in type 2 diabetes mellitus. The purpose of the study was to understand the mutations of KATP in a type 2 diabetes mellitus family.METHODS: We studied the mutation of the exon 16 -3C→T, exon 18ACC→ACT, exon 31 AGG→AGA in SUR1 and the Kir6.2 E23K by PCR-single strand conformation polymorphism (PCR-SSCP) and followed DNA sequencing.RESULTS: (1) The exon 18 ACC→ACT and the exon 31 AGG→AGA in SUR1 were not found; (2) The T allele frequency for the exon 16 -3C/T in SUR1 was 65%, 8% higher than that in type 2 diabetes mellitus. The exon 16 -3C→T in SUR1 occured in all T2DM patients of the family (100%); (3) The K allele frequency for the Kir6.2 E23K was 38%, 3% lower than that in type 2 diabetes. The E/K genetype occurred in the four T2DM patients of the family (66.7%).CONCLUSIONS: The mutation of the exon 16 -3C→T in SUR1 and Kir6.2 E23K is correlated with type 2 diabetes mellitus in this family.