Groop L C, Kankuri M, Schalin-Jäntti C, Ekstrand A, Nikula-Ijäs P, Widén E, Kuismanen E, Eriksson J, Franssila-Kallunki A, Saloranta C
Fourth Department of Medicine, Helsinki University, Finland.
N Engl J Med. 1993 Jan 7;328(1):10-4. doi: 10.1056/NEJM199301073280102.
The storage of glucose as glycogen in skeletal muscle is frequently impaired in patients with non-insulin-dependent diabetes mellitus (NIDDM) and their nondiabetic relatives. Despite an intensive search for candidate genes associated with NIDDM, no data have been available on the gene coding for the key enzyme of this pathway, glycogen synthase.
Using a human complementary DNA probe, the restriction enzyme Xbal, and Southern blot analysis, we identified two polymorphic alleles, A1 and A2, in the glycogen synthase gene. The gene was localized to chromosome 19. The A1A2 or A2A2 genotype was found in 30 percent of 107 patients with NIDDM but in only 8 percent of 164 nondiabetic subjects without a family history of NIDDM (P < 0.001). The diabetic patients with the A2 allele had a stronger family history of NIDDM (P = 0.019), a higher prevalence of hypertension (P = 0.008), and a more severe defect in insulin-stimulated glucose storage (P = 0.001) than the diabetic patients with the A1 allele. The concentration of the glycogen synthase protein in biopsy specimens of skeletal muscle from the patients with the A2 allele was normal, however, suggesting that expression of the gene was unaltered. The Xbal polymorphism was due to a change of a single base in an intron.
The Xbal polymorphism of the glycogen synthase gene identifies a subgroup of patients with NIDDM characterized by a strong family history of NIDDM, a high prevalence of hypertension, and marked insulin resistance.
在非胰岛素依赖型糖尿病（NIDDM）患者及其非糖尿病亲属中，骨骼肌中葡萄糖作为糖原的储存功能常常受损。尽管人们对与NIDDM相关的候选基因进行了深入研究，但关于该途径关键酶糖原合酶的编码基因尚无相关数据。
我们使用人互补DNA探针、限制性内切酶Xbal及Southern印迹分析，在糖原合酶基因中鉴定出两个多态性等位基因A1和A2。该基因定位于19号染色体。在107例NIDDM患者中，30%发现为A1A2或A2A2基因型，而在164例无NIDDM家族史的非糖尿病受试者中，只有8%为此基因型（P<0.001）。与携带A1等位基因的糖尿病患者相比，携带A2等位基因的糖尿病患者NIDDM家族史更强（P = 0.019），高血压患病率更高（P = 0.008），胰岛素刺激的葡萄糖储存缺陷更严重（P = 0.001）。然而，携带A2等位基因患者骨骼肌活检标本中糖原合酶蛋白浓度正常，提示该基因的表达未改变。Xbal多态性是由于一个内含子中的单个碱基变化所致。
糖原合酶基因的Xbal多态性可识别出一组NIDDM患者，其特征为NIDDM家族史强、高血压患病率高及明显的胰岛素抵抗。
