Vestergaard H, Klein H H, Hansen T, Müller J, Skovby F, Bjørbaek C, Røder M E, Pedersen O
Steno Diabetes Center, Copenhagen, Denmark.
J Clin Invest. 1995 Apr;95(4):1925-32. doi: 10.1172/JCI117874.
Congenital muscle fiber type disproportion myopathy (CFTDM) is a chronic, nonprogressive muscle disorder characterized by universal muscle hypotrophy and growth retardation. Histomorphometric examination of muscle shows a preponderance of smaller than normal type 1 fibers and overall fiber size heterogeneity. Concomitant endocrine dysfunctions have not been described. We report the findings of altered insulin secretion and insulin action in two brothers affected with CFTDM and glucose intolerance as well as in their nonconsanguineous glucose-tolerant parents. Results are compared with those of six normoglycemic control subjects. All study participants underwent an oral glucose tolerance test to estimate insulin secretion. The oldest boy and his parents volunteered for studies of whole-body insulin sensitivity consisting of a 4-h euglycemic hyperinsulinemic clamp in combination with indirect calorimetry. Insulin receptor function and glycogen synthase (GS) activity and expression were examined in biopsies of vastus lateralis muscle. Despite a 45-90-fold increase in both fasting and postprandial serum insulin levels, both CFTDM patients had diabetes mellitus. Clamp studies revealed that the oldest boy had severe insulin resistance of both liver and peripheral tissues. The impaired insulin-stimulated glucose disposal to peripheral tissues was primarily due to reduced nonoxidative glucose metabolism. These changes were paralleled by reduced basal values of muscle GS total activity, allosterical activation of GS by glucose-6-phosphate, GS protein, and GS mRNA. The father expressed a lesser degree of insulin resistance, and studies of muscle insulin receptor function showed a severe impairment of receptor kinase activity. In conclusion, CFTDM is a novel form of severe hyperinsulinemia and insulin resistance. Whether insulin resistance is causally related to the muscle disorder awaits to be clarified.
先天性肌纤维类型比例失调性肌病（CFTDM）是一种慢性、非进行性肌肉疾病，其特征为全身性肌肉萎缩和生长发育迟缓。肌肉组织形态计量学检查显示，I型纤维小于正常且普遍存在，整体纤维大小不均一。尚未有伴发内分泌功能障碍的相关描述。我们报告了两例患有CFTDM和葡萄糖耐量异常的兄弟及其非近亲的糖耐量正常父母胰岛素分泌和胰岛素作用改变的研究结果。将结果与6名血糖正常的对照受试者进行比较。所有研究参与者均接受口服葡萄糖耐量试验以评估胰岛素分泌。年龄最大的男孩及其父母自愿参与全身胰岛素敏感性研究，包括4小时正常血糖高胰岛素钳夹试验及间接测热法。在外侧股四头肌活检中检测胰岛素受体功能、糖原合酶（GS）活性及表达。尽管空腹和餐后血清胰岛素水平均升高了45 - 90倍，但两名CFTDM患者均患有糖尿病。钳夹试验显示，年龄最大的男孩肝脏和外周组织均存在严重胰岛素抵抗。胰岛素刺激的外周组织葡萄糖摄取受损主要是由于非氧化葡萄糖代谢减少所致。这些变化与肌肉GS总活性基础值降低、6 - 磷酸葡萄糖对GS的变构激活、GS蛋白及GS mRNA降低相平行。父亲的胰岛素抵抗程度较轻，肌肉胰岛素受体功能研究显示受体激酶活性严重受损。总之，CFTDM是一种新型的严重高胰岛素血症和胰岛素抵抗形式。胰岛素抵抗是否与肌肉疾病存在因果关系有待进一步阐明。
