Perreault Leigh, Færch Kristine, Kerege Anna A, Bacon Samantha D, Bergman Bryan C
Division of Endocrinology, Metabolism, and Diabetes (L.P., A.A.K., S.D.B., B.C.B.), University of Colorado Anschutz Medical Campus, Aurora, Colorado 80045; and Steno Diabetes Center (K.F.), DK-2820 Gentofte, Denmark.
J Clin Endocrinol Metab. 2014 Jul;99(7):E1154-62. doi: 10.1210/jc.2013-3248. Epub 2014 Apr 14.
Abnormal endogenous glucose production (EGP) is a characteristic feature in people with impaired fasting glucose (IFG). We sought to determine whether impaired hepatic glucose sensing contributes to abnormal EGP in IFG and whether it could be experimentally restored.
Glucose production (rate of appearance; Ra) and flux (glucose cycling) were assessed during a hyperglycemic-euinsulinemic somatostatin clamp with an infusion of [6,6-(2)H2-]glucose and [2-(2)H]glucose before and after enhanced hepatic glucokinase activity via an infusion of low-dose fructose in people with IFG and normal glucose tolerance (NGT).
During euglycemia, neither endogenous glucose production [(6,6-(2)H2)-glucose Ra; P = 0.53] or total glucose output (TGO; [2-(2)H]-glucose Ra; P = .12) was different between groups, but glucose cycling ([2-(2)H]glucose Ra to [6,6-(2)H2-]glucose Ra; a surrogate measure of hepatic glucokinase activity in the postabsorptive state) was lower in IFG than NGT (P = .04). Hyperglycemia suppressed EGP more in NGT than IFG (P < .01 for absolute or relative suppression, NGT vs IFG), whereas TGO decreased similarly in both groups (P = .77). The addition of fructose completely suppressed EGP in IFG (P < .01) and tended to do the same to TGO (P = .01; no such changes in NGT, P = .39-.55). Glucose cycling (which reflects glucose-6-phosphatase activity during glucose infusion) was similar in IFG and NGT (P = .51) during hyperglycemia and was unchanged and comparable between groups with the addition of fructose (P = .24).
In summary, glucose sensing is impaired in IFG but can be experimentally restored with low-dose fructose. Glucokinase activation may prove to be a novel strategy for the prevention of diabetes in this high-risk group.
内源性葡萄糖生成（EGP）异常是空腹血糖受损（IFG）人群的一个特征。我们试图确定肝脏葡萄糖感知受损是否导致IFG患者EGP异常，以及是否可以通过实验恢复。
在高血糖 - 正常胰岛素 - 生长抑素钳夹期间，通过输注[6,6-(2)H2 -]葡萄糖和[2-(2)H]葡萄糖评估葡萄糖生成（出现率；Ra）和通量（葡萄糖循环），在IFG和糖耐量正常（NGT）人群中，通过输注低剂量果糖增强肝葡萄糖激酶活性前后进行评估。
在血糖正常期间，两组之间内源性葡萄糖生成[（6,6-(2)H2） - 葡萄糖Ra；P = 0.53]或总葡萄糖输出（TGO；[2-(2)H] - 葡萄糖Ra；P = 0.12）均无差异，但IFG组的葡萄糖循环（[2-(2)H]葡萄糖Ra与[6,6-(2)H2 -]葡萄糖Ra之比；吸收后状态下肝葡萄糖激酶活性的替代指标）低于NGT组（P = 0.04）。高血糖对NGT组EGP的抑制作用比对IFG组更强（绝对或相对抑制，NGT组与IFG组相比，P < 0.01），而两组的TGO下降相似（P = 0.77）。添加果糖完全抑制了IFG组的EGP（P < 0.01），对TGO也有类似趋势（P = 0.01；NGT组无此类变化，P = 0.39 - 0.55）。在高血糖期间，IFG组和NGT组的葡萄糖循环（反映葡萄糖输注期间葡萄糖 - 6 - 磷酸酶活性）相似（P = 0.51），添加果糖后两组之间无变化且相当（P = 0.24）。
总之，IFG患者的葡萄糖感知受损，但低剂量果糖可通过实验恢复。葡萄糖激酶激活可能被证明是预防这一高危人群糖尿病的新策略。
