Fructose normalizes specific counterregulatory responses to hypoglycemia in patients with type 1 diabetes

We have previously reported that specific counterregulatory responses to hypoglycemia were augmented by an infusion of fructose in nondiabetic humans. We hypothesized that this effect was due to the interaction of a "catalytic" dose of fructose with the regulatory protein for glucokinase in glucose-sensing cells that drive counterregulation. To examine whether fructose could restore counterregulatory responses in type 1 diabetic patients with defective counterregulation, we performed stepped hypoglycemic clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l glucose steps, 50 min each) in eight intensively treated patients (HbA_1c 6.4 ± 0.7%) on two separate occasions: without (control) or with coinfusion of fructose (1.2 mg·kg^-1·min^-1). Fructose induced a resetting of the glycemic threshold for secretion of epinephrine to higher plasma glucose concentrations (from 3.3 ± 0.1 to 3.9 ± 0.1 mmol/l; P = 0.001) and markedly augmented the increment in epinephrine (by 56%; P < 0.001). The amplification of epinephrine responses was specific; plasma norepinephrine, glucagon, growth hormone, and cortisol were unaffected. Hypoglycemia-induced endogenous glucose production ([3-³H]-glucose) rose by 90% (P < 0.001) in the fructose studies, compared with -2.0% (NS) in control. In concert, the glucose infusion rates during the 3.9- and 3.3-mmol/l steps were significantly lower with fructose (2.3 ± 0.6 and 0.0 ± 0.0 vs. 5.9 ± 1.15 and 3.9 ± 1.0 μmol·kg ^-1·min^-1, respectively; P < 0.001 for both), indicating the more potent counterregulatory response during fructose infusion. We conclude that infusion of fructose nearly normalizes the epinephrine and endogenous glucose production responses to hypoglycemia in type 1 diabetic patients with impaired counterregulation, suggesting that defects in these responses may be dependent on glucokinase-mediated glucose sensing.