Impaired nonoxidative glucose metabolism in patients with liver cirrhosis: effects of two insulin doses.

Glucose intolerance is encountered in the majority of cirrhotic patients. This alteration has been attributed to a defective insulin-mediated glucose uptake in peripheral tissue, where nonoxidative glucose disposal seems to be chiefly impaired. To further investigate insulin action under euglycemic conditions, we studied how physiological (100 microU/mL) and pharmacological (1,000 microU/mL) plasma insulin concentrations affect whole-body insulin-mediated glucose uptake, as well as oxidative and nonoxidative glucose disposal, in cirrhotic patients and controls. To this aim, a sequential two-step insulin euglycemic clamp combined with indirect calorimetry was performed in eight cirrhotic patients and six control subjects. During the first step of the clamp, total glucose uptake was reduced by 40% in cirrhotic patients versus controls (4.42 +/- 1.39 v 7.63 +/- 1.60 mg/kg/min, P = .002). By increasing insulin to pharmacological levels, glucose disposal increased in both groups. However, the maximum rate of glucose metabolism achieved in cirrhotic patients was lower than in controls at all times (10.29 +/- 2.04 v 12.82 +/- 0.51 mg/kg/min, P = .012). Glucose oxidation was lower in cirrhotics in the basal state, but similar in both groups during insulin/glucose infusion. On the other hand, the reduced nonoxidative glucose disposal observed in cirrhotic patients was not normalized even by increasing insulin to pharmacological levels. In conclusion, in liver cirrhosis a reduced insulin sensitivity is associated with a reduced insulin responsiveness that is mainly caused by defective nonoxidative glucose disposal.

Effects of spontaneous chronic hypoglycemia on central and peripheral nervous system in insulinoma patients before and after surgery: a neurophysiological follow-up.

To investigate the effects of spontaneous chronic hypoglycemia on the peripheral and central nervous system, a multimodal neurophysiological evaluation [median somatosensory (mSEP), brain stem auditory (BAEP), and visual (VEP) evoked potentials recordings] was performed in seven insulinoma patients before and 3 and 6 months after surgical removal of tumor. Before surgery, mSEP findings showed abnormal reduction in peripheral wrist-Erb conduction velocity in three patients as well as a pathological increase in Erb-N13, N13-N20, and Erb-N20 conduction times in five cases. BAEP and VEP recordings gave pathological results in two patients. Moreover, during hypoglycemia, the III-V and I-V interpeak latencies of BAEPs were significantly prolonged (P < 0.01 and P < 0.005, respectively) compared to recordings in euglycemia. After 6 months, a mSEP recovery, even if partial was noted in four patients, BAEPs were normalized in one case, and VEPs were unmodified. Compared to presurgery data, these recordings showed a significant (P < 0.05), but incomplete, shortening of BAEPs (III-V and I-V interpeak latencies) and mSEPs (Erb-N13 and Erb-N20 conduction times). Our findings demonstrate that multiple and selective neurophysiological abnormalities are present in insulinoma patients, confirm that hypoglycemia impairs suddenly brain stem function, and show that after tumor removal, long recovery times for improvement of some neurophysiological anomalies are requested.

Increased nonoxidative glucose metabolism in idiopathic reactive hypoglycemia.

Idiopathic reactive hypoglycemia (IRH) is responsible for postprandial hypoglycemia. Normal insulin secretion and reduced response of glucagon to acute hypoglycemia, but mostly increased insulin sensitivity, represent the metabolic features of this syndrome- The present study has two aims: first, to investigate the fate of glucose utilization inside the cells to assess whether increased glucose disposal in IRH is due to the oxidative and/or nonoxidative pathway; and second, to evaluate glucagon response to prolonged insulin-induced hypoglycemia. In eight patients with IRH and eight normal (N) subjects, we performed two studies on different days: (1) 120-minute euglycemic-hyperinsulinemic (1.0 mU . kg-1 . min-1 regular human insulin) clamp associated with indirect calorimetry; and (2) 180-minute hypoglycemic (2.22 to 2.49 mmo/L achieved through 0.85 mU . kg-1 . min-1 intravenous [IV] regular human insulin) clamp. The results showed an increased insulin-mediated glucose uptake in IRH (9.10 +/- 0.19 v 6.78 +/- 0.18 mg kg-1 . min-1, P < .005). Glucose oxidation was similar in IRH subjects and controls both in basal conditions (1.39 +/- 0.16 v 1.42 +/- 0.15 mg . kg-1 . min-1 and during the clamp studies (2.57 +/- 0.21 v 2.78 +/- 0.26 mg . kg-1 . min-1. In contrast, nonoxidative glucose disposal was significantly higher in IRH than in N subjects (6.53 +/- 0.30 v 4.00 +/- 0.21 mg . kg-1 . min-1, P < .001). During insulinization, fat oxidation was reduced slightly more in IRH than in control subjects. During the hypoglycemic clamp, a significant (P < .01) increase in plasma glucagon concentrations was observed in normal subjects as compared with baseline, whereas no change occurred in IRH patients. In conclusion, in IRH: (1) increased insulin-mediated glucose disposal is due to the increase of nonoxidative glucose metabolism; and (2) glucagon secretion has been confirmed to be inadequate. The increase of insulin sensitivity associated with a deficiency in glucagon secretion can widely explain the occurrence of hypoglycemia in the late postprandial phase.