Normal splanchnic but impaired peripheral insulin-stimulated glucose uptake in cirrhosis

Abstract

The site of impaired glucose uptake in cirrhosis is uncertain. We therefore performed hyperglycemic clamps (glucose 10 mmol/L) in 10 patients with compensated alcoholic cirrhosis and impaired glucose tolerance and in six control subjects. Muscle glucose uptake was estimated in patients and controls with the forearm technique. In the cirrhotic subjects splanchnic glucose uptake was measured with hepatic vein catheterization and primed continuous infusions of indocyanine green and [6-3H]glucose. To assess insulin-independent glucose uptake and the effects of elevated nonesterified fatty acid levels on glucose uptake, we repeated the study with somatostatin to induce insulin deficiency and a nicotinic acid analog, acipimox, to inhibit lipolysis. Substrate disposal was assessed on indirect calorimetry. Despite similar stimulated insulin levels, total glucose utilization was lower in the cirrhotic subjects (3.9 +/- 0.3 vs. 8.8 +/- 1.7 mg/kg/min, p = 0.006). This deficiency was accounted for by lower nonoxidative glucose disposal (1.2 +/- 0.2 vs. 5.8 +/- 1.6 mg/kg/min, p = 0.002). Forearm glucose uptake was lower in the cirrhotic subjects (0.39 +/- 0.06 vs. 1.21 +/- 0.3 mg/100 ml/min, p = 0.001). However, splanchnic glucose uptake at 1.59 +/- 0.14 mg/kg/min was similar to that reported in other studies of normal subjects. Insulin-independent glucose uptake was normal, and acipimox had no effect on total or forearm glucose utilization. Glucose intolerance in cirrhosis is characterized by impaired peripheral insulin-stimulated non-oxidative glucose disposal. The high nonesterified fatty acid levels seen in cirrhosis most likely do not contribute to this defect. Splanchnic glucose uptake is normal in cirrhosis.

Hepatogenous diabetes: Is it time to separate it from type 2 diabetes?

“…A large body of evidence indicates that insulin resistance is a major defect in chronic liver disease, since the pre-cirrhotic stages. 42 Insulin resistance in cirrhosis is characterized by reduced whole body glucose uptake, mainly due to reduced non-oxidative glucose disposal, 43 although glucose oxidation was also found to be impaired. 39 Glucose uptake is decreased in the peripheral tissues, ie, adipose tissue and particularly muscle, 39,43,44 also as a consequence of cirrhosis-induced sarcopenia, 45 but not in the splanchnic area.…”

“…42 Insulin resistance in cirrhosis is characterized by reduced whole body glucose uptake, mainly due to reduced non-oxidative glucose disposal, 43 although glucose oxidation was also found to be impaired. 39 Glucose uptake is decreased in the peripheral tissues, ie, adipose tissue and particularly muscle, 39,43,44 also as a consequence of cirrhosis-induced sarcopenia, 45 but not in the splanchnic area. 43 Indeed, hepatic glucose production is unaffected or even reduced in cirrhosis, 39,44 mainly due to a failure of glucagon to stimulate glycogenolysis, 46 although glucose output increases with development of overt DM.…”

Nuclear Magnetic Resonance Studies of Hepatic Glucose Metabolism in Humans

“…Hepatic glucose metabolism is generally thought to be altered in liver cirrhosis, although rates of glucose production were found to be decreased only in some (Owen et al, 1981;Merli et al, 1986) but not all studies (Shmueli et al, 1993;Petrides et al, 1991). To examine hepatic glycogen metabolism, Petersen and coworkers (1999) studied patients with biopsy-confirmed liver cirrhosis by combining r3C NMR spectroscopy with [6,6-2H]glucose infusion and the 2H20 method described above.…”

Temporal changes in insulin sensitivity following the development of acute liver failure secondary to acetaminophen

“…The peripheral insulin insensitivity seen in ALF is similar to changes that have been shown in CLD using both hyperglycemic and hyperinsulinemic euglycemic clamping techniques combined with isotopic glucose tracer infusion. 10,31 The mechanisms underlying the development of peripheral insulin insensitivity are still unclear in both CLD and ALF. A combined insulin receptor and postreceptor defect has been suggested in CLD, but the cellular mechanisms of this have been poorly characterized.…”

“…8,9 In hyperglycemic and hyperinsulinemic euglycemic clamp observations performed in CLD, total body glucose uptake was reduced by 40% to 50%. 10,11 Endogenous glucose production was suppressed normally during these clamp studies, suggesting that hepatic sensitivity to insulin was not impaired, and that peripheral insulin insensitivity was the major cause of insulin resistance. The observed reduction in peripheral insulin sensitivity may be accounted for by a defect in nonoxidative glucose metabolism, 12 reflecting muscle glycogen synthesis, insulin-induced glucose oxidation having been demonstrated to increase normally.…”