title: Pathogenesis of glucose intolerance and diabetes mellitus in cirrhosis.
abstract: Glucose intolerance and diabetes mellitus are both prevalent in cirrhosis, yet the pathogenesis of impaired glucose metabolism remains unknown. Therefore insulin secretion (hyperglycemic clamp, +125 mg/dl), insulin sensitivity (euglycemic hyperinsulinemic insulin clamp, +10 microU/ml and +50 microU/ml), whole-body glucose oxidation (indirect calorimetry) and glucose turnover ([6,6-2H2]glucose isotope dilution) were evaluated in a homogenous group of cirrhotic patients with glucose intolerance (n = 7) or frank diabetes mellitus (n = 6). The results were compared with those obtained in control subjects (n = 8). In glucose-intolerant patients, whole-body glucose uptake (mainly reflecting glucose utilization by muscle) was significantly impaired in patients during both insulin infusions as a result of decreased stimulation of the two major intracellular pathways of glucose disposal--nonoxidative glucose disposal (i.e., glycogen synthesis) and glucose oxidation. Hepatic glucose production was normal in the basal state and was normally suppressed during stepwise insulin infusion (by 65% and 85%, respectively, p = NS vs. controls). Hyperglycemia-induced increases of plasma C-peptide concentrations were comparable to those in controls (p = NS). In diabetic patients, insulin-mediated glucose uptake was significantly reduced, mainly because of impaired non-oxidative glucose disposal. Glucose oxidation appeared to be reduced, too. Hepatic glucose production was significantly increased in the basal state (3.03 +/- 0.24 vs. 2.34 +/- 0.10 mg/kg min, p < 0.02) and during insulin infusion (+50 microU/ml: 0.67 +/- 0.17 vs. 0.13 +/- 0.08 mg/kg min, p < 0.05) compared with that in controls. Both the first and second phases of beta-cell secretion were significantly reduced in response to steady-state hyperglycemia (both p < 0.01 vs. control values). In conclusion, glucose intolerance in cirrhosis results from two abnormalities that occur simultaneously: (a) insulin resistance of muscle and (b) an inadequate response (even when comparable to that of controls) of the beta-cells to appropriately secrete insulin to overcome the defect in insulin action. Diabetes mellitus in insulin-resistant cirrhotic patients develops as the result of progressive impairment in insulin secretion together with the development of hepatic insulin resistance leading to fasting hyperglycemia and a diabetic glucose tolerance profile.
authors.affiliation: Department of Internal Medicine, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: A S
authors.initials: AS
authors.lastname: Petrides
authors.forename: C
authors.initials: C
authors.lastname: Vogt
authors.forename: D
authors.initials: D
authors.lastname: Schulze-Berge
authors.forename: D
authors.initials: D
authors.lastname: Matthews
authors.forename: G
authors.initials: G
authors.lastname: Strohmeyer
mesh_terms: D000328:Adult; D000368:Aged; D001786:Blood Glucose / Q000032:analysis; D002096:C-Peptide / Q000097:blood; D003920:Diabetes Mellitus / Q000209:etiology*; D005260:Female; D005947:Glucose / Q000378:metabolism / Q000494:pharmacology; D015309:Glucose Clamp Technique; D018149:Glucose Intolerance / Q000209:etiology*; D006801:Humans; D006943:Hyperglycemia / Q000097:blood; D007328:Insulin / Q000097:blood; D007773:Lactates / Q000097:blood; D019344:Lactic Acid; D008103:Liver Cirrhosis / Q000150:complications*; D008297:Male; D008875:Middle Aged; D012016:Reference Values
chemical_list: D001786:Blood Glucose; D002096:C-Peptide; D007328:Insulin; D007773:Lactates; D019344:Lactic Acid; D005947:Glucose