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.

Pharmacokinetics in Patients with Chronic Liver Disease and Hepatic Safety of Incretin-Based Therapies for the Management of Type 2 Diabetes Mellitus

“…Type 2 diabetes mellitus (T2DM) favours non-alcoholic fatty liver disease (NAFLD), progressing from steatosis to non-alcoholic steatohepatitis, (NASH) and possibly cirrhosis [3] , while alcoholic cirrhosis and chronic hepatitis C virus are frequently associated with glucose metabolism disturbances [4] . Diabetes, which frequently develops as a complication of cirrhosis, is known as "hepatogenous diabetes" [5] ; it has a complex pathophysiology combining both impaired insulin secretion and insulin resistance [6,7] . Liver tests are commonly altered in patients with overweight/obesity and in patients with T2DM.…”

Insulin resistance in non-diabetic patients with non-alcoholic fatty liver disease: sites and mechanisms

“…Furthermore, the increased lipid flux that occurs during the fasting state results not only from insulin resistance, but also from "accelerated starvation", with the early recruitment of alternative fuels for energy needs and for gluconeogenesis (as the glycogen stores of the cirrhotic liver are significantly reduced) [26]. Moreover, hyperinsulinism is also caused by hepatocellular dysfunction and intrahepatic shunting in liver cirrhosis [57]; these mech-anisms were not operative in our patients, who had normal liver function and no histological evidence of cirrhosis. In summary, the insulin resistance associated with NAFLD shows similarities to, as well as differences from, other well-characterised insulin-resistant states in terms of the sites and mechanisms involved.…”

High-dose thiamine therapy counters dyslipidaemia in streptozotocin-induced diabetic rats

“…Thiamine therapy has been shown to decrease hyperglycaemia in cirrhosis [18], where hyperglycaemia is linked to insulin resistance of muscle and inadequate insulin secretion by beta cells [19], and in thiamine-responsive megaloblastic anaemia (due to mutated high-affinity thiamine transporter), where hyperglycaemia is linked to impaired insulin secretion [20]. Remedial intervention by thiamine in both cases is likely to involve improved beta cell metabolism and insulin secretion.…”