Contribution of reduced insulin sensitivity and secretion to the pathogenesis of hepatogenous diabetes: Effect of liver transplantation

Abstract

Diabetes mellitus frequently complicates cirrhosis but the pathogenic mechanisms are unknown. To assess the contribution of reduced insulin action and secretion, 24 cirrhotic-diabetic patients waiting for liver transplant because of an unresectable hepatocarcinoma underwent an oral glucose tolerance test (OGTT) to assess the ␤-cell function and an insulin clamp combined with [3-3 H]glucose infusion to measure whole body glucose metabolism before and 2 years after the transplant. Seven cirrhotic nondiabetic patients, 11 patients with chronic uveitis on similar immunosuppressive therapy, and 7 healthy subjects served as control groups. Cirrhotic patients showed a profound insulin resistance, and diabetics in addition also showed increased endogenous glucose production (P Ͻ .05) and insulin deficiency during the OGTT (P Ͻ .05). Liver transplantation normalized endogenous glucose production and insulin sensitivity but failed to cure diabetes in 8 of the 24 patients because a markedly low insulin response during the OGTT. Age, body mass index, family history of diabetes, immunosuppressive drugs, and pathogenesis of cirrhosis did not predict in whom liver transplant was going to cure diabetes. On the contrary, a reduced secretory response characterized the patients in whom the transplant would not be curative. In summary, insulin resistance was a primary event complicating cirrhosis but additional ␤-cell secretory defects were crucial for development of diabetes. Liver transplantation, lessening insulin resistance, cured hepatogenous diabetes in 67% of cirrhotic-diabetic patients; nevertheless 33% were still diabetics because the persistence of a reduced ␤-cell function, which makes these patients eventually eligible for combined islet transplantation. (HEPATOLOGY 2000;31:694-703.)Cirrhotic patients are characterized by impaired glucose metabolism 1 ; 60% to 80% are glucose intolerant and 10% to 15% develop overt diabetes mellitus. [2][3][4] The development of diabetes following liver cirrhosis seems also to be relatively rapid; during a period of 5 years nearly 15% to 20% of cirrhotic patients develop frank hyperglycemia. 5 The high incidence of diabetes among cirrhotic patients was recognized to be secondary to the hepatic disease since 1906 when the term ''hepatogenous diabetes'' was first coined. 6 Diabetes does not affect short-term survival, but it seems to be significantly correlated with poor prognosis in long-term follow-up, the higher mortality rate being mainly caused by an increased risk of hepatocellular failure. 7 The sequence, the relative importance, and the molecular mechanisms of the pathogenic factors are still largely unknown because liver cirrhosis is characterized by heterogeneous clinical pictures related to etiologic and environmental factors, nutritional state, complex physiologic endocrine interactions, and stage and stability of the liver disease. Recently liver transplantation was found to be an effective treatment for small unresectable hepatocellular carcinomas in patients with cirrhosis,...

Liver transplantation in cirrhotic patients with diabetes mellitus: Midterm results, survival, and adverse events

“…A recent report from Italy may help explain these findings. 8 In their study, Perseghin et al found that patients with cirrhosis with DM may have insulin resistance and reduced ␤-cell function. The first of these 2 alterations is reversed after OLT, but reduced ␤-cell secretion is not.…”

“…Glucose intolerance and insulin resistance of patients with cirrhosis are reversed after orthotopic liver transplantation (OLT), 8 but the use of such immunosuppressive drugs as cyclosporine, tacrolimus, or prednisone can alter glucose metabolism either by direct effect on pancreatic ␤-cells or by contributing to insulin resistance. [9][10][11] Thus, the global effect of OLT on glucose metabolism may be both prodiabetogenic and antidiabetogenic.…”

Long-term management of the liver transplant patient: Diabetes, hyperlipidemia, and obesity

“…10 In addition, there may be a component of defective insulin secretion by the pancreatic beta cell in some cirrhotics, notwithstanding the elevated circulating insulin levels commonly found in cirrhosis. 11 Chronic hyperinsulinemia itself may be the cause of insulin resistance, because the latter is ameliorated if blood insulin levels can be lowered for a prolonged period of time. 12 Theoretically, at least, liver transplantation could cure hepatogenous diabetes, because removal of the diseased liver should reverse the insulin resistance of cirrhosis and permit normal glucose handling and carbohydrate metabolism.…”

Diabetes in chronic liver disease: from old concepts to new evidence

“…An improvement in glucose tolerance has been recognized in HCV-positive diabetic patients following liver transplantation, even without complete regression of insulin resistance [10]. In fact, transplanted patients still maintained the reduced muscle glucose uptake and the decreased non-oxidative glucose disposal observed before transplantation, indicating persistence of insulin resistance in peripheral tissues, particularly in the skeletal muscle [9,10]. Glucose metabolism has also been evaluated in patients with cirrhosis of viral aetiology, in which impaired insulin action has been detected.…”

“…Glucose metabolism impairment becomes worse with the progression of chronic hepatitis to liver cirrhosis. In cirrhotic patients, the prevalence of impaired glucose tolerance (IGT) is estimated to be about 60-80% [9,10], and that of overt diabetes is about 7-15%. Since, in CLD, numerous aetiological, environmental, nutritional and metabolic factors are involved, and the term CLD embraces different stages of liver dysfunction, the pathogenic mechanisms underlying the relationship between IGT or diabetes and CLD remain to be elucidated.…”