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NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.

ABSTRACT: Type 2 diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC exclusively in male mice. Tumor development is preceded by increased interleukin-6 (IL-6) expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced NCOA5 expression is associated with a fraction of human HCCs and HCCs with comorbid T2D. These findings suggest that NCOA5 is a haploinsufficient tumor suppressor and that NCOA5 deficiency increases susceptibility to both glucose intolerance and HCC, partially by increasing IL-6 expression. Thus, our findings open additional avenues for developing therapeutic approaches to combat these diseases.

SUBMITTER: Gao S

PROVIDER: S-EPMC3891053 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.

Gao Shenglan S Li Aimin A Liu Feiye F Chen Fengsheng F Williams Mark M Zhang Chengliang C Kelley Zakiya Z Wu Chin-Lee CL Luo Rongcheng R Xiao Hua H

Cancer cell 20131201 6

Type 2 diabetes (T2D) and male gender are associated with hepatocellular carcinoma (HCC) development. We demonstrate that heterozygous deletion of the Ncoa5 gene causes spontaneous development of HCC exclusively in male mice. Tumor development is preceded by increased interleukin-6 (IL-6) expression, early-onset glucose intolerance, and progressive steatosis and dysplasia in livers. Blockading IL-6 overexpression averts glucose intolerance and partially deters HCC development. Moreover, reduced ...[more]

PMID: 24332041

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Project description:OBJECTIVES:Metabolic alterations after burn injury have been well described in children; however, in adult patients, glucose metabolism and insulin sensitivity are essentially unknown. We sought to characterize metabolic alterations and insulin resistance after burn injury and determine their magnitude and persistence at discharge. DESIGN:Prospective, cohort study. SETTING:Tertiary burn centre. PATIENTS:Nondiabetic adults with an acute burn involving greater than or equal to 20% total body surface area. INTERVENTIONS:An oral glucose tolerance test was administered at discharge. MEASUREMENTS AND MAIN RESULTS:Glucose, insulin, and C-peptide levels were measured to derive surrogate measures of insulin resistance and ?-cell function, including quantitative insulin sensitivity check index, homeostasis model assessment of ?-cell function, homeostasis model assessment of insulin sensitivity, homeostasis model assessment of insulin resistance, and the composite whole-body insulin sensitivity index. Patients were grouped according to the degree of glucose tolerance: normal glucose tolerance, impaired fasting glucose/impaired glucose tolerance, or diabetes. Forty-five adults, 44?±?15 years old and with 38% ± 14% total body surface area burned, underwent an oral glucose tolerance test at discharge. Median quantitative insulin sensitivity check index (0.348 [0.332-0.375]) and median homeostasis model assessment of insulin resistance (1.13 [0.69-1.45]) were abnormal, indicating insulin resistance and impaired insulin production at discharge. Two-thirds of patients (n = 28) met criteria for impaired fasting glucose/impaired glucose tolerance or diabetes. CONCLUSIONS:We have demonstrated that burn-injured adults remain hyperglycemic, are insulin resistant, and express defects in insulin secretion at discharge. Patients with lower burn severity (total body surface area, 20-30%) express similar metabolic alterations as patients with larger burns (total body surface area, ? 30%). Glucose tolerance testing at discharge offers an opportunity for early identification of burn patients who may be at high risk of prediabetes and diabetes. Our findings demonstrated that two-thirds of burn patients had some degree of glucose intolerance. With this in mind, surveillance of glucose intolerance post discharge should be considered. As hyperglycemia and insulin resistance are associated with poor outcomes, studies should focus on how long these profound alterations persist.

Dataset Information

NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.

Publications

NCOA5 haploinsufficiency results in glucose intolerance and subsequent hepatocellular carcinoma.

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