Subtle metabolic and liver gene transcriptional changes underlie diet-induced fatty liver susceptibility in insulin-resistant mice

Type 2 diabetes (T2D) is one of the fastest increasing diseases worldwide. Although it is defined by a single metabolite, glucose, it is increasingly recognized as a highly heterogeneous disease with varying clinical manifestations. Identification of different subtypes at an early stage of disease when complications might still be prevented could hopefully allow for more personalized medicine. An important step towards precision medicine would be to target the right resources to the right patients, thereby improving patient health and reducing health costs for the society. More well-defined disease populations also offer increased power in experimental, genetic and clinical studies. In a recent study, we used six clinical variables (GAD autoantibodies, age at onset of diabetes, HbA1c, BMI, and simple measures of insulin resistance and insulin secretion (so called HOMA estimates) to cluster adult-onset diabetes patients into five subgroups. These subgroups have been robustly reproduced in several populations worldwide and are associated with different risks of diabetic complications and responses to treatment. Importantly, the group with severe insulin-deficient diabetes (SIDD) had increased risk of retinopathy and neuropathy, whereas the severe insulin-resistant diabetes (SIRD) group has the highest risk for diabetic kidney disease (DKD) and fatty liver. This emphasizes the key role of insulin resistance in the pathogenesis of DKD and fatty liver in T2D. In conclusion, this novel sub-classification, breaking down T2D in clinically meaningful subgroups, provides the prerequisite framework for expanded personalized medicine in diabetes beyond what is already available for monogenic and to some extent type 1 diabetes.

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Is liver fat detrimental to vessels?: intersections in the pathogenesis of NAFLD and atherosclerosis

Clinical Science ◽

10.1042/cs20070311 ◽

2008 ◽

Vol 115 (1) ◽

pp. 1-12 ◽

Cited By ~ 45

Author(s):

Paola Loria ◽

Amedeo Lonardo ◽

Giovanni Targher

Keyword(s):

Liver Disease ◽

Fatty Liver ◽

Fatty Liver Disease ◽

Molecular Mechanisms ◽

Treatment Strategies ◽

Liver Fat ◽

Cvd Risk ◽

Alcoholic Fatty Liver ◽

Insulin Resistant ◽

Major Player

NAFLD (non-alcoholic fatty liver disease) encompasses the spectrum of fatty liver disease in insulin-resistant individuals who often display T2DM (Type 2 diabetes mellitus) and obesity. The present review highlights the pathophysiological basis and clinical evidence for a possible causal linkage between NAFLD and CVD (cardiovascular disease). The role of traditional and non-traditional CVD risk factors in the pathophysiology of NAFLD is considered in the first part of the review, with the basic science shared by atherogenesis and hepatic steatogenesis discussed in depth in the second part. In conclusion, NAFLD is not an innocent bystander, but a major player in the development and progression of CVD. NAFLD and CVD also share similar molecular mechanisms and targeted treatment strategies. On the research side, studies should focus on interventions aimed at restoring energy homoeostasis in lipotoxic tissues and at improving hepatic (micro)vascular blood supply.

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Inflammatory change of fatty liver induced by intraportal low-dose lipopolysaccharide infusion deteriorates pancreatic insulin secretion in fructose-induced insulin-resistant rats

Liver International ◽

10.1111/j.1478-3231.2008.01714.x ◽

2008 ◽

Vol 28 (8) ◽

pp. 1167-1175 ◽

Cited By ~ 6

Author(s):

Po-Shiuan Hsieh

Keyword(s):

Insulin Secretion ◽

Fatty Liver ◽

Low Dose ◽

Inflammatory Change ◽

Insulin Resistant ◽

Pancreatic Insulin

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Insulin Resistance, the Metabolic Syndrome, and Nonalcoholic Fatty Liver Disease

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-1024 ◽

2005 ◽

Vol 90 (3) ◽

pp. 1578-1582 ◽

Cited By ~ 181

Author(s):

F. Angelico ◽

M. Del Ben ◽

R. Conti ◽

S. Francioso ◽

K. Feole ◽

...

Keyword(s):

Insulin Resistance ◽

Metabolic Syndrome ◽

Liver Disease ◽

Fatty Liver ◽

Nonalcoholic Fatty Liver Disease ◽

Fatty Liver Disease ◽

Oral Glucose ◽

Nonalcoholic Fatty Liver ◽

Insulin Resistant ◽

The Metabolic Syndrome

Background/Aims: An association of nonalcoholic fatty liver disease with the insulin-resistant metabolic syndrome has been suggested. The aim of the study was to assess the association of fatty liver to different degrees of insulin resistance and secretion. Methods and Results: The study was performed in 308 alcohol- and virus-negative consecutive patients attending a metabolic clinic, who underwent a complete clinical and biochemical work-up including oral glucose tolerance test and routine liver ultrasonography. Steatosis was graded as absent/mild, moderate, and severe. In nondiabetic subjects, a progressive (P < 0.05) increase in mean homeostasis model of insulin resistance was recorded from the group without steatosis to the groups with mild/moderate and severe steatosis. Severe steatosis was associated with the clustering of the five clinical and biochemical features proposed for the clinical diagnosis of the metabolic syndrome. Subjects with the metabolic syndrome with a more pronounced insulin resistance had a higher prevalence of severe steatosis (P < 0.01) compared with those with homeostasis model of insulin resistance below the median. Conclusions: The findings stress the heterogeneous presentation of patients with the metabolic syndrome when the diagnosis is based on the broad Adult Treatment Panel III clinical criteria and demonstrate that those who are more insulin resistant have a higher prevalence of severe steatosis.

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Characterization of Polybrominated Diphenyl Ether Toxicity in Wistar Han Rats and Use of Liver Microarray Data for Predicting Disease Susceptibilities

Toxicologic Pathology ◽

10.1177/0192623311429973 ◽

2012 ◽

Vol 40 (1) ◽

pp. 93-106 ◽

Cited By ~ 30

Author(s):

J. K. Dunnick ◽

A. Brix ◽

H. Cunny ◽

M. Vallant ◽

K. R. Shockley

Keyword(s):

False Discovery Rate ◽

Polybrominated Diphenyl Ethers ◽

Diphenyl Ether ◽

Male Rats ◽

Gene Transcript ◽

Cell Functions ◽

False Discovery ◽

Transcriptional Changes ◽

Liver Gene ◽

Cycle Regulation

The toxicity of polybrominated diphenyl ethers (PBDEs), flame-retardant components, was characterized in offspring from Wistar Han dams exposed by gavage to a PBDE mixture (DE71) starting at gestation day 6 and continuing to weaning on postnatal day (PND) 21. Offspring from the dams underwent PBDE direct dosing by gavage at the same dose as their dams from PND 12 to PND 21, and then after weaning for another thirteen weeks. Liver samples were collected at PND 22 and week 13 for liver gene expression analysis (Affymetrix Rat Genome 230 2.0 Array). Treatment with PBDE induced 1,066 liver gene transcript changes in females and 1,200 transcriptional changes in males at PND 22 (false discovery rate < 0.01), but only 263 liver transcriptional changes at thirteen weeks in male rats (false discovery rate < 0.05). No significant differences in dose response were found between male and female pups. Transcript changes at PND 22 coded for proteins in xenobiotic, sterol, and lipid metabolism, and cell cycle regulation, and overlapped rodent liver transcript patterns after a high-fat diet or phenobarbital exposure. These findings, along with the observed PBDE-induced liver hypertrophy and vacuolization, suggest that long-term PBDE exposure has the potential to modify cell functions that contribute to metabolic disease and/or cancer susceptibilities.

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