ABSTRACT
OBJECTIVES: The objective of this study was to examine the associations between indices of liver insulin resistance (IR) and whole-body insulin sensitivity and different cardiovascular disease (CVD) risk factors. DESIGN AND SUBJECTS: A total of 8750 nondiabetic men (age 57.2 ± 7.1 years, body mass index 26.8 ± 3.8 kg m(-2) ) were included in this study from the population-based cross-sectional Metabolic Syndrome In Men (METSIM) cohort. Liver IR index and Matsuda insulin sensitivity index (ISI) were used as markers of liver IR and whole-body insulin sensitivity, respectively. Pearson correlation analysis was performed to examine the associations between these indices and various CVD risk factors. RESULTS: Total cholesterol (r = -0.088 vs. r = 0.020; P < 0.0019), high-sensitivity C-reactive protein (CRP) (r = 0.284 vs. r = -0.219; P < 0.0019) and total triglycerides (r = 0.507 vs. r = -0.477; P < 0.05) were more highly correlated with liver IR index than with Matsuda ISI. By contrast, Matsuda ISI was nominally more highly correlated with systolic and diastolic blood pressure (r = -0.234 and r = -0.275 vs. r = 0.202 and r = 0.239, respectively) compared to liver IR index. Furthermore, the variance explained by liver IR index was larger than that explained by Matsuda ISI for the majority of CVD risk factors measured. CONCLUSIONS: Liver IR index correlated more strongly than Matsuda ISI with levels of total cholesterol, CRP and triglycerides. Therefore, liver IR might be a significant indicator of CVD risk amongst men.
Subject(s)
Cardiovascular Diseases/etiology , Insulin Resistance , Liver/metabolism , Humans , Male , Middle Aged , Risk FactorsABSTRACT
AIMS/HYPOTHESIS: Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study. METHODS: Non-diabetic participants (n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m(2); mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010. We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels. RESULTS: Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly (p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally (p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR. CONCLUSIONS/INTERPRETATION: The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity.
Subject(s)
Adipocytes/physiology , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/physiopathology , Insulin Resistance/physiology , Liver/physiopathology , ADAM Proteins/genetics , ADAMTS9 Protein , Adipocytes/metabolism , Antigens, Neoplasm/genetics , Cation Transport Proteins/genetics , Cell Cycle Proteins/genetics , Co-Repressor Proteins , Cyclin-Dependent Kinase 5/genetics , Cyclin-Dependent Kinase Inhibitor p15/genetics , DNA-Binding Proteins , Finland , Genetic Predisposition to Disease/genetics , Hepatocyte Nuclear Factor 1-beta/genetics , Homeodomain Proteins/genetics , Humans , Insulin Resistance/genetics , Liver/metabolism , Male , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Middle Aged , Neoplasm Proteins/genetics , PPAR gamma/genetics , Polymorphism, Single Nucleotide , Potassium Channels, Inwardly Rectifying/genetics , RNA-Binding Proteins/genetics , Receptor, Notch2/genetics , Tetraspanins , Transcription Factor 7-Like 2 Protein/genetics , Transcription Factors/genetics , Zinc Transporter 8 , tRNA MethyltransferasesABSTRACT
AIMS/HYPOTHESIS: In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance. METHODS: A sample of 368 non-diabetic participants (age 43.0 ± 8.2 years, BMI 26.0 ± 4.0 kg/m(2); mean ± SD) whose endogenous glucose production (EGP) was measured with [6-6(2)H(2)]glucose in the fasting state and during the euglycaemic-hyperinsulinaemic clamp were included in the study. EGP multiplied by fasting plasma insulin (FPI) concentration was the reference measurement for liver insulin resistance (liver IR). Liver IR index was calculated with linear regression analysis including age, obesity indices, lipids, lipoproteins and several variables regulating glucose metabolism. RESULTS: The following variables were significantly associated with liver IR in multiple forward stepwise regression analysis: insulin AUC in an OGTT, fat mass, HDL-cholesterol and BMI. Liver IR index correlated significantly with EGP×FPI (r = 0.65, p < 0.001). In participants with abnormal glucose tolerance, the correlation of liver IR with EGP×FPI was slightly stronger (r = 0.69, p < 0.001) than in those with normal glucose tolerance (r = 0.62, p < 0.001). CONCLUSIONS/INTERPRETATION: We generated a novel surrogate index for liver insulin resistance correlating strongly with EGP × FPI.
