Johanna Rissanen

The Trp64Arg Polymorphism of the β3-Adrenergic Receptor Gene: Lack of association with NIDDM and features of insulin resistance syndrome

OBJECTIVE To investigate the association of the Trp64Arg polymorphism of the β3-adrenergic receptor gene with NIDDM and the features of insulin resistance syndrome in subjects from eastern Finland. RESEARCH DESIGN AND METHODS We determined the prevalence of the Trp64Arg polymorphism of the β3-adrenergic receptor gene by restriction fragment length polymorphism analysis in 110 patients with NIDDM (54 men and 56 women, age 63 ± 1 years, BMI 30.4 ± 0.5 kg/m2), in 183 patients with features of insulin resistance syndrome (103 men and 80 women, age 44 ± 0 years, BMI 31.1 ± 0.4 kb/m2), and in 82 normoglycemic control men (age 54 ± 1 years, BMI 26.3 ± 0.4 kg/m2). RESULTS The allele frequency of the Trp64Arg polymorphism of the β3-adrenergic receptor gene was similar in patients with NIDDM, in patients with insulin resistance syndrome, and in control subjects (0.08, 0.07, and 0.07, respectively; NS). In addition, this polymorphism was not associated with low resting metabolic rate, abdominal obesity, increased lipid oxidation, hypertension, or earlier development of NIDDM as previously described. Furthermore, in 82 normoglycemic male control subjects the Trp64Arg polymorphism was not associated with insulin resistance evaluated by the euglycemic-hyperinsulinemic clamp. CONCLUSIONS The Trp64Arg polymorphism of the beta β3-adrenergic receptor gene is unlikely to be a major genetic predisposer to NIDDM or insulin resistance syndrome in subjects from eastern Finland.

The Ala54Thr Polymorphism of the Fatty Acid Binding Protein 2 Gene Does Not Influence Insulin Sensitivity in Finnish Nondiabetic and NIDDM Subjects

Insulin resistance and hyperinsulinemia are major predictors of NIDDM. Since several studies have demonstrated that heredity plays a significant role in the development of insulin resistance (1), defects in genes that regulate insulin action could potentially contribute to the risk of NIDDM. A locus on chromosome 4q has been shown to be linked with fasting insulin levels (2), 2-h insulin levels (3,4), and insulin action (2) in Pima Indians and Mexican-Americans, suggesting that the fatty acid binding protein 2 (FABP2) gene is a promising candidate gene for insulin resistance and NIDDM.

Different regulation of free fatty acid levels and glucose oxidation by the Trp64Arg polymorphism of the β3-adrenergic receptor gene and the promoter variant (A-3826G) of the uncoupling protein 1 gene in familial combined hyperlipidemia

Familial combined hyperlipidemia (FCHL) is characterized by variable expression of dyslipidemias and insulin resistance. Because the genetic background for FCHL is unknown, we investigated the effect of the Trp64Arg polymorphism of the beta3-adrenergic receptor (beta3-AR) gene and the promoter variant A --> G (-3826) of the uncoupling protein 1 (UCP1) gene on glucose and lipid metabolism in FCHL families. Both polymorphisms were screened in 228 members from 27 families with FCHL and in 82 control men from a random population sample. The frequency of the polymorphisms of the beta3-AR and UCP1 genes did not differ between patients with FCHL and controls. Although the rate of insulin-stimulated whole-body glucose uptake evaluated by the euglycemic clamp in family members of patients with FCHL was unaffected by both polymorphisms, subjects with the Trp64Arg genotype of the beta3-AR gene had higher rates of glucose oxidation (17.6+/-4.5 v 15.8+/-4.1 micromol/kg/min, P=.017) and lower levels of free fatty acids (FFAs) in the fasting state (0.56+/-0.27 v 0.61+/-0.28 mmol/L, P=.027) and during the euglycemic clamp (0.12+/-0.10 v 0.21+/-0.15 mmol/L, P=.041) than subjects with the Trp64Trp genotype. We conclude that in FCHL families, codon 64 polymorphism of the beta3-AR gene may influence the rate of glucose oxidation via FFA levels.

Glucokinase gene islet promoter region variant (G→A) at nucleotide -30 is not associated with reduced insulin secretion in finns

OBJECTIVE To investigate the effect of the islet promoter region variant (G→A) at nucleotide −30 of the glucokinase (GCK) gene on insulin levels in subjects with normal glucose tolerance (NGT), impaired glucose tolerance (IGT), and NIDDM. RESEARCH DESIGN AND METHODS The study population included 294 subjects with NGT, 83 subjects with IGT, and 36 subjects with NIDDM. Oral glucose tolerance tests (OGTTs) were performed in all subjects, and intravenous glucose tolerance tests (IVGTTs) were performed in subjects with NGT. The islet promoter region of the GCK gene was amplified with polymerase chain reaction and screened for the variant (−30) using single-strand conformation polymorphism analysis. RESULTS The islet promoter variant (−30) of the GCK gene was found in 17% of subjects with NGT, 23% of subjects with IGT, and 14% of patients with NIDDM (NS between the groups). Fasting, 1-h, and 2-h insulin levels, measured by OGTT, did not differ between subjects with and without this variant in any of the three groups. Furthermore, first-phase insulin secretion, determined by an IVGTT in subjects with NGT, did not associate with presence of the islet promoter region variant (−30) of the GCK gene. CONCLUSIONS These results indicate that the variant (−30) of the islet promoter region of the GCK gene does not have a significant effect on insulin secretion in Finnish subjects with NGT, IGT, or NIDDM.