Päivi Kekäläinen

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.

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.

Glucokinase Gene Variants in Subjects With Late-Onset NIDDM and Impaired Glucose Tolerance

OBJECTIVE To investigate the frequency of variants of the glucokinase (GCK) gene in subjects with late-onset non-insulin-dependent diabetes mellitus (NIDDM) and in subjects with late-onset impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS The study population included 36 Finnish patients with late-onset NIDDM who were treated with diet for >8 years or who were newly diagnosed and 40 subjects with late-onset IGT who had low or normal insulin levels when tested by an oral glucose tolerance test. All exons, exon-intron junctions, and islet and liver promotor regions of the GCK gene were amplified with the polymerase chain reaction and screened for mutations using single-strand conformation polymorphism analysis. RESULTS A silent third-base substitution (TAC→TAT) in codon 215 of exon 6 was found in 2.8% of NIDDM patients and in 5.0% of IGT subjects. Polymorphisms were found in islet exon 1 at nucleotide 403 (C→G) in 16.7% of NIDDM patients and in 17.5% of IGT subjects and in the noncoding region of the islet promotor at nucleotide -30 (G→A) in 13.9% of NIDDM patients and in 25.0% of IGT subjects. Furthermore, in liver intron 1 a variant (C→T), 12 base pairs upstream from the splice acceptor site, was found in 5.6% of NIDDM patients and in 7.5% of IGT subjects. CONCLUSIONS These results indicate that the mutations in the coding region of the GCK gene are not likely to play a major role in the pathogenesis of late-onset NIDDM or IGT in the Finnish population.

Family history of coronary heart disease is a stronger predictor of coronary heart disease morbidity and mortality than family history of non-insulin dependent diabetes mellitus

The aim of this study was to compare the effect of family history of non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD) as risk factors for CHD morbidity and mortality. Altogether, 394 siblings of NIDDM probands and non-diabetic probands, with and without CHD, were followed for 8 years with respect to CHD events in a prospective population-based study. The baseline study was conducted from 1983 to 1985. Age- and sex-adjusted cumulative occurrence of CHD events was higher in the siblings of the probands with CHD and with NIDDM (13.1%; P = 0.037) and in the siblings of the probands with CHD and without NIDDM (15.4%; P = 0.054), compared with the siblings of the probands without NIDDM and without CHD (4.8%). The incidence of fatal CHD events tended to be higher in a group with a family history of NIDDM and CHD, but the trend was not statistically significant. In univariate logistic regression analyses, a family history of CHD was positively associated with cumulative occurrence of CHD events (odds ratio 2.53, P = 0.009), whereas a family history of NIDDM had no significant association (odds ratio 1.39, P = 0.312). After adjustment for age, sex, family history of NIDDM and major cardiovascular risk factors, the association between family history of CHD and cumulative occurrence of CHD events remained significant (odds ratio 2.25, P = 0.048). In conclusion, the present study indicates that a family history of CHD is a stronger predictor of future CHD events than a family history of NIDDM.

A nationwide study on parathyroid carcinoma

Abstract Background: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. Material and methods: We performed a nationwide study on all cases (n= 32) diagnosed in 2000–2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955–1999 was compared to that in 2000–2013. Results: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 μmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2–13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52–2.14) to 7.14 (range 3.42–10.38)/10.000.000/years; (p < .001). Conclusions: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.