Patients with non-insulin-dependent diabetes mellitus (NIDDM) exhibit decreased rates of skeletal muscle insulin-mediated glucose uptake (IMGU). Because IMGU is equal to the product of the ...arteriovenous glucose difference (AVG delta) across and blood flow (F) into muscle (IMGU = AVG delta x F), reduced tissue permeability (AVG delta) and/or glucose and insulin delivery (F) can potentially lead to decreased IMGU. The components of skeletal muscle IMGU were studied in six obese NIDDM subjects (103 +/- 9 kg) and compared with those previously determined in six lean (weight 68 +/- 3 kg), and six obese (94 +/- 3 kg) with normal glucose tolerance. The insulin dose-response curves for whole body and leg muscle IMGU were constructed using the combined euglycemic clamp and leg balance techniques during sequential insulin infusions (range of serum insulin 130-80,000 pmol/L). In lean, obese, and NIDDM subjects, whole body IMGU, femoral AVG delta, and leg IMGU increased in a dose-dependent fashion over the range of insulin with an ED50 of 400-500 pmol/L in lean, 1000-1200 pmol/L in obese, and 4000-7000 pmol/L in NIDDM subjects (P less than 0.01 lean vs. obese and NIDDM). In lean and obese subjects, maximally effective insulin concentrations increased leg blood flow approximately 2-fold from basal with an ED50 of 266 pmol/L and 957 pmol/L, respectively (P less than 0.01 lean vs. obese). In contrast, leg F did not increase from the basal value in NIDDM subjects (2.7 +/- 0.1 vs. 3.5 +/- 0.5 dl/min, NS).
Familial combined hyperlipidemia (FCHL) is a common dyslipidemia predisposing to premature coronary heart disease (CHD). The disease is characterized by increased levels of serum total cholesterol ...(TC), triglycerides (TGs), or both. We recently localized the first locus for FCHL, on chromosome 1q21-q23. In the present study, a genomewide screen for additional FCHL loci was performed. In stage 1, we genotyped 368 polymorphic markers in 35 carefully characterized Finnish FCHL families. We identified six chromosomal regions with markers showing LOD score (
Z) values >1.0, by using a dominant mode of inheritance for the FCHL trait. In addition, two more regions emerged showing
Z>2.0 with a TG trait. In stage 2, we genotyped 26 more markers and seven additional FCHL families for these interesting regions. Two chromosomal regions revealed
Z>2.0 in the linkage analysis: 10p11.2,
Z=3.20 (θ=.00), with the TG trait; and 21q21,
Z=2.24 (θ=.10), with the apoB trait. Furthermore, two more chromosomal regions produced
Z>2.0 in the affected-sib-pair analysis: 10q11.2-10qter produced
Z=2.59 with the TC trait and
Z=2.29 with FCHL, and 2q31 produced
Z=2.25 with the TG trait. Our results suggest additional putative loci influencing FCHL in Finnish families, some potentially affecting TG levels and some potentially affecting TC or apoB levels.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hypertrophic cardiomyopathy (HCM) is a genetically and clinically heterogeneous myocardial disease caused by mutations in genes encoding sarcomeric proteins. To assess the genetic background and ...phenotypic expression of HCM in eastern Finland, we screened 35 unrelated patients with HCM from the Kuopio University Hospital area for variants in 9 genes encoding sarcomeric proteins with the PCR-SSCP method. We herewith describe our previous findings in five sarcomeric genes and also report hitherto unpublished data on four additional sarcomeric genes. Mutations in the cardiac myosin-binding protein C gene (MYBPC3) were most frequent, accounting for 26% of cases. A novel mutation (Gln1061X) in this gene was the most common mutation, found in 6 of 35 families and accounting for 17% of all cases. Other novel mutations in MYBPC3 (IVS5-2A → C, IVS14-13G → A, and Ex25 Lys) were found in one family each. A previously described -tropomyosin (TPM1) mutation (Asp175Asn) was found in 11% of cases. Haplotype analysis suggested that the two most common variants (MYBPC3-Gln1061X and TPM1-Asp175Asn) were founder mutations. Only one mutation (Arg719Trp) in the -myosin heavy chain gene (MYH7) was found in one family, and no disease-causing mutations were found in the genes encoding -actin, cardiac troponin I, T, C, or myosin essential and regulatory light chains. Altogether, the aforementioned 6 mutations found in MYBPC3, TPM1, and MYH7 accounted for 61% of familial and 40% of all HCM cases. The mutations were associated mostly with benign or intermediary phenotypes with only few HCM-related deaths. We conclude that the genetic profile of HCM in eastern Finland is unique, characterized by few founder mutations with benign or intermediary phenotypes.
Variants in the hepatocyte nuclear factor-1alpha and -4alpha genes in Finnish and Chinese subjects with late-onset type 2
diabetes.
J Rissanen ,
H Wang ,
R Miettinen ,
P Kärkkäinen ,
P Kekäläinen ,
L ...Mykkänen ,
J Kuusisto ,
P Karhapää ,
L Niskanen ,
M Uusitupa and
M Laakso
Department of Medicine, University of Kuopio, Finland.
Abstract
OBJECTIVE: To determine the role of the hepatocyte nuclear factor (HNF)-1alpha and HNF-4alpha genes in the etiology of late-onset
type 2 diabetes in Finnish and Chinese subjects. RESEARCH DESIGN AND METHODS: The whole coding regions of the genes encoding
for HNF-1alpha and HNF-4alpha, including approximately 800 bp of the HNF-1alpha promoter, were investigated in 40 Finnish
subjects (fasting C-peptide 50-570 pmol/l) and 47 Chinese subjects with type 2 diabetes by single-strand conformation polymorphism
(SSCP) analysis. Frequencies of the variants of these genes were analyzed by restriction fragment-length polymorphism analysis
in additional samples of 100 Finnish diabetic patients and 82 Finnish control subjects and in 58 Chinese diabetic patients
and 51 Chinese control subjects. RESULTS: No previously reported gene defects were detected, but one novel functionally silent
GCC-->GCG variant (nucleotide 73, exon 10) was observed in the HNF-4alpha gene in a Chinese diabetic patient. Interestingly,
the Ala98Val substitution of the HNF-1alpha gene occurred at a significantly higher frequency in 140 Finnish diabetic patients
compared with 82 control subjects (P = 0.014). The Ala98Val variant was not, however, associated with abnormalities in insulin
secretion evaluated by oral and intravenous glucose tolerance tests in subjects with normal (n = 295) or impaired (n = 38)
glucose tolerance. CONCLUSIONS: Variants in the HNF-1alpha and HNF-4alpha genes are unlikely to play a major role in the pathogenesis
of late-onset type 2 diabetes in Finnish and Chinese subjects. However, the association of the Ala98Val variant of the HNF-1alpha
gene with type 2 diabetes in Finnish subjects may indicate a diabetogenic locus close to the HNF-1alpha gene.
To prospectively investigate the relationship between myocardial contractile impairment and left ventricular (LV) hypertrophy measured at cardiac magnetic resonance (MR) imaging in patients with ...hypertrophic cardiomyopathy (HCM) caused by the substitution of aspartic acid 175 with asparagine (ie, Asp175Asn mutation) in the alpha-tropomyosin gene (TPM1).
The study protocol was approved by the hospital ethics committee, and all subjects gave written informed consent. LV mass, maximal LV wall thickness, and myocardial fractional thickening during systole were measured at cine MR imaging in 24 subjects (11 male, 13 female; mean age, 42 years; age range, 17-68 years) with the Asp175Asn mutation in TPM1 and in 17 healthy volunteers (eight men, nine women; mean age, 38 years; age range, 23-60 years). The proportion of hypokinetic LV segments was calculated as the number of LV segments with fractional thickening of less than 30% divided by the total number of segments measured. Anthropometric and biochemical correlates of LV hypertrophy were determined. Univariate and multiple linear regression analyses were used to investigate the association of the proportion of hypokinetic segments and other correlates of LV hypertrophy with LV mass and maximal wall thickness.
The proportion of hypokinetic segments was higher in patients with HCM than in control subjects (37% +/- 20 standard deviation vs 12% +/- 12, P < .001). In stepwise multiple regression analysis, the proportion of hypokinetic segments accounted for 42% (P < .001); the LV end-diastolic volume, for 24% (P = .003); and male sex, for 10% (P = .014) of the variability in LV mass in patients with HCM. The proportion of hypokinetic LV segments, which accounted for 48% of the variability in LV maximal wall thickness (P < .001), was the only variable significantly associated with maximal wall thickness.
The extent of myocardial contractile impairment is strongly and independently related to LV mass and maximal wall thickness in patients with HCM attributable to the Asp175Asn mutation in TPM1.
Patients with type 1 diabetes mellitus, especially those with nephropathy, are at increased risk for coronary heart disease (CHD). However, information on the predictive value of cardiovascular risk ...factors and the degree of hyperglycemia with respect to CHD events in patients with type 1 diabetes without nephropathy is still incomplete. Therefore, we performed a prospective study on risk factors for CHD in patients with type 1 diabetes free of clinical nephropathy. At baseline examination, cardiovascular risk factor levels of CHD were determined in 177 patients with type 1 diabetes (87 men and 90 women), age 45 to 64 years at baseline and >or=to30 years at the time of diagnosis of diabetes. These patients were followed up to 7 years with respect to CHD events. Altogether, 20 patients with type 1 diabetes (13 men 7.3% and 7 women 3.9%) died of CHD and 28 patients with type 1 diabetes (17 men 9.6% and 11 women 6.2%) had a serious CHD event (death from CHD or nonfatal myocardial infarction). In multivariate Cox regression analysis, a previous history of myocardial infarction (hazard ratio HR and its 95% confidence interval, 8.0 3.1 to 21.0, P<0.001), high glycohemoglobin A1 (>10.4%, the highest tertile, HR 5.4 1.4 to 20.4, P=0.013), and the duration of diabetes (>16 years, the highest tertile, HR 4.2 1.3 to 12.9, P=0.013) were the only variables associated with CHD death even after adjustment for other cardiovascular risk factors. These variables also predicted the incidence of all CHD events. Our results indicate that poor metabolic control is a strong predictor of CHD events in patients with late-onset type 1 diabetes without nephropathy, independently of other cardiovascular risk factors. (Arterioscler Thromb Vasc Biol. 1999;19:1014-1019.)
Intestinal fatty acid binding protein (I‐FABP) participates in the metabolism of fatty acids in the intestinal enterocytes. Threonine encoding allele in codon 54 of the I‐FABP gene has been suggested ...as regulating the absorption of long‐chain fatty acids. We examined the fatty acid composition of serum lipid fractions and the concentration of serum free fatty acids after an overnight fast in obese subjects, aged 24–56 years, on their habitual diet. The body mass index of the subjects ranged from 29.7 to 43.3 kg m−2. Six subjects were homozygous for the Thr‐54 allele of the I‐FABP gene, 37 subjects were heterozygous for the Thr‐54/Ala‐54 allele and 24 subjects were homozygous for the Ala‐54 allele. We did not find any consistent differences in the proportions of long‐chain fatty acids in serum triglycerides, cholesterol esters or phospholipids, but the concentration of serum free fatty acids tended to be higher in subjects who were homozygous for the Thr‐54 allele (P = 0.13, for trend). In conclusion, our findings suggest that a polymorphism at codon 54 of the I‐FABP2 gene does not substantially modify the fatty acid composition of serum lipids in obese Finns.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Asymptomatic hyperglycemia and atherosclerotic vascular disease in the elderly.
L Mykkänen ,
M Laakso and
K Pyörälä
Department of Medicine, University of Kuopio, Finland.
Abstract
OBJECTIVE--To ...investigate the relationship between asymptomatic hyperglycemia (IGT or newly diagnosed NIDDM) and atherosclerotic
vascular disease. RESEARCH DESIGN AND METHODS--A representative cross-sectional population sample of 1431 subjects (511 men,
920 women; 65-74 yr old). Altogether, 312 men and 515 women had NGT, 84 men and 158 women had IGT, 33 men and 59 women had
newly diagnosed NIDDM, and 82 men and 188 women had previously diagnosed NIDDM. Participation rate was 71%. Main outcome measures
were prevalence rates of CHD, stroke, and intermittent claudication. RESULTS--There was no difference in the prevalence of
definite or possible MI verified at hospital between subjects with asymptomatic hyperglycemia and NGT (15.5 vs. 13.3% in men,
6.3 vs. 5.3% in women). Men with asymptomatic hyperglycemia had 1.5 x higher prevalence of angina pectoris (29.4 vs. 19.3%,
P less than 0.05), major Q-QS changes (21.1 vs. 12.0%, P less than 0.05), ischemic ECG changes (59 vs. 45%, P less than 0.05),
and silent MI on ECG (14.8 vs. 7.9%, P less than 0.05) compared to men with NGT. Women with asymptomatic hyperglycemia had
more often ischemic ECG changes compared to women with NGT (48.3 vs. 39.7%, P less than 0.05). There was no difference (NS)
in the prevalence of verified stroke (3.5 vs. 4.6% in men, 2.7 vs. 2.5% in women) or claudication (7.0 vs. 7.7% in men, 4.6
vs. 4.3% in women) between subjects with asymptomatic hyperglycemia and NGT. In multiple logistic regression analyses, the
association between risk factors and MI or ischemic ECG changes in subjects with asymptomatic hyperglycemia was not consistent.
CONCLUSION--Elderly subjects with asymptomatic hyperglycemia (particularly men) tended to have an increased prevalence of
CHD. Thus, asymptomatic hyperglycemia in the elderly is not a benign phenomenon but is associated with cardiovascular morbidity.
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