Glomerular filtration rate and parathyroid hormone are associated with 1,25-dihydroxyvitamin D in men without chronic kidney disease.

BACKGROUND AND AIM: Vitamin D, estimated glomerular filtration rate (eGFR) and parathyroid hormone (PTH) are related to cardiovascular disease risk. We examined the associations between the levels of 25-hydroxyvitamin D (25-D) and 1,25-dihydroxyvitamin D (1,25-D) and both eGFR and PTH. DESIGN AND SETTING: Cross-sectional population-based study in Kuopio, Eastern Finland. SUBJECTS: A total of 909 men without known chronic kidney disease (CKD) and not receiving antidiabetic medication, aged from 45 to 73 years, were included in the study. Main outcome measures. Fasting levels of 25-D, 1,25-D, creatinine and PTH were measured, and an oral glucose tolerance test (OGTT) was performed. RESULTS: High levels of 25-D were associated with low levels of eGFR and PTH (ß = -0.17, P = 9 × 10(-7) and ß = -0.28, P = 6 × 10(-17) , respectively, adjusted for age, body mass index and levels of calcium, phosphorus and glucose in a 2-h OGTT, and also for either eGFR or PTH). By contrast, high 1,25-D levels were associated with high levels of eGFR and PTH (ß = 0.17, P = 2 × 10(-6) and ß = 0.19, P = 5 × 10(-8) , respectively, adjusted as mentioned earlier and additionally for 25-D). Eighteen per cent of men in the highest 25-D quartile were in the lowest 1,25-D quartile and also had a lower eGFR than men with high levels of both 25-D and 1,25-D (P = 4 × 10(-5) ). Finally, 15% of men in the lowest 25-D quartile were in the highest 1,25-D quartile and also had higher PTH levels than men with low levels of both 25-D and 1,25-D (P = 2 × 10(-3) ). CONCLUSION: Our findings suggest that both eGFR and PTH are significantly associated with vitamin D metabolism in men without known CKD.

Diverse associations of 25-hydroxyvitamin D and 1,25-dihydroxy-vitamin D with dyslipidaemias.

BACKGROUND AND AIM: Previous studies have suggested a link between circulating levels of 25-hydroxyvitamin D (25-D) and dyslipidaemias. However, it is not known whether 25-D and the active hormone 1,25-dihydroxyvitamin D (1,25-D) have similar associations with dyslipidaemias. Therefore, we studied the associations between both 25-D and 1,25-D and total cholesterol (total-C), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) and triglycerides in a population-based study. DESIGN: Cross-sectional population-based study. SETTING: Kuopio, Eastern Finland. SUBJECTS: A total of 909 men, aged from 45 to 70 years, who were not receiving antidiabetic medication were enrolled. MAIN OUTCOME MEASURES: Fasting serum samples were obtained for measurement of 25-D, 1,25-D and lipid levels. An oral glucose tolerance test was performed, and insulin sensitivity was evaluated using the Matsuda insulin sensitivity index (Matsuda ISI). RESULTS: We found a significant inverse association between 25-D and total-C, LDL-C and triglycerides (ß = -0.15, -0.13 and -0.17, respectively, P < 0.001), but no association between 25-D and HDL-C was observed. By contrast, 1,25-D was associated with HDL-C (ß = 0.18, P < 0.001), whereas no relationship was found between 1,25-D and LDL-C or triglycerides. The associations remained significant after the exclusion of subjects receiving statin treatment and after adjustment for age, waist circumference, body mass index, alcohol consumption, smoking, renal function, glucose tolerance and Matsuda ISI. CONCLUSION: Low levels of active vitamin D (1,25-D) are associated with low HDL-C levels, whereas low levels of the storage form 25-D are associated with high levels of total-C, LDL-C and triglycerides. Our findings may provide new insights into the understanding of the link between vitamin D deficiency and cardiovascular disease.

Risk factors for end-stage renal disease in a community-based population: 26-year follow-up of 25,821 men and women in eastern Finland.

BACKGROUND AND OBJECTIVE: There are very few European cohort studies assessing the risk factors of end-stage renal disease (ESRD) in a community-based population. This study investigated the predictors of ESRD in Finland. DESIGN: Prospective cohort study. SETTING: Eastern Finland. SUBJECTS: A random sample of 25,821 men and women aged 25-64 years from the national population register participating in three independent cross-sectional population surveys in 1972, 1977 and 1982. Only the subjects without diagnosis of ESRD or chronic kidney disease based on the national register data were included in the study. MAIN OUTCOME MEASURE: Initiation of renal replacement therapy (dialysis or kidney transplantation) identified from the Finnish Registry for Kidney Diseases through December 31, 2006. RESULTS: A total of 94 cases with ESRD were identified during a mean follow-up period of 26.5 years. In a multivariate proportional subdistribution hazard regression analysis, taking into account death as a competing risk event, diabetes (hazard ratio [HR] 4.76, 95% confidence interval [CI] 2.32-9.79), hypertension (HR 2.21, 95% CI 1.19-4.12), obesity defined as body mass index > or =30 kg m(-2) (HR 2.02, 95 %CI 1.10-3.71) and male gender (HR 1.68, 95% CI 1.19-4.12) were independent risk factors for ESRD. CONCLUSION: The findings of the present study confirm that modifiable risk factors play a major role in the development of ESRD in the North-European population. People with diabetes, hypertension or obesity should be considered as the target groups when planning preventive measures to control the future epidemic of ESRD.

Isolated low HDL cholesterol. An insulin-resistant state.

High levels of very-low-density lipoprotein (VLDL) triglycerides (TGs) and low levels of high-density lipoprotein (HDL) cholesterol have been found to be associated with insulin resistance. However, direct evidence that patients with isolated low HDL cholesterol are insulin resistant is still lacking. Therefore, we investigated the degree of insulin resistance and intracellular metabolism of glucose by the euglycemic glucose clamp technique and indirect calorimetry in three groups of subjects with normal glucose tolerance: 17 male control subjects with normolipidemia, 12 male patients with isolated low HDL cholesterol (low HDL group), and 10 male patients with low HDL cholesterol and hypertriglyceridemia (low HDL/high TG group). Fasting, 1-h, and 2-h glucose levels did not differ between the groups in an oral glucose tolerance test (OGTT). In contrast, insulin levels during an OGTT were significantly higher in the low HDL group than in the control group (fasting insulin: 85 +/- 11 vs. 50 +/- 6 pM, P = 0.005; 1-h insulin: 622 +/- 92 vs. 394 +/- 64 pM, P = 0.004; and 2-h insulin: 343 +/- 73 vs. 194 +/- 40 pM, P = 0.006). Similarly, insulin levels were also higher in the low HDL/high TG group than in the control group (fasting insulin: 82 +/- 14 pM, P = 0.037; 1-h insulin: 795 +/- 179 pM, P = 0.063; and 2-h insulin: 488 +/- 145 pM, P = 0.040).(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin resistance, body fat distribution, and sex hormones in men.

Although many studies have suggested that increased androgenicity is associated with insulin resistance and hyperinsulinemia in both pre- and postmenopausal women, relatively few data are available on this relationship in men. We examined the association of body mass index (BMI), waist-to-hip ratio (WHR), sex hormone-binding globulin (SHBG), total and free testosterone, dehydroepiandrosterone sulfate (DHEA-SO4), and estradiol with insulin concentrations and whole-body glucose disposal in 87 men from a population-based study in Kuopio, Finland. BMI was significantly correlated with fasting insulin (r = 0.46), total whole-body glucose disposal (r = -0.30), glucose oxidation (r = -0.21), and nonoxidative glucose disposal (r = -0.25). WHR also was significantly associated with fasting insulin (r = 0.61), total whole-body glucose disposal (r = -0.54), glucose oxidation (r = -0.23), and nonoxidative whole-body glucose disposal (r = -0.50). SHBG and total and free testosterone were significantly associated with insulin concentrations and total and nonoxidative glucose disposal but not with glucose oxidation. DHEA-SO4 and estradiol were not associated with insulin, glucose concentrations, or whole-body glucose disposal in univariate analysis. In multivariate analysis, total whole-body glucose disposal was associated negatively with WHR and positively associated with total testosterone and SHBG; nonoxidative whole-body glucose disposal was associated negatively with WHR and positively associated with total and free testosterone. Glucose oxidation was significantly associated only with WHR. In conclusion, higher WHR and lower testosterone were strongly associated with a decrease in total and nonoxidative whole-body glucose disposal in men.

New amino acid substitutions in the IRS-2 gene in Finnish and Chinese subjects with late-onset type 2 diabetes.

We investigated the significance of the variants of the IRS-2 gene in patients with type 2 diabetes. The entire coding part of the IRS-2 gene was screened by single-strand conformation polymorphism analysis in 40 Chinese and 40 Finnish patients with late-onset type 2 diabetes. The association of the variants of the IRS-2 gene with type 2 diabetes was studied in 85 Finnish diabetic patients and 82 Finnish control subjects and in 100 Chinese diabetic patients and 85 Chinese control subjects. The four variants predicting structural changes in the insulin receptor substrate (IRS)-2 protein included an insertion of AAC (Asn) in the Asn repeat sequence centered around codons 29-36 (allele frequencies of 0 vs. 0.6% and 1.5 vs. 0%), the Ala157Thr substitution (0 vs. 0% and 0.5 vs. 0%), the Leu647Val substitution (0.6 vs. 0% and 0 vs. 0%), and the Gly1057Asp polymorphism (31 vs. 31% and 35 vs. 30%) (P = NS for all comparisons). Furthermore, six silent variants were observed (CGC147CGG, CCC155CCG, GCC156GCT, AGT723AGC, TGT816TGC, and CCC829CCT). The Gly1057Asp polymorphism was not associated with insulin resistance or impaired insulin secretion in Finnish subjects with normal glucose tolerance (n = 295) or impaired glucose tolerance (n = 38). These data indicate that structural variants of the IRS-2 gene were uncommon in Finnish and Chinese patients with type 2 diabetes. Thus, the variants in the coding part of the IRS-2 gene are unlikely to have a major role in the development of type 2 diabetes in Finnish or Chinese subjects.

Insulin sensitivity and Lp(a) concentrations in normoglycemic men.

OBJECTIVE: Increased lipoprotein(a) [Lp(a)] concentrations have been recognized as a risk factor for coronary heart disease. Little data exists on the relationship of Lp(a) concentrations to insulin resistance. RESEARCH DESIGN AND METHODS: We examined insulin resistance (as determined by the euglycemic clamp) together with indirect calorimetry in relation to Lp(a) concentrations, apolipoprotein(a) [apo(a)] molecular weight, and apo(a) phenotype in 87 normoglycemic men. RESULTS: Lp(a) concentrations were significantly related to total (r = 0.225) and nonoxidative (r = 0.256) whole-body glucose disposal. These results suggest a positive but weak association between insulin sensitivity (restricted to the nonoxidative whole-body glucose disposal) and Lp(a) concentrations. However, after adjustment for apo(a) molecular weight [which accounts for some of the genetic influences on Lp(a) levels], total and nonoxidative body glucose disposal were not significantly related to Lp(a) concentrations. CONCLUSIONS: Normoglycemic insulin-resistant subjects do not have elevated Lp(a) concentrations.

Variants in the hepatocyte nuclear factor-1alpha and -4alpha genes in Finnish and Chinese subjects with late-onset type 2 diabetes.

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.

Sulfonylurea receptor 1 gene variants are associated with gestational diabetes and type 2 diabetes but not with altered secretion of insulin.

OBJECTIVE: To investigate the possible association of the variants in the nucleotide binding fold regions of the sulfonylurea receptor 1 (SUR1) gene with gestational diabetes mellitus (GDM), type 2 diabetes, and altered insulin secretion in Finnish subjects. RESEARCH DESIGN AND METHODS: The nucleotide binding fold regions of the SUR1 gene were amplified with polymerase chain reaction and screened by the single-strand conformational polymorphism analysis in 42 subjects with GDM and 40 subjects with type 2 diabetes. Detected variants were further investigated in 377 normoglycemic subjects by restriction fragment-length polymorphism analysis. The effect of the variants of the SUR1 gene on first-phase insulin secretion was studied in 295 normoglycemic subjects. RESULTS: In subjects with GDM or type 2 diabetes, one amino acid change (S1369A), four silent substitutions (R1273R, L829L, T759T, and K649K), and three intron variants were identified in the nucleotide binding fold regions of the SUR1 gene. A tagGCC allele of exon 16 splice acceptor site was more frequent in subjects with GDM (0.55 allele frequency, n = 42) and type 2 diabetes (0.60, n = 40) than in normoglycemic subjects (0.43, n = 377) (P1 = 0.024 and P2 = 0.009, respectively). Similarly, an AGG allele of the R1273R polymorphism was more common in subjects with GDM (0.87) and type 2 diabetes (0.87) than in normoglycemic subjects (0.74) (P1 = 0.009 and P2 = 0.001, respectively). However, the S1369A, R1273R, and cagGCC-->tagGCC variants of the SUR1 gene were not associated with altered first-phase insulin secretion in 295 normoglycemic subjects. CONCLUSIONS: These results suggest that a functional variant that contributes to the risk of GDM and type 2 diabetes may locate close to the SUR1 gene.

Leptin concentrations, sex hormones, and cortisol in nondiabetic men.

Leptin, the product of the human ob gene, is increased in obese individuals, suggesting resistance to its effect. However, there is a variability in leptin levels at each level of body mass index, suggesting that genetic and environmental factors other than overall adiposity may regulate leptin concentrations. No data currently exist on the relation of sex hormones to leptin concentrations in men. We examined the relation ofleptin levels to sex hormone-binding globulin, total and free testosterone, dehydroepiandrosterone sulfate, estradiol, and cortisol in 87 normoglycemic men. Leptin levels were significantly correlated with free testosterone (r = -0.14; P < 0.05), sex hormone-binding globulin (r = -0.26; P < 0.05), total testosterone (r = -0.32; P < 0.01), and cortisol (r = -0.09; P = NS). However, after adjustment for body mass index (or, alternatively, waist or hip circumference), leptin concentrations were not significantly related to sex hormones or cortisol. Our data suggest that in men, sex hormones are not important independent modifiers of leptin concentrations.

Low levels of sex hormone-binding globulin and testosterone are associated with smaller, denser low density lipoprotein in normoglycemic men.

Recently, the phenotype with a preponderance of small, dense low density lipoprotein (LDL) has been associated with increased coronary heart disease. Although previous data indicated that decreased sex hormone-binding globulin (SHBG) and testosterone concentrations are associated with increased triglyceride and decreased high density lipoprotein (HDL) cholesterol levels in men, no data are available on the relationship of LDL composition to sex hormones. Therefore, we examined the relationship of SHBG, total and free testosterone, estradiol, and dehydroepiandrosterone sulfate to LDL size (as determined by gradient gel electrophoresis) in 87 normoglycemic men. LDL size was significantly positively related to SHBG (r = 0.354) and total testosterone (r = 0.313) and inversely related to dehydroepiandrosterone sulfate (r = -0.247), but not to free testosterone or estradiol concentrations. After adjustment for age, waist circumference, overall glucose disposal, fasting glucose, triglyceride, and HDL cholesterol, LDL size remained significantly associated with SHBG (r = 0.312) and total testosterone (r = 0.269). The relationship between LDL size and total testosterone and SHBG tended to be stronger in nonobese subjects. We conclude that SHBG and total testosterone concentrations are significantly associated with LDL size in men, and these relationships appear to be independent of known confounding variables, such as triglyceride and HDL cholesterol levels. Our data suggest that endogenous sex hormones may have an independent modifying effect on LDL composition in men.

Effects of bezafibrate on insulin sensitivity and glucose tolerance in subjects with combined hyperlipidemia.

To investigate whether the lowering of triglyceride levels has beneficial effects on glucose metabolism, we studied 13 nondiabetic men with combined hyperlipidemia (phenotype IIB) before and after 2 months of treatment with a slow-release formulation of bezafibrate (400 mg daily). The rates of whole body glucose disposal were quantitated by the euglycemic hyperinsulinemic clamp technique (insulin infusion rate of 80 mU/m2/min). In an oral glucose tolerance test, fasting glucose level decreased slightly (5.0 +/- 0.2 versus 4.8 +/- 0.2 mmol/L; p < 0.05) during bezafibrate treatment. Glucose and insulin levels after an oral glucose load remained unchanged. Rates of whole body glucose disposal did not change during bezafibrate treatment (39.5 +/- 3.3 mumol/kg/min before treatment versus 40.6 +/- 2.7 mumol/kg/min after treatment; difference not significant). Basal hepatic glucose output also remained unchanged (8.2 +/- 0.2 mumol/kg/min before treatment versus 8.3 +/- 0.2 mumol/kg/min after treatment; difference not significant). Our findings show that bezafibrate has a triglyceride-lowering effect without any significant influence on insulin sensitivity.

Effects of two high-fat diets with different fatty acid compositions on glucose and lipid metabolism in healthy young women.

Effects of two experimental diets with a relatively high fat content--one enriched with saturated fatty acids (SAFA-diet) and the other with a low content of erucic acid rapeseed oil and rich in monounsaturated fatty acids (MUFA-diet)--on glucose and lipid metabolism were examined in healthy young women. The study was carried out with a randomized, crossover study design with each diet lasting 3 wk and a 2-wk washout period between the experimental diets. Glucose area under the curve during the intravenous glucose tolerance test (glucose dose 300 mg/kg, plasma samples before glucose dose and at 10-min intervals for 90 min) was significantly lower and the glucose disappearance rate after a glucose injection tended to be steeper after the MUFA-diet than after the SAFA-diet. After the MUFA-diet serum total cholesterol was 21.6% lower and serum low-density-lipoprotein cholesterol 29.5% lower than after the SAFA-diet, but high-density-lipoprotein cholesterol did not differ between the diets. The results give suggestive evidence that the dietary fatty acid composition affects glucose tolerance of healthy subjects.

A 100-kDa urinary protein is associated with insulin resistance in offspring of type 2 diabetic patients.

AIMS/HYPOTHESIS: One-third of normoalbuminuric type 1 diabetic patients show immunoreactive nephrin in urine. Offspring of type 2 diabetic patients are insulin-resistant and susceptible to the development of diabetes. We investigated whether the offspring of type 2 diabetic patients show nephrin in urine and whether possible nephrinuria is associated with insulin resistance. METHODS: Urinary proteins from timed overnight urine collections from 128 offspring of type 2 diabetic patients and 9 control subjects were analysed by western blotting using an antibody against nephrin. Glucose metabolism was assessed by OGTT and IVGTT and the euglycaemic-hyperinsulinaemic clamp technique. RESULTS: Of the offspring, 12.5% were strongly and 14.1% weakly positive for a 100-kDa urinary protein. All controls were negative. During the first 10 min of an IVGTT, the offspring strongly positive for the urinary protein had a higher insulin response than the offspring without the protein (3,700 vs 2,306 pmol l(-1)min(-1), p=0.007). Insulin sensitivity (the rate of whole-body glucose uptake divided by the steady-state insulin level x 100) was lower among the offspring strongly positive for the urinary protein than among the offspring negative for the protein (11.3 vs 15.8 micromol kg(-1)min(-1)pmol(-1)l(-1), p=0.008). CONCLUSIONS/INTERPRETATION: A 100-kDa urinary protein detectable with a nephrin antibody is associated with insulin resistance in offspring of type 2 diabetic patients.

Obese men with type IIB hyperlipidemia are insulin resistant.

By using the euglycemic clamp technique and indirect calorimetry, we determined the degree of insulin resistance in 12 obese (body mass index > 27.0 kg/m2), normotensive patients with type IIB hyperlipidemia (HLIIB) (total cholesterol > or = 6.5 mmol/L and total triglycerides > or = 2.0 mmol/L) and 17 control subjects (total cholesterol < or = 6.1 mmol/L and total triglycerides < 1.8 mmol/L) who were carefully matched for sex, age, and obesity. Fasting plasma insulin was higher in HLIIB patients than in control subjects (18.4 +/- 4.6 versus 8.9 +/- 1.2 mU/L, respectively; P = .010). The rates of whole-body glucose uptake were significantly lower in HLIIB patients than in control subjects during the last hour of the clamp (42.2 +/- 3.9 versus 54.6 +/- 2.8 mumol/kg per minute, respectively; P = .013). Glucose oxidation during the last 30 minutes of the euglycemic clamp was lower in HLIIB patients than in control subjects (14.6 +/- 0.9 versus 19.0 +/- 1.3 mumol/kg per minute, respectively; P = .017). Nonoxidative glucose disposal during the last 30 minutes of the euglycemic clamp was also lower in HLIIB patients than in control subjects, but the difference was not statistically significant (27.6 +/- 3.3 versus 35.8 +/- 2.8 mumol/kg per minute, respectively; P = .069). Lipid oxidation during the clamp was completely suppressed in control subjects (-0.24 +/- 0.44 mumol/kg per minute) but was significantly less suppressed in the HLIIB patients (0.94 +/- 0.29 mumol/kg per minute, P = .024).(ABSTRACT TRUNCATED AT 250 WORDS)

Impaired insulin-stimulated glucose oxidation and free fatty acid suppression in patients with familial combined hyperlipidemia: a precursor defect for dyslipidemia?

Familial combined hyperlipidemia (FCHL) is characterized by hyperlipidemia and insulin resistance, but intracellular defect in insulin action is unknown. Therefore, we investigated insulin action by applying the hyperinsulinemic euglycemic clamp technique with indirect calorimetry in 58 FCHL family members (28 with FCHL; 30 without dyslipidemia; aged 49+/-12 years; body mass index [BMI], 25. 2+/-4.0 kg/m2) and in 72 healthy control subjects (aged 54+/-6 years; BMI, 26.3+/-3.1 kg/m2). In the fasting state, FCHL patients had higher levels of total cholesterol, total triglycerides, and apolipoprotein B than control subjects (P<0.001 after adjustment for gender, age, and BMI). During the euglycemic clamp, FCHL patients had lower rates of glucose oxidation (15.93+/-3.55 versus 19.65+/-4. 60 micromol/kg/min; P=0.001) and higher rates of lipid oxidation (0. 15+/-0.13 versus 0.01+/-0.25 mg/kg/min; P=0.024), as well as higher levels of serum-free fatty acids (FFA) (0.24+/-0.17 versus 0.06+/-0. 06 mmol/L; P<0.001) compared with those of control subjects. Relatives without dyslipidemia differed similarly from control subjects with respect to rates of glucose and lipid oxidation and FFA suppression during the hyperinsulinemic clamp. In FCHL family members, during the euglycemic clamp FFAs correlated negatively with the rates of glucose oxidation (P<0.001) but not with the rates of glucose nonoxidation (P=0.408). In FCHL family members without dyslipidemia and in control subjects, FFAs during the clamp correlated positively with levels of total triglycerides (P<0.001) and very low density lipoprotein cholesterol (P=0.008). We conclude that in patients with FCHL, and also in their first-degree relatives, insulin's suppressive effect on FFA levels is impaired, which may precede dyslipidemia in FCHL.

Insulin resistance in familial and nonfamilial hypercholesterolemia.

High levels of very low density lipoprotein triglycerides and low levels of high density lipoprotein cholesterol have been found to be associated with insulin resistance measured by the euglycemic clamp technique. In contrast, the association of isolated hypercholesterolemia with insulin resistance has not been systematically studied. Therefore, we performed two separate studies designed to investigate the degree of insulin resistance in familial hypercholesterolemia (FH) (study 1) and nonfamilial hypercholesterolemia (non-FH) (study 2). Study 1 included eight young adults with FH and 13 corresponding control subjects. Fasting blood glucose, insulin, and C-peptide levels were similar in FH patients and control subjects during an oral glucose tolerance test. During the euglycemic hyperinsulinemic (1,200-1,300 pmol/l) clamp studies, FH patients and control subjects had similar rates of whole-body glucose uptake (73 +/- 6 versus 70 +/- 3 mumol/kg per minute, respectively; p = NS). Glucose oxidation, glucose nonoxidation, lipid oxidation, suppression of free fatty acid levels, and potassium disposal were similar in both groups. Study 2 included 25 middle-aged non-FH patients and 18 corresponding control subjects. Glucose, insulin, and C-peptide responses in an oral glucose tolerance test were similar in both groups. During the euglycemic hyperglycemic clamp studies, non-FH patients and control subjects had similar rates of whole-body glucose uptake (61 +/- 3 versus 58 +/- 3 mumol/kg per minute, p = NS). In addition, glucose oxidation, glucose nonoxidation, lipid oxidation, and suppression of free fatty acid levels as well as potassium disposal were similar in non-FH patients and control subjects. We conclude that FH and non-FH are not insulin-resistant states.

The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.

BACKGROUND: Insulin resistance in the most common familial dyslipidemia, familial combined hyperlipidemia (FCHL), could be due to variations in the hormone sensitive lipase (HSL) gene. MATERIALS AND METHODS: The coding region of the HSL gene was screened with the single strand conformation polymorphism analysis in probands of 27 FCHL families with 228 members. In addition, the C-60G promoter substitution of the HSL gene was determined by the restriction fragment length polymorphism analysis in these subjects. RESULTS: No variants in the coding region of the HSL gene were found and the allele frequencies of the C-60G promoter substitution and the silent variant (G3138A) in the 3' untranslated region did not differ between 110 control subjects and 27 probands with FCHL. However, in control women the C-60G substitution was associated with high body mass index [30.6 +/- 0.9 kg m(-2) (mean +/- SD) in subjects with the C/G genotype and 24.8 +/- 4.6 in subjects with the C/C genotype, P = 0.012], and in control men with high rates of insulin-stimulated whole body glucose uptake (70.1 +/- 14.7 vs. 56.7 +/- 14.2 micromol kg(-1) min(-1), P = 0.014). In 228 FCHL family members this substitution was associated with high low-density lipoprotein cholesterol levels in men (4.51 +/- 1.12 vs. 5.17 +/- 1.28 mmol L(-1), P = 0.049), but not in women. CONCLUSIONS: The HSL gene is not a major gene for FCHL. However, the - 60G allele of this gene may affect body weight, insulin sensitivity and serum cholesterol levels.

Leptin concentrations and insulin sensitivity in normoglycemic men.

OBJECTIVE: Leptin is a hormone regulating weight in the mouse. Leptin regulates food intake and appetite. Leptin concentrations are increased in obese individuals suggesting resistance to its effect. However, there is considerable variability in leptin levels at each level of adiposity suggesting that environmental and genetic factors may regulate leptin concentrations. We examined whether subjects with decreased insulin sensitivity have increased leptin levels. METHODS: We used a radioimmunoassay to measure serum leptin levels and the hyperinsulinemic euglycemic clamp (with indirect calorimetry) to measure insulin sensitivity in 87 normoglycemic relatively lean men. RESULTS: Leptin levels were significantly correlated with fasting insulin (r = 0.58), insulin area (r = 0.45), overall (r = -0.57), non-oxidative (r = -0.51) and oxidative (r = -0.51) whole body glucose disposal (all P-values < 0.001). After adjustment for body mass index, leptin levels remained significantly correlated with fasting insulin (r = 0.44), insulin area (r = 0.40), overall (r = -0.40), non-oxidative (r = -0.28) and oxidative (r = -0.33) whole body glucose disposal although the magnitude of the associations was considerably decreased. Leptin levels were significantly related to insulin sensitivity in both less obese and more obese subjects. CONCLUSIONS: We conclude that leptin concentrations are related to insulin resistance and insulin concentrations in relatively lean normoglycemic men and these associations are to some extent independent of body mass index. Thus, subjects with insulin resistance may be relatively resistant to the effects of leptin.