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  • 1
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    Impaired Insulin-Stimulated Glucose Oxidation and Free Fatty Acid Suppression in Patients with Familial Combined Hyperlipidemia : A Precursor Defect for Dyslipidemia?
    Ovid Technologies (Wolters Kluwer Health) ; 1998
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 18, No. 10 ( 1998-10), p. 1548-1553
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 18, No. 10 ( 1998-10), p. 1548-1553
    Abstract: Abstract —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/m 2 ) and in 72 healthy control subjects (aged 54±6 years; BMI, 26.3±3.1 kg/m 2 ). 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 μmol/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.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.18.10.1548
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1998
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  • 2
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    The C-174G Promoter Polymorphism of the IL-6 Gene Affects Energy Expenditure and Insulin Sensitivity
    American Diabetes Association ; 2003
    In:  Diabetes Vol. 52, No. 2 ( 2003-02-01), p. 558-561
    Details
    In: Diabetes, American Diabetes Association, Vol. 52, No. 2 ( 2003-02-01), p. 558-561
    Abstract: Interleukin-6 (IL-6) is a pleiotropic cytokine expressed in many tissues. IL-6 null mice show low energy expenditure, but the effect of the variants of the IL-6 gene on energy expenditure has not been previously studied in humans. Therefore, we investigated the effect of the C-174G promoter polymorphism of the IL-6 gene on energy expenditure, measured by indirect calorimetry in healthy Finnish subjects (n = 124). We also measured insulin sensitivity by the hyperinsulinemic-euglycemic clamp. Subjects with the C-174C genotype of the IL-6 gene had significantly lower energy expenditure than subjects with the G-174C or G-174G genotypes both in fasting (CC 13.68 ± 1.98, CG 14.73 ± 1.57, GG 14.81 ± 2.01 kcal · kg−1 · min−1; P = 0.012) and during the euglycemic-hyperinsulinemic clamp (CC 15.24 ± 2.05, CG 16.62 ± 2.06, GG 16.66 ± 2.50 kcal · kg−1 · min−1; P = 0.007). Moreover, subjects homozygous for the C allele had lower rates of whole-body glucose uptake than carriers of the G allele (CC 50.95 ± 13.91, CG 59.40 ± 14.17, GG 59.21 ± 15.93 μmol · kg−1 · min−1; P = 0.016). The rates of both oxidative (P = 0.013) and nonoxidative (P = 0.016) glucose disposal were significantly affected by the IL-6 promoter polymorphism. In conclusion, the C-174C promoter polymorphism of the IL-6 gene influences energy expenditure and insulin sensitivity in healthy normoglycemic subjects. Whether this polymorphism is a risk factor for obesity or type 2 diabetes can be estimated only in prospective population-based studies.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.52.2.558
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2003
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  • 3
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    The K121Q Polymorphism of the PC-1 Gene Is Associated With Insulin Resistance but not With Dyslipidemia
    American Diabetes Association ; 2003
    In:  Diabetes Care Vol. 26, No. 2 ( 2003-02-01), p. 464-467
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 26, No. 2 ( 2003-02-01), p. 464-467
    Abstract: OBJECTIVE—To investigate the relationship of the K121Q polymorphism of the plasma cell glycoprotein 1 (PC-1) gene with insulin resistance, insulin secretion, and lipids and lipoproteins. RESEARCH DESIGN AND METHODS—Altogether, 110 normoglycemic subjects (group I) underwent a hyperinsulinemic-euglycemic clamp for evaluation of insulin sensitivity. The first-phase insulin secretion was determined by the intravenous glucose tolerance test (IVGTT) in a separate sample of 295 normoglycemic subjects (group II). RESULTS—The 121Q allele (genotypes K121Q and Q121Q) compared with the K121K genotype was related to higher fasting insulin levels (group I: 69.6 ± 45.6 vs. 51.9 ± 28.4 pmol/l [mean ± SD], P = 0.050; group II: 66.6 ± 38.8 vs. 53.8 ± 26.6 pmol/l, P = 0.009). In group I, subjects carrying the 121Q allele compared with subjects with the K121K genotype had lower rates of whole-body glucose uptake (51.17 ± 12.07 vs. 60.12 ± 14.86 μmol · kg−1 · min−1, P = 0.012) and nonoxidative glucose disposal (33.71 ± 10.51 vs. 41.51 ± 13.36 μmol · kg−1 · min−1, P = 0.015) during the clamp. In group II, there was no significant difference between the 121Q allele carriers and subjects with the K121K genotype in total first-phase insulin secretion during the first 10 min of the IVGTT (2,973 ± 2,224 vs. 2,520 ± 1,492 pmol · l−1 · min−1, P = 0.415). No association of the K121Q polymorphism with serum lipids and lipoproteins was found. CONCLUSIONS—In healthy normoglycemic Finnish subjects, the K121Q polymorphism of the PC-1 gene is associated with insulin resistance but not with impaired insulin secretion or dyslipidemia.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.26.2.464
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2003
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  • 4
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    Leptin Concentrations, Sex Hormones, and Cortisol in Nondiabetic Men1
    The Endocrine Society ; 1997
    In:  The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 6 ( 1997-06-01), p. 1807-1809
    Details
    In: The Journal of Clinical Endocrinology & Metabolism, The Endocrine Society, Vol. 82, No. 6 ( 1997-06-01), p. 1807-1809
    Type of Medium: Online Resource
    ISSN: 0021-972X , 1945-7197
    URL: Article
    DOI: 10.1210/jcem.82.6.3978
    RVK:
    XA 10000
    Language: English
    Publisher: The Endocrine Society
    Publication Date: 1997
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    detail.hit.zdb_id: 3029-6
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  • 5
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    G-250A Substitution in Promoter of Hepatic Lipase Gene Is Associated With Dyslipidemia and Insulin Resistance in Healthy Control Subjects and in Members of Families With Familial Combined Hyperlipidemia
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 7 ( 2000-07), p. 1789-1795
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 7 ( 2000-07), p. 1789-1795
    Abstract: Abstract —Low activity of hepatic lipase (HL) has been associated with high levels of triglycerides and high density lipoproteins, but the association of the HL promoter variants with insulin sensitivity has not been investigated. Therefore, in this study, the relationship of the G-250A promoter variant of the HL gene to the rates of insulin-stimulated glucose uptake measured by the hyperinsulinemic euglycemic clamp was investigated in 110 control subjects (82 men and 28 women, aged 50.7±7.6 [mean±SD] years, body mass index 26.1±3.6 kg/m 2 ) and in 105 first-degree relatives (65 men and 40 women, aged 47.8±16.0 years, body mass index 26.9±5.3 kg/m 2 ) of 34 families with familial combined hyperlipidemia (FCHL). The A-250 allele of the HL promoter was associated with low rates of insulin-stimulated whole-body nonoxidative glucose disposal in control subjects (41.1±12.7 μmol · kg −1 · min −1 in subjects with the G-250G genotype, 36.9±13.1 μmol · kg −1 · min −1 in subjects with the G-250A genotype, and 29.9±13.5 μmol · kg −1 · min −1 in subjects with the A-250A genotype; P =0.012 adjusted for age and sex) and with low rates of insulin-stimulated whole-body glucose oxidation in FCHL family members (16.7±4.2 versus 15.0±4.4 versus 14.1±4.4 μmol · kg −1 · min −1 , P =0.024). In addition, the A-250 allele was associated with high levels of fasting insulin ( P =0.047), very low density lipoprotein cholesterol ( P =0.007), and total ( P =0.009) and very low density lipoprotein ( P =0.005) triglycerides in control subjects and with high levels of low density lipoprotein triglycerides ( P =0.001) in FCHL family members (n=340). We conclude that the G-250A promoter variant of the HL gene is associated with dyslipidemia and insulin resistance. Mechanisms via which this polymorphism could affect insulin sensitivity remain to be elucidated.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.7.1789
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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  • 6
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    Insulin Sensitivity and Lp(a) Concentrations in Normoglycemic Men
    American Diabetes Association ; 1995
    In:  Diabetes Care Vol. 18, No. 2 ( 1995-02-01), p. 193-199
    Details
    In: Diabetes Care, American Diabetes Association, Vol. 18, No. 2 ( 1995-02-01), p. 193-199
    Abstract: 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) phe-notype 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.
    Type of Medium: Online Resource
    ISSN: 0149-5992 , 1935-5548
    URL: Article
    DOI: 10.2337/diacare.18.2.193
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 1995
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  • 7
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    New Amino Acid Substitutions in the IRS-2 Gene in Finnish and Chinese Subjects With Late-Onset Type 2 Diabetes
    American Diabetes Association ; 2001
    In:  Diabetes Vol. 50, No. 8 ( 2001-08-01), p. 1949-1951
    Details
    In: Diabetes, American Diabetes Association, Vol. 50, No. 8 ( 2001-08-01), p. 1949-1951
    Abstract: 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.
    Type of Medium: Online Resource
    ISSN: 0012-1797 , 1939-327X
    URL: Article
    DOI: 10.2337/diabetes.50.8.1949
    Language: English
    Publisher: American Diabetes Association
    Publication Date: 2001
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    detail.hit.zdb_id: 1501252-9
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  • 8
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    Relationship of LDL Size to Insulin Sensitivity in Normoglycemic Men
    Ovid Technologies (Wolters Kluwer Health) ; 1997
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 17, No. 7 ( 1997-07), p. 1447-1453
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 17, No. 7 ( 1997-07), p. 1447-1453
    Abstract: Abstract A preponderance of small, dense LDL has been suggested to be more atherogenic than larger, more buoyant LDL. Although several studies have suggested associations of small, dense LDL with hyperinsulinemia, few data are available on the relation of small, dense LDL to insulin resistance. We examined the association of LDL particle size determined by gradient gel electrophoresis with the rates of whole-body glu-cose uptake (WBGU) as determined by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 87 Finnish normoglycemic men. LDL size was significantly positively correlated with the rates of WBGU (overall, r =.31, P 〈 .01; oxidative, r =.23, P 〈 .05; and nonoxidative, r =.31, P 〈 .01). Rates of WBGU were also significantly lower in subjects with small LDL particles (≤26.0 nm) compared with those in sub-jects with larger LDL particles ( 〉 26.0 nm). This relation was not explained by obesity. Serum triglyceride concentrations were found to significantly affect the relationship of LDL particle size to WBGU. Specifically, LDL size was correlated with the rates of WBGU in men with mildly elevated triglyceride levels but not in men with low triglyceride levels. Serum VLDL triglyceride concentration was a substantially stronger determinant of LDL size than were the rates of WBGU. WBGU was not significantly related to LDL size when adjusted for triglycerides. We conclude that a preponderance of small, dense LDL particles is associated with insulin resistance and that serum triglyceride concentration modifies this relationship.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.17.7.1447
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 1997
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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  • 9
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    Impaired Free Fatty Acid Suppression During Hyperinsulinemia Is a Characteristic Finding in Familial Combined Hyperlipidemia, but Insulin Resistance Is Observed Only in Hypertriglyceridemic Patients
    Ovid Technologies (Wolters Kluwer Health) ; 2000
    In:  Arteriosclerosis, Thrombosis, and Vascular Biology Vol. 20, No. 1 ( 2000-01), p. 164-170
    Details
    In: Arteriosclerosis, Thrombosis, and Vascular Biology, Ovid Technologies (Wolters Kluwer Health), Vol. 20, No. 1 ( 2000-01), p. 164-170
    Abstract: Abstract —Insulin resistance has been associated with hypertriglyceridemia, combined hyperlipidemia, and familial combined hyperlipidemia (FCHL). Whether all FCHL patients with different types of dyslipidemia have low insulin sensitivity has not been evaluated. We measured insulin sensitivity by the hyperinsulinemic euglycemic clamp with indirect calorimetry in 110 healthy controls and in 105 nondiabetic, FCHL family members: in 50 without dyslipidemia, in 19 with hypercholesterolemia (total cholesterol ≥7.7 mmol/L), in 22 with hypertriglyceridemia (total triglycerides ≥2.4 mmol/L in men 2.4 mmol/L in women), and in 14 with combined hyperlipidemia. During the hyperinsulinemic clamp, FCHL family members had higher free fatty acid levels than did controls (0.06±0.06 [mean±SD] in controls versus 0.16±0.11 in relatives without dyslipidemia versus 0.15±0.07 in hypercholesterolemic patients versus 0.29±0.14 in hypertriglyceridemic patients versus 0.27±0.17 mmol/L in patients with combined hyperlipidemia; P 〈 0.001 after adjustment for age, sex, and body mass index). Relatives without dyslipidemia (16.4±4.4 μmol · kg −1 · min −1 , P =0.001) and patients with hypertriglyceridemia (12.8±3.8 μmol · kg −1 · min −1 , P 〈 0.001) and with combined hyperlipidemia (13.7±3.1 μmol · kg −1 · min −1 , P 〈 0.001) had lower rates of insulin-stimulated glucose oxidation than did controls (19.4±4.7 μmol · kg −1 · min −1 ). Also, the rates of nonoxidative glucose disposal were lower in patients with hypertriglyceridemia ( P =0.001) and combined hyperlipidemia ( P =0.011) than in controls. In contrast, subjects with hypercholesterolemia and control subjects had similar rates of insulin-stimulated glucose uptake. We conclude that a defect in free fatty acid suppression during hyperinsulinemia, probably located in adipose tissue, is characteristic for all FCHL patients with varying types of dyslipidemia, whereas insulin resistance in skeletal muscle is observed only in FCHL patients with elevated triglyceride levels.
    Type of Medium: Online Resource
    ISSN: 1079-5642 , 1524-4636
    URL: Article
    DOI: 10.1161/01.ATV.20.1.164
    Language: English
    Publisher: Ovid Technologies (Wolters Kluwer Health)
    Publication Date: 2000
    detail.hit.zdb_id: 1221433-4
    detail.hit.zdb_id: 1494427-3
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