A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients

Ascaso, Juan F.; Merchante, Ángel Muñoz; Lorente, Rosario I.; Real, Jordi; Martínez-Valls, José Francisco; Carmena, Rafael

doi:10.1016/s0026-0495(98)90232-3

Cited by 45 publications

(30 citation statements)

References 39 publications

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“…Similar findings using the frequently sampled intravenous glucose tolerance test were reported by Ascaso and colleagues. 29,30 Subsequent studies using the clamp technique confirmed that whole-body glucose uptake is reduced in FCHL subjects compared with control subjects. 28,31,32 When the FCHL subjects in these studies were subdivided by lipid phenotype (high cholesterol, high triglycerides, or combined hyperlipidemia), Si was found to be reduced only in those …”

Section: Discussionmentioning

confidence: 95%

“…32,33 In addition, when the FCHL subjects were separated by degree of adiposity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratios), those with the highest BMIs and waist-to-hip ratios were found to be the most insulin resistant. 30,32,33 In FCHL family members, also reported were significant correlations of free fatty acid levels during the clamp with triglyceride levels but not with apoB levels. 31,32 Visceral adiposity has been associated with a number of metabolic abnormalities, including insulin resistance, increased triglyceride levels, lower HDL 2 cholesterol, more cholesterol in small dense LDL particles, 24,25 increased apoB production rates, 44 and increased apoB levels.…”

Section: Purnell Et Almentioning

confidence: 93%

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Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Purnell

Kahn

Schwartz

et al. 2001

ATVB

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Abstract-Familial combined hyperlipidemia (FCHL) is one of the most common familial dyslipidemias associated with premature heart disease. Subjects with FCHL typically have elevated apolipoprotein B (apoB) levels, variable elevations in cholesterol and/or triglycerides, and a predominance of small, dense, low density lipoprotein particles. It is thought that insulin resistance is important in the expression of the combined hyperlipidemia phenotype. To further characterize the relationship between insulin resistance and increased apoB levels, 11 subjects from well-characterized FCHL families and normal control subjects matched for weight and/or age underwent measurement of intra-abdominal fat (IAF) and subcutaneous fat (SQF) by CT scan, insulin sensitivity (Si) by the frequently sampled intravenous glucose tolerance test, and lipoprotein levels. Body mass index and IAF were higher and Si was lower (more insulin resistant) in the FCHL group than in the age-matched group, but the values were similar in the FCHL group and the age-and weight-matched control group. When the relationship between body fat distribution and Si was tested with multiple linear regression, only IAF was significantly correlated with Si after the addition of SQF and body mass index as independent variables. For any level of insulin sensitivity or IAF, however, apoB levels remained higher in the FCHL subjects than in the control groups. In conclusion, in FCHL, visceral obesity is an important determinant of insulin resistance. Visceral obesity and insulin resistance, however, do not fully account for the elevated levels of apoB in this disorder, and this study provides physiological support for separate, but additive, genetic determinants in the etiology of the lipid phenotype.

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Section: Discussionmentioning

confidence: 95%

Section: Purnell Et Almentioning

confidence: 93%

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Purnell

Kahn

Schwartz

et al. 2001

ATVB

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“…Although hyperlipidemia is not always present with obesity, the combination of the two has been shown to have an increased effect on the abnormalities linked with the metabolic syndrome (2,5). Much attention has been focused recently on the observation that macrophages infiltrate WAT in obesity; however, the impact of hyperlipidemia on this process has yet to be established.…”

Section: Discussionmentioning

confidence: 99%

“…In fact, individuals with familial combined hyperlipidemia are more insulin resistant compared with normolipidemic relatives, even after correcting for BMI (4). Moreover, insulin sensitivity is significantly lower in obese hyperlipidemic subjects compared with nonobese hyperlipidemic subjects (5). Therefore, the presence of both obesity and hyperlipidemia can exert an additive effect on insulin resistance.…”

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confidence: 99%

Diet-Induced Increases in Adiposity, but Not Plasma Lipids, Promote Macrophage Infiltration Into White Adipose Tissue

et al. 2007

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“…Because of the known association between high serum triglycerides and insulin resistance both in the general population (49) and in FCHL families (6,8), the novel loci that have been linked to FCHL (17,18), especially with serum triglycerides in FCHL families (50,51), also are promising with respect to insulin resistance. In fact, genes may have a pleiotropic effect on several lipoprotein traits and insulin sensitivity, and therefore the search for novel FCHL genes may be more effective if combined phenotypes are used (52).…”

Section: Discussionmentioning

confidence: 99%

A Major Gene Effect on Fasting Insulin and Insulin Sensitivity in Familial Combined Hyperlipidemia

et al. 2001

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The most common inherited dyslipidemia, familial combined hyperlipidemia (FCHL), is associated with insulin resistance. Whether insulin sensitivity in these families is inherited is not known. Therefore, we investigated the inheritance of insulin sensitivity in 352 nondiabetic family members from 37 families with FCHL, 105 of whom had undergone testing using the hyperinsulinemiceuglycemic clamp technique for the measurement of insulin sensitivity. First, complex segregation analysis of fasting insulin levels (both unadjusted and age-, age 2 -, and BMI-adjusted) was used for modeling of the variance in fasting insulin levels. In these analyses, Mendelian codominant inheritance (P ‫؍‬ 0.320 for unadjusted and P ‫؍‬ 0.295 for adjusted insulin values) was not rejected over the most general model and fit the data significantly better than the sporadic model (P < 0.001). Polygenic and environmental models were rejected (P < 0.001). The Mendelian codominant model explained 44 and 45% of the variance in unadjusted and adjusted fasting insulin levels, respectively. The proposed genotypes of this locus, based on segregation analysis, were associated with directly measured insulin sensitivity in 105 FCHL family members who underwent the hyperinsulinemic-euglycemic clamp (P < 0.001). These results provide evidence for a major gene regulating insulin sensitivity in FCHL families. Possible pleiotropic effects of this insulin sensitivity locus on dyslipidemias in FCHL remain to be elucidated. Diabetes 50:2396 -2401, 2001 F amilial combined hyperlipidemia (FCHL) is the most common familial dyslipidemia and is associated with increased risk of cardiovascular diseases (1). The prevalence in Western populations is reported to be ϳ1%, but in patients who have coronary heart disease at young age, the prevalence may be as high as 20% (2,3). FCHL is characterized by different types of dyslipidemias (2,3) and insulin resistance (4 -8). Most likely, FCHL is an oligogenic disorder (8,9). Major genes for triglycerides (2,10), apolipoprotein B (apoB) (11-13), and small, dense LDL (14,15) have been proposed, but so far no major genes for these traits have been mapped. However, several loci identified in genome-wide random searches have been proposed to modify lipid levels (16 -18).Insulin resistance, defined as insulin's impaired ability to exert its normal function (19), can be quantified directly with the hyperinsulinemic-euglycemic clamp (20). In Pima Indians, insulin sensitivity measured by this technique has been reported to be distributed as a mixture of three normal distributions. This suggests that a major codominant gene may determine insulin sensitivity (21). Because the clamp study is difficult to perform in large families with several generations, fasting insulin level has been used as a surrogate of insulin action (22). Using segregation analysis in families randomly ascertained (23) or through siblings with type 2 diabetes (24), major genes have been proposed to determine fasting and postglucose insulin levels. These segregati...

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A study of insulin resistance using the minimal model in nondiabetic familial combined hyperlipidemic patients

Cited by 45 publications

References 39 publications

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Relationship of Insulin Sensitivity and ApoB Levels to Intra-abdominal Fat in Subjects With Familial Combined Hyperlipidemia

Diet-Induced Increases in Adiposity, but Not Plasma Lipids, Promote Macrophage Infiltration Into White Adipose Tissue

A Major Gene Effect on Fasting Insulin and Insulin Sensitivity in Familial Combined Hyperlipidemia

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