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Insulin resistance is associated with hypertriglyceridemia and combined hyperlipidemia but not with hypercholesterolemia in familial combined hyperlipidemia
Thursda): 27 May 1999 Workshop: The metabolic syndrome
12
interaction with hormone nuclear receptors such asHNF-4; and ii) factors which regulate the expression of SMAD proteins in hepatic cells could play an important role in cholesterol homeostasis and lipoprotein metabolism.
Workshop: The metabolic syndrome SYNDROME X: PAST, PRESENT, & FUTURE
G.M. Reaven. Stanford UniuersiO,School of Medicine, Stanford, California, USA The ability of insulin to mediate glucose disposal varies approximately 10-fold in apparently healthy human beings. Approximately 50% of this variability can be attributed to differences in behavior, i.e., obesity, physical inactivity, and cigarette smoking all increase degree of insulin resistance. The other 50% of the variability in insulin-mediated glucose disposal is likely to be related to genetic differences. In this context, the effect of ethnic differences is quite powerful, with individuals of European ancestry appearing to be by far the most insulin sensitive population. Irrespective of the relative effects of nature versus nurture, insulin resistant individuals can remain glucose tolerant only if the pancreas is capable of responding to this defect by secreting large amounts of insulin. Type 2 diabetes develops when insulin resistant persons cannot sustain the necessary degree of compensatory hyperinsulinemia. However, the ability of hyperinsulinemia to prevent decompensation of glucose tolerance appears to be a mixed blessing, and in addition to its role in the etiology of type 2 diabetes, insulin resistance and associated abnormalities are involved in the pathogenesis and clinical course of hypertension and coronary heart disease (CHD). Although the overall prevalence of these diseases is slowly growing or stable in most Western countries, all three are increasing at an alarming rate in underdeveloped countries, as well as in individuals of nonEuropean descent living in developed countries. It does not seem excessive to conclude at this time that there is an importam need to focus more on understanding these events, as well as attempting to intervene in an effort to halt this epidemic related to insulin resistance. In this presentation, an effort will be made to contribute to this process by addressing issues which, although not often considered in discussion of insulin resistance and its consequence, are important in expanding our understanding of these phenomena. Specifically, the presentation will focus on addressing the following three rhetorical questions. 1) What do we mean by insulin resistance? 2) Why is insulin resistance important? 3) How does insulin resistance increase risk of CHD? The answers to these three questions will hopefully aid in attempts to overcome the abnormality that is likely to become the major health problem of the next millennium
IMPAIRED GLUCOSE TOLERANCE, THE METABOLIC SYNDROME AND CAROTID INTIMA-MEDIA THICKNESS: THE RIAD STUDY
total), tissue-type-plasnlinogen-activator, albuminuria, true insulin, proinsulin, IMT, as well as a decrease of high-density-lipoprotein cholesterol. In univariate analysis after adjustment for age and sex, 2 h postprandial glucose was significantly correlated to body mass index, waist to hip ratio, systolic and diastolic blood pressure, triglycerides, plasminogen-activatorinhibitor-I (active and total), tissue-typ-plasminogen-activator, albuminuria, true insulin, proinsulin, C-peptide, IMT, inversely to high-density-lipoprotein cholesterol. In multivariate analysis age, ratio total cholesterol to HDLcholesterol, albuminuria, 2 h postprandial glucose but not fasting plasma glucose, male sex and triglycerides were found to be independent determinants of carotid IMT. These results show that already in the prediabetic phase, in the stage of IGT, carotid IMT is significantly increased, which could be due to the clustering of risk factors for atherosclerosis. INSULIN RESISTANCE IS ASSOCIATED WITH HYPERTRIGLYCER]DEMIA AND COMBINED HYPERLIPIDEMIA BUT NOT WITH HYPERCHOLESTEROLEMIA IN FAMILIAL COMBINED HYPERLIPIDEMIA
J. Pihlajamiiki, L. Karjalainen, M. Laakso. Department of Medicine. UniversiO, of Kuopio, Finland Insulin resistance has been associated with hypertriglyceridemia (type IV dyslipidemia), combined hyperlipidemia (type lib) and familial combined hyperlipidemia (FCHLI Whether subjects with hypercholesterolemia (type Ila) in FCHL families are insulin resistant has not been studied. We measured insulin sensitivity by hyperinsulinemic euglycemic clamp study with indirect calorimetry in 105 nondiabetic FCHL family members: in 50 without dyslipidemia (cut-off points for lipids were total cholesterol < 7.7 mmol/L and total triglycerides < 2.4 mmol/L in men and <2.2 mmol/L in menh in 19 with type Ila dyslipidemia, in 22 with type IV dyslipidemia and in 14 with type Ilb dyslipidemia. Subjects with type IV had higher age- and gender-adjusted body mass index (p = 0.0021 and fasting insulin levels (p = 0.013) than subjects without dyslipidemia. More importantly, subjects with type IV and llb dyslipidemias had lower rates of insulin stimulated glucose oxidation [16.4±4.4 mmol/kg/min (mean+SD) in subjects without dyslipidemia vs. 17.65:3.0 in type Ila vs. 12.8±3.8 in type IV. p = 0.003 vs. 13.7±3.1 in type lib, p = 0.031], glucose nonoxidation (35.6 5:12.3 mmol/kg/min vs. 35.9±10.8 vs. 27.9+10.4o p = 0.012 vs. 27.7±11.4, p = 0.038) and higher free fatty acid levels (0.16±0.11 mmol/L vs. 0.155:0.07 vs, 0.29-1-0.14, p < 0.001 vs. 0.27±0.17, p = 0.008) during hyperinsulinemic clamp than did relatives without dyslipidemia. However, subjects with type IIa dyslipidemia did not differ from relatives without dyslipidemia. This finding suggests divergent genetic backround for insulin resistance and hypercholesterolemia in FCHL families. DYSLIPIDEMIA IN INSULIN RESISTANCE: A SILENT VILLAIN? M.-R. Taskinen. Department of Medicine. UniuersiO, of Helsinki. Helsinki,
Finland C. Koehler, T. Temelkova-Kurktschiev, E. Henkel, E Scharper, M. Hanefeld.
Institute for Clinical Metabolic Research. Technical Universi.ty Dresden. Germany Impaired glucose tolerance (IGT), a part of the metabolic syndrome, is an established risk factor for atherosclerosis. However, the data of long-term follow up studies using end points may be biased by a higher percentage of undiaguosed diabetics and comorbid diseases. Carotid intima-media thickness (1MT) is an accepted marker for atherosclerosis. Therefore, the aim of our study was to investigate the IMT and atherosclerosis risk factors in IGT in comparison to normal glucose tolerance (NGT) and newly detected asymptomatic type 2 diabetes (NDM). Subjects (n = 1139) were examined from the Risk Factors in _IGT for _A_therosclerosisand Diabetes (RIAD) Study. Inclusion criteria: age 40-70 years, family history of type 2 diabetes and/or history of obesity and/or high blood pressure and/or hyperlipoproteinemia. A standard oral glucose tolerance test with 75 g glucose was conducted. Plasma glucose, HbAic, lipids and fibrinolytic and coagulation parameters were measured by conventional methods; proinsulin, true insulin and Cpeptide by spezific enzyme immuno assays. Albuminuria was ascertained with a nephelomelrical method. The carotid IMT was examined by B-mode ultrasound. The IMT level was increased in parallel to glucose intolerance: 0.82+0.17 (mean4-SD) in NGT, 0.90+0.19 in IGT and 0.95+0.18 in NDM (p < 0.001 IGT, NDM vs. NGT). Also parallel to glucose intolerance we found an elevation of body mass index, waist to hip ratio, systolic and diastolic blood pressure, triglycerides, plasminogen-activator-inhibitor-I (active and
Common features of dyslipidemia in insulin resistance are elevation of plasma triglycerides and lowering of HDL cholesterol. Dyslipidemia is an inherent feature of insulin resistance evidenced by the observations that normolipidemic glucose-tolerant but hyperinsulinemic relatives of NIDDM subjects have qualitatively similar abnormalities as NIDDM patients. These abnormalities develop in concert with insulin resistance. In both sexes there is a stepwise increase of Tg but lowering of HDL chol over the quintiles of fasting plasma insulin and waist/hip (W/H) ratio. Recently it has been discovered that small dense LDL pattern and postprandial lipemia also coexist with dyslipidemia in insulin resistance. Substantial evidence indicate that the concentration of plasma triglycerides and insulin resistance are closely related to LDL size. However, in most studies only plasma triglycerides are the single, most important, independent predictor of LDL size. Importantly several studies suggest a threshold effect of triglyceride concentration on LDL size. The shift in LDL size towards small dense LDL is observed if plasma triglycerides exceed 1.3-1.5 mmol/l. We have recently demonstrated that a novel physiological action of insulin is to suppress the release o f large buoyant VLDLI particles (Sf 60--400) from the liver. This action o f insulin is defective in Type 2 diabetic patients. This failure of insulin to suppress VLDL1 particle release in insulin resistant state would result in inappropriate production of VLDLI particles in the postprandial phase and most likely to contribute to postprandial lipemia and to the excess formation of small dense LDL. Other factors which may modulate LDL distribution are hepatic lipase activity and cholesteryl ester transfer activity (CETP). Since LPL activity is commonly subnormal in insulin resistant
71st EAS Congress and Satellite Symposia
12
interaction with hormone nuclear receptors such asHNF-4; and ii) factors which regulate the expression of SMAD proteins in hepatic cells could play an important role in cholesterol homeostasis and lipoprotein metabolism.
Workshop: The metabolic syndrome SYNDROME X: PAST, PRESENT, & FUTURE
G.M. Reaven. Stanford UniuersiO,School of Medicine, Stanford, California, USA The ability of insulin to mediate glucose disposal varies approximately 10-fold in apparently healthy human beings. Approximately 50% of this variability can be attributed to differences in behavior, i.e., obesity, physical inactivity, and cigarette smoking all increase degree of insulin resistance. The other 50% of the variability in insulin-mediated glucose disposal is likely to be related to genetic differences. In this context, the effect of ethnic differences is quite powerful, with individuals of European ancestry appearing to be by far the most insulin sensitive population. Irrespective of the relative effects of nature versus nurture, insulin resistant individuals can remain glucose tolerant only if the pancreas is capable of responding to this defect by secreting large amounts of insulin. Type 2 diabetes develops when insulin resistant persons cannot sustain the necessary degree of compensatory hyperinsulinemia. However, the ability of hyperinsulinemia to prevent decompensation of glucose tolerance appears to be a mixed blessing, and in addition to its role in the etiology of type 2 diabetes, insulin resistance and associated abnormalities are involved in the pathogenesis and clinical course of hypertension and coronary heart disease (CHD). Although the overall prevalence of these diseases is slowly growing or stable in most Western countries, all three are increasing at an alarming rate in underdeveloped countries, as well as in individuals of nonEuropean descent living in developed countries. It does not seem excessive to conclude at this time that there is an importam need to focus more on understanding these events, as well as attempting to intervene in an effort to halt this epidemic related to insulin resistance. In this presentation, an effort will be made to contribute to this process by addressing issues which, although not often considered in discussion of insulin resistance and its consequence, are important in expanding our understanding of these phenomena. Specifically, the presentation will focus on addressing the following three rhetorical questions. 1) What do we mean by insulin resistance? 2) Why is insulin resistance important? 3) How does insulin resistance increase risk of CHD? The answers to these three questions will hopefully aid in attempts to overcome the abnormality that is likely to become the major health problem of the next millennium
IMPAIRED GLUCOSE TOLERANCE, THE METABOLIC SYNDROME AND CAROTID INTIMA-MEDIA THICKNESS: THE RIAD STUDY
total), tissue-type-plasnlinogen-activator, albuminuria, true insulin, proinsulin, IMT, as well as a decrease of high-density-lipoprotein cholesterol. In univariate analysis after adjustment for age and sex, 2 h postprandial glucose was significantly correlated to body mass index, waist to hip ratio, systolic and diastolic blood pressure, triglycerides, plasminogen-activatorinhibitor-I (active and total), tissue-typ-plasminogen-activator, albuminuria, true insulin, proinsulin, C-peptide, IMT, inversely to high-density-lipoprotein cholesterol. In multivariate analysis age, ratio total cholesterol to HDLcholesterol, albuminuria, 2 h postprandial glucose but not fasting plasma glucose, male sex and triglycerides were found to be independent determinants of carotid IMT. These results show that already in the prediabetic phase, in the stage of IGT, carotid IMT is significantly increased, which could be due to the clustering of risk factors for atherosclerosis. INSULIN RESISTANCE IS ASSOCIATED WITH HYPERTRIGLYCER]DEMIA AND COMBINED HYPERLIPIDEMIA BUT NOT WITH HYPERCHOLESTEROLEMIA IN FAMILIAL COMBINED HYPERLIPIDEMIA
J. Pihlajamiiki, L. Karjalainen, M. Laakso. Department of Medicine. UniversiO, of Kuopio, Finland Insulin resistance has been associated with hypertriglyceridemia (type IV dyslipidemia), combined hyperlipidemia (type lib) and familial combined hyperlipidemia (FCHLI Whether subjects with hypercholesterolemia (type Ila) in FCHL families are insulin resistant has not been studied. We measured insulin sensitivity by hyperinsulinemic euglycemic clamp study with indirect calorimetry in 105 nondiabetic FCHL family members: in 50 without dyslipidemia (cut-off points for lipids were total cholesterol < 7.7 mmol/L and total triglycerides < 2.4 mmol/L in men and <2.2 mmol/L in menh in 19 with type Ila dyslipidemia, in 22 with type IV dyslipidemia and in 14 with type Ilb dyslipidemia. Subjects with type IV had higher age- and gender-adjusted body mass index (p = 0.0021 and fasting insulin levels (p = 0.013) than subjects without dyslipidemia. More importantly, subjects with type IV and llb dyslipidemias had lower rates of insulin stimulated glucose oxidation [16.4±4.4 mmol/kg/min (mean+SD) in subjects without dyslipidemia vs. 17.65:3.0 in type Ila vs. 12.8±3.8 in type IV. p = 0.003 vs. 13.7±3.1 in type lib, p = 0.031], glucose nonoxidation (35.6 5:12.3 mmol/kg/min vs. 35.9±10.8 vs. 27.9+10.4o p = 0.012 vs. 27.7±11.4, p = 0.038) and higher free fatty acid levels (0.16±0.11 mmol/L vs. 0.155:0.07 vs, 0.29-1-0.14, p < 0.001 vs. 0.27±0.17, p = 0.008) during hyperinsulinemic clamp than did relatives without dyslipidemia. However, subjects with type IIa dyslipidemia did not differ from relatives without dyslipidemia. This finding suggests divergent genetic backround for insulin resistance and hypercholesterolemia in FCHL families. DYSLIPIDEMIA IN INSULIN RESISTANCE: A SILENT VILLAIN? M.-R. Taskinen. Department of Medicine. UniuersiO, of Helsinki. Helsinki,
Finland C. Koehler, T. Temelkova-Kurktschiev, E. Henkel, E Scharper, M. Hanefeld.
Institute for Clinical Metabolic Research. Technical Universi.ty Dresden. Germany Impaired glucose tolerance (IGT), a part of the metabolic syndrome, is an established risk factor for atherosclerosis. However, the data of long-term follow up studies using end points may be biased by a higher percentage of undiaguosed diabetics and comorbid diseases. Carotid intima-media thickness (1MT) is an accepted marker for atherosclerosis. Therefore, the aim of our study was to investigate the IMT and atherosclerosis risk factors in IGT in comparison to normal glucose tolerance (NGT) and newly detected asymptomatic type 2 diabetes (NDM). Subjects (n = 1139) were examined from the Risk Factors in _IGT for _A_therosclerosisand Diabetes (RIAD) Study. Inclusion criteria: age 40-70 years, family history of type 2 diabetes and/or history of obesity and/or high blood pressure and/or hyperlipoproteinemia. A standard oral glucose tolerance test with 75 g glucose was conducted. Plasma glucose, HbAic, lipids and fibrinolytic and coagulation parameters were measured by conventional methods; proinsulin, true insulin and Cpeptide by spezific enzyme immuno assays. Albuminuria was ascertained with a nephelomelrical method. The carotid IMT was examined by B-mode ultrasound. The IMT level was increased in parallel to glucose intolerance: 0.82+0.17 (mean4-SD) in NGT, 0.90+0.19 in IGT and 0.95+0.18 in NDM (p < 0.001 IGT, NDM vs. NGT). Also parallel to glucose intolerance we found an elevation of body mass index, waist to hip ratio, systolic and diastolic blood pressure, triglycerides, plasminogen-activator-inhibitor-I (active and
Common features of dyslipidemia in insulin resistance are elevation of plasma triglycerides and lowering of HDL cholesterol. Dyslipidemia is an inherent feature of insulin resistance evidenced by the observations that normolipidemic glucose-tolerant but hyperinsulinemic relatives of NIDDM subjects have qualitatively similar abnormalities as NIDDM patients. These abnormalities develop in concert with insulin resistance. In both sexes there is a stepwise increase of Tg but lowering of HDL chol over the quintiles of fasting plasma insulin and waist/hip (W/H) ratio. Recently it has been discovered that small dense LDL pattern and postprandial lipemia also coexist with dyslipidemia in insulin resistance. Substantial evidence indicate that the concentration of plasma triglycerides and insulin resistance are closely related to LDL size. However, in most studies only plasma triglycerides are the single, most important, independent predictor of LDL size. Importantly several studies suggest a threshold effect of triglyceride concentration on LDL size. The shift in LDL size towards small dense LDL is observed if plasma triglycerides exceed 1.3-1.5 mmol/l. We have recently demonstrated that a novel physiological action of insulin is to suppress the release o f large buoyant VLDLI particles (Sf 60--400) from the liver. This action o f insulin is defective in Type 2 diabetic patients. This failure of insulin to suppress VLDL1 particle release in insulin resistant state would result in inappropriate production of VLDLI particles in the postprandial phase and most likely to contribute to postprandial lipemia and to the excess formation of small dense LDL. Other factors which may modulate LDL distribution are hepatic lipase activity and cholesteryl ester transfer activity (CETP). Since LPL activity is commonly subnormal in insulin resistant
71st EAS Congress and Satellite Symposia