Insulin resistance is associated with increased cholesterol synthesis and decreased cholesterol absorption in normoglycemic men

Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin (r = 0.36–0.46, P < 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r = −0.37–0.40, P < 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU (P < 0.05). Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for.We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism. Type 2 diabetes has been associated with high synthesis and low absorption of cholesterol independent of weight, indicating that insulin resistance may be a link between glucose and cholesterol metabolism. Therefore, we investigated the relationship of serum cholesterol precursors, reflecting cholesterol synthesis, and serum plant sterols and cholestanol, reflecting cholesterol absorption efficiency, with insulin sensitivity measured with the hyperinsulinemic euglycemic clamp in 72 healthy normoglycemic men. Men in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05), whereas no significant differences in serum absorption sterols were observed. In bivariate analysis, cholesterol synthesis markers correlated with fasting insulin (r = 0.36–0.46, P < 0.01) and the rates of insulin-stimulated whole-body glucose uptake (WBGU; r = −0.37–0.40, P < 0.01). Also, cholesterol absorption markers correlated with fasting insulin and WBGU (P < 0.05). Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when the rates of WBGU and body mass index (BMI) were controlled for. We conclude that insulin resistance is linked to high cholesterol synthesis and decreased cholesterol absorption. Because fasting insulin correlated with cholesterol synthesis independent of the rates of BMI and WBGU, it is possible that regulation of cholesterol synthesis by hyperinsulinemia may be a link between insulin resistance and cholesterol metabolism. Insulin resistance and type 2 diabetes (T2DM) have been constantly associated with high triglyceride and low HDL-cholesterol levels. Increased synthesis of VLDL particles in the liver has been proposed to be the main cause of increased concentrations of triglyceride-rich lipoproteins. This overproduction of VLDL and triglycerides in the liver has been proposed to be driven by high levels of serum FFAs in patients with insulin resistance. In T2DM, high levels of VLDL cholesterol have also been observed, and because of that, mildly increased levels of LDL cholesterol may occur [for review, see refs. (1Reaven G.M. Insulin resistance and compensatory hyperinsulinemia: role in hypertension, dyslipidemia, and coronary heart disease.Am. Heart J. 1991; 121: 1283-1288Crossref PubMed Scopus (247) Google Scholar, 2Taskinen M.R. Diabetic dyslipidemia.Atheroscler. Suppl. 2002; 3: 47-51Abstract Full Text Full Text PDF PubMed Scopus (164) Google Scholar)]. These observations are in agreement with the findings that increased cholesterol synthesis has been observed in obese subjects (3Miettinen T.A. Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity.Atherosclerosis. 2000; 153: 241-248Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar) and in patients with the metabolic syndrome (4Chan D.C. Watts G.F. Barrett P.H. O'Neill F.H. Thompson G.R. Plasma markers of cholesterol homeostasis and apolipoprotein B-100 kinetics in the metabolic syndrome.Obes. Res. 2003; 11: 591-596Crossref PubMed Scopus (28) Google Scholar). Because similar findings have been observed in patients with T2DM independent of weight (5Simonen P.P. Gylling H.K. Miettinen T.A. Diabetes contributes to cholesterol metabolism regardless of obesity.Diabetes Care. 2002; 25: 1511-1515Crossref PubMed Scopus (113) Google Scholar), insulin resistance could explain the increase in cholesterol synthesis in patients with obesity and T2DM. This hypothesis is supported by the finding that in subjects with normal glucose tolerance, high glucose is linked to increased synthesis of cholesterol (6Stranberg T.E. Salomaa V. Vanhanen H. Miettinen T.A. Associations of fasting blood glucose with cholesterol absorption and synthesis in nondiabetic middle-aged men.Diabetes. 1996; 45: 755-761Crossref PubMed Google Scholar). Increase in cholesterol synthesis is always accompanied by low rates of cholesterol absorption; therefore, it has been difficult to determine which of these two is primarily affected in subjects with obesity or T2DM. In this study, we tried to answer the following questions. 1) Is directly measured insulin sensitivity linked to cholesterol metabolism in normoglycemic subjects? 2) Is cholesterol absorption or synthesis more strongly associated with insulin resistance? To this end, serum cholesterol precursors, reflecting cholesterol synthesis, and plant sterols and cholestanol, reflecting cholesterol absorption efficiency (7Miettinen T.A. Tilvis R.S. Kesaniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Crossref PubMed Scopus (556) Google Scholar), were quantitated with gas-liquid chromatography in 72 healthy men. Insulin sensitivity was measured in these men using the hyperinsulinemic euglycemic clamp. Study subjects were 72 healthy unrelated Finnish men without family history of diabetes or premature coronary heart disease randomly selected from the population living in the Kuopio University Hospital region. All subjects had normal glucose tolerance according to World Health Organization criteria (8Diabetes Mellitus: Report of a WHO Study Group. World Health Organization, Geneva, Switzerland1985Google Scholar) and did not have hypertension, symptoms or signs of coronary heart disease, or continuous drug treatment. Furthermore, they had normal liver, kidney, and thyroid function and no history of excessive alcohol intake. Informed consent was obtained from all subjects after the purpose and potential risks of the study were explained to them. The protocol was approved by the Ethics Committee of the University of Kuopio and was in accordance with the Helsinki Declaration. Insulin sensitivity was measured by the euglycemic clamp technique (9DeFronzo R. Tobin J. Andres R. Glucose clamp technique: a method for quantifying insulin secretion and insulin resistance.Am. J. Physiol. 1979; 237: E214-E223PubMed Google Scholar) after a 12 h fast as previously described (10Haffner S. Karhapää P. Mykkänen L. Laakso M. Insulin resistance, body fat distribution, and sex hormones in men.Diabetes. 1994; 43: 212-219Crossref PubMed Scopus (276) Google Scholar). After the baseline blood drawing, a priming dose of insulin (Actrapid 100 IU/ml; Novo Nordisk, Gentofte, Denmark) was administered during the initial 10 min to increase plasma insulin concentration quickly to the desired level, at which it was maintained by a continuous insulin infusion of 480 pmol/m2/min. Under these study conditions, hepatic glucose production is completely suppressed in nondiabetic subjects (11Bergman R. Finegood D. Ader M. Assessment of insulin sensitivity in vivo.Endocr. Rev. 1985; 5: 45-86Crossref Scopus (953) Google Scholar). Blood glucose was clamped at 5.0 mmol/l for the next 180 min by the infusion of 20% glucose at varying rates according to the blood glucose measurements performed at 5 min intervals. The mean rates of glucose infusion during the last hour of the clamp were used to calculate the rates of insulin-stimulated whole-body glucose uptake (WBGU). Indirect calorimetry was performed with a computerized flow-through canopy gas analyzer system (Deltatrac; Datex, Helsinki, Finland) as previously described (12Laakso M. Uusitupa M. Takala J. Majander H. Reijonen T. Penttilä I. Effects of hypocaloric diet and insulin therapy on metabolic control and mechanisms of hyperglycemia in obese non-insulin-dependent diabetic subjects.Metabolism. 1988; 37: 1092-1100Abstract Full Text PDF PubMed Scopus (88) Google Scholar). Gas exchange and urinary nitrogen excretion were measured in the fasting state and during the last 30 min of the euglycemic clamp procedure. Data from the first 10 min of each measurement were discarded, and the mean values of data from the last 20 min were used in calculations. Respiratory quotient, the rates of glucose and lipid oxidation (or net synthesis during the hyperinsulinemic clamp procedure), and energy expenditure were calculated according to Ferrannini (13Ferrannini E. The theoretical bases of indirect calorimetry: a review.Metabolism. 1988; 37: 287-301Abstract Full Text PDF PubMed Scopus (1251) Google Scholar). The rates of nonoxidative glucose disposal during the euglycemic clamp procedure were estimated by subtracting the rates of glucose oxidation from the rates of WBGU. Plasma glucose in the fasting state and after an oral glucose load and blood glucose during the euglycemic clamp procedure were measured by the glucose oxidase method (2300 Stat Plus; Yellow Springs Instrument Co., Inc., Yellow Springs, OH). For the determination of plasma insulin, blood was collected in EDTA-containing tubes, and after centrifugation, the plasma was stored at −20°C until analysis. Plasma insulin concentration was determined by a commercial double-antibody solid-phase radioimmunoassay (Phadeseph Insulin RIA 100; Pharmacia Diagnostics AB, Uppsala, Sweden). Lipoprotein fractionation was performed by ultracentrifugation and selective precipitation, as previously described (14Laakso M. Sarlund H. Mykkänen L. Insulin resistance is associated with lipid and lipoprotein abnormalities in subjects with varying degrees of glucose tolerance.Arteriosclerosis. 1990; 10: 223-231Crossref PubMed Scopus (263) Google Scholar). Cholesterol and triglyceride levels from whole serum and lipoprotein fractions were assayed by automated enzymatic methods (Boehringer-Mannheim, Mannheim, Germany). Apolipoprotein B levels were determined by a commercial immunoturbidometric method (Kone Instruments, Espoo, Finland), and serum FFAs from fresh frozen samples were determined by an enzymatic method (Wako Chemicals GmbH, Neuss, Germany). Nonprotein urinary nitrogen was measured by an automated Kjeldahl method (15Hawk P. Oser B. Summerson W. Practical Physiological Chemistry. 12th edition. Blakiston, Toronto, Canada1947: 814-822Google Scholar). The serum cholesterol precursors squalene, cholestenol, desmosterol, and lathosterol, i.e., sterols reflecting cholesterol synthesis (7Miettinen T.A. Tilvis R.S. Kesaniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Crossref PubMed Scopus (556) Google Scholar), and the plant sterols campesterol and sitosterol and cholestanol (a metabolite of cholesterol), i.e., sterols reflecting cholesterol absorption efficiency (7Miettinen T.A. Tilvis R.S. Kesaniemi Y.A. Serum plant sterols and cholesterol precursors reflect cholesterol absorption and synthesis in volunteers of a randomly selected male population.Am. J. Epidemiol. 1990; 131: 20-31Crossref PubMed Scopus (556) Google Scholar, 16Gylling H. Miettinen T.A. Inheritance of cholesterol metabolism of probands with high or low cholesterol absorption.J. Lipid Res. 2002; 43: 1472-1476Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar), were quantitated with gas-liquid chromatography on a 50 m long capillary column (Ultra 1; Hewlett-Packard, Wilmington, DE) using 5α-cholestane as an internal standard (17Miettinen T.A. Koivisto P. Non-cholesterol sterols and bile acid production in hypercholesterolaemic patients with ileal bypass.in: Paumgartner G.A. Stiehl A.W. Gerok W. Bile Acids and Cholesterol in Health and Disease. MTP Press, Lancaster, PA1983: 183-187Google Scholar). The squalene and noncholesterol sterol values were expressed in terms of 102× millimoles per mole of cholesterol (called ratio in the text), dividing the squalene and sterol values by the cholesterol value of the same run to eliminate the effects of different cholesterol concentrations. All basic calculations were performed with the SPSS/Win programs (version 10.0; SPSS, Inc.). The differences in the parameters among the tertiles of insulin sensitivity were tested by the ANOVA with age, gender, and body mass index (BMI) as covariates. Triglycerides, insulin, and FFA levels were logarithmically transformed to obtain a normal distribution before statistical analyses. A value of P < 0.05 was considered statistically significant. All data are presented as means ± SD. Factor analysis is a multivariate correlation method that is used to reduce a large set of intercorrelating variables, in this case plant sterols and cholesterol precursors, into a smaller set of latent underlying factors (18Meigs J.B. Invited commentary: insulin resistance syndrome? Syndrome X? Multiple metabolic syndrome? A syndrome at all? Factor analysis reveals patterns in the fabric of correlated metabolic risk factors.Am. J. Epidemiol. 2000; 152: 908-911Crossref PubMed Scopus (322) Google Scholar). The three main steps in factor analysis are as follows: 1) extraction of initial components; 2) rotation of components resulting in elucidation of factors; and 3) interpretation of factors. We used the principal components method for extraction of the initial components. The analysis was conducted with all plant sterols and cholesterol precursors. Varimax orthogonal rotation was then used to delineate two factors that are not correlated with each other. The resulting factor pattern was interpreted using factor loadings of ≤0.4, i.e., variables with a loading of greater than 0.4 were taken in to that factor. The characteristics of study subjects divided into tertiles according to insulin sensitivity (n = 24 in each tertile; WBGU cut-off points were 51.7 and 61.7 μmol/kg/min) are in in the most insulin-resistant tertile had higher fasting plasma glucose and insulin, and and VLDL triglycerides (P < of study subjects according to the tertiles of insulin sensitivity measured with the hyperinsulinemic euglycemic (n = (n = (n = ± ± ± ± ± ± < for the the ± ± ± < for the the blood ± ± ± blood ± ± ± glucose ± ± ± < for the the insulin ± ± ± < for the the cholesterol ± ± ± ± ± ± ± ± ± ± ± ± triglycerides ± ± ± < 0.05 for the the ± ± ± < for the the ± ± ± ± ± ± ± ± ± body mass Data are means ± P < for the the P < 0.05 for the the P < for the the in a body mass Data are means ± SD. 2 that subjects in the most insulin-resistant tertile had higher serum cholesterol precursor ratios (P < 0.05 for than whereas the ratios of serum plant sterols or cholestanol to be in insulin-resistant subjects (P = Factor analysis in factor each cholesterol absorption and Serum squalene levels did not load on of the factors The factor for cholesterol synthesis was higher in the most insulin-resistant tertile (P = whereas the for cholesterol absorption did not among the tertiles (P = for BMI or insulin differences in cholesterol synthesis between the tertiles of cholesterol absorption and synthesis among study subjects according to the tertiles of insulin sensitivity measured with the hyperinsulinemic euglycemic (n = (n = (n = absorption markers ± ± ± ± ± ± ± ± ± precursors ± ± ± ± ± ± ± ± ± ± ± ± are means ± divided by serum in a of the factor analysis of cholesterol absorption markers and cholesterol precursors divided by serum 2 explained principal rotation Varimax with in three did not load on factor. in a Data are means ± divided by serum principal rotation Varimax with in three did not load on factor. To determine which of the components of the insulin resistance syndrome or directly measured insulin had the correlation with cholesterol synthesis, bivariate between fasting insulin, WBGU, and cholesterol absorption markers and cholesterol precursors were The were between fasting insulin and cholesterol synthesis markers In BMI and WBGU correlated with high levels of cholesterol precursors. between components of the insulin resistance syndrome and cholesterol absorption markers were significant. Fasting insulin correlated with desmosterol (r = 0.286, P = 0.015) and lathosterol (r = 0.248, P = 0.037) even when WBGU and BMI were after for two components of the insulin resistance syndrome were not significant. that the correlation between fasting insulin was higher with cholesterol synthesis factor (r = P < than with cholesterol absorption factor (r = P = of fasting insulin, and the rates of WBGU with different markers of cholesterol absorption and absorption < < < < < < < < < synthesis < < < < < < < < < < < < < whole-body glucose P < P < P < in a WBGU, whole-body glucose were between FFA levels in the fasting state or during the hyperinsulinemic clamp procedure and markers of cholesterol metabolism (r < P the rates of lipid synthesis in the fasting state correlated with cholesterol synthesis factor (r = P = between lipid synthesis during the clamp procedure and cholesterol metabolism was observed (r = P = T2DM, and the metabolic syndrome have been associated with increased cholesterol synthesis and decreased cholesterol absorption (3Miettinen T.A. Gylling H. Cholesterol absorption efficiency and sterol metabolism in obesity.Atherosclerosis. 2000; 153: 241-248Abstract Full Text Full Text PDF PubMed Scopus (116) Google Scholar, D.C. Watts G.F. Barrett P.H. O'Neill F.H. Thompson G.R. Plasma markers of cholesterol homeostasis and apolipoprotein B-100 kinetics in the metabolic syndrome.Obes. Res. 2003; 11: 591-596Crossref PubMed Scopus (28) Google Scholar, P.P. Gylling H.K. Miettinen T.A. Diabetes contributes to cholesterol metabolism regardless of obesity.Diabetes Care. 2002; 25: 1511-1515Crossref PubMed Scopus (113) Google Scholar). In this study, we used markers in serum for the measurement of cholesterol synthesis and absorption. ratios to cholesterol of cholestenol, desmosterol, and lathosterol with cholesterol synthesis measured with the sterol and of cholestanol, and sitosterol are to absorption of The of these markers has been in subjects with different degrees of insulin resistance, healthy obese and patients with T2DM (5Simonen P.P. Gylling H.K. Miettinen T.A. Diabetes contributes to cholesterol metabolism regardless of obesity.Diabetes Care. 2002; 25: 1511-1515Crossref PubMed Scopus (113) Google Scholar, T.E. Salomaa V. Vanhanen H. Miettinen T.A. Associations of fasting blood glucose with cholesterol absorption and synthesis in nondiabetic middle-aged men.Diabetes. 1996; 45: 755-761Crossref PubMed Google Scholar, P.P. Gylling H. Miettinen T.A. weight cholesterol metabolism in type 2 Res. 2002; 10: PubMed Scopus Google Scholar). In this study, we that insulin resistance was associated with high rates of cholesterol synthesis and low rates of cholesterol absorption not with lipid levels and VLDL Fasting insulin had a correlation with increased cholesterol synthesis than did BMI or the rates of WBGU, that fasting or hepatic insulin resistance, may be the link between insulin resistance and cholesterol metabolism. main finding was that insulin resistance, determined by the hyperinsulinemic clamp is associated with high rates of cholesterol in patients with T2DM (5Simonen P.P. Gylling H.K. Miettinen T.A. Diabetes contributes to cholesterol metabolism regardless of obesity.Diabetes Care. 2002; 25: 1511-1515Crossref PubMed Scopus (113) Google Scholar) and the metabolic syndrome (4Chan D.C. Watts G.F. Barrett P.H. O'Neill F.H. Thompson G.R. Plasma markers of cholesterol homeostasis and apolipoprotein B-100 kinetics in the metabolic syndrome.Obes. Res. 2003; 11: 591-596Crossref PubMed Scopus (28) Google Scholar), no determination could be of cholesterol absorption or synthesis was primarily Because are associated with insulin resistance, the that insulin resistance primarily absorption or synthesis and then to compensatory in the resulting in the observed in cholesterol absorption and on this study, we that a in cholesterol absorption is to increased cholesterol synthesis in subjects with insulin resistance for two the of insulin resistance with markers of cholesterol synthesis was than with markers of cholesterol absorption. when we used factor analysis to two factors that cholesterol absorption and synthesis, insulin resistance was linked to cholesterol synthesis factor and not to absorption factor. cholesterol metabolism was more strongly correlated with fasting insulin than with the rates of WBGU. in obesity to even more in cholesterol absorption and synthesis in patients with T2DM P.P. Gylling H. Miettinen T.A. weight cholesterol metabolism in type 2 Res. 2002; 10: PubMed Scopus Google Scholar), the between fasting insulin and cholesterol synthesis even after BMI was In no significant correlation between serum which are increased in obesity and insulin resistance, and cholesterol metabolism was observed. This that insulin may have a on cholesterol an increase in FFA which be could explain an increase in VLDL synthesis and VLDL cholesterol levels in insulin-resistant subjects G.F. of hepatic lipoprotein overproduction in insulin 11: PubMed Scopus Google Scholar). Insulin is to liver which in and at in cholesterol synthesis as factors in acid and cholesterol 2002; Full Text Full Text PDF PubMed Scopus Google Scholar). This regulation of and cholesterol synthesis, possible of the of cholesterol and acid synthesis in the 2002; PubMed Scopus Google Scholar), may also explain the correlation between the rates of lipid synthesis, on indirect and cholesterol synthesis factor in Because cholesterol absorption markers with insulin resistance and fasting insulin, the insulin resistance could directly cholesterol absorption. increased cholesterol synthesis is to from high VLDL synthesis that is by hyperinsulinemia or high FFA levels in subjects with insulin cholesterol absorption could be to increased cholesterol it is possible that hyperinsulinemia directly cholesterol absorption. For of by hyperinsulinemia could to increased of and L. J. D. of cholesterol excretion by the liver and 2003; Full Text Full Text PDF PubMed Scopus Google Scholar) and cholesterol absorption. In that an increase in the rates of cholesterol synthesis be This is supported by findings that weight and in insulin to cholesterol absorption without a significant in cholesterol synthesis in obese patients with T2DM P.P. Gylling H. Miettinen T.A. weight cholesterol metabolism in type 2 Res. 2002; 10: PubMed Scopus Google Scholar). a using the of cholesterol synthesis and absorption in insulin-resistant may be the most for the that in cholesterol synthesis or absorption could have an on insulin For of cholesterol synthesis, have been to insulin M. E. M. M. M. Effects of and on insulin resistance and in diabetic 2000; Full Text Full Text PDF PubMed Scopus Google Scholar, J. D. E. P. M. insulin sensitivity and insulin secretion in obese type 2 2002; PubMed Scopus Google Scholar). In an of on insulin in the liver has been proposed in L. L. with hepatic lipoprotein overproduction in an of insulin resistance, the that is accompanied by hepatic insulin 2002; Full Text PDF PubMed Scopus Google Scholar). this of has been linked to mechanisms that link the of with insulin may also of the of cholesterol absorption by or cholesterol on insulin sensitivity are In this study that cholesterol synthesis is increased and cholesterol absorption is decreased in insulin-resistant normoglycemic men. Fasting insulin was more strongly correlated with cholesterol synthesis than were BMI or the rates of WBGU, and no of FFA levels with cholesterol metabolism was observed. These findings that the regulation of cholesterol metabolism by or as a of hepatic insulin resistance, is the link between insulin resistance and cholesterol metabolism. This study was supported by from the of the of the the Finnish Heart and the body mass index liver type 2 diabetes whole-body glucose uptake

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