Hypertriglyceridemia and carbohydrate intolerance: Interrelations and therapeutic implications

Hypertriglyceridemia andCarbohydrate Intolerance: InterrelationsandTherapeutic Implications GEORGE STEINER, MD

Atherosclerosis, the most frequent complication of diabetes, could be the resuft of hyperitpidemia, among other factors. Mounting evidence suggests that reducing the concentration of triglyceride-rich lipoprotein, which influences the production of the possibly atherogenic intermediate density lipoprotein (IDL), might diminish the circulating level of potentially atherogenic lipoproteins. Hypertrigiyceridemia, even in the absence of obesity, is associated with insulin resistance. To compensate, pancreatic B ceils respond to glucose chaiienge by producing hyperinsuiinemia. if the B ceils cannot respond adequately, carbohydrate intoierante ensues. insulin-treated diabetics may also become hyperinsuiinemic because routine insulin injection may not reflect physiologic need and because the insulin is administered peripherally rather than portally. Hyperinsuiinemia increases the production of circulating triglyceride. it appears to do this in rats

by causing the production of more triglyceride-rich Ipoprotein particles rather than by increasing the triglyceride content of each particle. Further, at least in rats, the insulin-induced increase in triglyceride production requires the presence of supplementary dietary fructose. Hyperinsuiinemia also increases the activity of adipose tissue lipoprotein iipase and the degradation of very low density lipoprotein (VLDL). The concentration of VLDL depends on balance of production and degradation. Accelerated VLDL degradation leads to an increase in IDL production. Because there is mounting evfdence that IDL may be atherogenic, this cycle could accelerate atherogenesis. As such, it is reasonable to postulate that reducing the concentration of triglyceride-rich lipoproteins would break this cycle and would diminish the circulating level of potentially atherogenic lipoproteins. (Am J Cardioi 1988;57:276-30G)

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of circulating triglyceride is borne by lipoproteins with a density l2. These lipoproteins include intermediate density lipoproteins (IDLs), very low density lipoproteins (VLDLs) and chylomicrons. The latter transport exogenous triglycerides and normally are not found in fasting blood. Traditionally, VLDL has been defined as that fraction of endogenous triglyceride-bearing lipoprotein that floats on ultracentrifuging plasma at its own density (1.006 g/ml) for 16 hours. IDL has then fallen into the 1.006 to 1.019 density range, for which the corresponding Svedberg flotation rate range would be 12 to 20. This Svedberg flotation rate 12-20 fraction accounts for 75% of the Svedberg flotation rate 12-60 fraction that, for kinetic reasons, Reardon et al4 originally and we5 subsequently have considered a more suitable definition of IDL. This is the same Svedberg flotation rate range as that suggested for IDL on the basis of Schlieren patterns obtained by analytical ultracentrifuge.6 The importance of recognizing and defining these ranges lies in the fact that lipoproteins do not fall into discrete populations but are parts of a continuum,

therosclerosis is the most frequent complication of diabetes.l Hyperlipidemia is one of the many possible factors responsible for this increased atherogenesis in diabetics1 Of the several forms of hyperlipidemia, hypertriglyceridemia is the one most commonly associated with carbohydrate intolerance.1-3 Against this background, we and many others have been investigating the relation between glucose-insulin homeostasis and the triglyceride-rich lipoproteins.

Subfractionsof Triglyceride-Richlipoproteins Triglyceride may originate from dietary (exogenous] or nondietary (endogenous) sources. The vast majority From the Division of Endocrinology and Metabolism, Toronto General Hospital, and the Department of Medicine, University of Toronto, Toronto, Ontario, Canada. This study was supported by grants from the Medical Research Council of Canada and the Heart and Stroke Foundation of Ontario. Address for reprints: George Steiner, MD, ENll-225, Toronto General Hospital, 200 Elizabeth Street, Toronto, Ontario, M5G 224 Canada. 276

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and studies can be misleading unless they are as pre- proportion of the plasma triglyceride-rich lipoprocise as current methodology will permit in defining the teins, with @lipoproteins could thus have prevented identification of an association of IDL with CAD. Anlipoprotein population under study. One example of the misconceptions arising from a other prospective study, in Stockholm, indicated that failure to define the lipoprotein fractions adequately is hypertriglyceridemia, even in the absence of hyperseen in patients with chronic renal failure. These pa- cholesterolemia, is a risk factor for CAD.12J3Similar conclusions were reached in a separate study conducttients have been described as having a triglycerideed on men in Uppsala. l4 Both of these studies used rich low density lipoprotein (LDL).7 LDL is now recog nized to be the Svedberg flotation rate O-12 fraction of “hard” endpoints of coronary disease. Carlson and lipoproteins4v5 However, early methods used to sepa- Bottiger felt that the failure of the Western Collaborarate LDL actually separated Svedberg flotation rate O- tive Study15 to observe a risk effect of hypertriglyceri20 lipoproteins. Thus, the “LDL” fraction also con- demia resulted from its failure to use endpoints as tained Svedberg flotation rate 12-20 lipoproteins. As definite as those in the Swedish studies.16Hypertriglypointed out earlier, the Svedberg flotation rate 12-20 ceridemia has also been noted more frequently than fraction is actually a portion, in fact the major portion, expected in families of myocardial infarct survivors.17 One issue that has not been fully resolved is if any of the IDL. Nestel et al* recently observed that patients with chronic renal failure have high concentrations of risk effect of hypertriglyceridemia is independent of IDL. In view of the triglyceride content of IDL, it can the risk resulting from low levels of high density lipoprotein. Levels of plasma triglyceride and high density be seen that the “triglyceride-rich LDL,” previously described in renal failure, is in fact a mixture of LDL lipoprotein are often,l* but not invariably,lg inversely related to each other. The protective relation between and IDL. Another example arises from the definition of “@” lipoprotein as Svedberg flotation rate O-20, as high density lipoprotein and CAD is well recogused in the Framingham Study. The investigators con- nized.20J1 Hence, it is important to know if any risk sidered VLDL to be Svedberg flotation rate 20-400 that results from hypertriglyceridemia is independent of the risk associated with low levels of&high density lipoprotein. Hence, a major portion of the triglyceridetransporting lipoproteins (the Svedberg flotation rate lipoprotein. One other problem is the tendency to consider all 12-20 portion of IDL) was not included in the fraction (Svedberg flotation rate 20-400) examined by that hypertriglyceridemia as 1 disorder and the failure to study when it explored the relation of triglycerides to recognize its multiple facets. Clearly, exogenous hypertriglyceridemia (hyperchylomicronemia) cannot be coronary artery disease (CADJg lumped together with endogenous hypertriglyceridemia. Even in patients with primary endogenous hyperIntermediateDensitylipoprotein triglyceridemia, there are 2 monogenic disorders, faandTriglycerideTransport milial hypertriglyceridemia and familial combined The significance of IDL (Svedberg flotation rate hyperlipidemia. I7 This distinction could be very im12-601 in the transport of triglyceride is demonstrated portant, because Brunzell et a122have suggested that by our observation that in the plasma of fasting sub- only the latter disorder is associated with accelerated jects with plasma triglyceride concentrations up to atherosclerosis. In this regard, it is also interesting that 1,200 mg/dl, 80% of the triglyceride-rich lipoproteins there appears to be an association between familial are found in the IDL fraction? Further, 70% of the combined hyperlipidemia and hyperapobetalipoprodifferences in the concentration of triglyceride in such teinemia.23 The latter entity is also associated with individuals can be accounted for by an increase in the early atherosclerosis. numbers of these IDL particles, rather than by an inAnother potential problem arises from the tendencrease in the size of the triglyceride-rich lipoprotein.9 cy to examine only total plasma triglyceride concentraHence, when studying the causes and atherogenic tions, ignoring the specific subfractions of the triglycconsequences of endogenous hypertriglyceridemia, it eride-rich lipoproteins. We have examined the relais important to consider IDL as a distinct fraction of the tion of IDL to CAD because of IDL’s importance as one triglyceride-rich lipoproteins. of the triglyceride-rich lipoproteins. In a preliminary study, we found that patients with CAD had higher Triglyceride-Richlipoproteins IDL levels than did comparable patients who were andAtherosclerosis free from CAD.l This led to a case-control designed There has been considerable controversy about the study of men, aged 45 to 65 years, with and without epidemiologic studies that examined the relations be- CAD. The subjects had no other CAD risk factors, tween hypertriglyceridemia and atherosclerosis. Al- including hypercholesterolemia. As in the preliminary brink et all* were among the first to suggest that they study, those with CAD were found to have elevated are associated. The Framingham Study also observed IDL levels. X2 analysis revealed a significant associaan association that, it felt, was not attributable to an tion of CAD with high levels of IDL apoB (p <0.006), increase in the VLDL concentration (defined as Sved- with high levels of IDL triglyceride (p <0.032) and with berg flotation rate 20-400 lipoproteins) but to a con- high levels of the product of IDL triglyceride times IDL comitant increase in so-called B lipoprotein (Svedberg apoB (p <0.006]. Step-wise logistic regression analysis flotation rate 0-20).~ This inclusion of the Svedberg indicated that the most important lipoprotein parameflotation rate 12-20 fraction, which comprises a major ter of CAD was IDL apoB times IDL triglyceride, a

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product reflecting the interaction of both the numbers of particles and the amount of triglyceride contained within the IDL fraction. This was not related to any difference in high density lipoprotein concentration and, because of patient selection, there was no association with increased levels of LDL. Our findings were consistent with earlier epidemiologic observations of an association of IDL with CAD in the Japanesez4and of increased IDL levels in male myocardial infarct survivors.25 These epidemiologic studies all add weight to the pathophysiologic data that suggest an atherogenic role for the remnants of the triglyceriderich lipoproteins.26

IntermediateDensitylipoprotein and Disorders of GlucoseHomeostasis Classically, hypertriglyceridemia in diabetic patients has been attributed to a combination of an increased supply of free fatty acids as a substrate for lipogenesis and an impairment of triglyceride removal as a consequence of decreased lipoprotein lipase activity, both resulting from insulin deficiency.27 However, except for those in ketoacidosis, few diabetics today have gross insulin deficiency. In fact, either because the amount of injected insulin surpasses physiologic requirements or because the pancreatic B cells are secreting insulin in an attempt to compensate for insulin resistance, most diabetics are hyperinsulinemic. Thus, the relation between hyperinsulinemia and the triglyceride-rich lipoproteins must be explored. An early examination of the various subfractions of triglyceride-rich lipoprotein in diabetic patients supports the possibility that they have increased IDL levelsz8 This is consistent with some pathophysiologic evidence that indicates that hyperinsulinemic states may be associated with an increase in IDL production.2g There have been a number of reports of an association between hypertriglyceridemia and hyperinsulinemia, either in the fasting state or after glucose challenge.30z31 This probably reflects the pancreatic B cells’ attempt to compensate for the insulin resistance. That resistance may be caused by the mild obesity that is frequently associated with hypertriglyceridemia. However, we have aiso found that hypertriglyceridemia, even in the absence of obesity, is associated with insulin resistance.30 This insulin resistance may be a direct consequence of hypertriglyceridemia, as suggested by the finding that VLDL in vitro is able to down-regulate insulin receptors on M-9 lymphocytes and on adipocytes .30Recently Bieger et a132found that circulating monocytes and erythrocytes from hypertriglyceridemic subjects bind less insulin than do those of normal subjects. However, whether the insulin resistance of the hypertriglyceridemic can be entirely ascribed to this decrease in insulin binding still remains to be determined. In this regard, it is interesting that Berliner et a133observed that B-VLDL induced a postbinding resistance to the effects of insulin on aortic endothelial aminoisobutyrate uptake. Conditions that are accompanied by chronic endogenous hyperinsulinemia in humans, such as obesity or disorders requiring steroid therapy, are also ac-

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companied by an increase in the production of QLDL triglyceride.34,35 Unfortunately, these conditions are also characterized by other associated variables that might alter triglyceride production. Hence, it has been necessary to turn to an animal model to determine if this effect was caused by hyperinsulinemia or one of the other associated variables. Similar results were seen in 2 models using hyperinsulinemic rats. One model used twice-a-day subcutaneous insulin injections,36 and the other used continuous insulin infusions, delivered either subcutaneously or intraperitoneally.37z38In both models, the rats received 6 units of insulin per day for 2 weeks. To protect the hyperinsulinemic rats from hypoglycemia, they were given 10% sucrose solutions in place of drinking water. The hyperinsulinemic rats were compared with normal rats that had received the same amount of sucrose solution. Hyperinsulinemia led to increased production of VLDL triglyceride, despite a decrease in circulating free fatty acids. This suggested that insulin increased the production of VLDL triglyceride from sources other than free fatty acids. It was particularly interesting to note that the insulin-induced increase in triglyceride production occurred in rats that received drinking solutions of sucrose or fructose but not in those that received an equal amount of glucose solution.3QThis increased triglyceride production could not be attributed to any differences in body weight, obesity, plasma glucose concentrations or counterregulatory hormones. The insulininduced increase in triglyceride production was not always accompanied by an increase in the plasma triglyceride concentration. In those rats receiving insulin subcutaneously, the increased triglyceride production was accompanied by a decline in plasma triglyceride concentrations, This obviously indicated that the triglyceride removal was increased even more than triglyceride production. Triglyceride production in those rats receiving insulin intraperitoneally increased to the same extent as in those receiving subcutaneous insulin I-Iowever, the plasma triglyceride concentration did not decrease in those that received intraperitoneal insulin. This suggested that their triglyceride removal had not been stimulated to the extent it had in the rats receiving insulin subcutaneously. It is interesting that both groups of rats had the same portal venous concentration of insulin. This may account for the similar increase in triglyceride production. However, the rats receiving insulin intraperitoneally did not have as great an increase in their peripheral insulin levels, which could account for the decreased stimulation of triglyceride removal in them. These observations paralleled the changes seen in adipose tissue lipoprotein lipase (T. Kazumi, H. Bar-On and C. Steiner, unpublished observations], an insulin-sensitive enzyme that limits the rate of triglyceride removal.40

TherapeuticImplications From the foregoing, it is possible to visualize a vicious cycle in which hyperinsulinemia increases triglyceride production, If removal does not increase to an equivalent extent, the plasma triglyceride concen-

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nation will rise. The hypertriglyceridemia, either alone or in combination with coexisting factors, such as obesity, will lead to insulin resistance, for which the pancreas then attempts to compensate, resulting in further hyperinsulinemia. Increased VLDL turnover results in increased production of the catabolic remnants of VLDL, which are found in the Svedberg flotation rate 12-60 lipoprotein or LDL fraction and which may be atherogenic. If this vicious cycle does carry an atherogenic potential, it is reasonable to predict that breaking the cycle would decrease a person’s risk for atherosclerosis. One of the therapeutic aims would, be to reduce the patient’s insulin resistance. In the obese, one would attempt to do this by restoring body weight to the ideal. In the hypertriglyceridemic patient, one would also aim to decrease triglyceride concentrations. This would not only decrease another factor that contributes to insulin resistance. but it would also decrease the plasma concentration of potentially atherogenic IDL. The first approach to reducing triglycerides would be dietary. Such diets have often restricted simple sugars, such as sucrose, but have allowed starch, a glucose polymer. Our observations with fructose and glucose in hyperinsulinemic rats suggest that one reason to restrict simple sugars might be to restrict fructose, in contrast to glucose. Clearly, if this reasoning is borne out and if diet alone is not sufficient to reduce plasma triglyceride and IDL, it would be reasonable to use a triglyceride-lowering medication as an adjunct. One such medication is gemfibrozil, in a dosage of 600 mg 2 times a day. Experiments with hyperinsulinemic rats also raise the possibility that in diabetic patients, achieving glycemic control with insulin secreted from the pancreas may be better than with subcutaneously injected insulin. Pancreatic insulin would be delivered intraportally in response to stimuli. One could argue that such delivery would be more appropriate to the body’s needs and would avoid the possibility of hyperinsulinemia induced by subcutaneous insulin injection and its potential consequences.

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Comptnison of portal vs peripheral hypcrinsulinemin on VLDLfriglycsride kinetics. In: Seventh lnternutionul Crmgrcss of Endocrmology. Abstracls. Amsterdam: F:xcerpfo Medico. 1984:097. 39. Kazumi T. Vranic M, Steiner G. Triglyceride kinefics: effects of dietory glucose, sucrose. or frircfose olone or with llyperinsulirlslniu. Am l Physiol lwG;250:t:325-E3:to. 40. Reardon hlK. Sakai H. Steiner G. The roles of lipoprotein lipose and heputic friglyccride liposc in the cutobolism in viva of triglycerrdr-rich lipoprofrins. Arferiosclerosis 1982;2:396-402.