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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 9 3085-3088
Copyright © 2000 by The Endocrine Society

From the Clinical Research Centers

Carbohydrate-Induced Hypertriglyceridemia: An Insight into the Link between Plasma Insulin and Triglyceride Concentrations1

T. McLaughlin, F. Abbasi, C. Lamendola, H. Yeni-Komshian and G. Reaven

Department of Medicine, Stanford University School of Medicine, Stanford, California 94305

Address correspondence and requests for reprints to: G. M. Reaven, M.D., Shaman Pharmaceuticals, Inc., 213 East Grand Avenue, South San Francisco, California 94080.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
This study was initiated to test the hypothesis that endogenous hypertriglyceridemia results from a defect in the ability of insulin to inhibit the release of very low-density lipoprotein-triglyceride (TG) from the liver. To accomplish this goal, plasma glucose, insulin, free fatty acid (FFA), and TG concentrations were compared in 12 healthy volunteers, in response to diets containing either 40% or 60% of total calories as carbohydrate (CHO). The protein content of the two diets was similar (15% of calories), and the fat content varied inversely with the amount of CHO (45% or 25%). The diets were consumed in random order, and measurements were made of plasma glucose, insulin, FFA, and TG concentrations at the end of each dietary period, fasting, and at hourly intervals following breakfast and lunch. The results indicated that the 60% CHO diet resulted in higher fasting plasma TG concentrations associated with higher day-long plasma insulin and TG concentrations, and lower FFA concentrations. These results do not support the view that hypertriglyceridemia is secondary to a failure of insulin to inhibit hepatic TG secretion.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
EVIDENCE OF AN association between hyperinsulinemia and hypertriglyceridemia was published more than 30 yr ago (1). The nature of this relationship was subsequently extended to include correlations between: 1) insulin resistance and compensatory hyperinsulinemia; 2) hyperinsulinemia and hepatic very low-density lipoprotein (VLDL)-triglyceride (TG) synthesis and secretion; and 3) hepatic VLDL-TG secretion rate and plasma TG concentrations (2, 3). Based on these findings, it was proposed that compensatory hyperinsulinemia was the link between insulin resistance and hypertriglyceridemia, related to the ability of insulin to enhance hepatic VLDL-TG synthesis and secretion (2, 3).

Although the existence of the correlations noted above has received general acceptance, a diametrically opposed formulation of the causal nature of the relationships has emerged. Specifically, the results of studies, both in vitro (4, 5) and in vivo (6, 7, 8, 9) have demonstrated that insulin acutely inhibits hepatic VLDL-TG secretion. Based on these findings, it has been suggested that the physiological effect of insulin is to inhibit, not enhance, hepatic VLDL-TG secretion. As a consequence, it is argued that hypertriglyceridemia occurs in association with insulin resistance due to the loss of insulin’s ability to inhibit VLDL-TG secretion in resistant individuals.

The present study was initiated to evaluate these two disparate views of the role of hyperinsulinemia in regulation of plasma TG concentrations. To accomplish this goal, we took advantage of the ability of carbohydrate (CHO)-enriched diets to increase both plasma TG and insulin concentrations (10, 11). Specifically, we compared fasting and day-long plasma glucose, insulin, free fatty acid (FFA), and TG concentrations in 12 healthy volunteers, consuming two different diets—one relatively high and the other relatively low in CHO. By determining the relevant hormone and substrate concentrations on each diet, and relating them to the dietary-induced changes in plasma TG concentration, we endeavored to gain insight into which of the two dichotomous versions of the causal relationship between hyperinsulinemia and hypertriglyceridemia was most consistent with the experimental results.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
The study group consisted of 12 healthy volunteers who had responded to an advertisement in the local newspaper. Potential volunteers were screened at the Stanford General Clinical Research Center (GCRC) with a medical history, physical examination, and basic laboratory measurements. The seven men and five women who participated in the study had a mean (±SEM) age of 58 ± 2 yr, a body mass index of 25.9 ± 0.9 kg/m2, were free of major medical problems and/or medications known to affect lipid metabolism, and nondiabetic (12).

Subjects were randomized to one of two, 14-day, eucaloric diet phases, varying in composition of CHO and fat. The macronutrient composition of one diet was 40% CHO, 15% protein, and 45% fat; the alternate diet composition was 60% CHO, 15% protein, and 25% fat. The CHO in both diets consisted of starches and sugars, mainly from fruits and vegetables. The glycemic index and the ratio of complex to simple carbohydrates were similar on the two diets. Similarly, saturated fat and the ratio of polyunsaturated fat to monoundaturated fat was 1.0 in both diets. Dietary fiber intake was also quite similar, 13.5 g/1000 kcals in the high CHO diet and 10.5 g/1000 kcals in the low CHO diet. Finally, the Harris-Bendict equation (13) was used to estimate each volunteer’s basal energy expenditure, and an activity factor was added to estimate total caloric requirement (basal energy expenditure x 1.3–1.5).

The experimental diets consisted of three rotating menus prepared in the Stanford GCRC Research Kitchen. Subjects were scheduled to visit the GCRC three times per week during the diet intervention phases. At each visit subjects met with the dietitian to discuss compliance, verify body weight maintenance, eat the noon meal, and pick up their research meals. On the 15th day of each dietary phase, subjects were admitted to the GCRC for metabolic testing. Subjects were studied for an 8-h period, during which test meals, with the same proportion of CHO, protein, and fat as the study diet, were given at 0800 and 1200 h, with breakfast comprising 20% and lunch 40% of the estimated daily caloric requirement. Blood was drawn fasting, and then hourly, beginning 1 h after the first study meal, for measurement of plasma, glucose (14), insulin (15), FFA (16), and TG (17) concentrations.

Subjects then entered a 2-week washout phase, followed by randomization to the other diet. After 2 weeks on the second diet, subjects were studied in the GCRC as described above. The subjects weighed 74.6 ± 3.9 kg and 74.2 ± 3.8 kg at the beginning of the 60% and 40% CHO diets, respectively, and weighed 0.0 ± 0.3 kg less at the end of both dietary periods.

There were no statistical differences in any metabolic measurement as a function of either gender or the order in which the two diets were consumed. Thus, the data were combined for analysis of the statistical significance of differences in the metabolic responses to the two diets. Data are expressed as the mean ± SEM. Metabolic responses during the 8-h study period following each of the two dietary phases were compared by two-way ANOVA, in which the dependent variables (metabolic responses) were analyzed with respect to diet (high vs. low CHO) and time (hour during 8-h test period). In addition, the total integrated responses during the 8-h period of observation were compared by Student’s t test, using log-transformed data because the metabolic variables were not normally distributed.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Table 1Go compares the effects of the two diets on fasting plasma glucose, insulin, FFA, and TG concentrations. It is apparent from these results that whereas fasting plasma glucose and FFA concentrations were similar on the two diets, fasting plasma insulin (P = 0.03) and TG concentrations were significantly higher (P < 0.006) in response to the 60% CHO diet. When analyzed by gender, the results were similar in that fasting glucose and FFA concentration were similar on both diets, whereas the increase in fasting plasma insulin was similar in both genders (57 ± 7 to 74 ± 11 vs. 49 ± 4 to 66 ± 9 pMol/L), as was the increment in TG concentration (1.4 ± 0.2 to 2.3 ± 0.5 vs. 1.7 ± 0.3 to 2.4 ± 0.4 mMol/L).


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  		Table 1. Dietary-induced changes in fasting plasma concentrations of the experimental variables

 
The day-long responses of the four variables measured are shown in Fig. 1Go. These results show that the variation in dietary fat and CHO intake had no effect on the day-long plasma glucose responses. This was not true of the other three variables measured, with the 60% CHO diet leading to higher day-long insulin (P < 0.01) and TG (P < 0.001) concentrations, and lower FFA responses (P < 0.001) as determined by ANOVA.



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  		Figure 1. Plasma glucose, insulin, FFA, and TG concentrations measured at hourly intervals flow 0800 to 1600 h on the 40% ({circ}) and 60% (•) CHO diets. Breakfast was served at 0800 h and lunch at 1200 h.

 
To further evaluate the effect of the two diets on day-long plasma glucose, insulin, FFA, and TG responses, we calculated the total integrated response area during the 8-h period of observation. These results are shown in Table 2Go. The data in Table 2Go are the numerical values for these variables, but the statistical analysis (Student’s t test) was performed on log-transformed values to deal with the lack of a normal distribution. These results support the findings shown in Fig. 1Go, demonstrating that the integrated plasma insulin responses were higher (P = 0.02) and FFA responses lower (P < 0.001) on the 60% CHO diet. The only difference between the results shown in Fig. 1Go and Table 2Go is that the increase in the total integrated TG response was of only marginal statistical significance (P = 0.09) as compared with the statistically significant increase in day-long plasma TG concentrations. This apparent discrepancy is presumably due to the narrowing of the difference in TG concentrations as the day continued because of a greater influx of chylomicrons following breakfast and lunch. As in the case of the fasting values shown in Table 1Go, these were no gender-related differences, with both men and women having significantly lower integrated FFA responses (P < 0.005 vs. P < 0.02, respectively), essentially identical glucose responses, and higher insulin and TG responses (P < 0.05–0.12).


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  		Table 2. Dietary-induced changes in the total integrated response of the experimental variables

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
If the physiological role of insulin is to inhibit hepatic TG secretion (4, 5, 6, 7, 8, 9), the fasting and day-long higher insulin levels on the 60% CHO diet should have resulted in a decrease, not an increase, in plasma TG concentration. The fact that plasma FFA concentrations were lower on the 60% CHO diet should have further accentuated the ability of the higher ambient insulin levels to inhibit hepatic TG secretion. The only possible way to reconcile the experimental data consistent with the view that insulin inhibits hepatic VLDL-TG secretion is to propose that the 60% CHO diet made the liver even more resistant to insulin’s putative inhibitory effect. However, this notion is in conflict with the considerable evidence that insulin sensitivity is either unchanged, or enhanced, in response to CHO-enriched diets (18, 19, 20). Furthermore, even this unlikely possibility does not explain how lower FFA concentrations on the 60% CHO diet can increase hepatic TG secretion. Finally, we have shown that the ability of insulin to inhibit hepatic glucose production is normal in patients with endogenous hypertriglyceridemia (21).

These data strongly support the view that although exogenous hyperinsulinemia may acutely inhibit hepatic TG secretion (4, 5, 6, 7, 8, 9), these observations have little, or no, relevance to the metabolic impact of endogenous hyperinsulinemia resulting from the pancreatic ß-cell response to the 60% CHO diet. To put it most simply, there is no reason to believe that the metabolic effects of an acute increase in exogenous insulin will be similar to the chronic effects of a compensatory elevation of endogenous insulin secretion.

Perhaps the most persuasive evidence of the profound differences on TG metabolism of acute vs. chronic hyperinsulinemia can be found in the recent publication by Aarsland et al. (22). In this study, hyperinsulinemia was induced for 4 days by feeding volunteers hypercaloric, high CHO diets. Plasma insulin concentrations increased to ~60 µU/mL after 1 day and remained elevated for the remainder of the study. Both VLDL-TG secretion and plasma TG concentration did not change statistically after 1 day of the dietary intervention. However, by day 4, both VLDL-TG secretion and plasma TG concentration had increased ~5-fold. On the basis of their observations, the authors concluded that the increases in VLDL-TG secretion and plasma TG concentration seen in association with chronic, endogenous hyperinsulinemia were due to an increase in the use of FFA by the liver for TG synthesis.

In this study, we have elevated the endogenous plasma insulin concentration by increasing the CHO intake of a group of healthy volunteers. The use of this protocol permitted us to provide experimental evidence that the increase in plasma TG concentration produced by this dietary manipulation was inconsistent with the view that the primary effect of insulin is to inhibit hepatic TG secretion. However, this should not be construed to mean that high CHO diets inevitably lead to hyperinsulinemia and hypertriglyceridemia. For example, if weight loss in overweight individuals occurs, with ad libitum high CHO diets, hypertriglyceridemia does not develop (23). Furthermore, the choice of the type of CHO consumed can modulate the associated increase in plasma TG concentration, as does a concomitant increase in physical activity (24, 25). Furthermore, the conclusion that CHO-induced hypertriglyceridemia does not result from the failure of insulin to suppress hepatic VLDL-TG secretion (i.e. hepatic insulin resistance) is independent of the conflicting results as to whether or not CHO-induced hypertriglyceridemia is due to an increase in hepatic VLDL-TG secretion (2, 3, 22) or a decrease in hepatic VLDL-TG removal from plasma (26). This latter controversy results from differences in the isotopic method used in the various studies, and our results provide no useful information as to which of these disparate views are most correct. On the other hand, our results do seem to make highly unlikely the view that hypertriglyceridemia is due to a failure of insulin to inhibit hepatic VLDL-TG secretion in insulin-resistant individuals, and that was the goal of our study. We did not plan the experimental protocol to evaluate the potential clinical use of diets varying in fat and CHO content.

In conclusion, observations (4, 5, 6, 7, 8, 9) that the addition of exogenous insulin to liver cells in culture, or the injection of exogenous insulin into human beings, acutely inhibit VLDL-TG secretion does not mean that the physiological role of circulating insulin is to inhibit hepatic VLDL-TG secretion or that the causal relationships between hyperinsulinemia and hypertriglyceridemia are due to a failure of insulin to inhibit hepatic VLDL-TG secretion.


   Footnotes
 
1 Supported by NIH Research Grants HL-08506 and RR-00070. Back

Received December 30, 1999.

Revised May 25, 2000.

Accepted June 15, 2000.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

  1. Reaven GR, Lerner RL, Stern MP, Farquhar JW. 1967 Role of insulin in endogenous hypertriglyceridemia. J Clin Invest. 46:1756–1767.
  2. Olefsky JM, Farquhar JW, Reaven GM. 1974 Reappraisal of the role of insulin in hypertriglyceridemia. Am J Med. 57:551–560.[CrossRef][Medline]
  3. Tobey TA, Greenfield MS, Kraemer FB, Reaven GM. 1981 Relationship between insulin resistance, insulin secretion, very low density lipoprotein kinetics and plasma triglyceride levels in normotriglyceridemia in man. Metabolism. 30:165–171.[CrossRef][Medline]
  4. Durrington PN, Newton RS, Weinstein DB, Steinberg D. 1982 Effects of insulin and glucose on very low density lipoprotein triglyceride secretion by cultured rat hepatocytes. J Clin Invest. 70:63–73.
  5. Patsch W, Franz S, Schonfeld G. 1983 Role of insulin in lipoprotein secretion by cultured rat hepatocytes. J Clin Invest. 71:1161–1174.
  6. Lewis GF, Uffelman KD, Szeto LW, Steiner GP. 1993 Effects of acute hyperinsulinemia on VLDL triglyceride and VLDL apoB production in normal weight and obese individuals. Diabetes. 42:833–842.[Abstract]
  7. Lewis GF, Uffelman KD, Szeto LW, Weller B, Steiner G. 1995 Interaction between free fatty acids and insulin in the acute control of very low density lipoprotein production in humans. J Clin Invest. 95:158–166.
  8. Malmstrom R, Packard CJ, Watson TDC, et al. 1997 Metabolic basis of hypotriglyceridemic effects of insulin in normal men. Arterioscler Thromb Vasc Biol. 17:1454–1464.[Abstract/Free Full Text]
  9. Malstrom R, Packard CJ, Caslake M, et al. 1997 Defective regulation of triglyceride metabolism by insulin in the liver in NIDDM. Diabetologia. 40:454–462.[CrossRef][Medline]
  10. Ahrens EH, Hirsch Jr J, Oette K. 1961 Carbohydrate-induced and fat induced lipemia. Trans Assoc Am Phys. 74:134–146.[Medline]
  11. Farquhar JW, Frank A, Gross RC, Reaven GM. 1966 Glucose, insulin and triglyceride responses to high and low carbohydrate diets in man. J Clin Invest. 45:1648–1656.
  12. The Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. 1998 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care. 21:S5–S22.
  13. Harris JA, Benedict FG. A biometric study of basal metabolism in man, publication 279. Washington, DC: Carnegie Institute of Washington; 1919.
  14. Kadish AK, Little RL, Sternberg JC. 1963 A new and rapid method for determination of glucose by measurement of rate of oxygen consumption. Clin Chem. 14:116–131.
  15. Hales CN, Randle PJ. 1963 Immunoassay of insulin with insulin-antibody precipitate. Biochem J. 88:137–146.[Medline]
  16. Noma A, Okabe H, Kita M. 1973 A new calorimetric micro-determination of free fatty acids in serum. Clin Chim Acta. 43:317–320.[CrossRef][Medline]
  17. Wahlefeld AW. 1974 Triglycerides: determination after enzymatic hydrolysis. In: Bergmeyer HU, ed. Methods of enzymatic analysis, vol 11. New York: Academic; 1831–1835.
  18. Borkman M, Campbell LV, Chisholm DJ, Storlien LH. 1991 High carbohydrate low-fat diets do not enhance insulin sensitivity in normal subjects. J Clin Endocrinol Metab. 72:432–437.[Abstract/Free Full Text]
  19. Hughes VA, Fiatarone MA, Fielding RA, Ferrara CM, Elahi D, Evans WJ. 1995 Long-term effects of a high-carbohydrate diet and exercise on insulin action in older subjects with impaired glucose tolerance. Am J Clin Nutr. 62:426–433.[Abstract/Free Full Text]
  20. Kolterman OG, Greenfield M, Reaven GM, Saekow M, Olefsky JM. 1979 Effect of a high carbohydrate diet on insulin binding to adipocytes and on insulin action in vivo in man. Diabetes. 28:731–736.[Abstract]
  21. Bernstein RJ, Davis BM, Olefsky JM, Reaven GM. 1978 Hepatic insulin responsiveness in patients with endogenous hypertriglyceridemia. Diabetologia. 14:249–253.[CrossRef][Medline]
  22. Aarsland A, Chinkes D, Wolfe RR. 1996 Contributions of de novo synthesis of fatty acids to total VLDL-triglyceride secretion during prolonged hyperglycemia/hyperinsulinemia in normal man. J Clin Invest. 98:2008–2017.[Medline]
  23. Schaefer EJ, Lichtenstein H, Lamon-Fava S, et al. 1995 Body weight and low-density lipoprotein cholesterol changes after consumption of a low-fat ad libitum diet. J Am Med Assoc. 27:1450–1455.
  24. Hallfrisch J, Reiser S, Prazher ES. 1983 Blood lipid distribution of hyperinsulinemic men consuming three levels of fructose. J Clin Nutr. 37:740–748.
  25. Diehl HA. 1998 Coronary risk reduction through intensive community-based lifestyle intervention: the coronary health improvement project (CHP) experience. Am J Cardiol. 82:83T–87T.
  26. Parks EJ, Krauss RM, Christiansen MP, Neese RA, Hellerstein MK. 1999 Effects of a low-fat, high-carbohydrate diet on VLDL-triglyceride assembly, production, and clearance. J Clin Invest. 104:1087–1096.[Medline]



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