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VI. METABOLIC EFFECTS OF CARBOHYDRATE AND FIBER IN TYPE 2 DIABETES A. Single Meal Studies Numerous reports have examined the actions of different test meals on the postprandial blood glucose and insulin profiles of diabetics. A comprehensive analysis of many of these test meal studies is presented elsewhere (32). More recent studies have examined the actions of novel food formulations containing either supplementary dietary fiber (33,34) or plant cultivars or strains with greater concentrations of dietary fiber (35,36). Reduced glycemic responses are most commonly observed with soluble dietary fibers that hydrate rapidly and develop significant viscosity in vitro (37). The inhibition of glucose digestion and absorption is dependent upon the continued actions of the dietary fiber to elevate the viscosity of the gastrointestinal contents, although factors other than the viscosity alone contribute to the resultant glycemia (38). Closer examination of the factors present in food that were predictive of the resultant glycemia demonstrated that that in vitro digestion rate, to mimic the in vivo actions, only weakly correlated with total dietary fiber content of foods and failed to correlate with soluble fiber (39).Indeed, complex interactions between chemical and physical factors within food were found to modulate digestion rate. Important factors identified included the degree of food refinement, extent of cooking, starch structure, and degree of hydration as well as the cellulose and uronic acid content (39). To account for the complex interaction of many components of foods that contribute to determine the ultimate rate of glucose appearance in the blood stream following the ingestion of a carbohydrate-rich food source, the glycemic index (GI) was developed. The GI has proven to be a robust tool to determine the relative glycemic responses of both single foods and mixed meals (40,41). Accompanying the liberalization of sucrose intake in diabetic diets has been the analysis of the glycemic impact of foods rich in sucrose and other sugars,

including fructose. Interestingly, foods rich in sucrose were found to have GI comparable to those of many starchy foods including bread and many cereal products (41). Indeed, the addition of sucrose to an unsweetened high-GI breakfast cereal lowered the total glycemic response of the meal (41). Fructose, whichis sweeter than sucrose, has a lower GI than sucrose, because fructose is slowly absorbed and almost entirely removed from the circulation by the liver. Substitution of starch for either sucrose or fructose has been shown not to alter glucose metabolism (42,43), although there is one report of improvement in insulin action following the substitution of starch for fructose (44). Importantly, the impact of either sucrose or fructose on plasma lipids needs to be considered. To date, the impact of diets rich in fructose, in particular, is controversial, with studies demonstrating either no change (43,45,46) or increased plasma triglyceride concentrations (47,48) in diabetics. Analysis of endogenous very-low-density lipoprotein (VLDL) synthesis has also shown it to be unaltered by fructose-rich diets in five individuals with NIDDM, although considerable variability of responses were observed (49). However, given the marked variability in plasma lipid levels following diets containing considerable amounts of sugar shown in clinical studies and the considerable heterogeneity of postprandial lipid responses in people with NIDDM (50), monitoring and individualized prescription of sugars may be advisable. 1. Mechanisms of Action It remains a matter of conjecture how slowed carbohydrate absorption might ultimately act to improve insulin sensitivity in diabetics. To date, four distinct mechanisms have been proposed to account for how meals containing increased amounts of dietary fiber may act to improve glucose metabolism at subsequent meals. a. Inhibition of Fatty Acid Oxidation. One hypothesized mechanism for the subsequent improvement in insulin action following the ingestion of a slowly digested and absorbed carbohydrate-rich meal is the inhibitory effect nonesterified

fatty acids (NEFAs) have on glucose utilization. Elevated NEFA concentrations have been shown to increase fat oxidation rates, which lead to a commensurate reduction in glucose oxidation, a metabolic relationship known as the glucosefatty acid cycle, first described by Randle et al. (51). Indeed, the tendency for diabetics to have elevated plasma NEFA levels may contribute to the impairment of insulin action (52). Slowed carbohydrate absorption leads to moderated, although sustained elevations in plasma glucose paralleled by sustained plasma insulin concentrations. The maintained insulin secretion may maximize glucose uptake and oxidation by insulin-sensitive tissues while simultaneously suppressing lipolysis and NEFA availability, thus lowering fat oxidation. Rapid glucose absorption is, however, speculated to rapidly increase plasma insulin concentrations, leading to rebound hypoglycemia and the release of counterregulatory hormones, including the catecholamines. Catecholamine release activates lipolysis and increases plasma free fatty acid (FFA) levels. However, there is limited in vivo evidence for this hypothesis (53). Two studies have reported sustained suppression of NEFA levels and fat oxidation following a high-fiber meal when compared to an isocaloric low-fat meal (54,55). Yet other studies, despite wide variations in blood glucose absorption profiles, have been unable to demonstrate altered substrate oxidation(56,57). b. Transient Reductions in Blood Glucose. Further hypothesized actions of slowed carbohydrate digestion include the impact transient minimization of plasma hyperglycemia and hyperinsulinemia following a meal exerts directly on insulin action. Acute hyperglycemia in vitro rapidly downregulates tyrosine kinase activity of the insulin receptor (58), GLUT4 abundance (59), and potentially dysregulates protein synthesis by modulating gene expression (60). It is well established that chronic hyperglycemia impairs both insulin secretion and sensitivity, a phenomenon known as glucose toxicity (11), but

evidence that acute postprandial modifications act to improve this glucose toxic effect has yet to be established. c. Gastrointestinal Hormone Secretion. A number of studies have provided evidence of altered gastrointestinal hormone secretion, including glucagon-like peptide 1 (GLP-1), somatostatin, vasoactive intestinal polypeptide (VIP), and insulin-like growth factor 1 (IGF-1), following the ingestion of high-fiber meals (6164). However, the plasma levels differ significantly between studies, with altered gastrointestinal hormone secretion not observed in all studies (65,66). Most notably, GLP-1 and IGF-1 have crucial roles in regulating insulin secretion and action (6770), yet it remains to be established if modulated circulatory concentrations can acutely affect insulin action. Further research is required to fully elucidate the impact altered secretion of these gastrointestinal hormones may have on glucose and lipid metabolism in the diabetic. d. Short-Chain Fatty Acids. Colonic fermentation by the resident microflora of malabsorbed starch and undigestible carbohydrates (including, fructooligosaccharides, nonstarch polysaccharides, pectins, and gums) has been suggested to affect glucose and lipid metabolism. The major nongaseous by-product of this anaerobic fermentation is shortchain fatty acids (SCFAs), of which acetate, propionate, and butyrate, produced in the approximate molar ratio of 60:25:12, are the predominant products (71). These SCFAs are rapidly absorbed by the colonic epithelia, with significant quantities of acetate and propionate entering the portal blood stream (72). Acetate is the only SCFA found in appreciable concentrations in the peripheral blood (72). Peripheral concentrations of acetate increase in response to a high-fiber diet (73). One study has demonstrated that oral acetate supplementation and cecal infusion may decrease adipose tissue lipolysis, lowering plasma NEFA levels (74), although glucose oxidation or glucose tolerance remained unaltered (75,76).

Propionate is removed from the portal circulation by the liver, where in ruminants it is a major gluconeogenic precursor. In nonruminants, including humans and rats, propionate may act to inhibit gluconeogenesis and stimulate glycolysis (77,78). Oral propionate, supplied in capsules, had no impact on blood glucose levels, although oral glucose tolerance was marginally improved (79). Incorporation of propionate in bread led to improved glucose responses, although this observation may be the result of propionate inhibiting starch digestion (80). The rapid absorption of ingested propionate may fail to mimic the in vivo situation of sustained portal release.Studies utilizing rectal or ileal propionate infusion to better reflect the in vivo situation have been unable to demonstrate any impact of propionate on either liver glucose production or peripheral insulin sensitivity (8183).Propionate has also been suggested to regulate the rate of liver cholesterol synthesis in both in vivo and in vitro rodent studies (8486). While physiologically relevant concentrations of propionate may inhibit cholesterol synthesis in rat hepatocytes, a comparative study has failed to demonstrate inhibition in human hepatocytes, with inhibition of cholesterol synthesis requiring a 100-fold increase in propionate levels (87). Propionate supplementation in human volunteers has tended to show reduced HDL cholesterol and increased triglyceride concentrations (79,80). There is good evidence from a rodent study, in which cecectomized rats were fed a diet containing guar gum, that the removal of a cecum does not affect glucose metabolism when compared to noncecectomized rats (88). This evidence, combined with the data described above, presents a scenario in which SCFA metabolism is unlikely to significantly affect peripheral carbohydrate or lipid metabolism in nonruminants. Currently, no clear mechanism has emerged upon which to base dietary strategies to maximize the effectiveness of high-carbohydrate and high-fiber meals. The lack of an acute mechanism can be considered as a factor hampering the design of high-fiber

diets, which can be considered to be most effective in improving both carbohydrate and lipid metabolism in type 2 diabetics. C. High-Carbohydrate and High-Fiber Diets 1. Effects on Glucose Metabolism Given the substantial evidence obtained from studies manipulating GI or glucose absorption profiles, it is surprising that few studies have designed achievable and acceptable high-fiber diets that are likely to impact on postprandial glucose absorption profiles. Fewer dietary interventions have actually measured the glucose and insulin meal responses. Of the dietary interventions examining the actions of a high-fiber diet, there are two distinct modes of dietary modification. The first is to provide supplemental viscous soluble dietary fibers at doses likely to retard glucose absorption. The second broad grouping of studies have utilized very high doses of dietary fiber that at least double daily intake. Most studies examining the impact on carbohydrate metabolism of dietary interventions containing a single isolated viscous soluble fiber have predominately utilized guar gum, although pectin (105), glucomannan (106), and xanthan gum (107) have been trialed. Guar gum supplementation to a high-carbohydrate diet has in the majority of studies lowered glycosylated hemoglobin (108,109) and glycosurea (110) and improved insulin sensitivity (111). However, the dose of soluble fiber required to achieve these actions is difficult to achieve from food alone. Food products incorporating guar gum (108,112) or that are rich in oat bran (-glucans) (113) have been trailed with some measure of success, yet commonplace integration into diabetic dietary therapy and widespread acceptance is still lacking. Evidence supporting the beneficial actions of diets rich in carbohydrate and fiber in diabetic management is, at best, unconvincing. Several studies in diabetics have reported improvements in insulin action of diabetic subjects, but the dietary fiber contents of the diets ranged from 90 to 45 grams daily (114117). Of these studies, matched carbohydrate and fat intake with either low or high fiber content

demonstrated that the beneficial actions on insulin sensitivity were present only following the high-fiber diet (118). Contradicting these studies are the observations that diets in which an approximate daily dose of 40 g of dietary fiber was achieved had no effect on insulin action (119121). Irrespective of resultant glucose metabolism, these studies are clearly unrealistic and not applicable to the wider diabetic population. Estimates of dietary fiber intake suggest that in westernized nations the average intake is in the order of 10 13 g daily (122). It is clearly uncertain then if realistic longer-term dietary modifications aimed at providing more dietary fiber will be beneficial in the management of blood glucose levels in type 2 diabetes. Of the evidence accrued to date, the more appropriate approach is to modulate both carbohydrate and the soluble dietary fiber fraction to maximize the likelihood that carbohydrate digestion and absorption will be retarded following each meal. However, the impact of high-carbohydrate diets on plasma lipids must also be considered. 2. Effects on Lipid Metabolism High-carbohydrate diets have been shown to increased plasma triglyceride and lower HDL cholesterol concentrations (119,123125). Although this finding is not universal (118,126,128), it is clear that high-carbohydrate diets have the capacity to accentuate postprandial hypertriglyceridemia (92,125), due predominantly to increased hepatic secretion of VLDL triglycerides (129).The incorporation of dietary fiber into the high-carbohydrate diet tends to minimize these disturbances of triglyceride metabolism. Indeed dietary fiber, particularly soluble dietary fiber, lowers plasma cholesterol and LDL levels in the majority of studies (130,131). Equally effective in lowering plasma lipids and improving atherogenic risk are diets rich in monounsaturated fats (93). Recent analysis suggests that the combination of monounsaturated fatty acids with dietary fiber, more comparable to a traditional Mediterranean diet, is most effective in improving postprandial plasma lipid profiles (132). VII. ADDITIONAL BENEFITS OF HIGH-CARBOHYDRATE, HIGH-FIBER

DIETS IN DIABETES MANAGEMENT Despite the uncertainty surrounding the benefit of a high-carbohydrate, highfiber diet in the management of glucose and lipid metabolism in type 2 diabetes, there remains additional convincing evidence that high-carbohydrate diets have other beneficial attributes. Epidemiological evidence suggests that there is a positive relationship between the amount of dietary fat and body weight (133). Although fat and carbohydrate have equivalent satiation power (134), highfat foods are likely to result in greater energy intake. Higher-fat foods are in many instances preferred when unrestricted food access is available, with many studies reporting a greater rating of desirability, flavor, and enjoyment with the higher-fat food (135). However, studies comparing intake of identical food products, differing only in fat content, show that consumption is based on volume, rather than energy content, leading to passive energy overconsumption (135). The capacity of storage and metabolic responses to carbohydrate and fat differ markedly. Carbohydrate stores, primarily as glycogen, are small (200500 g), and the capacity for synthesis of fats from carbohydrate precursors, de novo lipogenesis, is insignificant in humans (136). The precise maintenance glycogen stores, despite wide variations in daily carbohydrate intake, are achieved by modulating the rate of carbohydrate oxidation. Carbohydrate ingestion elicits an initial repletion of the bodies glycogen stores, followed by compensatory modulation of carbohydrate oxidation to rapidly restoring total body carbohydrate balance. However, unlike carbohydrate, humans possess an enormous capacity for fat storage, predominantly in adipose depots. Fat balance is determined primarily by the difference between total energy expenditure and the energy ingested as carbohydrates or protein (136). Increasing fat intake resulting in paralleled fat storage, rather than a concomitant increase in fat oxidation. There is also little evidence, with respect to energy metabolism, that monounsaturated fatty acids differ from other fatty acid

species (137). Deliberate overfeeding of isoenergetic quantities of either carbohydrate or fat results in less weight gain in the carbohydrate-fed group as carbohydrate oxidation and total energy expenditure are increased (138). Yet dietary interventions aimed at increasing the carbohydrate content of the diet lead to reductions in energy intake and body weight (139,140). Clearly then, diets rich in carbohydrates are favorable for adequate weight control in diabetics. Energy restriction, per se, prior to weight loss may improve insulin action in diabetic individuals (141). With continued energy restriction, weight loss provides marked improvements in glycemic control and diabetes complications (142,143). Diabetic management aimed at aggressively lowering body weight with use of very low calorie diets (VLCD) or gastric restriction surgery is particularly effective in improving insulin action (144). While aggressive weight restriction is appropriate for a small proportion of the adult diabetic population (145), gradual weight loss and, importantly, weight management remains a central priority for many diabetics. The evidence from studies conducted in obese populations suggests that a 10% reduction in fat energy produces on average a 4 to 5 kg weight loss (146). The critical issue is the sustainability of this weight loss with successful, postobese weight management characterized by the continued consumption and enjoyment of a low-fat, high-carbohydrate diet, combined with a regular exercise regime (147,148). There are currently few data to suggest that diets rich in dietary fiber aid in weight loss and weight maintenance (149). However, whether the dietary fiber is soluble or insoluble may be expected to exert differing effects on postingestive satiety (150). Supplemental soluble fiber has been reported to reduce hunger immediately following meals (151,152), although total daily energy intake may be unaffected (153). VIII. CONCLUSIONS Arguments have been strongly made that type 2 diabetics should avoid highcarbohydrate diets, choosing instead a diet rich in monounsaturated fatty acids. This is based on the evidence available that weight-maintaining high-carbohydrate diets

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chosen without regard for their likely glycemic impact and dietary fiber content may be marginally detrimental to blood glucose and lipid levels. However, minimization of the glycemic impact of the meal combined with the use of low-GI foods or selecting foods rich in dietary fiber may provide some protection. Despite this evidence there is little justification for the selection of diets aimed at providing very high amounts of dietary fiber. While significantly increased dietary fiber may provide some additional health benefit, successful lifestyle adoption is likely to be restricted only to highly motivated individuals. Nutritional therapy for type 2 diabetes need not focus particular attention on the dietary fiber content of the diet beyond that recommended for the general population. Most appropriate, as described by the American Diabetes Association (1998), is the continued need to emphasize healthful food choices consistent with the dietary guidelines for the general population. Particular focus in type 2 diabetes management should be given to weight loss and/or management. Central to weight management is the selection of high-carbohydrate diets in which diverse meal planning options are provided. Overall, nutritional therapy for type 2 diabetes should continue to focus on personalization, diversity, and sustainability of dietary plans in which a highcarbohydrate diet remains central.