Multicenter randomized trial of a comprehensive prepared meal program in type 2 diabetes.

OBJECTIVE: To evaluate the clinical effects of a comprehensive prepackaged meal plan, incorporating the overall dietary guidelines of the American Diabetes Association and other national health organizations, relative to those of a self-selected diet based on exchange lists in free-living individuals with type 2 diabetes. RESEARCH DESIGN AND METHODS: A total of 202 women and men (BMI < or = 42 kg/m2) whose diabetes was treated with diet alone or an oral hypoglycemic agent were enrolled at 10 medical centers. After a 4-week baseline period, participants were randomized to a nutrient-fortified prepared meal plan or a self-selected exchange-list diet for 10 weeks. On a caloric basis, both interventions were designed to provide 55-60% carbohydrate, 20-30% fat, and 15-20% protein. At intervals, 3-day food records were completed, and body weight, glycemic control, plasma lipids, and blood pressure were assessed. RESULTS: Food records showed that multiple nutritional improvements were achieved with both diet plans. There were significant overall reductions in body weight and BMI, fasting plasma glucose and serum insulin, fructosamine, HbA1c, total and LDL cholesterol, and blood pressure (P < 0.001 or better for all). In general, differences in major end points between the diet plans were not statistically significant. CONCLUSIONS: Glycemic control and cardiovascular risk factors improve in individuals with type 2 diabetes who consume diets in accordance with the American Diabetes Association guidelines. The prepared meal program was as clinically effective as the exchange-list diet. The prepared meal plan has the additional advantages of being easily prescribed and eliminating the complexities of meeting the multiple dietary recommendations for type 2 diabetes management.

Glycemic effect of a single high oral dose of the novel sweetener sucralose in patients with diabetes.

OBJECTIVE: To examine the effect of a single high oral dose of the novel noncaloric sweetener sucralose on short-term glucose homeostasis in patients with IDDM or NIDDM. RESEARCH DESIGN AND METHODS: A total of 13 IDDM and 13 NIDDM patients with glycosylated hemoglobin levels < 10% completed this double-blind cross-over study. After an overnight fast, patients were administered opaque capsules containing either 1,000 mg sucralose or cellulose placebo, followed by a standardized 360-kcal liquid breakfast. Plasma glucose and serum C-peptide levels were measured over the next 4 h. RESULTS: Regardless of the type of diabetes, areas under the curves for changes of plasma glucose and serum C-peptide levels after sucralose administration were not significantly different from those after placebo. During test meals with sucralose, one episode of symptomatic hypoglycemia occurred in each of three IDDM patients, but these episodes were not considered the result of sucralose administration. CONCLUSIONS: The present results support the conclusion that sucralose consumption does not adversely affect short-term blood glucose control in patients with diabetes.

Relationship of adipocyte size to hyperphagia in developing male obese Zucker rats.

In growing male obese Zucker rats, hyperphagia reaches a maximum or "breakpoint" and declines at an earlier age with high fat than with chow-type diets. A serial adipose tissue biopsy technique was used to correlate changes of retroperitoneal adipocyte size and feeding behavior in 5- to 7-wk-old male lean and obese rats fed laboratory chow or a 35% fat diet until 30 wk of age. Although chow-fed groups had significantly greater cumulative intake, fat-fed groups had significantly greater body weight gain, retroperitoneal depot weight, and adipocyte number. Mean adipocyte size increased continuously in chow-fed groups but decreased over weeks 20-30 in fat-fed groups, reflecting increased adipocyte number. In fat-fed obese rats, hyperphagia reached a breakpoint at 11 wk and disappeared by 13 wk. In chow-fed obese rats, hyperphagia reached a breakpoint at 15-16 wk and disappeared by 19 wk. Biopsy samples revealed that adipocyte size of fat-fed obese rats was already close to maximal at 10 wk (1.12 micrograms lipid), while that of chow-fed obese rats only approached maximal at 20 wk (0.81 microgram lipid). At these time points, lipoprotein lipase activity paralleled adipocyte size. These data indicate that the duration of the growing obese rat's hyperphagia coincides with adipocyte filling and suggest the existence of feeding stimulatory and inhibitory signals from adipose tissue.

Diet composition determines course of hyperphagia in developing Zucker obese rats.

Previous observations from this laboratory indicate that, during growth, the hyperphagia of the male genetically obese Zucker rat reaches a peak or "breakpoint" and then declines. To examine the effect of dietary macronutrient content on the course of hyperphagia, groups of male lean and obese rats were maintained from 5-28 weeks of age on powdered chow, or isocaloric diets (3.6 kcal/g) containing 72% of calories as corn oil, dextrose, or soy isolate protein (n = 5 lean and obese rats/diet). On chow, hyperphagia was maintained at a level of 7-8 g above lean control intake until a "breakpoint" was reached at 17 weeks, and obese intake declined to lean control level. On the fat diet, hyperphagia was increased to 10 g/day when a breakpoint was reached at 8 weeks. On the dextrose and protein diets, hyperphagia at a level of 3-4 g/day reached breakpoints at weeks 18 and 16, respectively. On all diets, the intakes of obese rats were precisely equal to the intakes of lean control rats by weeks 19-20. These data show that the magnitude and duration of hyperphagia in the developing obese rat are influenced by diet composition. Previously, we have proposed that the obese rat's hyperphagia arises from rapid adipocyte filling. Since high-fat diets facilitate adipocyte enlargement, the early "breakpoint" of hyperphagia seen with the high-fat diet may indicate that this feeding stimulation decreases as the fat cells of the obese rat approach maximal size.

Satiety in the obese Zucker rat: effects of carbohydrate type and acarbose (Bay g 5421).

Despite the obese Zucker rat's hyperphagia on carbohydrate diets such as laboratory chow, this laboratory has found that its satiety response to glucose and other simple sugars is comparable to that of its lean control rat. To further investigate carbohydrate satiety in the Zucker rat, the short-term feeding behavior of obese and lean rats was observed following intragastric infusions (7.2 kcal in 10 ml) of corn starch and the starch hydrolysates Polycose and dextrin. There were no reliable between-genotype differences in the feeding inhibitory effects of Polycose and dextrin. However, in obese rats, the satiety effect of corn starch was delayed and reduced compared to that observed in lean rats (p less than 0.04). To modify the effect of corn starch, rats were administered 0.2 or 0.6 mg/infusion of the carbohydrate digestive inhibitor acarbose (Bay g 5421). Acarbose significantly reduced the satiety effect of corn starch in lean rats (p less than 0.001), and further attenuated satiety in obese rats (p less than 0.02). Since secretion of pancreatic amylase, the enzyme that initiates starch digestion, is decreased in obese rats, this result suggests that alterations of digestive and/or absorptive processes may underlie the obese rat's impaired satiety response to complex carbohydrate.

Diet composition alters the satiety effect of cholecystokinin in lean and obese Zucker rats.

Although exogenous administration of the peptide cholecystokinin (CCK) has been shown to reduce food intake in a variety of experimental situations, few studies have examined the influence of dietary content upon CCK's effectiveness, particularly in obese states. To evaluate the effectiveness of CCK administration in animals consuming high fat diets, groups of obese and lean Zucker rats were maintained on laboratory chow (CH), a high fat diet isocaloric to chow (IF), or a hypercaloric fat diet (HF). After a 17 hr fast, rats were given intraperitoneal injections of saline or ascending doses of 0.06 to 2.0 micrograms/kg of the synthetic octapeptide of CCK. On all diets, obese rats required higher doses of CCK to significantly reduce feeding and showed smaller intake reductions than lean rats (p less than 0.001). Despite higher baseline caloric intakes (p less than 0.001), rats of both genotypes maintained on HF displayed larger reductions of intake than those fed IF or CH (p less than 0.001). Intake reductions by either genotype maintained on IF or CH were not reliably different. The manner in which the satiety effect of CCK was enhanced in rats consuming the calorically dense, palatable HF diet is unclear but may be related to orosensory and/or postingestive attributes of the diet.

Satiety effects of intragastric meals containing triglycerides with different chain lengths.

Intragastric meals containing triglycerides with chain length of 2-18 significantly reduced intake in deprived Sprague-Dawley rats feeding 20 min after infusion. Satiety after long-chain triglyceride (LCT) infusions must have been mediated via a gastroenteric signal, since feeding was reduced prior to delivery of these fats into the bloodstream. Equicaloric infusions of triglycerides with chain length of 6 to 18 had similar inhibitory effects, indicating that the satiety effects of these triglycerides depended more on the number of calories infused than on chain length. Shorter-chain triglycerides were initially more effective in reducing feeding. Except for a poorly absorbed LCT the infusions did not result in conditioned taste aversion and thus did not appear to induce discomfort. Gastric recovery of a nonabsorbable marker at the time of the feeding test indicated that gastric emptying, like satiety, was related to the caloric properties of the infusions. These effects could be mediated through neural and/or hormonal mechanisms that are stimulated through energy-related properties of triglycerides.

Differential effects of sugars and the alpha-glucosidase inhibitor acarbose (Bay g 5421) on satiety in the Zucker obese rat.

To examine the satiety responses of Zucker obese and lean rats to simple sugars, adult male rats were given equicaloric intragastric infusions of fructose, glucose, and sucrose. All three sugars reduced the short-term intakes of both genotypes, although no reliable between-genotype differences in the satiety effects of the sugars were observed. Within each genotype, fructose had a larger satiety effect than sucrose. To examine a potential basis for the observed effects, rats were given sucrose infusions containing the intestinal glucosidase inhibitor acarbose (Bay g 5421). In obese rats, addition of a low dose of acarbose increased the satiety effect of sucrose infusion. Delaying carbohydrate absorption via acarbose administration may alter gastrointestinal and/or postabsorptive satiety processes, and may prove useful as a probe for investigating the nature of satiety signals.

Naltrexone and human eating behavior: a dose-ranging inpatient trial in moderately obese men.

To investigate the effects of the long-acting opiate antagonist naltrexone on spontaneous human eating behavior, eight moderately obese male paid volunteers were housed in a hospital metabolic unit for 28 days and offered palatable foods ad lib by a platter service method. Under double-blind conditions, equally divided doses of 100, 200 and 300 mg naltrexone, or an acetaminophen placebo, were administered twice daily in tablet form for 3-day periods each, according to a Latin Square design. The doses of naltrexone resulted in decreases of daily caloric intake from placebo level, but these reductions were neither statistically significant nor dose-related. When the averaged effects of the doses were compared to placebo, five subjects showed intake reductions but the overall intake reduction of 301.5 +/- 198.1 kcal/day (mean +/- SEM) was not statistically significant. Naltrexone administration failed to selectively alter intakes of individual meals and snacks or macronutrient consumption patterns. During active drug periods, subjects lost 0.62 +/- 0.22 lb over 3 days, while during the placebo period, subjects gained 0.46 +/- 0.68 lb. However, there was no reliable change of basal metabolic rate as a function of naltrexone administration. The present results, which indicate that naltrexone administration is relatively ineffective in reducing food intake and inducing body weight loss in obese humans, are thus in contrast with reports that administration of opiate antagonist agents promote significant reductions of food intake and attenuations of body weight gain in experimental animals.

The satiety effects of intragastric macronutrient infusions in fatty and lean Zucker rats.

To evaluate satiety in the hyperphagic, genetically obese Zucker "fatty" (fafa) rat, food-deprived fatty and lean (FaFa) control rats were given equicaloric intragastric infusions consisting largely of fat, carbohydrate, or protein. Relative to distilled water infusion, these infusions resulted in immediate reductions of food intake in both fatty and lean rats allowed to feed 20 min post-infusion. Cumulative food intakes remained reduced throughout the 2 hr period of observation. Thus, despite its hyperphagia, the fatty rat is responsive to the satiating effect of infused nutrients. However, the relative satiating effectiveness of the macronutrient infusions differed for the two genotypes. In lean rats, the different macronutrient infusions resulted in equivalent reductions of feeding. In contrast, in fatty rats, fat was the least satiating and protein was the most satiating macronutrient. Moreover, compared to lean rats, fatty rats displayed less initial suppression of feeding after fat infusion and greater overall suppression after protein infusion. These effects are consistent with the long-term feeding behavior of the fatty rat for the different macronutrients and may be related to pre- and postabsorptive metabolic alterations that have been documented in this animal.

Effects of a glucosidase inhibitor (acarbose, BAY g 5421) on the development of obesity and food motivated behavior in Zucker (fafa) rats.

BAY g 5421 (acarbose) inhibits carbohydrate digestion in the gut, thereby reducing the rate of glucose absorption. This experiment tested whether long term administration of acarbose to developing Zucker "fatty" (fafa) rats would, by reducing several lipogenic factors, attenuate lipid deposition and reduce the hyperphagia and increased food motivated behavior of these animals. From 7 to 20 weeks of life groups of fatty and lean (FaFa) control rats were fed 0, 20 or 40 mg acarbose/100 g maintenance diet (45% carbohydrate, 35% fat, 20% protein calories), while an additional fatty and lean group were pair-fed to respective 40 mg acarbose groups. Lean groups fed acarbose exhibited dose dependent reductions of body weight, insulin, triglycerides, retroperitoneal and epididymal pad weight, adipocyte size, LPL activity/cell (retroperitoneal pad only), and lipid deposition both in total grams of fat and as a percentage of carcass weight. Fatty groups fed acarbose exhibited dose dependent reductions of insulin, blood glucose, retroperitoneal pad weight, and, at one of the two doses used, significantly lowered body weight, (40 mg), triglycerides (20 mg) and cholesterol (20 mg). However, acarbose-fed fatty groups failed to show significant reductions of adipocyte size, number or LPL activity/cell in retroperitoneal and epididymal fat pads, and maintained their obese body composition, on a percentage basis, at levels not significantly different from that of the 0 mg fatty control group. Acarbose administration led to an initial dose dependent reduction of food intake in both genotypes, which persisted for the lean groups. Fatties fed the 20 mg dose showed a gradual tendency (ns) towards increased daily intake, lever pressed at elevated rates for food pellets, and refed at faster rates following fasting. Fatties fed the 40 mg dose maintained their daily intake at fatty control levels, did not lever press at elevated rates, and showed significantly reduced refeeding following fasting. The 40 mg fatty and both lean acarbose treated groups had decreased sucrose solution preference. Possible bases for these differing effects of the drug on feeding behavior by the groups are considered.

Adipose tissue lipoprotein lipase (LPL) and triglyceride uptake in zucker rats.

To investigate the relationship between elevated adipose tissue lipoprotein lipase (LPL) activity and triglyceride uptake in Zucker obese rats, fed and 12 hour fasted female obese and lean Zucker rats were given intrajugular infusion of radio-labelled triglyceride and label clearance and uptake were examined over 35 minutes. In the fed state, obese rats showed more rapid clearance of the label from the bloodstream and, in both fed and fasted states, greater uptake into retroperitoneal and parametrical fat pads than lean rats. Obese rats showed proportionally less uptake into heart and liver. Regardless of feeding condition, obese rats exhibited elevations in adipose tissue LPL, which was significantly correlated with label uptake in adipose tissue. These results show that, in Zucker obese rats, elevated adipose tissue LPL is associated with increased adipose tissue triglyceride uptake. A preferential "shunting of calories" into adipose tissue, which is presumably mediated by LPL, could underlie the intractability of the Zucker obesity syndrome as well as the altered feeding behavior of Zucker obese rats.

Effect of high fat weanling diets containing either medium-chain triglycerides or long-chain triglycerides on the development of obesity in the Zucker rat.

Zucker rats were early weaned onto either medium-chain (MCT) or long-chain triglycerides (LCT) to examine the effect on the development of obesity. Preobese and lean pups were weaned at 16 days to isocaloric, isonitrogenous liquid diets containing either 65% MCT or LCT (by calories) or to a "stocklike" (5.5% fat, 72.6% carbohydrate) control diet or were pair-fed stocklike diet to MCT-fed rats until day 45. MCT-feeding lowered body weight gain and fat pad weight in obese and lean rats compared to stocklike-fed controls. Additionally, fat cell size and lipoprotein lipase (LPL) activity and hepatic acetyl CoA carboxylase activity were reduced in obese MCT-fed rats compared to obese controls fed stocklike diet. Except for altered LPL activity the effects produced by MCT-feeding were attributable to its anorectic effect. However, all obese rats, including the MCT group, developed an obese body composition and were hyperinsulinemic. The development sequence leading to obesity may be derived from a fundamental cellular defect that results in metabolic alterations in different tissues at critical periods of development. Thus, effective treatment of this genetic obesity requires a better understanding of fa gene action.

Food intake after intragastric meals of short-, medium, or long-chain triglyceride.

Food-deprived Sprague-Dawley rats were given equicaloric intragastric infusions of mixed meals consisting largely of short- (SCT), medium- (MCT), or long-chain triglyceride (LCT). When animals were allowed to feed 20 min after infusion, there was an immediate reduction of food intake that was sustained over the 2 hr feeding period. During the first hour of feeding, the SCT, which is digested and absorbed more rapidly than the MCT or the LCT, was more effective per calorie in reducing food intake than these longer-chain triglycerides. However, during the second hour, cumulative intakes after the different triglyceride infusions were not significantly different. Equicaloric infusions of the MCT and the LCT resulted in equivalent reductions of food intake at all times. The satiety effects of these two triglycerides appear to be related to their caloric properties rather than to chain length. Since the LCT reduced food intake before the absorbed fat could have entered the blood to stimulate satiety signals, this satiety effect may be mediated by a gastroenteric signal. None of the triglyceride infusions resulted in a conditioned taste aversion suggesting that food intake was reduced through normal satiety rather than through discomfort.

Zucker fafa rats maintain their obese body composition ten months after jejunoileal bypass surgery.

In order to evaluate the long-term effects of intestinal bypass surgery in an animal model of early onset hypercellular-hypertrophic obesity, adult female obese and lean Zucker rats were given jejunoileal bypass surgery or sham operations. At sacrifice ten months post-surgery, body weights of obese bypass rats were nearly reduced to lean bypass levels. This reduction in body weight was not accompanied by normalization of body composition or of the hyperinsulinemia and hypertriglyceridemia characteristic of this obese syndrome. Obese bypass rats maintained 44 percent of their weight as lipid compared to 12 percent in lean bypass rats and 15 percent in sham-operated lean rats. In addition, obese bypass rats maintained elevated adipose tissue lipoprotein lipase activity and increased fat cell size and were hyperinsulinemic and hypertriglyceridemic. Furthermore, obese bypass rats had reduced carcass protein and reduced weight and DNA and/or protein contents in heart, liver, muscle and kidney. Therefore, although bypass surgery resulted in significant weight loss, it did not normalize the obese syndrome and may result in serious reductions in the weight and cellularity of vital organs.

The effects of specified chemical meals on food intake.

Rats received intragastric infusions of various specified chemical meals and were subsequently tested for a reduction in food intake. A second experiment, using a novel technique, tested for conditioned aversion to the meal infusions. The nonnutritive substances, kaolin clay and emulsified fluorocarbon, had no significant effect on food intake. Infusions of 1 M glucose and 1 M sorbitol reduced feeding behavior, but the 1 M sorbitol infusion also produced a conditioned aversion to flavored pellets paired with the sorbitol infusion, showing that the reduced feeding could have been caused by discomfort. Infusion of a high-fat meal consisting of emulsified triolein mixed with small amounts of sugar and protein or the rat's normal liquid diet, Nutrament, also reduced food intake, and both infusions failed to produce a conditioned aversion. The use of specified meals to understand the chemical basis of satiety requires a sensitive behavioral test to establish that the meal does not cause discomfort or other nonspecific effects.