Introduction

Excess body fat is recognized to result in key metabolic disturbances in obese subjects with type 2 diabetes (1) (2) (3) (4) and excess body fat is a common trait among a large proportion of patients with type 2 diabetes (5). Successful management of weight loss in obese patients with type 2 diabetes has been shown to be capable of correcting many of the metabolic abnormalities associated with type 2 diabetes, such as hyperinsulinemia, hyperglycemia, and hypertriglyceridemia (6) (7) (8). However, weight reduction in this population is often difficult to achieve. Liquid meal replacements (MRs) have been shown in several previous trials to promote long-term weight loss in obese patients (9) (10) (11). Consequently, it may be of benefit to use MRs for weight loss in overweight patients with diabetes. However, MRs often contain simple sugars derived from milk (lactose), fruit (fructose), and refined sugar (sucrose); therefore, some health care providers are concerned about the potential for hyperglycemia when MRs are used by patients with diabetes. The primary goal of our study was to evaluate the safety and feasibility of using a MR strategy for glycemic control of obese patients with type 2 diabetes.

Research Methods and Procedures

Study Design

The institutional review board of the University of California, Los Angeles approved the study protocol. Obese subjects with type 2 diabetes were recruited and randomized to use an MR diet plan or an individualized EDP for 12 weeks. Throughout the 12-week study, body weight, glycemic control, insulin, lipid levels, and adverse side effects were monitored.

Inclusion and Exclusion Criteria

Subjects had type 2 diabetes treated with oral hypoglycemic agents. Subjects were required to have a body mass index (BMI) of 27 to 40 kg/m² inclusive, hemoglobin A1c (HbA1c) of 7% to 12% inclusive, and no change in diabetic medications for 3 months before entering the trial.

Subjects were excluded if they had been on insulin therapy or if they had significant diabetes-related complications, such as diabetic retinopathy, neuropathy, and proteinuria. Furthermore, subjects were also excluded if they had significant psychiatric or other major medical conditions, such as liver disease, kidney disease, and coronary artery disease.

Meal Tolerance Test

In a separate study designed to compare the glucose and insulin response between consuming an exchange diet breakfast and drinking a liquid MR, 16 participants were invited to participate in the meal tolerance test. Each subject was randomized to receive one of the two possible sequences of test meals: an exchange breakfast on day 1 and a canned MR (Slim-Fast) on day 4 or canned MR (Slim-Fast) on day 1 and an exchange breakfast on day 4. The composition of the MR and EDP meals are shown in Table 1.

Table 1 - Composition of test meals.

Full table

Each test meal session began between 8:00 AM and 9:00 AM. An intravenous catheter was placed in an arm vein using aseptic technique. For each participant, the serum glucose levels between days 1 and 4 were matched to within 20 mg/dL of each other before initiation of the test meal. Serum glucose and insulin levels were measured at baseline, 15, 30, 60, 90, 120, 150, 180, 210, 240, 270, and 300 minutes after test meal consumption.

Dietary Intervention Study

Randomization.

A random, permuted, block design was used for randomization. The eligible subjects were equally assigned into one of the three diet-plan arms: an MR preparation containing lactose, fructose, and sucrose (Slim-Fast; MR1); an MR in which sucrose and fructose were replaced by nonsugar-containing glucose oligosaccharides (sugar-free Slim-Fast; MR2); and a comparison group in which participants were given an individualized EDP with a macronutrient composition similar to that recommended by the American Diabetes Association (ADA). Both investigators and participants were blinded to which liquid MRs the participants in the MR groups were taking.

Composition of MR1 vs. MR2

MR1 (Slim-Fast Foods, New York, NY) contained 11 g of lactose, 13 g of fructose, 8.5 g of sucrose, and 14 g of protein. MR2 was identical to MR1, but fructose and sucrose were replaces with equivalent levels of maltodextrins.

Dietary Intervention Protocol

Each participant received individual consultation with a registered dietitian at the baseline and weeks 2, 4, 8, and 12 of the study. Subjects who were randomized into the MR groups replaced their three meals with MRs for the first 5 days of the study and supplemented these meals with fruits and vegetables. Subsequently, they used two MRs and ate a portion-controlled dinner high in fruits and vegetables for the remainder of the 12-week study. Subjects randomized into the EDP group were instructed on how to use food exchanges and were provided with goals that met the criteria recommended by the ADA of consuming <30% of calories from fat, 10% to 20% from protein, and 55% to 65% from carbohydrates (12). For both groups of subjects, an individualized caloric target was calculated to achieve a daily caloric deficit of 500 calories per day below estimated resting metabolic rates. Resting metabolic rates were estimated based on lean body mass measured by bioelectrical impedance analysis according to the Cunningham equation estimate of 13.8 kcal per day per pound of lean body mass. For the meal tolerance testing, participants were instructed to eat a breakfast with one slice of wheat toast with margarine, a 7-in banana and a one-half cup of low-fat cottage cheese, or to drink a canned liquid MR (Slim-Fast).

Procedures

Weight was measured with a doctor's scale calibrated to 0.25 lb, and height was measured with a wall-mounted stadiometer to the nearest 0.125 in. Insulin was measured using a commercial double antibody I¹²⁵ method. Glucose was measured using a spectrophotometric technique at an absorbance of 505 nm. Plasma total cholesterol, triglyceride, and high-density lipoprotein (HDL) cholesterol concentrations were determined by using standard enzymatic methods established in the University of California, Los Angeles Center for Human Nutrition Biomarker Research Laboratory. The interassay coefficients of variation are <4% and intra-assay variation is usually <2%. Plasma triglyceride is determined using standard enzymatic methods. The HDL -cholesterol concentrations were determined after precipitation of apoprotein B-rich lipoproteins with heparin and manganese chloride. The low-density lipoprotein (LDL) cholesterol concentrations were calculated by using the Friedewald equation (13), which assumes that circulating very–low-density lipoproteins consist of 80% triglycerides and 20% cholesterol. Our laboratory is certified by the Centers for Disease Control Lipid Standardization Program (Laboratory LSP266).

Statistical Analyses

Meal Tolerance Test.

This is a two-period cross-over study designed to compare the serum glucose and insulin level after consuming MR and EDP breakfasts. Subjects acted as their own controls and were randomly assigned to one of the two treatment sequences: MR on day 1 and EDP on day 4 or EDP on day 1 and MR on day 4. For each subject and each type of breakfast, the area under glucose (insulin) level over time curve is calculated.

Dietary Intervention Study.

In this randomized study, the outcome variables were repeatedly measured over time: weight, BMI, insulin, glucose, and lipids were measured at baseline and at weeks 4, 8, and 12, respectively. HbA1c was measured at baseline and at weeks 8 and 12. Descriptive statistics, such as means and SD, were used to summarize the outcomes for each study group at each time-point. The change of each outcome variable from baseline within each diet group was tested using paired t test. The differences among the diet groups at each time-point were examined using a general linear model with baseline value as covariate. A mixed model was used to test the overall diet effect:

where Y is the outcome; baseline Y is the baseline measurement; _g is the diet effect for group g after taking baseline value into account; is a vector of error; MVN (0, R); and R is block diagonal with a block for each subject. Each block has a compound symmetric covariance structure. Log transformation was taken for some Y and baseline Y due to nonnormality. The data also have been analyzed as a two-arm study: ADA vs. MR.

Results

Meal tolerance testing demonstrated that the MR had no different effects on glucose levels after a meal than a standard breakfast recommended commonly to obese patients with diabetes. Figures 1 and 2 show the average glucose and insulin levels after a meal for all participants. Because the carry-over effect and the sequence effects were very insignificant, Wilcoxon sign-rank test was used to examine the difference in area under the curve (AUC) for glucose and insulin with the two meals. There were no statistically significant differences in the AUC when comparing the consumption of an EDP meal and an MR for glucose (p = 0.107) and for insulin (p = 0.252). In the dietary intervention study, 57 subjects (19 in the MR1, 22 in the MR2, and 16 in the EDP groups) completed the 12-week protocol. No subjects withdrew from the study due to serious adverse side effects. Table 2 shows the baseline characteristics of the participants in the study. There were no statistical differences among the three groups of subjects in reference to age, body weight, BMI, glucose, or insulin levels. However, subjects in the MR2 group had significantly lower baseline HbA1c levels than the subjects in the other two groups.

Figure 1.

Glucose response over time. There is no significant difference in the AUC between the consumption of MR and the EDP breakfast.

Full figure and legend (71K)

Figure 2.

Insulin response over time. There is no significant difference in the AUC between the consumption of MR and the EDP breakfast.

Full figure and legend (66K)

Table 2 - Baseline characteristics.

Full table

Over the course of the study, there were no significant differences between the MR groups in regards to body weight, glucose, insulin, HbA1c, and lipid changes. Therefore, data on the MR groups were pooled and a comparison to the EDP group was reported as follows. Subjects in both the MR and the EDP group lost weight significantly during the study (Figure 3). At week 12, subjects in the MR group lost 6.10 4.4 kg, whereas subjects in the EDP group lost 4.2 4.7 kg. There was a 2.1-kg/m² reduction in BMI in the MR group and a 1.9-kg/m² reduction in BMI in the EDP group. Weight loss over the course of the 12-week study was significantly higher in the MR group than the EDP group (p = 0.009).

Figure 3.

Body weight changes in MR and EDP groups over the course of study, where error bars represent 1 SEM from mean. The weight loss of the pooled MR groups was significantly greater than that of the EDP group (p = 0.009).

Full figure and legend (60K)

Figure 4 shows the serum glucose concentrations over time. In the MR group, there was a significant reduction of serum glucose over time (p < 0.001). In the EDP group, average serum glucose level was reduced at weeks 4 and 8 compared with baseline, but showed no significant difference at week 12. Glucose levels in the MR group were significantly lower than in the EDP group over time (p = 0.012).

Figure 4.

Serum glucose concentrations over time. Glucose levels in the MR group were significantly lower than those of the EDP group over time (p = 0.012). Error bars represent 1 SEM from the mean.

Full figure and legend (61K)

Table 3 shows the changes in insulin and HbA1c levels over time. Insulin levels in the MR group were significantly reduced at weeks 4, 8, and 12 compared with baseline. Insulin levels in the EDP group were also reduced at weeks 4, 8, and 12 compared with baseline. However, there was no significant difference in insulin levels over time between the MR and the ADA groups. The HbA1c in the MR group decreased from 8.7 1.3% at baseline to 7.7 1.4% at week 8 (p = 0.0001), and to 7.9 1.4% (p = 0.0005) at week 12, whereas HbA1c levels in the EDP group decreased from 9.3 1.5% at baseline to 8.5 1.5% at week 8 (p = 0.010) and to 8.7 1.6% (p = 0.1) at week 12. There was no significant overall difference in HbA1c over time between the MR and EDP groups.

Table 3 - Insulin and HbA1c concentrations.

Full table

Twenty-four of 41 subjects in the MR group reduced their oral hypoglycemic agents during the study, whereas 6 of 16 subjects in the ADA group reduced their oral hypoglycemic medications.

Table 4 shows the results of lipid concentrations over the course of the study. In the MR group, there was a significant reduction in total cholesterol and LDL cholesterol over time. At week 12, the MR group showed a 7.6% reduction in total cholesterol and a 12.6% reduction in LDL cholesterol. At week 12, there was a reduction in triglyceride and an increase in HDL cholesterol in MR group, but neither of these values reached statistical significance. No differences in lipid concentrations between the MR and EDP groups were observed over the course of this 12-week study.

Table 4 - Lipids.

Full table

Discussion

In previous studies, liquid MRs have been shown to be a useful tool for both weight loss and weight maintenance in obese subjects (6) (7). There are concerns, however, that the high sugar content in most MRs could cause adverse glycemic excursion in patients with type 2 diabetes. In this study, we explored the effects of liquid MRs on immediate glucose response and 12-week glycemic control in obese patients with type 2 diabetes.

Two different MRs were studied containing either sugar or a polysaccharide classified by standard labeling as sugar-free. Because the results with the two different MRs were the same with regard to weight loss, the data from these two groups were merged to assess the safety and efficacy of the MR approach compared with individualized diet plans used in standard diabetes treatment protocols.

Throughout the study, no subjects developed any serious adverse effects to MRs, and no participants experienced major hypoglycemic reactions. In the meal tolerance test, our data demonstrate that consumption of a liquid MR does not lead to significant acute hyperglycemia compared with consumption of an exchange diet breakfast. In the 12-week study, we found that using MRs as a strategy for weight loss in obese subjects with type 2 diabetes is safe and effective.

Obesity is now at epidemic proportions in the United States affecting one of every three Americans (14) (15). The increasing prevalence of obesity over the past two decades is alarming because it translates into increased medical care and disability costs. Obese patients with type 2 diabetes pose a real challenge for the clinicians responsible for their care (16). Although an elevated glucose level is the hall-mark of both types 1 and 2 diabetes, the pathophysiology of these two diseases is entirely different. In type 1 diabetes, primary insulin deficiency results from autoimmune destruction of the pancreas, whereas in type 2 diabetes insulin resistance combined with abnormal insulin secretion ultimately leads to insulin deficiency after many years. There is increasing scientific evidence to suggest that excess visceral fat in obese type 2 diabetes may play a key role in the evolution of the metabolic abnormalities manifested in this patient population. Several recent clinical trials have shown that weight loss in obese type 2 diabetes can result in a favorable correction of several key metabolic disturbances (10) (11). However, successful weight management in this population is often difficult to achieve. Weight reduction through nutritional and pharmaceutical intervention as a primary approach to treatment of type 2 diabetes is starting to receive more attention nationally because the initiation of the National Institutes of Health-funded Study of Health Outcome for Weight Loss Trial. Six thousand adult subjects with DM will be randomized to various therapeutic modalities aimed at body weight management. The progression of atherosclerosis, assessed through the measurement of carotid intimal–medial thickness by ultrasound technique, will be studied as a primary endpoint. This multicenter national study is currently in its planning phase, and the results of various weight management strategies on macrovascular disease progression in patients with type 2 diabetes will not available for several years (17). The Diabetes Primary Prevention Trial has demonstrated that changes in diet and lifestyle can prevent progression from impaired glucose tolerance to frank diabetes and was terminated after 3 years due to the outstanding improvements in outcome with lifestyle change. In fact, weight losses of 5% to 7% and regular exercise resulted in a significantly lower rate of progression to diabetes (14%) than pharmacotherapy alone with metformin (29% progression to diabetes) (18).

For the majority of the study, participants in the MR group were instructed to replace two meals each day (breakfast and lunch) with MRs and to eat a sensible, portion-controlled dinner with fruits and vegetables. A typical breakfast, which is recommended by a dietitian for an obese person with type 2 diabetes, can often contain up to 350 calories. The MR used for this study contained only 250 calories. In this study, weight reduction in the MR group was slightly greater than that in the group using a calorie-restricted diet with macronutrients composition consistent with the ADA nutritional guidelines. We hypothesize that MRs may provide a convenient way for obese individuals to follow an energy-restricted diet. This may result in enhancement of compliance with caloric restriction and, subsequently, may lead to increased weight reduction.

Therefore, we have demonstrated that using MRs for 12 weeks in obese subjects with type 2 diabetes can help correct the metabolic abnormalities associated with excess body weight. During weight loss, there were associated reductions in glucose, insulin, and HbA1c levels. Furthermore, we reduced oral hypoglycemic medications in many of our participants during weight loss. In this 12-week study, weight reduction achieved through the use of liquid MRs resulted in improvements in glycemic control, insulin, and lipids levels. Future studies need to examine the long-term efficacy of MRs in this population. In conclusion, liquid MRs can be used safely as part of a comprehensive treatment program for management of obese subjects with type 2 diabetes.

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Acknowledgments

This research was supported by University of California, Los Angeles Nutrition and Obesity Training Grant DK, the University of California, Los Angeles Clinical Nutrition Research Unit National Institutes of Health Grant CA 42710, and Slim-Fast Nutrition Institute, West Palm Beach, Florida.