Very Low-Calorie Diet Mimics Roux-en-Y Gastric Bypass in T2D
Very Low-Calorie Diet Mimics Roux-en-Y Gastric Bypass in T2D
Contrary to our expectations, this study demonstrates that RYGB in subjects with T2DM does not result in greater improvement in β-cell function compared with equivalent weight loss achieved over the same time period by VLCD. As evaluated by fsIVGTT, both groups demonstrated significant and similar increases in acute insulin secretion and insulin sensitivity. We previously demonstrated a greater improvement in DI in subjects with T2DM after RYGB compared with individuals who achieved equivalent weight loss on an outpatient low-calorie diet. However, the degree to which calories were restricted was not equivalent to the RYGB, and therefore, the rate of weight loss for the RYGB was greater. Based on studies of caloric restriction, the degree of caloric restriction is a major factor that exerts a glucose-lowering effect independent from the amount of weight loss. This is the first study of individuals with T2DM that compares RYGB to a diet group matched for both the amount and rate of weight loss. Others have evaluated β-cell function after surgery, but there has not been a simulation of a gastric bypass diet without the surgery in patients with T2DM. Isbell et al., for example, evaluated RYGB with matched obese subjects on a VLCD 2–7 days after intervention. There was in both groups a 25% improvement in insulin sensitivity as quantified by HOMA-IR, but a significant decrease in fasting glucose levels was demonstrated in the diet group only. These results are somewhat difficult to interpret given that the groups were a mix of subjects with and without T2DM, and there may be a confounding effect of residual inflammation in this very early postoperative state.
Differences in the methods used to assess β-cell function, characteristics of the patient population, and differences in operative procedures among surgeons also make it difficult to compare studies with sometimes seemingly conflicting outcomes. For example, with use of the hyperglycemic clamp it was found that 4 weeks after RYGB there was an increase in insulin sensitivity, but DI remained unchanged. An explanation for this finding in comparison with our study is that metabolic testing was carried out when subjects were consuming an 800-calorie liquid diet prior to surgery. It is also unclear whether diabetes medications, including metformin and thiazolidinediones, were held prior to testing. Similar to our results, Lin et al. showed that DI improved 23-fold (from 23 to 403) 1 month after RYGB. Nannipieri et al. also showed that β-cell glucose sensitivity improved (but did not normalize) 45 days after RYGB in patients with T2DM. Interestingly, insulin sensitivity but not β-cell glucose sensitivity improved in proportion to weight loss. Certainly, duration of diabetes also influences β-cell function. Lim et al. studied patients with T2DM and restricted caloric intake to 600 kcal/day for 8 weeks and demonstrated not just improvement but normalization of both β-cell function and hepatic insulin sensitivity. The duration of diabetes, however, was <4 years, which limits comparison with our study cohort with a longer duration of diabetes. In the absence of a gold standard for assessing β-cell function and the inclusion of a diverse population, comparison of different studies is indeed problematic.
Similar to dietary interventions, there is considerable variability in the glycemic response after RYGB. From a clinical perspective, it would be helpful to predict the glycemic response to surgery from known or easily measureable baseline characteristics. In retrospective studies, it appears that patients with a longer history of diabetes or on insulin therapy were less likely to achieve euglycemia off antihyperglycemic medications. Magnitude of weight loss has been associated with better glycemic outcome. From our data, it appears that duration of T2DM, baseline β-cell function, or HbA1c and the amount of weight loss did not correlate with changes in DI. However, in this short-term study we are unable to assess the maximal improvement in glycemic parameters, as it has been shown that Si continues to improve with further weight loss between 6 and 24 months after surgery. Likewise, we cannot predict the durability of these changes, as weight tends to increase with time, and deterioration of glycemic control, even with maintenance of weight loss, has been observed.
It has been well documented that RYGB produces profound postprandial stimulation of GLP-1 secretion and a greater incretin effect than observed with diet-induced weight loss. RYGB also alters glucose absorption, causing a marked increase in the early rate of appearance of ingested glucose into the systemic circulation that would be expected to alter the pattern of insulin secretion. For these reasons, we evaluated β-cell function in the absence of enteral nutrient passage and without the confounding effect of altered glucose kinetics. Although gut hormones were not measured during the fsIVGTT, others have demonstrated that there is negligible change in GLP-1 concentrations upon intravenous glucose infusion. Thus, the findings in our study suggest that there are changes in β-cell function, independent of glucose absorption from the gut and the incretin effect, that occur to a similar extent after RYGB and VLCD. Because of the incretin effect, however, we did expect that overall glycemic control would improve to a greater extent after RYGB. Contrary to our expectations, decreases in fructosamine levels from baseline were of similar magnitude between RYGB and VLCD. It is likely that the greater incretin effect noted after larger meal challenges in RYGB patients may not have provided much advantage in the setting of very small meals and less demand for prandial insulin secretion. In this vein, it has been noted that β-cell function and clinical outcome after RYGB are better than equivalent weight loss achieved by LCD; however, the caloric intake and duration of the weight loss periods were greater in the diet groups of both studies.
Another component of insulin and glucose metabolism is insulin clearance, which has been demonstrated to increase after 11% weight loss on a 500–600 kcal/day diet. We did not directly measure insulin clearance, but given that fasting insulin was greater in the RYGB group at baseline while C-peptide levels were nearly identical it appears that insulin clearance may have been greater in the VLCD group. It is unclear why there was a difference, since groups were fairly well matched for some of the factors that are associated with clearance such as Si, AIR, fasting glucose, and BMI. Unfortunately, we do not have measurements of waist circumference or visceral adipose tissue that could conceivably be different in this relatively small sample size and might affect insulin clearance. Nevertheless, the change in the insulin–to–C-peptide ratio was nearly identical between groups, suggesting that the interventions do not differentially affect clearance.
Limitations of this study are the nonrandomized intervention scheme, as well as the relatively small sample size. The study was designed to detect a 1.3-SD difference in change in DI between groups. Smaller differences may not have been detected, but the clinical significance of smaller differences is somewhat questionable. It is possible that with more subjects changes in some of the secondary end points would reach statistical significance, such as the increase in adiponectin in the VLCD group and decrease in fructosamine after RYGB. Although the groups were matched for duration of diabetes, this was a self-reported time of diagnosis that likely varies from the actual onset of the disease. Another factor to consider is that acute inflammation, even with a minimally invasive laparoscopic procedure, could have increased insulin resistance blunting the response of the RYGB patients. We did not perform detailed assessment of residual inflammation; however, CRP levels were not statistically different between both groups. Physical activity levels were not monitored, although given the inpatient setting we were able to limit the activity in the VLCD group to that expected of postsurgical patients. The RYGB group was not studied under inpatient observation because the surgical procedure itself imposes limitation of caloric intake to ~500 kcal/day in the first 2–3 weeks after surgery.
These data indicate that the changes in glucose homeostasis that occur within 2–3 weeks after RYGB are primarily due to very low energy intake as opposed to specific surgically-induced hormonal effects. Clearly, this does not mean that RYGB is not more beneficial in the long term, since the degree of caloric restriction required to mimic surgical results cannot be maintained in most individuals. As in our prior study, even when the diet was 800 kcal/day instead of 500 kcal/day less improvement in β-cell function was noted. It would be expected that in the longer term, the average blood glucose would begin to increase in the VLCD group as caloric intake was liberalized even if the weight loss were maintained. The RYGB group may maintain or further their improvements by virtue of continued weight loss. Furthermore, even if it were possible to match caloric intake with RYGB for a much longer period, there may be changes in nutrient absorption (i.e., amino acids, fatty acids) and bile acid secretion specific to the bypass procedure that could affect clinical outcome independent of weight loss and calorie restriction.
In summary, our data suggest that RYGB is not superior to VLCD with regard to early changes in β-cell function in obese subjects with T2DM when tested in the absence of an enteral nutrient stimulus. Observing glucostatic parameters in the longer term would be useful to investigate the durability of these changes. Certainly, incretins play a role in improving glucose homeostasis after RYGB, but there are likely nonenteral mechanisms associated with glycemic control in the short and longer term that result from calorie restriction. Further study is required in order to define preoperative characteristics that could better predict an individual's response to surgical interventions for the treatment of type 2 diabetes.
Discussion
Contrary to our expectations, this study demonstrates that RYGB in subjects with T2DM does not result in greater improvement in β-cell function compared with equivalent weight loss achieved over the same time period by VLCD. As evaluated by fsIVGTT, both groups demonstrated significant and similar increases in acute insulin secretion and insulin sensitivity. We previously demonstrated a greater improvement in DI in subjects with T2DM after RYGB compared with individuals who achieved equivalent weight loss on an outpatient low-calorie diet. However, the degree to which calories were restricted was not equivalent to the RYGB, and therefore, the rate of weight loss for the RYGB was greater. Based on studies of caloric restriction, the degree of caloric restriction is a major factor that exerts a glucose-lowering effect independent from the amount of weight loss. This is the first study of individuals with T2DM that compares RYGB to a diet group matched for both the amount and rate of weight loss. Others have evaluated β-cell function after surgery, but there has not been a simulation of a gastric bypass diet without the surgery in patients with T2DM. Isbell et al., for example, evaluated RYGB with matched obese subjects on a VLCD 2–7 days after intervention. There was in both groups a 25% improvement in insulin sensitivity as quantified by HOMA-IR, but a significant decrease in fasting glucose levels was demonstrated in the diet group only. These results are somewhat difficult to interpret given that the groups were a mix of subjects with and without T2DM, and there may be a confounding effect of residual inflammation in this very early postoperative state.
Differences in the methods used to assess β-cell function, characteristics of the patient population, and differences in operative procedures among surgeons also make it difficult to compare studies with sometimes seemingly conflicting outcomes. For example, with use of the hyperglycemic clamp it was found that 4 weeks after RYGB there was an increase in insulin sensitivity, but DI remained unchanged. An explanation for this finding in comparison with our study is that metabolic testing was carried out when subjects were consuming an 800-calorie liquid diet prior to surgery. It is also unclear whether diabetes medications, including metformin and thiazolidinediones, were held prior to testing. Similar to our results, Lin et al. showed that DI improved 23-fold (from 23 to 403) 1 month after RYGB. Nannipieri et al. also showed that β-cell glucose sensitivity improved (but did not normalize) 45 days after RYGB in patients with T2DM. Interestingly, insulin sensitivity but not β-cell glucose sensitivity improved in proportion to weight loss. Certainly, duration of diabetes also influences β-cell function. Lim et al. studied patients with T2DM and restricted caloric intake to 600 kcal/day for 8 weeks and demonstrated not just improvement but normalization of both β-cell function and hepatic insulin sensitivity. The duration of diabetes, however, was <4 years, which limits comparison with our study cohort with a longer duration of diabetes. In the absence of a gold standard for assessing β-cell function and the inclusion of a diverse population, comparison of different studies is indeed problematic.
Similar to dietary interventions, there is considerable variability in the glycemic response after RYGB. From a clinical perspective, it would be helpful to predict the glycemic response to surgery from known or easily measureable baseline characteristics. In retrospective studies, it appears that patients with a longer history of diabetes or on insulin therapy were less likely to achieve euglycemia off antihyperglycemic medications. Magnitude of weight loss has been associated with better glycemic outcome. From our data, it appears that duration of T2DM, baseline β-cell function, or HbA1c and the amount of weight loss did not correlate with changes in DI. However, in this short-term study we are unable to assess the maximal improvement in glycemic parameters, as it has been shown that Si continues to improve with further weight loss between 6 and 24 months after surgery. Likewise, we cannot predict the durability of these changes, as weight tends to increase with time, and deterioration of glycemic control, even with maintenance of weight loss, has been observed.
It has been well documented that RYGB produces profound postprandial stimulation of GLP-1 secretion and a greater incretin effect than observed with diet-induced weight loss. RYGB also alters glucose absorption, causing a marked increase in the early rate of appearance of ingested glucose into the systemic circulation that would be expected to alter the pattern of insulin secretion. For these reasons, we evaluated β-cell function in the absence of enteral nutrient passage and without the confounding effect of altered glucose kinetics. Although gut hormones were not measured during the fsIVGTT, others have demonstrated that there is negligible change in GLP-1 concentrations upon intravenous glucose infusion. Thus, the findings in our study suggest that there are changes in β-cell function, independent of glucose absorption from the gut and the incretin effect, that occur to a similar extent after RYGB and VLCD. Because of the incretin effect, however, we did expect that overall glycemic control would improve to a greater extent after RYGB. Contrary to our expectations, decreases in fructosamine levels from baseline were of similar magnitude between RYGB and VLCD. It is likely that the greater incretin effect noted after larger meal challenges in RYGB patients may not have provided much advantage in the setting of very small meals and less demand for prandial insulin secretion. In this vein, it has been noted that β-cell function and clinical outcome after RYGB are better than equivalent weight loss achieved by LCD; however, the caloric intake and duration of the weight loss periods were greater in the diet groups of both studies.
Another component of insulin and glucose metabolism is insulin clearance, which has been demonstrated to increase after 11% weight loss on a 500–600 kcal/day diet. We did not directly measure insulin clearance, but given that fasting insulin was greater in the RYGB group at baseline while C-peptide levels were nearly identical it appears that insulin clearance may have been greater in the VLCD group. It is unclear why there was a difference, since groups were fairly well matched for some of the factors that are associated with clearance such as Si, AIR, fasting glucose, and BMI. Unfortunately, we do not have measurements of waist circumference or visceral adipose tissue that could conceivably be different in this relatively small sample size and might affect insulin clearance. Nevertheless, the change in the insulin–to–C-peptide ratio was nearly identical between groups, suggesting that the interventions do not differentially affect clearance.
Limitations of this study are the nonrandomized intervention scheme, as well as the relatively small sample size. The study was designed to detect a 1.3-SD difference in change in DI between groups. Smaller differences may not have been detected, but the clinical significance of smaller differences is somewhat questionable. It is possible that with more subjects changes in some of the secondary end points would reach statistical significance, such as the increase in adiponectin in the VLCD group and decrease in fructosamine after RYGB. Although the groups were matched for duration of diabetes, this was a self-reported time of diagnosis that likely varies from the actual onset of the disease. Another factor to consider is that acute inflammation, even with a minimally invasive laparoscopic procedure, could have increased insulin resistance blunting the response of the RYGB patients. We did not perform detailed assessment of residual inflammation; however, CRP levels were not statistically different between both groups. Physical activity levels were not monitored, although given the inpatient setting we were able to limit the activity in the VLCD group to that expected of postsurgical patients. The RYGB group was not studied under inpatient observation because the surgical procedure itself imposes limitation of caloric intake to ~500 kcal/day in the first 2–3 weeks after surgery.
These data indicate that the changes in glucose homeostasis that occur within 2–3 weeks after RYGB are primarily due to very low energy intake as opposed to specific surgically-induced hormonal effects. Clearly, this does not mean that RYGB is not more beneficial in the long term, since the degree of caloric restriction required to mimic surgical results cannot be maintained in most individuals. As in our prior study, even when the diet was 800 kcal/day instead of 500 kcal/day less improvement in β-cell function was noted. It would be expected that in the longer term, the average blood glucose would begin to increase in the VLCD group as caloric intake was liberalized even if the weight loss were maintained. The RYGB group may maintain or further their improvements by virtue of continued weight loss. Furthermore, even if it were possible to match caloric intake with RYGB for a much longer period, there may be changes in nutrient absorption (i.e., amino acids, fatty acids) and bile acid secretion specific to the bypass procedure that could affect clinical outcome independent of weight loss and calorie restriction.
In summary, our data suggest that RYGB is not superior to VLCD with regard to early changes in β-cell function in obese subjects with T2DM when tested in the absence of an enteral nutrient stimulus. Observing glucostatic parameters in the longer term would be useful to investigate the durability of these changes. Certainly, incretins play a role in improving glucose homeostasis after RYGB, but there are likely nonenteral mechanisms associated with glycemic control in the short and longer term that result from calorie restriction. Further study is required in order to define preoperative characteristics that could better predict an individual's response to surgical interventions for the treatment of type 2 diabetes.
