Gastric Bypass Resets Basal Insulin Levels and Improves Insulin Resistance
Gastric Bypass Resets Basal Insulin Levels and Improves Insulin Resistance
October 13, 2010 (Washington, DC) — Gastric bypass surgery appears to reset basal insulin levels, but peak levels remain unchanged. And the reversal of type 2 diabetes mellitus (T2DM) is not associated with an increased ability to produce insulin, according to the results of a study presented here at the American College of Surgeons 96th Annual Clinical Congress.
To investigate a possible mechanism for the rapid and durable remission of T2DM seen after gastric bypass, lead investigator John Pender, IV, MD, assistant professor of surgery at the Brody School of Medicine of East Carolina University in Greenville, North Carolina, explained that the study used the mixed-meal test to include the effect of the gut and an intravenous glucose tolerance test to exclude the influence of the gut.
The subjects in the study were 16 white women, 18 to 60 years of age, with a body mass index (BMI) of 35 to 65 kg/m, who were able to withhold their antidiabetic medications for 48 hours before visits. Exclusion criteria included taking thiazolidinediones or having revision surgery. Control subjects were lean euglycemic white women with a BMI below 25 kg/m who were not pregnant, did not smoke, and who exercised less than 1 hour 3 times per week.
Prior to and at 1 week and 3 months after surgery, the investigators drew fasting blood samples and then administered a 150 kcal mixed-meal challenge to morbidly obese nondiabetic subjects with a BMI above 35 kg/m (obese group), morbidly obese diabetic subjects (diabetic group), and to lean control subjects (control group). They then took blood samples at intervals up to 3 hours. intravenous glucose tolerance tests were conducted under conditions of fasting, glucose infusion, and insulin infusion. The blood samples were analyzed for glucose, insulin, C-peptide, and incretins, among other substances.
Using the homeostatic model assessment (HOMA) as a measure of insulin resistance, the investigators showed that "insulin resistance decreased following surgery, as HOMA significantly declined in the diabetic group at 1 week and at 3 months postsurgery," Dr. Pender reported (P < .05). "At 3 months postsurgery, the diabetic group's HOMA was completely restored to the normal of the lean control group." The nondiabetic obese patients had HOMA scores of about 3 before surgery and of about 1 at 3 months after surgery. In contrast, the diabetic obese patients started with HOMA scores of about 10, but these went down to about 1.5 after surgery, which was within the range of the control subjects.
Insulin sensitivity (SI, a measure of peripheral insulin sensitivity) of the diabetic patients prior to surgery was significantly lower than in the control group. One week after surgery, SI increased (P < .05) in the diabetic group but did not approach normal control values, whereas the SI of the obese group did approach that of the control group.
Dr. Pender asked why insulin resistance improved but insulin sensitivity did not. So the researchers investigated the acute insulin response to glucose (AIRg), which was lower in the diabetic than in the obese group before surgery (P < .05). The AIRg was higher in the obese than in the control group. But at 3 months postsurgery, both groups had AIRg values close to those in the control group. "Although our obese and diabetic peak levels did not change, baseline insulin levels decreased, which has allowed for a more perfect response to the glucose challenge after gastric bypass surgery," Dr. Pender explained.
He concluded that there was no incretin that would drive up baseline insulin levels; these molecules alter the response of insulin secretion to glucose but not baseline values. Any signal that inhibited insulin secretion tended to decrease the response to glucose, but the data show an increased response to a meal on top of a decreased baseline insulin level.
Furthermore, Dr. Pender noted that baseline insulin levels did not rise in the presence of insulin resistance. Although the diabetic patients were still very insulin resistant 3 months after surgery, with an SI of only about 40%, compared with control subjects, their fasting values were almost the same as those in the control group. He said it is likely that glucose production determines the rate of fasting insulin secretion.
Dr. Pender said it was interesting that 2 patients with longstanding diabetes (about 12 years) did not respond to surgery with an improvement in SI, "which shows evidence of a pancreatic insufficiency."
He summarized the study results, saying that gastric bypass surgery resets basal insulin levels, but peak insulin levels remain unchanged. Therefore, the reversal of T2DM was not associated with an improvement in the ability to produce insulin, but was associated with an ability to control basal insulin levels and an appropriate response to meals. Insulin resistance, measured by HOMA, returned to normal, but insulin sensitivity, (SI) only partially normalized. These findings "suggest that insulin sensitivity in the liver rather than in the muscle may play an important role in determining basal insulin levels," Dr. Pender concluded.
These results elicited a question about the mechanism of the effect, similar to one posed in response to a presentation at the recent meeting of the European Association for the Study of Diabetes in Stockholm, Sweden, where Ele Ferrannini, MD, from the University of Pisa Medical School in Italy, asked a presenter whether the changes seen with Roux-en-Y gastric bypass were specifically the result of the surgery or if chronic caloric restriction could be the driver. Sayeed Ikramuddin, MD, director of bariatric surgery and professor of surgery at the University of Minnesota in Minneapolis, raised this same issue after Dr. Pender's talk.
Dr. Ikramuddin told Medscape Medical News that for many years it has been well known that when people are put on a low caloric diet as inpatients, they will have "a profound and rapid improvement in [glycated hemoglobin] and lipid parameters just a few days after instituting the diet. And if you take people and do a gastric bypass and match them by caloric intake, you'll find in 1 week a significant reduction in HOMA levels and a reduction in fasting plasma glucose with minimal weight loss." He said that although the mechanism is not well understood, caloric reduction, "however achieved, appears to be a very significant driver of fasting plasma insulin levels."
Dr. Ikramuddin said that gastric bypass surgery might exert its beneficial effects on diabetes in 2 ways. First, massive caloric restriction has the near-term effects he mentioned; in the longer term, weight loss itself dramatically improves insulin resistance. The role of incretins, he said, is that they help provide "a more profound and robust improvement in response to a mixed meal" through better insulin secretion.
He noted that T2DM is a disease of both insulin resistance and decreased insulin secretion, "and all the incretins in the world aren't going to help you . . . if your insulin resistance stays high."
Johnson & Johnson, Inc. funded the research. Dr. Pender has disclosed no relevant financial relationships. Dr. Ikramuddin reports receiving grant support for diabetes survey research from Covidien.
American College of Surgeons (ACS) 96th Annual Clinical Congress: Session SP01. Presented October 4, 2010.
October 13, 2010 (Washington, DC) — Gastric bypass surgery appears to reset basal insulin levels, but peak levels remain unchanged. And the reversal of type 2 diabetes mellitus (T2DM) is not associated with an increased ability to produce insulin, according to the results of a study presented here at the American College of Surgeons 96th Annual Clinical Congress.
To investigate a possible mechanism for the rapid and durable remission of T2DM seen after gastric bypass, lead investigator John Pender, IV, MD, assistant professor of surgery at the Brody School of Medicine of East Carolina University in Greenville, North Carolina, explained that the study used the mixed-meal test to include the effect of the gut and an intravenous glucose tolerance test to exclude the influence of the gut.
The subjects in the study were 16 white women, 18 to 60 years of age, with a body mass index (BMI) of 35 to 65 kg/m, who were able to withhold their antidiabetic medications for 48 hours before visits. Exclusion criteria included taking thiazolidinediones or having revision surgery. Control subjects were lean euglycemic white women with a BMI below 25 kg/m who were not pregnant, did not smoke, and who exercised less than 1 hour 3 times per week.
Prior to and at 1 week and 3 months after surgery, the investigators drew fasting blood samples and then administered a 150 kcal mixed-meal challenge to morbidly obese nondiabetic subjects with a BMI above 35 kg/m (obese group), morbidly obese diabetic subjects (diabetic group), and to lean control subjects (control group). They then took blood samples at intervals up to 3 hours. intravenous glucose tolerance tests were conducted under conditions of fasting, glucose infusion, and insulin infusion. The blood samples were analyzed for glucose, insulin, C-peptide, and incretins, among other substances.
Using the homeostatic model assessment (HOMA) as a measure of insulin resistance, the investigators showed that "insulin resistance decreased following surgery, as HOMA significantly declined in the diabetic group at 1 week and at 3 months postsurgery," Dr. Pender reported (P < .05). "At 3 months postsurgery, the diabetic group's HOMA was completely restored to the normal of the lean control group." The nondiabetic obese patients had HOMA scores of about 3 before surgery and of about 1 at 3 months after surgery. In contrast, the diabetic obese patients started with HOMA scores of about 10, but these went down to about 1.5 after surgery, which was within the range of the control subjects.
Insulin sensitivity (SI, a measure of peripheral insulin sensitivity) of the diabetic patients prior to surgery was significantly lower than in the control group. One week after surgery, SI increased (P < .05) in the diabetic group but did not approach normal control values, whereas the SI of the obese group did approach that of the control group.
Dr. Pender asked why insulin resistance improved but insulin sensitivity did not. So the researchers investigated the acute insulin response to glucose (AIRg), which was lower in the diabetic than in the obese group before surgery (P < .05). The AIRg was higher in the obese than in the control group. But at 3 months postsurgery, both groups had AIRg values close to those in the control group. "Although our obese and diabetic peak levels did not change, baseline insulin levels decreased, which has allowed for a more perfect response to the glucose challenge after gastric bypass surgery," Dr. Pender explained.
He concluded that there was no incretin that would drive up baseline insulin levels; these molecules alter the response of insulin secretion to glucose but not baseline values. Any signal that inhibited insulin secretion tended to decrease the response to glucose, but the data show an increased response to a meal on top of a decreased baseline insulin level.
Furthermore, Dr. Pender noted that baseline insulin levels did not rise in the presence of insulin resistance. Although the diabetic patients were still very insulin resistant 3 months after surgery, with an SI of only about 40%, compared with control subjects, their fasting values were almost the same as those in the control group. He said it is likely that glucose production determines the rate of fasting insulin secretion.
Dr. Pender said it was interesting that 2 patients with longstanding diabetes (about 12 years) did not respond to surgery with an improvement in SI, "which shows evidence of a pancreatic insufficiency."
He summarized the study results, saying that gastric bypass surgery resets basal insulin levels, but peak insulin levels remain unchanged. Therefore, the reversal of T2DM was not associated with an improvement in the ability to produce insulin, but was associated with an ability to control basal insulin levels and an appropriate response to meals. Insulin resistance, measured by HOMA, returned to normal, but insulin sensitivity, (SI) only partially normalized. These findings "suggest that insulin sensitivity in the liver rather than in the muscle may play an important role in determining basal insulin levels," Dr. Pender concluded.
These results elicited a question about the mechanism of the effect, similar to one posed in response to a presentation at the recent meeting of the European Association for the Study of Diabetes in Stockholm, Sweden, where Ele Ferrannini, MD, from the University of Pisa Medical School in Italy, asked a presenter whether the changes seen with Roux-en-Y gastric bypass were specifically the result of the surgery or if chronic caloric restriction could be the driver. Sayeed Ikramuddin, MD, director of bariatric surgery and professor of surgery at the University of Minnesota in Minneapolis, raised this same issue after Dr. Pender's talk.
Dr. Ikramuddin told Medscape Medical News that for many years it has been well known that when people are put on a low caloric diet as inpatients, they will have "a profound and rapid improvement in [glycated hemoglobin] and lipid parameters just a few days after instituting the diet. And if you take people and do a gastric bypass and match them by caloric intake, you'll find in 1 week a significant reduction in HOMA levels and a reduction in fasting plasma glucose with minimal weight loss." He said that although the mechanism is not well understood, caloric reduction, "however achieved, appears to be a very significant driver of fasting plasma insulin levels."
Dr. Ikramuddin said that gastric bypass surgery might exert its beneficial effects on diabetes in 2 ways. First, massive caloric restriction has the near-term effects he mentioned; in the longer term, weight loss itself dramatically improves insulin resistance. The role of incretins, he said, is that they help provide "a more profound and robust improvement in response to a mixed meal" through better insulin secretion.
He noted that T2DM is a disease of both insulin resistance and decreased insulin secretion, "and all the incretins in the world aren't going to help you . . . if your insulin resistance stays high."
Johnson & Johnson, Inc. funded the research. Dr. Pender has disclosed no relevant financial relationships. Dr. Ikramuddin reports receiving grant support for diabetes survey research from Covidien.
American College of Surgeons (ACS) 96th Annual Clinical Congress: Session SP01. Presented October 4, 2010.