Although individuals with obesity and Type 2 diabetes are insulin resistant, pancreatic β-cell failure is the core defect that distinguishes individuals who eventually develop diabetes. This process is known to occur well before the onset of hyperglycemia.

Although clinical trial data support the effectiveness of intensive lifestyle modification in delaying the onset of diabetes in obese subjects, less is known about the effects of, and mechanisms underlying, bariatric surgery, particularly gastric bypass surgery, on diabetes.

-Team@CMHF

Introduction

• The current pandemic of Type 2 diabetes and obesity has created an urgent need to identify effective therapeutic interventions targeting both of these chronic debilitating conditions.
• Obesity and diabetes are closely interrelated in that risk factors such as physical inactivity and poor diet lead to weight gain and precipitate insulin resistance in important insulin sensitive tissues, particularly skeletal muscle, liver and adipose tissue.
• It is known that obese and insulin-resistant diabetic patients have a positive energy balance, high fat and high carbohydrate intake, increased abdominal adipose tissue, elevated free fatty acids, increased secretory products of adipocytes mediating inflammation, including TNF-α and IL-6, and reduced secretion of adiponectin.
• These factors have been shown to be part of the underlying mechanisms of glucose intolerance and contribute to reduced skeletal muscle glucose disposal and increased hepatic glucose output.
• Although insulin resistance is common in obese patients, diabetes is not always present because the pancreas augments insulin production as a means to offset the severity of impaired insulin action.
• The transition from a mild state of insulin resistance to Type 2 diabetes is heralded by progressive pancreatic β-cell dysfunction and eventual failure to secrete adequate amounts of insulin; all of this occurs well before the inception of diabetes.
• In obese individuals with a familial tendency for Type 2 diabetes, impaired insulin secretion is documented early on in the spectrum of glucose tolerance.
• As fasting hyperglycemia develops, insulin secretion decreases progressively and in patients with fasting glucose levels of 180–200 mg/dl, there is an absolute deficiency of insulin.
• Some major non heritable factors implicated in β-cell failure, particularly in obesity, include elevated free fatty acids and inflammatory cytokines, termed as ‘lipotoxicity’, and incretin deficiency and/or resistance
• Modest weight loss of 5–10% bodyweight is known to improve diabetes by reducing insulin resistance in obese individuals.
• Gastric bypass surgery has a profound effect on metabolism and can induce remission of Type 2 diabetes defined by normal glycemic control without the need for diabetic medications.

Summary of Methods & Results

• Hofso et al. compared the effects of either lifestyle intervention or gastric bypass surgery on pancreatic β-cell function in subjects with morbid obesity (mean BMI 45.5 kg/m2) without known diabetes.
• At the time of baseline testing, some subjects were found to have either impaired fasting glucose, impaired glucose tolerance or diabetes.
• Subjects self-selected (thus not randomized) their treatment options: either Roux-en-Y gastric bypass (RYGB) surgery or lifestyle change.
• The lifestyle group engaged in a program of organized physical activity and psychosocial intervention, with inpatient stays totaling 7 weeks. A standard glucose tolerance test was performed before and at 1 year of follow-up.
• Insulin sensitivity was assessed by the homeostatic model assessment and insulin secretion was measured by the insulinogenic index and the Stumvoll first-phase index during a standard oral glucose tolerance test.
• β-cell function was determined from the disposition index and the proinsulin/insulin ratio.
• Mean weight loss following gastric bypass was 30%, while it was 9% in the lifestyle group.
• Glucose intolerance was resolved in all patients who underwent RYGB and in 41% of those who followed the lifestyle intervention.
• However, it is noteworthy that post-challenge hypoglycemia was significantly more prevalent after RYGB.
• Insulin sensitivity was significantly improved after both interventions, but the magnitude of improvement was greater after surgery.
• Overall insulin secretion was reduced after both interventions, but there was an increase in the early-phase insulin secretion after surgery.

Discussion of Significance of Results

• The main strengths of the study include the controlled design and the intensity of the lifestyle approach.
• Previous studies of bariatric surgery for diabetes have been primarily observational, with a lack of appropriate control groups that encompass nonsurgical/medical weight loss.
• However, a major weakness when comparing two groups that are not randomized is that differences in baseline characteristics may account for different outcomes.
• For example, the surgical group was substantially younger and heavier than the lifestyle group.
• However, despite the difference in baseline characteristics, the prevalence of glucose intolerance and baseline levels of insulin sensitivity and secretion were similar between the two groups.
• A second weakness pertains to the failure to examine the incretin hormone hypothesis, which is considered an important mechanism underlying improvement in β-cell function, particularly after obesity surgery.
• Other weaknesses include the use of oral glucose tolerance test-derived indices for insulin sensitivity and β-cell function, since these have not been validated for bariatric surgery, the lack of stratification and separate analysis of normal glucose-tolerant, impaired glucose-tolerant and Type 2 diabetic patients and the inclusion of primarily Caucasian subjects.
• Surgery resulted in a threefold greater weight loss and a 1.5-fold greater improvement in insulin sensitivity as compared with the lifestyle intervention.
• The data reported by Hofso and colleagues is consistent with these studies and is supportive of previously published work from our group in which the effects of gastric bypass and gastric restrictive surgery was examined in patients with Type 2 diabetes.

Expert Commentary

• The twofold or greater increase in the disposition index in normal glucose-tolerant and abnormal glucose-tolerant individuals noted by Hofso et al. following gastric bypass surgery is of tremendous scientific interest and helps to explain the restoration of glucose homeostasis in diabetes.
• The timing of improved glycemic control following bariatric surgery is important.
• In most cases, a dramatic decrease in fasting glucose levels is seen within days to weeks following surgery, before major weight loss, but in the setting of enforced caloric restriction.
• Patients who undergo malabsorptive procedures improve sooner and maintain glucose control for longer periods than do patients treated by purely restrictive procedures.
• However, compared with patients following a very low calorie diet who achieve similar weight loss, patients who undergo RYGB experience increased glucose-induced secretion of insulin, c-peptide, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) consistent with an incretin effect.
• Greater improvement is seen in fasting and postprandial glucose levels following RYGB.
• Exercise training has been shown to improve insulin sensitivity independent of weight loss.
• These effects are primarily due to improved insulin action in skeletal muscle, leading to increased glucose and lipid oxidation, as well as effects independent of insulin.
• In addition, some studies have found elevated insulin responses to an oral glucose load after caloric restriction and exercise-induced weight loss.
• Following a moderate-to-high-intensity 12-week aerobic exercise program, older obese normal glucose tolerant subjects demonstrated marked improvements in insulin sensitivity and a reduction in fasting and postprandial hyperinsulinemia, which was associated with a decrease in GIP secretion.
• By contrast, Type 2 diabetic individuals showed increases in both insulin secretion and the disposition index. These changes directly corresponded to increased GIP secretion.
• It is noteworthy that these subjects only had a modest weight loss of approximately 5%, similar to levels observed in the study by Hofso.
• Alterations in dietary composition also have profound effects on β-cell function.
• Studies was done in older obese prediabetic individuals participating in a moderate-to-high-intensity 12-week aerobic exercise program in combination with isocaloric diets consisting of either high- or low-glycemic index carbohydrates.
• Both groups lost approximately 9% bodyweight and had equal improvements in insulin sensitivity and basal insulin secretion rates (ISR), but only the low-glycemic diet group reduced glucose-stimulated ISR, which was associated with a decrease in glucose-stimulated GIP secretion.
• After correction for improved insulin sensitivity, oral glucose-induced ISR was not different from preintervention in the low-glycemic diet group, while it was increased in the high-glycemic diet group, indicating further β-cell dysfunction.
• Thus, diet alone may have profound effects on β-cell function and incretin secretion.
• Considering the findings of these studies, it is evident that incretin hormones play a pivotal role in lifestyle-induced changes in glucose metabolism and that these changes differ based upon where an individual is on the β-cell dysfunction spectrum.
• Besides the effect on insulin secretion, incretin hormones induce satiety which may account for weight loss or maintenance of weight loss following lifestyle interventions in individuals with Type 2 diabetes and may further decrease lipotoxicity, leading to improvements in insulin sensitivity.
• Alternatively, in nondiabetic or prediabetic populations, lifestyle-induced reductions in incretin hormones may decrease β-cell secretion independent of weight loss.
• Thus weight loss alone improves the pathophysiology of Type 2 diabetes and may reverse it in certain clinical situations.

Five-year View

• Future research in this area will require randomized controlled trials examining the effects of intensive lifestyle modification versus various bariatric procedures on clinical outcomes in patients with Type 2 diabetes in the setting of morbid and modest obesity.
• Given the potential role of the intestine in treating Type 2 diabetes, future studies will target manipulations (surgical and/or biochemical via pharmacotherapy and lifestyle modifications) of intestinal biology to reverse pancreatic β-cell dysfunction, insulin resistance and cardiovascular risk associated with diabetes.
• Investigations into less invasive and safer methods for weight loss that achieve similar efficacy and durability following bariatric surgery are underway.
• Finally, consideration must be given to developing new drugs that mimic the effects of bariatric surgery and produce durable weight loss and remission of Type 2 diabetes.

For further reading log on to

http://www.medscape.com/viewarticle/746806?src=mp&spon=34