Weight Loss as a Cure for Type 2 Diabetes

Fact or Fantasy?

Sangeeta R Kashyap; Emily S Louis; John P Kirwan


Expert Rev Endocrinol Metab. 2011;6(4):557-561. 

In This Article

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.[10] 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.[9,15] Persistent cases of diabetes after this initial period gradually improve in parallel with weight loss.[16] 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.[15] When we studied glucose regulation in morbidly obese patients with Type 2 diabetes following similar amounts of weight loss related to enforced caloric restriction at 1 and 4 weeks following gastric restrictive (sleeve gastrectomy and gastric banding) versus RYGB procedures, we also noted a greater improvement in fasting and postprandial glucose levels following RYGB.[14] We attributed this to enhanced insulin secretion and β-cell responsiveness. Importantly, we observed this effect in response to a mixed meal, but the effect was not evident during intravenous glucose administration, highlighting a potent and important incretin effect. A greater improvement in insulin sensitivity during glucose infusion was also noted acutely after RYGB but not after gastric restrictive procedures. The incretin effect is characterized by robust increases in GLP-1 and either no change or increases in GIP levels.[14,17,18] In subjects with profound hypoglycemia and neuroglycopenia following RYGB, Goldfine et al. observed markedly higher postprandial insulin and GLP-1 levels as compared with those without hypoglycemia following RYGB.[19] Collectively, these data provide insights into the metabolic effects of RYGB to increase insulin sensitivity and preserve β-cell function, and to enhance insulin secretion through an incretin-mediated mechanism. Whether these effects, particularly hypoglycemia following RYGB, are specific to increased GLP-1 or GIP levels is currently under investigation.

Modest improvements in β-cell function following lifestyle intervention as documented by Hofso et al.[10] are consistent with a number of other studies,[20–23] as well as our own.[24–27] Exercise training has been shown to improve insulin sensitivity independent of weight loss.[23] 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. Dela et al.[21] and others[20,22,23] have provided strong evidence of exercise training-induced increases in β-cell function in response to intravenous glucose in Type 2 diabetic and obese subjects. In addition, some studies have found elevated insulin responses to an oral glucose load after caloric restriction and exercise-induced weight loss and, more recently, we demonstrated a possible incretin effect related to GIP that may contribute to increased insulin secretion following a hypocaloric diet and exercise training intervention.[27] 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. We studied 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.[26] 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. This 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.

In summary, weight loss alone improves the pathophysiology of Type 2 diabetes and may reverse it in certain clinical situations. As shown in Figure 1, exercise and gastric bypass surgery have weight-independent effects on insulin sensitivity and incretin stimulation, which collectively work to reverse β-cell dysfunction and restore normal glucose regulation.


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