Morbid obesity is associated with insulin resistance and marked insulin hypersecretion, but the function of β
-cell is preserved. On the other hand, diabetes and impaired glucose tolerance are characterized by a progressive loss of β
-cell glucose sensitivity, independent of insulin resistance. Bariatric surgery leads to an improvement in insulin sensitivity and decrease of insulin secretion [23
]. The duration and severity of T2DM also appear to be key factors for its remission after bariatric surgery. Hall et al. showed that patients with a baseline HbA1c > 10% had a 50% rate of remission, after RYGBP, compared to 77.3% with an HbA1c of 6.5–7.9%. The mean duration of T2DM preoperatively was 5.5 ± 7 years. A preoperative duration of T2DM > 10 years was shown to significantly reduce the chances of remission. The authors concluded that a shorter period of time with diabetes and better glycemic control before surgery may result in a better remission rate for T2DM, suggesting that bariatric surgery should be performed earlier in diabetic patients. Obese T2DM patients undergoing RYGB were more likely to achieve full remission if duration of disease was inferior to 5 years and/or glycemia was controlled only through diet). The remission rate in patients with T2DM for ≤5 years was 95% compared to 75% in patients who had diabetes for 6 to 10 years and 54% in those who had diabetes for more than 10 years (P
< 0.001) [13
A possible explanation for this observation is that the compensatory and inflammatory process of insulin resistance leads to the deterioration and loss of the pancreatic β
cells through increased apoptosis. However, there is a reversible component of β
cells deterioration, with weight loss improving β
cells responsiveness to glucose [24
]. The practice of early bariatric surgery before an irreversible β
cell failure could increase the probability of T2DM remission.
There have been many hypotheses concerning the mechanism of surgical resolution of diabetes. Weight loss, decreased caloric intake, malabsorption, the early delivery of nutrients to the distal small intestine, and the exclusion of the proximal small bowel have all been proposed as possible explanations. Moreover, euglycemia and normal insulin levels occur within days after surgery, long before any significant weight loss [26
In 2004, Rubino and Marescaux reported an experimental study that support the hypothesis that the bypass of duodenum and jejunum can control type 2 diabetes and directly and not secondarily to weight loss or treatment of obesity. A gastrojejunal bypass (GJB) with preservation of an intact gastric volume was performed in 10- to 12-week-old Goto-Kakizaki rats, a spontaneous nonobese model of type 2 diabetes. GJB significantly improved glycemic control. After surgery blood glucose was controlled better than after greater weight loss from food restriction or rosiglitazone therapy. These effects were not seen in the sham-operated animals despite similar operative time, same postoperative food intake rates, and no significant difference in weight gain profile [27
Two hypotheses have been proposed to explain the RYGB effect on the glucose homeostasis. The “hindgut hypothesis” holds that diabetes control results from the expedited delivery of nutrient chime to the distal intestine, enhancing a physiologic signal that improves glucose metabolism. The incretin glucagon-like peptide-1 (GLP-1) is implicated in this hypothesis as the L cells located primarily in the distal ileum and colon secrete it. GLP-1 induces insulin secretion in response to glucose and satiety, likely through action on hypothalamic and vagal receptors. Early stimulation of these cells after RYGB/BPD/DS could result in increased GLP-1 production and consequent enhanced insulin secretion. The role of GLP-1 on diabetes remission seems to be confirmed by the “ileal interposition” that causes an accelerate delivery of nutrients to the GLP-1 producing areas of intestine. Ileal interposition effectively improves glucose tolerance and it is associated with dramatically elevated ileal hormones, GLP-1, PYY, and glucagon in rats. Early results of ileal interposition on diabetic human patients seem to confirm the experimental data [22
The alternative hypothesis (“foregut hypothesis”) is that the exclusion of the duodenum and proximal jejunum from the transit of nutrients may prevent secretion of a putative signal that promotes insulin resistance and type 2 diabetes. In a rat model, in 2006, Rubino et al. demonstrated that whereas diabetes was controlled excluding the passage of nutrient through the proximal intestine (DJB) the disease would return when that passage was surgically restored. These findings suggest that a proximal intestinal bypass could be considered for diabetes treatment and that potentially undiscovered factors from the proximal bowel might contribute to the pathophysiology of type 2 diabetes. Both human and animal studies show that the prevention of duodenal passage of nutrients improves glucose tolerance only in diabetic patients. This indicates a mechanism likely attributable to aberrant gastrointestinal signalling unique to the diabetic state. This signalling is possibly removed when the proximal intestine is bypassed [29
The anti-incretin theory proposes that the proximal small bowel produces a hormone or a group of factors, to balance the action of incretin hormones. A dysfunction in the incretin/anti-incretin system, for example the overproduction of anti-incretins, would result in decreased insulin secretion, decreased insulin action (insulin resistance) and a depletion in β
-cell mass, leading to type 2 diabetes. Correction of this dysfunction in the anti-incretin system by duodenal exclusion may explain the resolution of type 2 diabetes after bypass surgery () [29
Several studies have also demonstrated a decrease in plasma levels of leptin and insulin, and increased levels of adiponectin and peptide YY3-36 after RYGB and BPD, confirming an endocrine effect of these operations. Analysing 90 morbidly obese patients subjected to laparoscopic bariatric surgery, it was observed the resolution of 91.7% of diabetes, 87.3% of impaired glucose tolerance and 100% of impaired fasting glucose. The authors demonstrated an increase of adiponectin plasma levels and the improvement of insulin-sensitivity measured by the euglycemic hyperinsulinemic clamp technique (M index) [30
Sleeve gastrectomy (SG) has recently emerged as a new “food limiting” bariatric procedure. Data from case series have shown that SG is associated with a high rate of resolution of type 2 diabetes and other obesity-associated comorbidities such as hypertension, hyperlipidemia, and sleep apnea. Vidal et al. showed that at 12 months after surgery, SG is as effective as RYGB (84.6% in both groups) in inducing remission of type 2 diabetes and the metabolic syndrome [31
]. In a prospective double-blind study, Karamanakos compares the effects of RYGB with SG. The results showed that PYY levels increased similarly after either procedure.
These data seem to suggest that SG is not a simple restrictive procedure but a hormonal mechanism involved in weight loss and diabetes remission. The markedly reduced ghrelin levels in addition to increased PYY levels after LSG are associated with greater appetite suppression and excess weight loss compared with LRYGB [33
] (). Peterli et al. analyzed the fasting and test meal-stimulated GLP-1, PYY, and ghrelin modifications after GBP and SG. A statistically significant reduction in fasting ghrelin concentrations was observed in both procedures. After a standard test meal, an early (1 week) significant increase in the GLP-1 and PYY area under the curve (AUC) and a significant decrease in the ghrelin AUC were reported in both procedures. The authors rejected the idea that the proximal small intestine mediates the improvement in glucose homeostasis after bariatric surgery [34
]. Recently, Pacheco et al. reported a restoration of the first phase of insulin secretion and improved insulin sensitivity in diabetic obese patients immediately after SG, before any food passage through the gastrointestinal tract, before any weight loss, related to ghrelin, GLP-1, and PYY hormonal changes neither meal- nor weight-change-related [35
]. Duration of the disease up to 10 years seems to be a major cut-off in the pathophysiological changes induced by SG.
Figure 8 Proposed model for mechanisms of T2DM resolution after bariatric surgery (simplified from ).