It is widely accepted that T2DM is a combination of dysfunctional insulin secretion by β-cells and insulin sensitivity (peripheral resistance) that results in impaired glucose homeostasis. Indeed, it is possible that a patient with T2DM possesses very robust β-cell function to compensate for impaired peripheral resistance or has combined attenuations in β-cell function and insulin sensitivity. Unfortunately, most patients with T2DM presenting for weight loss surgery have no information on the phenotype they possess.
In this study, we observed that patients with T2DM undergoing RYGB exhibit and early restoration of pancreatic β-cell function measured by AIRg at 1 month. There is a second phase of improved insulin-glucose metabolism as exhibited by profound improvements in peripheral Si at 6 months, which also led to an improved DI. However, although the amount of weight loss after AB was similar to RYGB, there is never an improvement observed in AIRg in patients undergoing AB, but only a modest improvement in insulin sensitivity at 6 months, which is presumably from weight loss.
Data for normoglycemic patients undergoing both weight loss procedures were also presented to give context to the data observed in patients with diabetes. Although it is beyond the scope of this discussion, it is readily evident that morbidly obese patients without diabetes probably maintain normoglycemia by high-output insulin secretion, and once peripheral insulin sensitivity improves after weight loss, insulin secretion is reduced below baseline levels. Although there was only one patient with diabetes who had AB, the data found in normoglycemic patients undergoing AB demonstrate that this procedure has virtually no effect on β-cell function. These data are also novel in that there are no reports to our knowledge using IVGTT to follow patients undergoing AB for weight loss.
It is not clear how the RYGB augments β-cell function so soon after surgery, but several plausible explanations have been proposed. Several experimental studies have shown that ghrelin inhibits insulin release in mice, rats, and humans.10
We and others have shown early decreases in the “hunger” hormone ghrelin after gastric bypass.11
Blockade of ghrelin signaling markedly increase glucose-induced insulin release in vitro. In high-fat diet-induced mildly obese mice, ghrelin deficiency enhances insulin release and prevents impaired glucose tolerance.12
If these observations are validated, it is potentially feasible to manipulate ghrelin signaling as a treatment for T2DM.
Another plausible and popular explanation is that the intestinal rearrangement sending nutrients rapidly to the distal small bowel induces a significant rise in GLP-1.13
Other investigators administering GLP-1 intravenously demonstrated a dose-dependent rise in insulin secretion as well.14
Insulin secretion by the β-cell undoubtedly occurs by multiple hormone stimuli and the mechanisms are incompletely understood.
There is also molecular explanation for the reversal of peripheral insulin resistance after weight loss.15
Bikman and colleagues demonstrated how muscles become desensitized to insulin transport by inappropriate phosphorylation of the subcellular insulin-receptor substrate-1 (by the inhibitor of kappa B kinase β, which commonly accumulates with high adipose volumes.
In summary, this study showed that weight loss between the patients undergoing AB and those undergoing RYGB follow the same early trends, but RYGB clearly induces an acute insulin response from β-cells early postoperatively, whereas AB does not. With this information, it is possible that patients with T2DM with intact or robust β-cell function should be offered a restrictive operation such as the sleeve gastrectomy or an adjustable gastric band as a way to increase insulin sensitivity and thereby increase the DI. In patients with attenuated β-cell function, gastric bypass may offer the more expeditious route to T2DM reversal. In essence, the decision to choose a restrictive procedure or a combined restrictive-malabsorptive procedure can potentially be made based on a patient’s insulin secretion and peripheral resistance profile. Although such a concept is ideal, there are other complementary biomarkers that predict resolution of T2DM such as inflammatory mediators16
Therefore, the ability to predict a patient’s response from weight loss surgery and choosing the ideal treatment will most likely rely on an aggregate of related physiological profiles rather than independent parameters.