Diabetes is a worldwide health crisis that affects morbidity and mortality (1) where 90% of diabetics suffer from type 2 diabetes mellitus (T2DM) (2). Worse yet, the prevalence of T2DM has been dramatically growing (1, 3, 4). Diabetes is a major risk factor of hypertension, cardiovascular disease, renal disorders, stroke, and other diseases.

In recent years, bariatric surgeries have emerged as recommended treatment methods for obesity and T2DM. Bariatric procedures are considered more effective for T2DM resolution than conventional medical therapy, especially for refractory diabetics (5, 6); however, the precise mechanisms are not fully understood. Among the various hypotheses, gastrointestinal (GI) transit seems to play a role in the antidiabetic effect, but the conclusion is not solid. It has been hypothesized that hyperglycemic control after Roux-en-Y bypass (RYGB) is mediated by the time needed to empty nutrients from the stomach to the distal intestine (7, 8). Vertical sleeve gastrectomy (VSG) is being reconsidered not only a restrictive procedure but also as a promoter of GI motility that enhances glucagon-like peptide-1 (GLP-1) release (7. 9), in agreement with “hindgut hypothesis” (10). On the other side, studies in adjusted gastric banding (AGB) reported that AGB has no influence or even delays gastric emptying (11, 12). Some GI devices were also reported to decrease GI emptying although the bariatric effects are good (13).

In this controversial issue, studies involving GI emptying time changes after other bariatric or metabolic procedures such as ileal interposition (IT) are lacking. IT is also widely used in diabetic research, and the effect of IT surgery also supports the hindgut hypothesis (10, 14), as the anatomic structure after IT causes an earlier contact between luminal nutrients and the interposed distal gut. It is not clear whether the increased gut peptides after IT, however, are also attributed to faster chyme delivery. Decades ago, a study by Ohtani et al. (15) showed that IT (referred to as “ileojejunal transposition”) inhibits postprandial gastric emptying because of “ileal break”, without affecting intestinal transit in dogs. There have not been any other reports on the change of GI transit after IT. Moreover, the role of GI transit in diabetic control following IT remains unclear.

Here, we tested glucose indexes, insulin tolerance, and GLP-1 concentration, under different GI peristalsis conditions, to study the relationship between glucose homeostasis and changed GI transit, seeking to understand the role of GI transit in alleviating diabetes after IT, in Goto-Kakizaki (GK) rat model (16), the most widely used nonobese animal model of T2DM. The implications and limitations of the studies are enumerated.

Before operation, all rats had the same levels of body weight, food intake, serum total GLP-1, and acetaminophen. All procedures were successfully performed, and all rats survived till the scheduled time of termination.

Studies of IT have been performed in rats for over 30 years (20). In recent years, IT has also been used in patients, with satisfactory outcomes (21–23). Unlike RYGB and VSG, IT does not involve gastrectomy; i.e., it is a “pure” intestinal operation which is suitable for GI research. The hindgut hormones are considered vital mediators of diabetic control following IT (17). Although it is known that the rapid delivery of mixed chyme to transposed ileum promotes the secretion of hindgut hormones, the role of GI emptying in accelerating these hormones and alleviating hyperglycemia post-IT requires further investigations.

To minimize the impact of different body weight on blood glucose and focus on the weight loss independent mechanism (24), we utilized nonobese animal model, i.e., GK rats, for the study. GK diabetic rats are characterized by insulin resistance and insufficient pancreatic beta cell function, which can appropriately simulate human T2DM (18, 25, 26). Using GK rat model, our experiments illustrate the GI transit time to be suppressed after IT, and gastric emptying gradually recovered over time. This represents the first study of the relationship between GI emptying and diabetic control after IT.

Although it is believed that sustainable weight loss benefits diabetic alleviation (27), previous data on weight change after IT are not unified. Some literature (14, 28) shows that IT does not affect body weight, while some others (29, 30) found a decrease in weight gain in IT rats. The paradox may be explained by the differences of studied strains, housing environments, operative details, etc. In our study, IT induced reduction of body weight, albeit the amount of food intake was not different. A study by Gaitonde et al. (14) also revealed an unchanged level of food intake after IT. Given that IT does not reduce the absorption area of gut, one reasonable speculation is that IT surgery may augment energy expenditure (31), in agreement with some literature on RYGB (32, 33), resulting in disparity of body weight. Another plausible explanation is that metabolic surgery reprograms the whole-body metabolism to maintain a reduced body weight, rather than lowering caloric intake (34).

Based on our data, glucose tolerance and insulin resistance were both ameliorated after IT, suggesting improved glucose homeostasis. Similarly, Yan et al. (30) and Culnan et al. (35) came to the same conclusion in GK rats and Zucker fatty rats, respectively. We speculate the increased GLP-1 contributes to the remission of glycometabolism (consistent with the hindgut theory), as GLP-1 has effects in improving beta cell function, insulin secretion, and insulin sensitivity (36, 37). In addition, GLP-1 can slow down gastric emptying and intestinal transit (37). Confirmatory to these observations, the movements of both stomach and small intestine were decreased in our IT group. Obviously, the early exposure of chyme is due to the short pathway rather than a rapid transit.

The role of GI emptying and transit was studied at 10 weeks postoperatively. After using atropine in IT rats and metoclopramide in sham rats, it can be speculated that the GI transit of IT decreased while that of sham increased since GI emptying can be inhibited by atropine (7) and promoted by metoclopramide (38). As a result, GLP-1 secretion of the two groups became equalized after the administration of the pharmaceuticals. Consequently, the body weight became comparable, and the differences in glucose tolerance decreased. In other words, increase in GI transit in sham can also be helpful to ameliorate diabetes, while slowing down the GI movement after IT can deteriorate glycemic control. Diabetic rats were found to show gastric hypomotility (39). Furthermore, Bharucha et al. (40) indicated that delayed gastric emptying in diabetes can affect hyperglycemia, which is confirmative of our study. Taken together, the decrease of GI transit following IT may be the result or the negative feedback of increased hindgut hormones, rather than a favorable outcome of diabetic alleviation. The “earlier contact” caused by IT promotes GLP-1 secretion and further changes body weight, glycometabolism, etc., which can be partly blocked by slower GI transit.

One interesting finding is that at 8 weeks postoperatively, the gastric emptying in the IT group was accelerated as compared with postoperative week 4, but it did not lead to further improvement of glucose metabolism or significant increase of GLP-1. This suggests that the acceleration of gastric emptying is not the key factor in diabetic control after IT. Further studies are needed to shed additional light on this issue.

Our study has some limitations. First, we did not test GI motility by scintigraphy, which is more accurate than acetaminophen absorption test and dye measurement, because of the need for complex methodology. Second, the role of other hormones, the measurement of energy expenditure, and the influence of drugs under longer-term application need to be further investigated. Third, gastric emptying and GI transit rate of rats may be different from that of humans, and hence the findings need to be validated in larger animals before translation. Gender-based differences also need to be explored in the future.

In conclusion, IT reduced body weight and alleviated diabetes in GK rats. The increased secretion of GLP-1 may at least partly contribute to the remission of T2DM. However, the inhibition of GI emptying is likely to disable the hypoglycemic effect caused by IT, while the acceleration of GI transit seems advantageous to achieve euglycemia. Following IT, the alteration of GI transit seems secondary to the operation instead of the cause of hyperglycemic control.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

The animal study was reviewed and approved by the Institutional Animal Care and Use Committee of California Medical Innovations Institute.

YW, XG, and DS performed animal procedures and experiments and data collection. YW and GK designed the study. All authors participated in drafting the manuscript. All authors listed have made a substantial, direct, and intellectual contribution to the work and approved it for publication.

This work was supported by 3DT Holdings. The authors declare that 3DT Holdings was not involved in the study design, collection, analysis, interpretation of data, the writing of this article or the decision to submit it for publication.

GK is founder of 3DT Holdings.

The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest

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