J Diabetes Res. 2015;2015:490365. doi: 10.1155/2015/490365.

Ileal interposition in rats with experimental type 2-like diabetes improves glycemic control independently of glucose absorption.

Jurowich CF, Otto C, Reddy Rikkala P, Wagner N, Vrhovac I, Saboli Germer CT, Koepsell H.

Department of General-, Visceral-, Vascular- and Paediatric Surgery, University Hospital of Würzburg, Oberdürrbacher Str. 6, 97080 Würzburg, Germany

 

Abstract

Bariatric operations in obese patients with type 2 diabetes often improve diabetes before weight loss is observed. In patients mainly Roux-en-Y gastric bypass with partial stomach resection is performed. Duodeno-jejunal bypass (DJB) and ileal interposition (IIP) are employed in animal experiments. Due to increased glucose exposition of L-cells located in distal ileum, all bariatric surgery procedures lead to higher secretion of antidiabetic glucagon like peptide 1 (GLP-1) after glucose gavage. After DJB also downregulation of Na+-D-glucose cotransporter SGLT1 was observed. This suggested a direct contribution of decreased glucose absorption to the antidiabetic effect of bariatric surgery. To investigate whether glucose absorption is also decreased after IIP, we induced diabetes with decreased glucose tolerance and insulin sensitivity in male rats and investigated effects of IIP on diabetes and SGLT1. After IIP, we observed weight-independent improvement of glucose tolerance, increased insulin sensitivity and increased plasma GLP-1 after glucose gavage. The interposed ileum was increased in diameter, showed increased length of villi, hyperplasia of the epithelial layer, and increased number of L-cells. The amount of SGLT1 mediated glucose uptake in interposed ileum was increased 2-fold reaching the same level as in jejunum. Thus, improvement of glycemic control by bariatric surgery does not require decreased glucose absorption.

PMID: 26185767

 

Supplement:

Morbid obesity is a worldwide health problem. It is often associated with diabetes mellitus type 2 which causes further diseases such as myocardial infarction, apoplectic seizure, diabetic nephropathy, and diabetic retinopathy. Bariatric surgery has proved to be the most effective long-term treatment for morbid obesity. (1) Whereas reduction of body weight is observed several months after bariatric surgery, symptoms of diabetes type 2 are improved several days after surgery. (2) In patients and experimental animals different bariatric surgery procedures are performed. The most popular procedure performed in patients is the Roux-en-Y-gastic biliary bypass (RYGB) in which part of the stomach is removed and the foregut (duodenum and proximal part of jejunum) is bypassed. Duodenal-jejunal bypass (DJB) and ileal interposition (IIP) are bariatric surgery procedures that have been well characterized in experimental animals (Figure 1). In DJB the foregut is bypassed whereas in IIP the distal part part of the ileum is interposed into the proximal part of the jejunum. In the present study, effects of DJB and IIP on glucose uptake and glucose metabolism are compared.

Fig_1

Figure 1. Illustrations of the normal gut, duodeno-jejunal bypass and ileal interposition. The abundance of the Na+-D-glucose cotransporter SGLT1 which mediates the rate limiting step in glucose absorption, is indicated by the strength of the red lines.

 

To understand the therapeutic effects of bariatric surgery procedures it must be known that the gut also regulates energy balance and metabolism in response to ingested nutrients. (3) This regulation involves recruitment of nutrient transporters into the absorptive surface, secretion of enterohormons which control glucose homeostasis and metabolism, and activation of enteric nerves that regulate gut motility and provide signals for central control of food intake and energy consumption.

Previous research studies have shown that RYGB and DJB reduce food intake and that RYGB, DJB and IIP increase secretion of enterohormons including glucagon-like peptide 1 (GLP-1). GLP-1 is critically involved in regulation of blood glucose. It is secreted by L-cells which are located mostly in the distal ileum (Figure 1). Glucose is an important stimulant for GLP-1 secretion. Reduction of glucose absorption in duodenum, jejunum and proximal ileum increases the concentration of glucose in the distal ileum leading to an increased secretion of GLP-1. GLP-1 enters the portal vein and stimulates the secretion of insulin by beta-cells in the pancreas. Insulin reduces the glucose concentration in the blood.

In the present investigation we compared effects of IIP with DJB surgery on experimental type 2 like diabetes of rats. We induced the diabetes by feeding the rats with high fat diet (HFD) and destroying part of the beta cells by streptozotocin (HFD-STZ-diabetes). (4) We observed key symptoms of diabetes mellitus type 2 which comprise increased blood glucose of fed animals, a pathological oral glucose tolerance test (OGTT) (upper left of Figure 2), and a decreased insulin sensitivity. For the OGTT a concentrated glucose solution is applied into the stomach of starved animals and blood glucose concentrations are measured after different times intervals. Previously we observed that the symptoms of diabetes in rats with HFD-STZ-diabetes were improved three weeks after DJB surgery (Figure 2). (5) In this study we also observed that after DJB the Na+-D-glucose cotransporter SGLT1 which is rate limiting for glucose absorption (6) was reduced in duodenum and jejunum (Figure 1). We discussed whether the improvement in OGTT after DJB is due to an increased glucose-dependent GLP‑1 secretion because more glucose reaches the distal ileum, whether it is due to the decreased glucose absorption in remaining alimentary path, or whether both mechanisms contribute to the therapeutic effect.

 

Fig_2

Figure 2. Effects of duodenal-jejunal bypass and ileal interposition surgery on oral glucose tolerance test in rats with experimental diabetes. Oral glucose tolerance tests were performed in nondiabetic rats on high fat diet (control), in rats with experimental diabetes (HFD-STZ-diabetes), in rats with HFDZ-STZ-diabetes after duodenal-jejunal bypass, and in in rats with HFDZ-STZ-diabetes after ileal interposition. Blood glucose concentrations after application of glucose by oral gavage are shown for indicated time points.

 

Employing ileal interposition (IIP), a bariatric surgery procedure in which the length of the alimentary path is not changed, we wanted to clarify whether a decrease of glucose ab­sorption in small intestine contributes to the antidiabetic effects of bariatric surgery. We performed IIP in rats with HDFD-STZ-diabetes (Figure 1), determined blood glucose levels, performed OGTTs, measured insulin sensitivities, determined glucose-dependent GLP-1 secretion, and analyzed SGLT1 mediated glucose uptake in small intestinal seg­ments. In addition, we investigated the morphology of the interposed ileum, the expression of SGLT1 in the absorptive surface of ileum, and determined the number of GLP-1 secreting L-cells. Consistent with previous reports, we observed that blood glucose levels were de­creased, OGTTs were improved (Figure 2), insulin sensitivity was reinforced, and glucose de­­­pendent GLP-1 secretion was increased. We obtained the unexpected result that the SGLT1 mediated glucose uptake in the interposed ileum was doubled com­pared to non-transposed ileum and reached the same level as in jejunum (indicated by strength of the red lines in Figures 1 and 3). Because glucose absorption in the proxi­mal gut was not impaired after IIP, the antidiabetic effect of IIP is independent of glucose ab­sorp­tion. We conclude that the increased GLP-1 secretion observed after IIP is the main rea­son for the antidiabetic effect of IIP. Because an increase of glucose dependent GLP-1 se­cre­ti­on is also observed after DJB and RYGB, effects on GLP-1 secretion rather than effects on glu­cose absorption are supposed to be responsible for the antidiabetic effects of bariatric surgery.

Comparing the morphology and expression of SGLT1 between the interposed ileal segment and normal non-transposed ileum we observed large differences (Figure 3). Whereas the length of the interposed segment was not changed the diameter was doubled and the absorptive surface containing SGLT1 increased fourfold. Because the density of SGLT1 at the surface was halved the total amount of SGLT1 at the absorptive surface was doubled. This is consistent with the observed doubled SGLT1 mediated glucose uptake. Interestingly, in the interposed ileum the total amount of L-cells was also increased. This increase is supposed to contribute to the observed increase of glucose dependent GLP-1 secretion after IIP.

 

 

Fig_3

Figure 3. Illustrations showing the morphological changes and the changes of SGLT1 expression after IIP. SGLT1 in the luminal brush-border membranes is indicated in red. L‑cells are indicated in blue.

 

In conclusion, the current study supports the central role of the increased GLP-1 secretion for antidiabetic effects of different bariatric surgery procedures. In bypass procedures like RYGB and DJB a decrease glucose absorption in the remaining alimentary path may contribute to the increased glucose dependent GLP-1 secretion.

 

References

  1. Christou NV, Sampalis JS, Liberman M, Look D, Auger S, McLean APH, MacLean LD 2004 Surgery decreases long-term mortality, morbidity, and health care use in morbidly obese patients. Annals of Surgery 240:416-424
  2. Cummings DE 2012 Metabolic surgery for type 2 diabetes. Nature Medicine18:656-658
  3. Murphy KG, Bloom SR 2006 Gut hormones and the regulation of energy homeostasis. Nature 444:854-859
  4. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P 2005 Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacological Research 52: 313-320, 2005.
  5. Jurowich CF, Rikkala PR, Thalheimer A, Wichelmann C, Seyfried F, Sander V, Kreissl M, Germer CT, Koepsell H, Otto C 2013 Duodenal-jejunal bypass improves glycemia and decreases SGLT1-mediated glucose absorption in rats with streptozotocin-induced type 2 diabetes. Annals of Surgery 258: 89-97
  6. Gorboulev V, Schürmann A, Vallon V, Kipp H, Jaschke A, Klessen D, Friedrich A, Scherneck S, Rieg T, Cunard R, Veyhl-Wichmann M, Srinivasan A, Balen D, Breljak D, Rexhepaj R, Parker HE, Gribble FM, Reimann F, Lang F, Wiese S, Sabolic I, Sendtner M, Koepsell H 2012 Na+-D-glucose cotransporter SGLT1 is pivotal for intestinal glucose absorption and glucose-dependent incretin secretion, Diabetes 61: 187-196

 

Acknowledgements: This study was supported by Grant KO 872/5-1 from the Deutsche Forschungsgemeinschaft to Hermann Koepsell.

Fig_4

From left to right: H. Koepsell, C. Otto, C.F. Jurowich

 

Contact: Hermann Koepsell, MD      

Professor emeritus

Department of Molecular

Plant Physiology and Biophysics

University of Würzburg

Julius-von- Sachs-Platz 2

97082 Würzburg

Hermann@Koepsell.de

 

 

 

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