Ann Surg Treat Res.  2021 Apr;100(4):218-227. 10.4174/astr.2021.100.4.218.

Beneficial effects of proximal intestinal bypass reconstruction on glucose metabolism in a type 2 diabetes animal model: a possible reconstruction strategy for diabetic gastric cancer patients

Affiliations
  • 1Department Surgery, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea
  • 2Gastric Cancer Center, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea

Abstract

Purpose
Proximal intestinal bypass (PIB), such as Billroth II or Roux-en-Y gastrojejunostomy after curative distal gastrectomy for gastric cancer induces beneficial effects on glycemic control in patients with type 2 diabetes. We aimed to characterize the long-term evolution of pancreatic beta cells and insulin signaling in target tissue after a PIB procedure.
Methods
Zucker diabetic fatty rats were randomly assigned to the PIB, sham-operated PIB pair-fed, and ad libitum fed groups. Oral glucose tolerance (GT) and plasma insulin levels were measured periodically at 16 weeks postoperatively. Histomorphometric analyses were performed to evaluate changes in islet architectures and intranuclear pancreatic duodenal homeobox 1 (PDX1) expression in beta cells. Insulin signaling changes in visceral adipocytes were measured by the phosphorylated Akt/Akt ratio.
Results
Contrary to the progressively deteriorating GT and plasma insulin levels in sham-operated animals, these were preserved in PIB animals (P < 0.01) at 16 weeks postoperatively. The proportion of the islets having asteroid-like expanding projection was higher in PIB animals than in sham-operated animals (P < 0.01). PIB animals had 3-fold wider fractional area of beta cells (P < 0.01) and 3-fold higher proportion of beta-cell nuclear PDX1 expression (P < 0.01) than shamoperated animals. PIB animals had significantly higher levels of Akt phosphorylation in the visceral adipocytes (P < 0.05). The PIB did not substantially affect weight and food intake postoperatively.
Conclusion
The PIB preserved the plasma insulin levels and the wider beta-cell area over time and facilitated insulin signaling in the visceral fats. It could be considered as a possible reconstruction strategy for diabetic gastric cancer patients.

Keyword

Beta cell; Diabetes mellitus; Gastric cancer; Insulin; Intestinal bypass

Figure

  • Fig. 1 Postoperative changes in food intake (FI) and body weight (BW). The transient difference in FI and BW between PIB and sham-AL rats weakened over time. There were no significant differences in the average daily FI and weight gain between the PIB and sham-operated rats at 16 weeks postoperatively. PIB, proximal intestinal bypass (n = 16); sham-PF, sham-operated paired-fed (n =10); sham-AL, sham-operated ad libitum fed (n = 10). ΔFI = FI (postoperative – preoperative)/preoperative ×100; daily FI = average daily FI during the 16-week study period; BW gain = BW (16 weeks – 1 week before surgery)/1 week before surgery × 100. Data are shown as mean ± standard error of the mean. *P < 0.05 (by analysis of variance test).

  • Fig. 2 Effect of the PIB procedure on glucose excursion (GE), glucose tolerance (GT), and the postoperative plasma insulin levels. Only the PIB rats had improvement in GE (A) and GT (B) at 2 weeks postoperatively. The PIB procedure inhibited progressive deterioration of GT, despite the fact that the PIB and sham-PF and -AL animals had similar FI and weight gain. The PIB procedure prevented the gradual decline of fasting (C) and oral glucose-challenged (D) plasma insulin levels of Zucker diabetic fatty rats at 16 weeks postoperatively. PIB, proximal intestinal bypass (n = 16); sham-PF, sham-operated paired-fed (n = 10); sham-AL, sham-operated ad libitum fed (n = 10); AUC-OGTT, area under the curve of oral glucose tolerance test. Δ = (postoperative – preoperative)/preoperative × 100. Data are expressed as mean ± standard error of the mean. *P < 0.01 (by 2-way repeated measures of analysis of variance with Tukey's post hoc test).

  • Fig. 3 Characterizing the development of overt diabetes and its progression in Zucker diabetic fatty (ZDF) rats (n = 6). Overt hyperglycemia is accompanied by decreased plasma insulin levels, confirming the decompensation of beta-cell function and progressive nature of insulin deficiency in ZDF rats. SD, Sprague-Dawley rats (n = 6). Data are expressed as mean ± standard error of the mean. *P < 0.01 (by one-way analysis of variance test).

  • Fig. 4 Effect of the PIB procedure on the preservation of the morphological modification of the islets in Zucker diabetic fatty (ZDF) rats. The majority of islets in the PIB rats aged 28 weeks (A) showed asteroid-like projections (arrow) similar to those seen in 12-week-old control ZDF rats (D) (F). In contrast, these projections of the islets were not frequently seen in the sham-operated animals at 16 weeks postoperatively and 28-week-old control ZDF rats (B, C, E) (F). Expanding islets = number of islets showing asteroid-like expansions/total number of islets in unit pancreas (H&E, ×200). PIB, proximal intestinal bypass (n = 16); sham-PF, sham-operated paired-fed (n = 10); sham-AL, sham-operated ad libitum fed (n = 10). *P < 0.01 (by analysis of variance test).

  • Fig. 5 Changes in the pancreatic beta-cell area, the beta-cell maturation, and the fibrous tissue infiltration in the islets after the PIB procedure in Zucker diabetic fatty rats. In the PIB rats (A), anti-insulin immunohistochemistry (IHC)-positive cells were present beyond the boundaries of typical discrete islets in the majority of islets, which was not observed in the sham-PF (B) and sham-AL (C) rats (anti-insulin IHC staining, pancreas, ×200). The PIB rats (D) had preservation of a wider fractional area of the anti-insulin IHC-positive beta-cell area (fluorescence in green) in the pancreatic islets than the sham-PF (E) and sham-AL (F) rats (G) (anti-insulin IHC staining, pancreas, ×200). The PIB rats (H) had higher anti-pancreatic duodenal homeobox 1 (PDX1) IHC-positivity rate (fluorescence in white) in the beta-cell (in red) of the nucleus (in blue) than the sham-PF (I) and sham-AL (J) rats (K) (anti-intranuclear PDX1 IHC stain, pancreas, ×200). The PIB rats (L) showed a similar marginal area of fibrosis infiltration to the sham-PF (M), but that was lower in the PIB rats than in the sham-AL (N) rats (O) (P = 0.07) (Masson's trichrome staining, pancreas, ×200). PIB, proximal intestinal bypass (n = 16); sham-PF, sham-operated paired-fed (n = 10); sham-AL, sham-operated ad libitum fed (n = 10). *P < 0.01 (by analysis of variance test).

  • Fig. 6 The effect of the proximal intestinal bypass (PIB) procedure on Akt phosphorylation in visceral fat tissues in Zucker diabetic fatty (ZDF) and Sprague-Dawley (SD) rats. The PIB animals (n = 16) showed an enhanced insulin signaling in the visceral adipocyte than the sham-operated paired-fed (PF, n = 10) and sham-operated ad libitum fed rats (AL, n = 10). Akt phosphorylation in visceral fat was evaluated by Western blotting. Western blots were probed with anti-P-Akt and anti-Akt antibodies. The results are expressed as the percentage of the P-Akt/Akt ratio. Data are expressed as means ± standard error of the mean. *P < 0.01 (by analysis of variance test). P-Akt, phosphorylated Akt.


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