Conclusions
We observed that islet-associated macrophage infiltration in type 2 diabetes increased compared with NGT, and this is the first study showing significant correlations between pancreatic fat deposition as well as hyperglycemia and islet inflammation.
We observed a significant correlation between the number of islet-associated macrophages and fat-cell area. In a previous report, a significantly higher number of macrophages were found in the islets located in proximity to adipocytes than in other islets.14 These results might indicate that macrophages are recruited to the islets by pancreatic fatty infiltration. One of the key substances that recruits macrophages to islets with pancreatic fatty infiltration may be a saturated fatty acid, palmitate. β cells respond to palmitate via the Toll-like receptor pathway and produce chemokines, including interleukin (IL)-8, IL-6 and monocyte chemotactic protein-1 (MCP-1)14 that recruit M1-type proinflammatory monocytes/macrophages to the islets.15 The pancreatic fat-cell area was positively correlated with BMI and HOMA-IR in this study, suggesting that pancreatic fat deposition might be exacerbated by obesity. This is consistent with some previous studies that report a significant correlation between pancreatic fat and BMI.9 10 16 In another report, fatty pancreas diagnosed by sonographic findings was also associated with visceral fat area and HOMA-IR in subjects without diabetes,17 which indicates that excess pancreatic fat deposition could be one of the components of metabolic syndrome. In our study, there was no significant difference in fat-cell area among the three stages of glucose tolerance groups, which might be derived from no significant difference in BMI among the groups.
This study has shown that islet inflammation in type 2 diabetes may be exacerbated not only in relation to excess pancreatic fat deposition but also hyperglycemia. Although there was no significant difference in pancreatic fat-cell area among the three glucose tolerance groups, the number of islet-associated macrophages was significantly increased in patients with diabetes compared with patients without diabetes, suggesting that the islet inflammation shown in our study could be greatly attributed to a hyperglycemic state. The mechanism that explains why macrophages are recruited to the islets by hyperglycemia may be as follows. Hyperglycemia increases IL-1β mRNA levels in β cells.18 Because β cells express IL-1 receptor type 1, β cells secrete chemokines in response to IL-1β in an autocrine or paracrine manner, which leads to the recruitment of macrophages and a vicious cycle of inflammation.8 On the other hand, a previous report showed that there was no significant difference in the number of islet-associated macrophages between patients with type 2 diabetes and those without.19 In that report, both groups of patients were obese, and obesity induced inflammation, as described previously.4 5 It is speculated that the impact of obesity on islet inflammation might obscure the impact of hyperglycemia in that study. Since most patients were not obese at all glucose tolerance stages in our study, the impact of hyperglycemia might become apparent.
CRP level, which is one of the sensitive physiological markers of systemic inflammation, did not show a significant difference among the three groups. CRP level, which is generally associated with BMI,20 was positively correlated with BMI (r=0.29, p=0.022) but not with the glycemic parameters or fat-cell area (online supplementary figure 1). These results might suggest that obesity causes both whole-body inflammation and islet inflammation, while hyperglycemia also affects islet inflammation rather than whole-body inflammation. We also evaluated serum total amylase level as one of the possible local inflammation parameters of pancreas. The amylase level did not show a significant difference among the three groups, and this level was not correlated with any clinical parameters or fat-cell area (online supplementary figure 2). In addition, the amylase level was not correlated with the number of islet-associated macrophages (data not shown). These results might suggest that macrophages recruited by pancreatic fatty infiltration and hyperglycemia might injure β cells rather than the entire pancreas.
A previous study reported that islet inflammation derived from lipotoxity could deteriorate β-cell function in experimental animal models.15 A direct negative association between islet inflammation and insulin-secreting capacity was not observed in our study, but referring to this report, we found that the increased islet inflammation observed in patients with type 2 diabetes might promote the worsening of glucose intolerance.
One patient with DM had received sodium-glucose co-transporter-2 (SGLT-2) inhibitor before pancreatic resection. We consider that SGLT-2 inhibitors might ameliorate pancreatic steatosis, where such effect is observed in visceral adipose tissue,21 and affect the results. Thus, we investigated again after excluding the patient; however, the results did not change (data not shown). The effect of SGLT-2 inhibitors on fat deposition and islet inflammation would be further investigated in the future.
There is a limitation in our study. It is difficult to exclude the impact of the primary diseases on histological findings or clinical backgrounds because some individuals in this study had malignant diseases of the pancreas, hepatobiliary system and duodenum. However, there were no significant differences in islet-associated macrophage and pancreatic fat-cell area between patients with malignant diseases and those without (data not shown).
In conclusion, islet inflammation occurs in association with pancreatic fatty infiltration and glucose intolerance and may contribute to further worsening of glucose intolerance.