Distinct function of the head region of human pancreas in the pathogenesis of diabetes

Abstract

The large size of the human pancreas challenges unbiased quantitative analyses that require a practical stereological approach. While many histological studies of the pancreas in the past lacked regional information, we have shown marked heterogeneity within an individual, where islet distribution/density is relatively low in the head and gradually increases through the body toward the tail region by > 2-fold.^{1, 2} Studies focusing on the tail region may be prone to overestimation of β-cell/islet mass when normalizing measured values per person by using pancreas weight or volume. In this article, beyond technical issues, we discuss the pathophysiological importance of studying the head region of the human pancreas regarding its unique characteristics in early development, and the anatomical disposition that may lead to a preferential loss of β-cells in patients with type 2 diabetes and the development of pancreatic cancer.

During embryogenesis, the pancreas arises from dorsal and ventral pancreatic protrusions from primitive gut endoderm. Regions of the adult pancreas are anatomically referred to head, body, and tail regions. The head region of the pancreas is located on the right side of the abdomen to the right and superior of the superior mesenteric vessels, while the uncinate process of the head is located to the right and posterior to the superior mesenteric vessels. The neck region overlies the superior mesenteric vessels, and the body region lies along the floor of the lesser sac covered by peritoneum derived from the superior leaf of the transverse mesocolon. The tail is defined as the part of the pancreas tracing toward the spleen on the left side of the abdomen that is not covered by peritoneum derived from the transverse mesocolon. We have shown marked regional heterogeneity in islet distribution within an individual,¹ suggesting that a random inter-specimen comparison between different regions confounds study accuracy. On the other hand, restricted measurement of a specific region (either head, body, or tail region) does not accurately represent the total β-cell/islet mass of a given subject.

The head of the pancreas is unique developmentally, as well as anatomically, in a way that differs from the rest of the pancreas. The head originates from the ventral pancreatic bud and exclusively contains the pancreatic polypeptide (PP) cell rich area. We have shown that the PP-cell rich region is more narrowly segregated than previously reported^3-7 and largely restricted to the uncinate process,¹ which is located posterior to the superior mesenteric vein and medial to the head of the pancreas. The uncinate process grows from the ventral bud during early fetal development. When the intestine undergoes ~270° anticlockwise rotation, the ventral pancreatic bud fuses with the dorsal bud. The failure of the full rotation may result in abnormal growth and malpositioning of the dorsal or ventral bud prior to fusion, leading to the enlargement of the head associated with hypoplasia or aplasia of the uncinate process. While it has received little attention in the field of endocrinology, radiologists have found this normal variation important to avoid misdiagnosis of the enlarged head region as pancreatic cancer.⁸ In diagnosis of neuroendocrine cancer, a false-positive uptake of a tracer ⁶⁸Ga-DOTA-TOC by the uncinate process has been reported.⁹ This is due to the densely localized PP-cells in the area, which highly express somatostatin receptors. Note that there is no delta-cell segregation in the head. The PP-cell rich and poor areas coexist with a clear boundary in the head region and PP-cell distribution in the latter is similar to the rest of the pancreas. It is noteworthy that β- and α-cell mass is significantly decreased in the PP-cell rich area compared with the PP-cell poor area. We, thus, recommend that the PP-cell rich area in the head region should be analyzed separately from the PP-cell poor area. The majority of recent studies, including ours, do not include PP-cells in examinations of β-cell/islet mass, since it is not clear to what extent PP plays a role in glucose homeostasis and other metabolic pathways in humans. In our study on regional differences in the human pancreas, we first identified the PP-cell rich area in the head region by PP-staining and excluded it from subsequent quantification using adjacent sections.²

The anatomical distinction of the head region is illustrated in Figure 1. It receives its blood supply from the superior pancreaticoduoodenal artery, whereas the body and tail region is supplied by the splenic artery. The bile from the liver (through the common hepatic duct) and the gall bladder (through the cystic duct) mix into the common bile duct and flow down to the head of the pancreas. The common bile duct connects with the pancreatic duct at the ampulla of Vater. This ductal network is all under the same innervation from the celiac plexus and vagus. The Oddi sphincter, a circular band of muscle at the bottom of this biliary tract, controls the flow of pancreatic juice and bile into the duodenum so that it functionally separates the pancreas from the intestinal environment.

Figure 1. Head region of the human pancreas.

The head region being the closest part of the pancreas to the duodenum, deterioration and malfunction of surrounding organs may affect the head first and more severely than the downstream regions as disease conditions progress. We have shown a preferential loss of β-cells in the head region in patients with T2D.² It is well known that the majority of pancreatic cancer is found in the head region.^10-14 In fact, diabetes increases the risk of developing pancreatic cancer ~2-fold.^15,16 Note that insulinoma is very rare (1 case per 250,000 person-years)^17-21 and the majority of pancreatic cancers are exocrine tumors, where adenocarcinomas account for 95% of them. Furthermore, an intriguing finding reported by Korsgren group links the anatomical distinction of the head region to the etiology of T1D that dysfunction of the sphincter of Oddi may allow microbiota to ascending into the pancreatic duct via the duodenum, which results in non-specific inflammation in both exocrine and endocrine pancreas and triggers development of T1D by activating adverse innate immune responses in vulnerable individuals.^22,23

In conclusion, the head region of the human pancreas has distinct properties, developmentally and anatomically, that predispose this region to be more affected in various disease states.

Wang X, Zielinski MC, Misawa R, Wen P, Wang TY, Wang CZ, Witkowski P, Hara M. Quantitative analysis of pancreatic polypeptide cell distribution in the human pancreas. PLoS One. 2013;8:e55501. doi: 10.1371/journal.pone.0055501.

Wang X, Misawa R, Zielinski MC, Cowen P, Jo J, Periwal V, Ricordi C, Khan A, Szust J, Shen J, et al. Regional differences in islet distribution in the human pancreas--preferential beta-cell loss in the head region in patients with type 2 diabetes. PLoS One. 2013;8:e67454. doi: 10.1371/journal.pone.0067454.