Pancreatic islets are more than beta cells secreting insulin. The islets contain four other endocrine cell types: alpha cells that release glucagon, delta cells that release somatostatin, gamma cells that release pancreatic polypeptide, and epsilon cells that release ghrelin. All five cell types interact with each other as well as the rest of the body.

“These islet cells do not operate as independent islands,” said Maria L. Golson, PhD, Assistant Professor of Medicine, Johns Hopkins School of Medicine. “Interactions between islet cells are an essential element in glucose homeostasis.”

Dr. Golson explored the mechanisms by which delta cells regulate beta cell function during The Islet-Cell Interactome. The session can be viewed on-demand by registered meeting participants at ADA2023.org. If you haven’t registered for the 83rd Scientific Sessions, register today to access the valuable meeting content through August 28.

Delta cells are activated by signals from beta cells and independently respond to changes in glucose, Dr. Golson said. Delta cells are known primarily for their production of somatostatin, but they are also highly enriched for leptin compared to beta cells.

Leptin decreases insulin secretion in isolated islets, but the mechanism is unclear. The leptin receptor (LEPR) mouse model has improved glucose tolerance on a chow diet but worsened glucose intolerance on a high-fat diet. Ablating LEPR in alpha and beta cells has little effect on blood glucose homeostasis in mouse models.

It is unclear how somatostatin could prevent beta cell exhaustion and protect beta cell health by limiting hypersecretion of insulin during metabolic stress. Somatostatin knockout has a greater effect on glucose homeostasis in male mice than on females, Dr. Golson reported, but the mechanisms remain unknown.

Liver-alpha cell axis

An interactome is the sum of all the interactions between biological entities in cells and organisms, explained Danielle Dean, PhD, Assistant Professor of Diabetes, Endocrinology, and Metabolism, Vanderbilt University Medical Center. When it comes to nutrient homeostasis, pancreatic islet cells interact with adipose tissue, skeletal muscle, the brain, intestines, and, most importantly, the liver.

The liver-alpha cell axis helps to regulate interactions between amino acids produced by the liver and glucagon produced by alpha cells, Dr. Dean said. The alpha cell, in its role as an amino acid sensor, can promote insulin secretion.

Decreasing hepatic glucose output and glycemia can impair amino acid clearance in the liver, resulting in hyperaminoacidemia. Increased levels of two amino acids, glutamine and arginine, stimulate alpha cells to increase amino acid transporter expression, resulting in glucagon hypersecretion, alpha cell proliferation, and hyperplasia. Hyperglucagonemia, in turn, continues the feedback loop by decreasing hepatic glucose output.

Work with knockout mice and human tissue shows that glutaminase (GLS) is highly expressed in alpha cells and is required for the alpha cell proliferation induced by hyperaminoacidemia. But knocking out GLS does not impair glucagon secretion. Arginine is a key player for both glucagon and insulin.

“Arginine is an important and required factor in both insulin and glucagon secretion,” Dr. Dean continued. “Arginine transport promotes glucagon secretion and alpha cell proliferation. The alpha cell is an amino acid sensor and its products promote insulin secretion.”

Sex influences sensory modulation in pancreas

Abdelfattah El Ouaamari, PhD, Associate Professor of Cell Biology and Anatomy, New York Medical College, discussed insights into sex differences in sensory modulation of pancreatic beta cell based on experiments with mice.

“The pancreas is very enriched in nerves and receives a supply of nerves from both sympathetic and parasympathetic branches of the autonomic nervous system. The vagus nerve relays the vagal innervation, and the spinal nerves relay the sciatic innervation, so we have two kinds of pathways,” he explained.

Dr. El Ouaamari’s research has shown that pancreas-projecting sensory neurons are more abundant in males than females, and that male sex hormones regulate the density of peri-islet sensory innervation in adulthood. Additionally, pancreatic islet- and sensory-autonomous factors regulate basal and glucose-induced insulin secretion differently in males and females, independently of sex hormones, he said.

A single pancreatic blood supply

Endocrinologists and gastroenterologists both focus on the pancreas but seldom overlap. Endocrinologists deal with the endocrine pancreas, gastroenterologists with the exocrine pancreas. One of the few areas the two specialties have shared was a model of separate circulation for their different areas of interest.

“Islets were traditionally considered to be isolated micro organs with their own blood supply,” said Manami Hara, DDS, PhD, Research Professor of Medicine, University of Chicago. “The endocrine pancreas and the exocrine pancreas actually share a common blood supply.”

In fact, 3-D imaging has revealed that islets can be connected to multiple capillaries and that capillaries branch directly out from arterioles. Islets located deeper in the pancreas may depend on different arterioles than islets near the pancreatic surface, and islets with direct arteriole contact are larger compared to islets with capillary contact.

“All islets and downstream exocrine cells are exposed to the same circulatory factors nearly simultaneously,” Dr. Hara said. “Pancreatic blood flow is regulated no differently for endocrine and exocrine cells.”