Pancreatic regulation of glucose homeostasis

Abstract

In order to ensure normal body function, the human body is dependent on a tight control of its blood glucose levels. This is accomplished by a highly sophisticated network of various hormones and neuropeptides released mainly from the brain, pancreas, liver, intestine as well as adipose and muscle tissue. Within this network, the pancreas represents a key player by secreting the blood sugar-lowering hormone insulin and its opponent glucagon. However, disturbances in the interplay of the hormones and peptides involved may lead to metabolic disorders such as type 2 diabetes mellitus (T2DM) whose prevalence, comorbidities and medical costs take on a dramatic scale. Therefore, it is of utmost importance to uncover and understand the mechanisms underlying the various interactions to improve existing anti-diabetic therapies and drugs on the one hand and to develop new therapeutic approaches on the other. This review summarizes the interplay of the pancreas with various other organs and tissues that maintain glucose homeostasis. Furthermore, anti-diabetic drugs and their impact on signaling pathways underlying the network will be discussed.

Figure 1

Anatomical organization of the pancreas. The exocrine function of the pancreas is mediated by acinar cells that secrete digestive enzymes into the upper small intestine via the pancreatic duct. Its endocrine function involves the secretion of various hormones from different cell types within the pancreatic islets of Langerhans. The micrograph shows the pancreatic islets. LM × 760 (Micrograph provided by the Regents of University of Michigan Medical School © 2012). Adapted from Human Anatomy and Physiology, an OpenStax College resource.

Figure 2

Maintenance of blood glucose levels by glucagon and insulin. When blood glucose levels are low, the pancreas secretes glucagon, which increases endogenous blood glucose levels through glycogenolysis. After a meal, when exogenous blood glucose levels are high, insulin is released to trigger glucose uptake into insulin-dependent muscle and adipose tissues as well as to promote glycogenesis.

Figure 3

Glucose-stimulated insulin release from a pancreatic β-cell. Exogenous glucose is taken up by GLUT2 and undergoes glycolysis inside the cell. Elevated adenosine triphosphate (ATP) levels alter the ATP/ADP ratio, which in turn leads to the closure of ATP-sensitive K⁺-channels. The subsequent membrane depolarization opens voltage-dependent Ca²⁺-channels in response to increasing intracellular calcium levels, which eventually trigger insulin secretion following vesicle fusion with the membrane.

Figure 4

The interplay of the pancreas with the brain, liver, gut as well as adipose and muscle tissue. The pancreas interacts with the brain, liver, gut and adipose and muscle tissue in a highly sophisticated network via various hormones, neurotransmitters and cytokines. BNDF, brain-derived neurotrophic factor; CCK, cholecystokinin; GIP, glucose-dependent insulinotropic peptide; GLP-1, glucagon-like peptide 1; GRP, gastrin-releasing peptide; IL-6, Interleukin 6; MCH, melanin concentrating hormone; NPY, neuropeptide Y; PACAP, pituitary adenylate cyclase-activating polypeptide; POMC, pro-opiomelanocortin; VIP, vasoactive intestinal peptide.