The pancreas is a complex gland active in digestion and metabolism through secretion of digestive enzymes from the exocrine portion and hormones from the endocrine portion. The exocrine pancreas, which accounts for more than 95-98% of the pancreas mass (43), is structurally comprised of lobules, with acinar cells surrounding a duct system. The endocrine pancreas makes up only 2% of the pancreatic mass and is organized into the islets of Langerhans— small semi-spherical clusters of about 1500 cells (73) dispersed throughout the pancreatic parenchyme— which produce and secrete hormones critical for glucose homeostasis. The existence of islets was described by Paul Langerhans in 1869, and the functional role of islets in glucose homeostasis was first demonstrated in 1890 when Joseph von Mering and colleagues showed that dogs developed diabetes mellitus following pancreatectomy (22). Though islet mass may vary between individuals—an example is the increase in the setting of adult obesity (83)— the average adult human pancreas is estimated to contain one to two million islets (33, 94). In humans, the concentration of islets is up to two times higher in the tail compared to the head and neck. However, the cellular composition and architectural organization of cell types within the islets is preserved throughout the pancreas (103).
Each pancreatic islet is composed of α, β, d, ε and PP (F) cells; these are primarily endocrine (hormone-secreting) cells, containing numerous secretory granules with stored hormone molecules, ready for release upon receipt of the appropriate stimulus. Insulin-producing b cells are the most common cell type, making up 50-70% of islet mass, with small islets containing a greater percentage of β-cells in contrast to moderate or large islets (4,5). b cells were first discovered in 1907 by silver staining (50) and were the second islet cell type discovered, thus designated “b”-cells. In addition to insulin, b cells also produce islet amyloid polypeptide (IAPP), or amylin, which is packaged and released within insulin-containing granules (44). Amylin reduces post-prandial hyperglycemia by slowing gastric emptying and promoting satiety.
Glucagon-producing a cells were discovered before b cells, by alcohol fixation, thereby garnering their name “a” –cells (50). As the second most abundant islet cell type, they make up about 35% of islet mass in humans (8) but less in rodents. Glucagon’s primary function is to prevent hypoglycemia by stimulating glycogenolysis and hepatic gluconeogenesis (6). Somatostatin-producing d cells comprise less than 10% of islet mass, and are evenly distributed throughout the pancreas (1). Somatostatin is an inhibitory peptide hormone, inhibiting both endocrine and gastrointestinal hormones. Pancreatic polypeptide (PP) producing cells, also known as Ɣ or "F" cells (43, 79), comprise less than 5% of islet mass, and like a cells, are most prominent in the head of the pancreas. PP has roles in exocrine and endocrine secretion functions of the pancreas (107). Ghrelin-producing e cells are the last discovered islet endocrine cell type. Although present in islets, ghrelin is predominately produced in the stomach; ghrelin suppresses insulin release, and plays a role in regulating energy homeostasis (101).
The close proximity of the acini and the islets of Langerhans mirrors their functional interplay. The anatomic structure of the pancreatic parenchyme allows for a paracrine effect of the islet hormones on adjacent acinar cells, termed the ‘islet-acinar’ axis (2, 108). Notably, the islets are highly vascularized—receiving 15% of pancreatic arterial blood flow despite composing only 2% of the pancreatic mass (41). Via the islet-acinar portal system, blood bathing the pancreatic islets flows into a capillary bed within the pancreatic acini, thus exposing the acinar pancreas to the islet hormones (66). Insulin binds to an insulin receptor on acinar tissue and potentiates amylase secretion (109). In contrast, somatostatin inhibits pancreatic exocrine secretion (64); endogenous PP is also largely noted to inhibit pancreatic exocrine secretion (90, 107). Studies have been inconsistent with regards to the effect of glucagon, some suggesting a stimulatory effect while many suggesting an inhibitor effect of glucagon on secretion of zymogen granules (2).
The hormone insulin was first isolated in the 1920’s by Dr. Frederick Banting and a medical student Charles Best, garnering Banting (jointly with John James Rickard Macleod) the Nobel Prize in Medicine in 1923. This was a critical step forward in diabetes care, as porcine insulin therapy was then made available for human use to treat type 1 diabetes, an otherwise fatal disease. In the 1950’s Frederick Sanger determined its primary amino acid structure, consisting of an A and a B chain connected by disulfide bonds (40, 84). Ten years following this discovery, these chains were found to be from the same polypeptide precursor, preproinsulin. In the 1960’s Dorothy Hodgkin defined its tertiary structure. During translation of preproinsulin from its mRNA, the N-terminal signal peptide is cleaved to yield proinsulin. The proinsulin molecule is a single chain polypeptide containing both the A-chain (21 amino acids long) and the B-chain (30 amino acids long). In proinsulin, two chains are connected by C-peptide, which is cleaved to release C-peptide and the remaining insulin molecule, which contains the A- and B-chains connected via two disulfide bonds (40). Although insulin and C-peptide are co-released from b cell secretory vesicles into circulation (81), only insulin is biologically active in regulating blood glucose. C-peptide, however, can serve as a useful clinical and research measure of endogenous insulin production, in patients receiving exogenous insulin injections.
The insulin gene on chromosome 11 is primarily expressed in pancreatic b cells, but is expressed in low levels in the brain, thymus, and in the yolk sak during fetal development (28, 52, 72). It has three exons and two introns, and its transcription results in the 446 base pair preproinsulin mRNA.
Glucose stimulates nuclear translocation of Pdx-1; promotes Pdx-1 and MafA phosphorylation and binding to the insulin promoter; and stimulates transcription of the insulin gene, pre-mRNA splicing, translation, and mRNA stability. (Used with permission from (74)).
Transcription of the insulin gene to preproinsulin mRNA is sophisticated and reflects the tight regulation by transcription factors and recruited coactivators. Pdx-1, NeuroD1 and MafA are important transcription factors in b cell function, respond to elevated glucose levels. Individual b cells respond to ambient glucose with differential insulin secretion, and these changes are apparent at the level of gene transcription (16). At the level of the islet, rapid increase in blood glucose results in rapid elevation in preproinsulin mRNA in the endocrine pancreas. A rapid decrease in blood glucose results in a slow decline in preproinsulin mRNA.
This is due to the unusual stability of preproinsulin mRNA, further stabilized by increased glucose concentrations (25). The specific regulation of this molecule’s translation is the primary mechanism of insulin production control (74).
Mature insulin-containing granules are retained from a few hours up to several days within the b cell, ready for transport to plasma membrane and exocytosis when stimulated. The storage of insulin in mature b granules is far greater than that secreted (58, 80). During a 1 hour glucose stimulation only ~1-2% of insulin within a primary islet b cell is released (102). The insulin content within a given b cell remains relatively constant in the short term, but in the long term will adapt in response to physiologic demands (102).
In an evolutionary milieu of sporadic access to nutrients, insulin became critical in facilitating survival. As an anabolic hormone, insulin controls metabolism of carbohydrates, lipids, and protein. It mediates the availability of energy sources in both fasting and fed states. Insulin promotes energy storage in the fasting state and energy utilization and uptake in the fed state. In so doing, it maintains serum glucose levels within a narrow physiologic range despite variation in energy intake and expenditure. Insulin acts at extracellular insulin receptors in multiple organ tissues including the liver, muscle, and adipose tissue (43), and its effect depends on interstitial insulin concentration which is influenced by insulin secretion rate from b cells and clearance from circulation (68).
The liver serves as the primary storage site for glucose, accounting for 80% of glucose production in fasting states with the kidney only contributing 20% (18, 96).
(Adapted from Masharani and German (60)).
To preserve glucose stores, the low insulin concentrations in the portal venous blood—as seen in the fasting state-- allows minimal glucose production, only enough to match the needs of essential glucose-dependent tissues including the red blood cells and the central and peripheral nervous systems. The liver also clears insulin more rapidly in the fasting state, thus maintaining low circulating insulin levels. Low insulin concentrations also contribute to lipolysis in adipocytes, releasing free fatty acids to encourage utilization of lipid over glucose to meet resting energy needs. Hepatic glucose release during fasting states through glycogenolysis and gluconeogenesis is stimulated by counter-regulatory, or ‘anti-insulin’ hormones. Glucagon plays a major role, with synergistic effects from catecholamines, cortisol, and growth hormone (68).
By contrast, in the fed state-- in response to digestion and absorption of nutrients-- circulating insulin concentration increases in the portal vein secondary to insulin secretion from pancreatic b cells. The increased insulin and glucose concentrations normally limit hepatic glucose production and stimulate liver glucose uptake through glycogen deposition (23, 32, 91). Insulin causes upregulation of hexokinase, phosphofructokinase, and glycogen synthase within hepatocytes, thus inhibiting glycogenolysis and gluconeogenesis and stimulating glycogen synthesis (18).
The effect of insulin on gluconeogenesis can be direct (via its effect on the liver) or indirect via its effect on islet a cells (by decreasing glucagon secretion), adipose tissue (by suppressing lipolysis), skeletal muscle (by reducing proteolysis), and the brain (pleiotropic effect) (32, 65).
In situations when there is poor insulin response such as type 2 diabetes mellitus or insulin resistance, the process of gluconeogenesis continues even in the fed state, thus, further compounding hyperglycemia (32).
Liver clearance of insulin is decreased in the fed state, thus further increasing the circulating insulin concentration. In adipocytes, insulin upregulates lipoprotein lipase and downregulates hormone sensitive lipase, which inhibits lipolysis and subsequent free fatty acid release (29). In hepatocytes, insulin instead stimulates hepatic free fatty acid synthesis from glucose, thereby increasing lipid stores. Proteolysis of skeletal muscle is also inhibited by insulin, which along with lipolysis inhibition, limits delivery of glucose precursors (glycerol and amino acids) to the liver. Systemic circulation of insulin stimulates glucose uptake and utilization in skeletal muscle and adipocytes.
In summary, the release of insulin in the fed state, (1) promotes accumulation of energy stores through glycogenesis and lipogenesis, (2) reduces new hepatic glucose output by preventing glycogenolysis and gluconeogenesis (in the non-insulin resistant, non-diabetic individual), and (3) promotes uptake of glucose by skeletal muscle and fat, the net effect of which is to maintain a normal circulating serum glucose levels while storing extra energy for use during later periods of fasting.
Glucose absorbed from the digestive tract enters the portal blood flow and then systemic circulation. In the fed state, increased glucose stimulates insulin release from the pancreatic β-cells. Insulin acts at the level of the liver to inhibit hepatic gluconeogenesis, at the skeletal muscle to promote storage of glucose as glycogen, and in the adipocytes to stimulate lipogenesis. High insulin levels inhibit the release of non-esterified fatty acids. Incretin hormones released from small intestine in response to a meal augment pancreatic glucose-stimulated insulin secretion. Brain and red blood cells take up glucose independently of insulin in the fasting and fed state. In the fasting state (not shown), in the setting of low circulating insulin, hepatic gluconeogenesis, glycogenolysis, and release of non-esterified fatty acids occurs. Solid line stimulation; das
