The pancreas is divided into three main compartments: exocrine acinar tissue (corresponds to approximately 95% of the organ) that produces digestive enzymes, the endocrine tissue (around 2% of the organ) composed of the islets of Langerhans and the duct tissue through which the digestive enzymes are driven into the digestive tube [1, 2].
The pancreas is located across the back of the abdomen, behind the stomach (Fig. 1). The head of the pancreas is on the right side of the abdomen and is connected to the duodenum (the first section of the small intestine) through a small tube called the pancreatic duct. The narrow end of the pancreas, called the tail, extends to the left side of the body.
FIG. 1: The pancreatic structure, location and organization. Adapted from [3].
1.1.1 The endocrine pancreas
The endocrine pancreas is composed of scattered islets of Langerhans within the exocrine tissue, representing 1-5% of the pancreatic mass. The islets are round, compact, highly vascularized with scanty connective tissue and are from endodermal origin. An adult islet is composed of five different cell types characterized by their specific hormone secretion- , ,
, PP and ε cells, each producing a different hormone: insulin, glucagon, somatostatin, pancreatic polypeptide and ghrelin, respectively [4-6]. The proportion of the different cells
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within the islets is rather constant: cells account for 65-80% of the islet cells, 15-20%, 3-10%, PP 3-5% and ε cells represent less than 1% [7-9].
In both humans and rodents the islets form a spherical structure. In rodents insulin producing cells are central, surrounded by a rim of α, δ and PP cells, while in humans the islets are less organized (Fig. 2) [8].
FIG. 2: Islets of Langerhans show striking interspecies differences. Confocal micrographs (1-μm optical sections), showing representative immunostained pancreatic sections containing islets of Langerhans from human (A), and (B) mouse Insulin-immunoreactive (red), glucagon-immunoreactive (green), and somatostatin-glucagon-immunoreactive (blue) cells are all found randomly distributed in human islets. By contrast, insulin-containing cells are located in the core, and glucagon- and somatostatin-containing cells in the mantle of mouse islets (Scale bar, 50 μm). Adapted from [8].
Insulin
Insulin is secreted in response to increased blood glucose (concentrations), to trigger glucose uptake in the liver, muscles and adipocytes. Insulin consists of 51 amino acids, forming two chains A and B linked by disulfic bridges. Insulin is synthesized as a precursor of 11.5 kDa, preproinsulin; the first 25 amino acids are hydrophobic and allow rapid penetration to the
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endoplasmic reticulum (ER) during synthesis. Preproinsulin is then cleaved by a sequence specific peptidase followed by structural changes in the Golgi. Insulin is then enclosed in clathrin vesicles where the acid milieu will activate Prohormone convertase 2 and 1/3 (PC2 and PC1/3) that will in turn cleave proinsulin into insulin and C-peptide. In parallel, the vesicles mature into granules that are then ready to release insulin and C-peptide in equimolar quantities [10, 11]. Insulin stimulates liver and muscle to synthesize glycogen and proteins and the adipose cells to synthesize triacylglycerols. Insulin represses glycogenolysis and neoglucogenesis and promotes glucose entry and processing into muscle cells and adipocytes. In addition, it stimulates acinar degranulation.
Glucagon
Glucagon is the antagonist hormone to insulin effects, and is secreted in response to hypoglycemia; it is inhibited by hyperglycemia, insulin, and somatostatin. It stimulates the release of glucose and fatty acids by increasing hepatic glycogenolysis and neoglucogenesis to restore normoglycemia. Additionally, it stimulates insulin secretion by the β-cells and represses acinar secretion [12, 13]. Glucagon consists of 29 amino-acids. The protein is derived from a larger precursor, preproglucagon, [14, 15], which in the intestines is cleaved to produce, in contrast to the pancreas, glucagon-like-peptide 1 and 2 (GLP1 and GLP2).
Somatostatin
Somatostatin is a cyclic tetradecapeptide hormone and neurotransmitter that inhibits the release of peptide hormones in many tissues. It is also released from the hypothalamus to inhibit growth hormone (GH, somatotropin) and thyroid-stimulating hormone (TSH) secretion from the anterior pituitary. It is secreted by δ-cells of the islets of Langerhans in the pancreas to inhibit the release of glucagon and insulin and by similar D cells in the gastrointestinal tract, the principal source of circulating somatostatin [4].
Pancreatic Polypeptide
Pancreatic polypeptide (PP) is an orexigenic hormone secreted during hyperglycemia, which inhibits gallbladder contraction, gut motility and pancreatic secretion while promoting gastric emptying by repressing hypothalamic feeding-regulatory peptides and by acting on the vago-vagal and vago-sypathetic reflex arcs [16].
21 Ghrelin
Ghrelin expressed ε-cells of the pancreas and represent 1% of the embryonic and adult endocrine pancreas, [17, 18]. Ghrelin levels increase before meals and decrease after meals.
It is considered the counterpart of the hormone leptin, produced by adipose tissue, which induces satiation when present at higher levels. Ghrelin is synthesized as a preprohormone, which is proteolytically processed to yield a 28-amino acid peptide. An interesting and unique modification is imposed on the hormone during synthesis in the form of the addition of an n-octanoic acid bound to one of its amino acids; this modification is necessary for biologic activity.
The predominant source of circulating ghrelin is the gastrointestinal tract, primarily the stomach, but also in smaller amounts the intestine. The hypothalamus in the brain is another significant source of ghrelin; smaller amounts are produced in the placenta, kidney, and pituitary gland. In the fetus,in contrast to the adult, the pancreas and not the stomach isa major source of circulating ghrelin. Furthermore, high ghrelin and ghrelin receptor gene expression in the fetal pancreas is intriguing and suggeststhat ghrelin may play an important role in islet-celldevelopment [19].
1.2 The exocrine pancreas
The exocrine tissue represents 95-99% of the pancreatic mass and consists of serous acini of highly polarized tall cells producing the digestive enzymes (amylase, lipase and phospholipase) as well as pro-enzymes (elastase, procarboxypeptidase, trypsinogen, pepsinogen, deoxyribonuclease and ribonuclease) stored in zymogen granules in the apical pole. Once secreted and activated in the lumen of the acinus, they are forwarded through the ductal network to the duodenum, allowing the intestinal digestion of nutrients. The ductal tree begins within the acini with a small duct lined by centro-acinar cells, followed by the intercalated ducts, lined by a single cubic epithelium. The intercalated ducts are followed by the intralobular ducts and finally by the interlobular ducts, often lined by a bistratified epithelium. The main pancreatic duct is joined by the common bile duct and finally ends up in the duodenum. Before entering the duodenum, pancreatic and hepatic secretion accumulate with the ampulla of Vater, closed by the sphincter which opens in response to nitric oxide and stimulation of the autonomous system [20-22].
22 Diabetes Mellitus
Diabetes mellitus is a group of metabolic disorders characterized by chronic high blood glucose levels (hyperglycemia). This is a result of impaired insulin secretion and/or impaired action of insulin on its target tissues: muscle, liver and adipose tissue. Diabetes Mellitus has several risk factors and has multiple etiologies. In the long term, hyperglycemia causes degenerative complications at the micro and macro vascular level with severe consequences for the diabetic patient.
2.1 Diagnosis
Diabetes is diagnosed by measurement of blood glucose levels. The current recommendations of the ADA (American Diabetes Association) for the diagnosis of diabetes are: Symptoms of diabetes and a casual plasma glucose ≥200 mg/dl (11.1 mmol/l). Casual is defined as any time of day without regard to time since last meal. The classic symptoms of diabetes include polyuria, polydipsia, and unexplained weight loss. More specifically, diagnostic criteria are fasting plasma glucose levels (FPG) ≥126 mg/dl (7.0 mmol/l) (fasting is defined as no caloric intake for at least 8 h). Or a 2-h plasma glucose ≥200 mg/dl (11.1 mmol/l) during an OGTT (oral glucose tolerance test). The test should be performed as described by the World Health Organization, using a glucose load containing the equivalent of 75-g anhydrous glucose dissolved in water [23].
2.2 Worldwide Prevalence
In 1985 there were an estimated 30 million people with diabetes. Today diabetes affects more than 230 million people, almost 6% of the world's adult population. In many countries in Asia, the Middle East, Oceania and the Caribbean, diabetes affects 12-20% of the adult population.
2.3 Classification
The classification of diabetes includes four clinical classes:
1. Type 1 diabetes (T1D), results from β-cell destruction, usually leading to absolute insulin deficiency.
2. Type 2 diabetes (T2D), results from a progressive insulin secretory defect on the background of insulin resistance.
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3. Other specific types of diabetes due to other causes, e.g., genetic defects of β-cell function, genetic defects in insulin action, diseases of the exocrine pancreas (such as in cystic fibrosis), endocrinopathies, drug- or chemical-induced diabetes (such as in the treatment of AIDS or after organ transplantation), infections, uncommon forms of immune-mediated diabetes, other genetic syndromes sometimes associated with diabetes.
4. Gestational diabetes mellitus (GDM) (diagnosed during pregnancy).
2.3.1 Type 1 Diabetes Mellitus
T1D is the form of diabetes due primarily to β-cell destruction. T1D accounts for 5-10% of diabetic patients worldwide, though its prevalence varies greatly between populations. It is sub-classified into two main categories - type 1A and 1B. Type 1A is diagnosed by the presence of antibodies against proteins of pancreatic islets such as insulin, anti-glutamate decarboxylase, anti-tyrosine phosphatase IA-2 and anti IA-2β antibodies.
However, especially in nonwhites, T1D can occur in the absence of these autoimmune antibodies and without evidence of any autoimmune disorder. Nevertheless, it is characterized by low insulin and C-peptide levels similar to type 1A, individuals with this type of diabetes are prone to ketoacidosis but the pathogenetic basis for their insulinopenia remains obscure. This is called type 1B diabetes [24].
Typically T1D affects young individuals and is diagnosed before the age of 20. The primary symptoms are often referred to as “cardinal syndrome”- polyuria, polydipsia and polyphagia accompanied by asthenia [24].
Causes
In Diabetes type 1A, hyperglycemia is the result of an attack of the immune system which causes the reduction in β-cell number. Pancreas biopsies from T1D patients show inflammation of T lymphocytes, B lymphocytes and macrophages. This immune attack causes a deficit in insulin production (insulinopenia) [25].
24 Treatments
Classically, T1D is a type of diabetes in which insulin is required for survival. This involves injecting insulin under the skin -in the fat - for it to get absorbed into the blood stream where it can then access all the cells of the body that require it.
2.3.2 Type 2 Diabetes Mellitus
T2D is the most common form of diabetes (90-95%). 80% of type 2 diabetes are preventable by changing diet, increasing physical activity and improving lifestyle. It is a chronic, complex disorder of a rapidly growing global importance. It is characterized by concomitant defects in both insulin secretion (from the β-cells in the pancreatic islets) and insulin action (in fat, muscle, liver and elsewhere), the latter being typically associated with obesity [26].
Causes
The diabetes pandemic, which consists primarily of type 2 diabetes, has evolved in association with rapid cultural changes, aging populations, increasing urbanization, dietary changes, decreased physical activity and other unhealthy lifestyles and behavioral patterns.
Without effective prevention and control programs, the incidence of diabetes is likely to continue rising globally.
Usually T2D develops after the age of 40. 80% of T2D patients are overweight or have abdominal obesity. T2D is frequently not diagnosed until complications appear, and approximately one-third of all people with diabetes may be undiagnosed. In contrast to T1D, it is characterized by a relative, rather than absolute, insulin insufficiency due to a defect in β-cell production and peripheral insulin resistance.
Several genome associations have been found to be linked to T2D revealing an important role of genetic inheritance in the development of T2D.
Treatment
People with type 2 diabetes may require oral hypoglycemic drugs to lower their blood glucose and some may need insulin injections at some point. Drugs for type 2 diabetes come in various classes — biguanides, α-glucosidase inhibitors, amylin agonists, dipeptidyl-peptidase 4 (DPP-4) inhibitors, meglitinides, sulfonylureas and thiazolidinediones. Each class
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contains one or more specific drugs. Some of these drugs are taken orally, others must be injected.
2.3.3 Other specific types of diabetes MODY-Maturity onset Diabetes of the Young
MODY corresponds to about 5% of diabetes cases. It is caused by mutations in a single gene.
The following genes have been identified: HNF4α, GCK, TCF1/HNF1α, Pdx1/Ipf, TCF2/HNF1β and Beta2/NeuroD1.
It superficially resembles T2D, but it is characterized by impaired insulin secretion with minimal or no defects in insulin action. MODY appears in childhood or young adulthood, before the age of 25 years, and in most cases, at least two other members of the immediate family are affected. It is believed to account for 2% to 3% of all cases of diabetes.
Causes
MODY is associated with specific monogenic defects of β-cell function. Most of these are characterized by a dominant pattern of inheritance.
MODY1- (hepatic nuclear factor 4α, HNF4α) MODY1 was the first gene defect discovered [27], it is an extremely rare form of MODY. The transcription factor HNF4α has an important role in pancreatic development and maintenance of β-cell function. It has similar effects to MODY3, usually respond very well to oral sulfonylurea drugs. Due to progressive β-cell failure, a large proportion of the patients will eventually require insulin therapy.
MODY2- (pancreatic glucokinase gene, GK). Glucokinase is the rate limiting enzyme for glucose metabolism and is critical to regulate insulin secretion in response to glucose.
MODY2 patients normally do not show signs or symptoms. Diagnosis is made during routine blood testing. Generally MODY2 has an excellent prognosis. It is non-progressive, rarely requires drug or insulin therapy, and can usually be managed by exercise and diet alone. It is most commonly diagnosed in childhood or during pregnancy.
MODY3- (hepatic transcription factor 1α, HNF1α). MODY3 occurs more frequently than other types of MODY. It is normally diagnosed later in life. MODY3 can cause progressive
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diabetes, which may result in diabetic complications. People with MODY3 may be at an elevated risk of developing diabetic retinopathy. Patients are often responsive to sulfoylureas, a class of antidiabetic agents. MODY3 may also cause a severe form of diabetes that may need to be controlled with insulin. HNF1α is a transcription factor known to control a regulatory network important for differentiation of β-cells.
MODY4- (insulin promoter factor1/pancreas duodenum homeobox1, IPF1/PDX1) MODY4 is a rare form of MODY that often is associated with a mild form of diabetes. Pdx1 is a transcription factor vital to the development of the embryonic pancreas and in adults it continues to play a role in the regulation and expression of genes coding for insulin, facilitated glucose transporter 2 (GLUT2), glucokinase, and somatostatin.
MODY5- (hepatic nuclear factor 1β, HNF1β/TCF2). This rare form of MODY is often associated with renal disease, including kidney dysfunction or cysts, which are frequently diagnosed before diabetes. It may require several different treatments because it leads to multiple organ abnormalities. TCF2 is involved in the early stages of embryonic development of several organs, including the pancreas, where it contributes to differentiation of pancreatic endocrine Ngn3+ cell progenitors from non-endocrine embryonic duct cells.
MODY6- (Beta2/NeuroD1 gene). This is an extremely rare form of MODY. Little is known about the severity of diabetes associated with MODY6. Beta2/NeuroD1 promotes transcription of the insulin gene as well as some genes involved in formation of β-cells and parts of the nervous system.
Other genes were recently identified as MODY genes coding for- KLF11 (a pancreatic transcription factor induced by glucose to regulate insulin) , CEL (carboxyl ester lipase, a major component of pancreatic juice and responsible for the duodenal hydrolysis of cholesterol esters), and BLK (a nonreceptor tyrosine-kinase of the src family, expressed in β-cells where it enhances insulin synthesis and secretion in response to glucose by up-regulating the transcription factors Pdx1 and Nkx6.1) [28-30]. However, mutations in these factors are extremely rare and only lately characterized.
27 MIDD-Maternity Inherited Diabetes and Deafness
A rare form of diabetes corresponding to 1-3% of diabetes cases is caused by mutations in the mitochondrial DNA. A point mutation in the gene coding for the tRNA of leucine was identified [31]. The molecular mechanism standing behind this mutation is yet to be demonstrated, but it has been shown that as a consequence of this point mutation, there is β-cell dysfunction evident by a defect in insulin secretion in response to glucose [32].
Neonatal diabetes
A rare form of diabetes, in Europe its prevalence is estimated to be 1:50000 births. It is characterized by severe hyperglycemia accompanied by low insulin levels, polyuria, dehydration, and insufficient weight gain in the first ten days after birth. This diabetes exists in two distinct clinical forms:
1. Permanent neonatal diabetes (PND) where there is a requirement for insulin therapy for life. PND has been associated with mutations in Pdx1, GCK, FOXP3 and KCNJ11 (Kir6.2) [33-35].
2. Transient neonatal diabetes (TND) where there is remission after insulin therapy with a higher risk of developing diabetes at the adulthood [34]. Genetic analyses have demonstrated a genetic transmission of TND. Two genes where identified to be in association with TND; ZAC, which regulates exit from the cell cycle, apoptosis and also regulates the protein PACAP1 (pituitary adenylate cyclase activating polypeptide receptor 1) which is involved in insulin secretion and the gene HYMAI which has an unknown function [36].
2.3.4 Gestational diabetes
Gestational diabetes is defined as hyperglycemia occurring during pregnancy. The causes have not yet been clearly defined. However, the strong decrease in insulin resistance after birth suggests a role of the placental hormones [37]. In the USA, gestational diabetes is responsible for about 7% of complications during pregnancy. A woman that suffered from gestational diabetes has a 70% risk of developing T2D in the next 10 years. Several genes were found to be associated with this kind of diabetes-e.g. Sur1, Capn10 [37].
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