Insulin In Pancreatic Diseases

Insulin is an anabolic hormone with powerful metabolic effects. It is synthesized by the beta cells of the islets of Langerhans as a single chain precursor called proinsulin. Insulin consists of 2 dissimilar polypeptide chains, an A chain with 21 amino acids and a B chain with 30 amino acids, which are linked by 2 disulfide bonds. Chain A and Chain B are derived from a 1-chain precursor, proinsulin. Proinsulin is converted to insulin by the enzymatic removal of a segment that connects the amino end of the A chain to the carboxyl end of the B chain. This segment is called the connecting C peptide.16-18 Like other growth factors, insulin uses phosphorylation and the resultant protein-protein interactions as essential tools to transmit and compartmentalize its signal. Insulin initiates its wide variety of growth and metabolic effects by binding to the insulin receptor. The insulin receptor belongs to the large family of growth factor

Figure 13.1 Normal human (rat) pancreas. Note the larger size of the acinar cells in the peri-insular (PI) area compared to those in the teleinsular (TI) region.

receptors with intrinsic tyrosine kinase activity.18 Following insulin binding, the receptor undergoes autophosphorylation on multiple tyrosine residues. This results in activation of the receptor kinase and tyrosine phosphorylation of a variety of docking proteins including insulin receptor substrate (IRS) proteins.18-20 Phosphorylated IRS proteins serve as docking proteins between the insulin receptor and a complex network of intracellular signaling molecules containing Src homology 2 (SH2) domains.19,20 Four members (IRS-1, IRS-2, IRS-3, IRS-4) of this family have been identified and they play different and specific roles in vivo.21,22 Activation of SH2 domain proteins initiates a cascade of a biochemical reactions and activation of intracellular pathways, including regulation of cell differentiation, growth, survival, and metabolism that ultimately transmit the insulin signal.

13.2.1 Insulin in the Normal Pancreas

Insulin is the hormone that is produced solely in the pancreas of mammals (see Chapter 1, Chapter 9, and Chapter 28). It is an important growth factor not only for the normal physiological function of the pancreas, but also for the repair of toxicological injuries. The effect of insulin on the pancreas is both through blood circulation and paracrine. Based on the insulo-acinar vessel architecture of the pancreas, as described in Chapter 4, the insulin released from the p-cells reaches the exocrine tissue via efferent branches of the arterial complex within the islet. Because the concentration of insulin is much higher in the tissue immediately surrounding the islets, peri-insular acini are larger and contain more protein and enzyme than acinar cells remote from the islets

Figure 13.2 Human pancreas. Random distribution of islets (black in photo) of various size. Anti-insulin antibody, Avidin-Biotin Complex Method x30.

(tele-insular acini).23-24 This paracrine function of the islet cells can be demonstrated histologically, particularly in the rat pancreas, where periinsular acinar cells distinguish themselves from the tele-insular acinar cells by their more intense esosinophilic color giving rise to the so-called "halo" phenomenon (Figure 13.1).23,25 A difference in the enzyme content of the peri-insular and tele-insular acini has been shown.26-27 The random distribution of islets within the pancreas occupying every 1.1 mm of the exocrine tissue (Figure 13.2)28 reflects the importance of the paracrine pathway of insulin for the normal digestive function and the repair of toxicological or mechanical injuries. This topographical insulin concentration may explain also the reason that in the hamster model most cancers develop within or immediately around the islets.3-29 The reason for the fast growth and expansion of tumors arising from within or around the islets could well be related to a suitable environment within or in the vicinity of islets, where high concentrations of growth factors are present.29

13.2.2 Insulin in AP

The importance of insulin in the repair of the damaged pancreas has been shown by several studies. Pancreatic endocrine function impairment following AP is associated with decreased plasma levels of both basal and glucose-stimulated insulin and it is more common after severe than after mild AP.31 Overall, the incidence of diabetes mellitus in patients after AP is about 15.8%. Alcoholic pancreatitis is more often complicated with impaired glucose tolerance and diabetes mellitus than other causes of pancreatitis. In addition, the severity of exocrine insufficiency in AP

patients correlates strongly with the severity of concomitant pancreatic endocrine insufficiency, the severity of which has been categorized according to insulin dependency.32

In the rat's AP model, both basal and glucose-stimulated insulin secretory response of pancreatic islets isolated from rats with AP is markedly decreased although pancreatic islets appear histologically intact.33,34 Moreover, the production of inducible nitric oxide (iNOS) by p-cells of isolated islet cells is markedly increased. Increased iNOS activity leads to an elevated nitric oxide (NO) production33 and high levels of NO are involved in pancreatic p-cell dysfunction and apoptosis. Therefore, it was suggested that the reduced insulin secretory response of islets in AP to glucose is a consequence of the toxic action of NO produced by iNOS in the p-cells.33 Recently, it was discovered in patients with AP that the patient's insulin is progressively degraded by gelatinase B (MMP-9), a key regulator in the pathophysiology of autoimmune diseases. In AP, gelatinase B is produced by the inflammatory cells that are mainly localized next to the insulin secreting p-cells in the islets suggesting that gelatinase B cleaves insulin, secreted by p-cells in close proximity, and this degradation of insulin could lead to the development of overt diabetes mellitus. Therefore, MMP inhibitors may have a beneficial effect on insulin levels in the treatment of diabetes mellitus.3

13.2.3 Insulin in CP

Diabetes, usually of insulin-dependent type, eventually develops in 30 to 50% of CP patients.36 In CP, a reduction in the number of p-cells induces p-cell neogenesis in extrainsular tissue compartments to compensate for the loss of insulin in islets. In CP patients, the extrainsular endocrine cells are the predominant insulin cell type.37 Despite the compensatory p-cell neogenesis, insulin secretion deficiency and development of diabetes mellitus still present a common complication in CP. More recently, it was found that the ductular epithelial cells in CP express considerable amounts of gelatinase B (MMP-9) and within the islets some cells stain positively for gelatinase B. It was furthermore demonstrated that insulin, which serves as an important substrate for gelatinase B, is progressively degraded by gelatinase B.35 This could explain the reduction of insulin secretion in early stages of CP despite histological and ultrastructural evidence for intact islets of Langerhans.38 In severe cases of CP associated with the atrophy of the islet cells and especially of p-cells,39 with the reduced insulin synthesis and discharge, the regenerative capability of the pancreas is reduced or abolished. Consequently, the damaged pancreas requires other growth factors for repair, although apparently noninsulin hormones do not have the same pancreatic-specific effects of insulin.

13.2.4 Insulin in PC

Abnormal glucose tolerance and overt diabetes mellitus develop in up to 80% of PC patients.37,40 The development of diabetes or altered glucose tolerance generally occurs shortly before the clinical manifestation of the disease.40 Thus, diabetes mellitus is considered to be an early symptom rather than the cause of PC.40 The cellular growth promoting effect of insulin has an unwanted effect on the cancer cells. Unfortunately, the growth of PC cells benefits greatly from the paracrine secretory ability of insulin. Most PC cell lines require insulin for their maintenance and growth in vitro. However, contrary to the normal tissue, cancer cells, which eventually destroy the surrounding insulin-providing islets, in the absence of insulin, acquire the ability to produce their own growth factors, including neuropeptides, except for insulin. For yet unknown reasons, the synthesis of insulin is restricted to the islet cells and tumor cells derived from them. Many investigators have shown that the majority of well-differentiated ductal adenocarcinomas contain a few or a conspicuous number of different types of islet cells including p-cells.4 Whether these cells serve as an energy provider for tumor cells or simply present bystanders is unknown. Moreover, these endocrine cells are found both in the invasive part of cancers42 and in their metastasis,41 which indicates that these endocrine cells are an integral part of the malignant exocrine tissue.

In PC patients, islets in the vicinity of cancer cells show a decreased number of p-cells and increased number of a-cells.37 It has been suggested that, the depletion of p-cells in PC is related to the effect of substances, such as amylin, released by cancer cells. In that case, suppression of all islets within the pancreas is expected. However, this has not been shown.37 It has been shown that the alterations of islets occur only in the vicinity of tumors perhaps through cancer cell derived substances that reach the islets by a paracrine pathway.37 Nevertheless, the alteration of p-cells in PC patients is mainly restricted to the endocrine cells within the islets and there is no compensatory proliferation of p-cells in other pancreatic areas.37 It has also been hypothesized that pancreatic ductal adenocarcinoma arises from within islets, most probably from undiffer-entiated cells or transdifferentiated cells, which loose the insulin secretory ability during carcinogenesis.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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