Autoantibodies to islet amyloid polypeptide in diabetes.

Islet amyloid polypeptide (IAPP) is the constituent peptide of amyloid in pancreatic islets of Type 2 diabetic patients and in insulinomas. Amyloid formation in Type 2 diabetes is associated with islet cell destruction which may promote formation of autoantibodies to IAPP. An ELISA method has been developed to detect IAPP autoantibodies and used to assay serum from 80 non-diabetic subjects, 49 Type 1 and 228 Type 2 diabetic patients, and 10 patients with insulinomas. Microtitre plates coated with IAPP 1-37 were used to detect antibody binding followed by an alkaline phosphatase conjugated anti-human IgG. ELISA binding decreased with sample dilution and with pre-incubation of the samples with IAPP. The optical density of the substrate reaction was compared with results from a standard serum from a non-diabetic subject (OD ratio). Elevated OD ratios were detected in some subjects from each patient group but the Type 2 diabetic group had significantly higher titres than the non-diabetic subjects (p less than 0.001). The OD ratio was elevated (greater than mean + 2SD non-diabetic group) in 15% of Type 2 and 18% of Type 1 diabetic patients and in 20% with insulinomas. IAPP antibody levels did not correlate with age or gender of subjects, or duration of diabetes. IAPP autoantibodies could be an additional marker for B-cell damage in diabetes.     

Role of islet amyloid polypeptide secretion in insulin-resistant humans

Summary Although it is generally accepted that islet amyloid polypeptide is cosecreted with insulin, relatively few data on its kinetics are available. We therefore studied the dynamics of islet amyloid polypeptide release following oral and frequently sampled intravenous glucose tolerance tests in comparison to insulin and C-peptide using mathematical model techniques in 14 control subjects, 10 obese and 11 hypertensive patients. The fractional clearance rate of islet amyloid polypeptide (0.034±0.004 min^–1 in control subjects, 0.058±0.008 in the obese and 0.050±0.008 in the hypertensive patients) was significantly different (p<0.01) in each group compared with that of insulin (0.14±0.03 min^–1) and similar to that of C-peptide (0.061±0.007 min^–1), at least in the insulin-resistant subjects. Based on the insulin sensitivity index derived from the minimal model analysis of intravenous glucose tolerance test data, both the hypertensive (2.4±0.4 min^–1/(μU/ml); p<0.0005) and the obese (2.7±0.5; p<0.001) patients demonstrated severe insulin resistance compared to control subjects (8.1±1.3). Marked insulin hypersecretion was found in the hypertensive (57.6±5.2 nmol·l^–1 in 180 min; p<0.001) and obese (60.8±10.1; p<0.003) patients in comparison with control subjects (32.4±3.2). The release of islet amyloid polypeptide was significantly higher in the hypertensive (83.1±16.6 pmol/l in 180 min; p<0.02) and obese (78.6±13.1; p<0.005) patients than in control subjects (40.5±6.4). No correlation was found between islet amyloid polypeptide release and the insulin sensitivity index in any group. We conclude that, due to a significantly slower clearance of islet amyloid polypeptide in comparison to insulin, reliance on molar ratios between these two peptides might be misleading in the interpretation of islet amyloid polypeptide secretion especially under non-steady-state conditions. [Diabetologia (1994) 37: 188–194] Received: 10 June 1993 and in revised form: 20 August 1993     

The effect of apolipoprotein E deficiency on islet amyloid deposition in human islet amyloid polypeptide transgenic mice

AIMS/HYPOTHESIS: Islet amyloid deposits are present in over 85% of Type 2 diabetic patients and have been suggested to be pathogenic. The mechanism that converts islet amyloid polypeptide (IAPP), the unique component of these deposits, into amyloid fibrils in vivo is not known. The amino acid sequence of IAPP is critical but insufficient for beta-pleated sheet formation. As apolipoprotein E (apoE), another component of islet amyloid deposits, plays a critical role in amyloid formation in Alzheimer's disease, we hypothesised that apoE could play an important role in islet amyloid formation. METHODS: Transgenic mice expressing the human form of IAPP ( hIAPP (+/0)) were crossbred with apoE deficient ( apoE (-/-)) mice and followed for 12 months, at which time the prevalence and severity of islet amyloid, as well as plasma glucose, hIAPP, immunoreactive insulin (IRI) and lipid concentrations were measured. RESULTS: The prevalence and severity of islet amyloid after one year of follow up were comparable among hIAPP (+/0) mice that were apoE (+/+), apoE (+/-) or apoE (-/-). Differences in glucose tolerance, lipid abnormalities or changes in pancreatic content or plasma concentrations of hIAPP and/or IRI did not account for these findings. CONCLUSION/INTERPRETATION: Our data shows that, unlike in the localized amyloidosis in the brain characteristic of Alzheimer's disease, apoE is not critical for islet amyloid formation in a transgenic mouse model of Type 2 diabetes mellitus. These results indicate that the mechanisms of localised amyloid formation probably vary among different amyloid-associated disorders. Therefore, therapeutic strategies targeting apoE might not apply equally to patients with different amyloid associated diseases.     

胃肠胰胰岛淀粉样多肽的定位和表达

胰岛淀粉样多肽(islet armyloid polypeptide,IAPP)是1986年瑞典学者Westermarket al[1,2 ]从胰岛素瘤患者的瘤组织,糖尿病猫及Ⅱ型糖尿病患者胰岛淀粉样沉积物中分离出来的一种多肽,几乎在同时,英国生物化学家Cooper et al[3,4]也从Ⅱ型糖尿病患者的胰岛淀粉样沉积物中分离出该肽.IAPP又称为amylin.对IAPP的分子结构、基因表达和生理作用等已有许多报道[5].近年来,在IAPP定位、表达及胃肠胰IAPP免疫反应(immunoreactive,IR)细胞定位、发生、发育方面的研究报道,为探讨IAPP的生理作用及疾病状态下的改变,提供了形态学依据,现综述如下.     

Membrane damage by human islet amyloid polypeptide through fibril growth at the membrane

Fibrillar protein deposits (amyloid) in the pancreatic islets of Langerhans are thought to be involved in death of the insulin-producing islet beta cells in type 2 diabetes mellitus. It has been suggested that the mechanism of this beta cell death involves membrane disruption by human islet amyloid polypeptide (hIAPP), the major constituent of islet amyloid. However, the molecular mechanism of hIAPP-induced membrane disruption is not known. Here, we propose a hypothesis that growth of hIAPP fibrils at the membrane causes membrane damage. We studied the kinetics of hIAPP-induced membrane damage in relation to hIAPP fibril growth and found that the kinetic profile of hIAPP-induced membrane damage is characterized by a lag phase and a sigmoidal transition, which matches the kinetic profile of hIAPP fibril growth. The observation that seeding accelerates membrane damage supports the hypothesis. In addition, variables that are well known to affect hIAPP fibril formation, i.e., the presence of a fibril formation inhibitor, hIAPP concentration, and lipid composition, were found to have the same effect on hIAPP-induced membrane damage. Furthermore, electron microscopy analysis showed that hIAPP fibrils line the surface of distorted phospholipid vesicles, in agreement with the notion that hIAPP fibril growth at the membrane and membrane damage are physically connected. Together, these observations point toward a mechanism in which growth of hIAPP fibrils, rather than a particular hIAPP species, is responsible for the observed membrane damage. This hypothesis provides an additional mechanism next to the previously proposed role of oligomers as the main cytotoxic species of amyloidogenic proteins.     

Amyloid protein in somatostatinoma differs from human islet amyloid polypeptide

Amyloid deposits in somatostatinomas are rare observations. To examine the characteristics of this amyloid, we compared amyloid deposits in a somatostatinoma to those found in pancreatic tissue in patients with Type II diabetes mellitus and in insulinomas, using immunohistochemical techniques and specific antibodies to islet amyloid polypeptide or other pancreatic hormones, as well as electron-microscopy. Antibodies to islet amyloid polypeptide regions 8-17 or 25-37 were confirmed to be specific. Amyloid deposits in patients with Type II diabetes mellitus and in insulinomas, but not those in the somatostatinoma strongly reacted with these antibodies, or to an antibody to amyloid P component. Amyloid deposits in the somatostatinoma were not reactive with antibodies to somatostatin or to other pancreatic hormones. Electron-microscopic examinations revealed that amyloid fibrils in the somatostatinoma were thinner and more randomly distributed than were those in islets from patients with Type II diabetes mellitus. As amyloid in somatostatinomas is unlike that consisting of islet amyloid polypeptide or other mature pancreatic hormones, it may be a novel type of local amyloid in pancreatic islets.     

Immunocytochemical staining for islet amyloid polypeptide in pancreatic endocrine tumors

Aims/hypothesis: Islet amyloid polypeptide is originally identified as the chief constituent of amyloid in insulinomas and type 2 diabetic islets. This study aimed to identify islet amyloid polypeptide by immunocytochemical staining in pancreatic endocrine tumors including 30 cases of insulinomas and non-β-cell pancreatic endocrine tumors. Results: In normal islets, 62% of islet cells and 52% of insulin cells were granularly positive for insulin and IAPP, respectively, with more insulin positive cells than IAPP positive cells and some densely positive staining for insulin and IAPP in irregularly shaped a nuclear, degenerating islet β-cells. In pancreatic endocrine tumors, all 10 insulinomas were positive for islet amyloid polypeptide but 2 glucogonomas, 1 somatostatinoma, 6 of 7 pancreatic polypeptidomas, all 7 gastrinomas and all 3 non-functioning pancreatic endocrine tumors were negative for islet amyloid polypeptide whereas one pancreatic polypeptidoma was positive for islet amyloid polypeptide. Methods: Using commercially available rabbit anti-islet amyloid polypeptide antibody, immunocytochemical staining was performed on 30 cases of pancreatic endocrine tumors, consisting of 10 insulinomas, 2 glucagonomas, 1 somatostatinoma, 7 pancreatic polypeptidomas, 7 gastrinomas and 3 non-functioning pancreatic endocrine tumors. Pancreatic tissues containing pancreatic endocrine tumors were systematically immunostained for insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and chromogranin A, in addition to islet amyloid polypeptide. When normal pancreatic tissues adjacent to pancreatic endocrine tumors were present, insulin, glucagon, somatostatin and islet amyloid polypeptide positive cells were counted for a total of 20 islets, which were divided into large islets and medium islets for each case. Conclusions/Interpretations: All 10 insulinomas and 1 pancreatic polypeptidoma were granularly positive for islet amyloid polypeptide, suggesting all 10 insulinomas contained enough insulin granules for IAPP whereas only one non-β-cell pancreatic endocrine tumor was co-localized with islet amyloid polypeptide in their secretary granules.     

Immunocytochemical staining for islet amyloid polypeptide in pancreatic endocrine tumors

Aims/hypothesis: Islet amyloid polypeptide is originally identified as the chief constituent of amyloid in insulinomas and type 2 diabetic islets. This study aimed to identify islet amyloid polypeptide by immunocytochemical staining in pancreatic endocrine tumors including 30 cases of insulinomas and non-β-cell pancreatic endocrine tumors.

Results: In normal islets, 62% of islet cells and 52% of insulin cells were granularly positive for insulin and IAPP, respectively, with more insulin positive cells than IAPP positive cells and some densely positive staining for insulin and IAPP in irregularly shaped a nuclear, degenerating islet β-cells. In pancreatic endocrine tumors, all 10 insulinomas were positive for islet amyloid polypeptide but 2 glucogonomas, 1 somatostatinoma, 6 of 7 pancreatic polypeptidomas, all 7 gastrinomas and all 3 non-functioning pancreatic endocrine tumors were negative for islet amyloid polypeptide whereas one pancreatic polypeptidoma was positive for islet amyloid polypeptide.

Methods: Using commercially available rabbit anti-islet amyloid polypeptide antibody, immunocytochemical staining was performed on 30 cases of pancreatic endocrine tumors, consisting of 10 insulinomas, 2 glucagonomas, 1 somatostatinoma, 7 pancreatic polypeptidomas, 7 gastrinomas and 3 non-functioning pancreatic endocrine tumors. Pancreatic tissues containing pancreatic endocrine tumors were systematically immunostained for insulin, glucagon, somatostatin, pancreatic polypeptide, gastrin and chromogranin A, in addition to islet amyloid polypeptide. When normal pancreatic tissues adjacent to pancreatic endocrine tumors were present, insulin, glucagon, somatostatin and islet amyloid polypeptide positive cells were counted for a total of 20 islets, which were divided into large islets and medium islets for each case.

Conclusions/Interpretations: All 10 insulinomas and 1 pancreatic polypeptidoma were granularly positive for islet amyloid polypeptide, suggesting all 10 insulinomas contained enough insulin granules for IAPP whereas only one non-β-cell pancreatic endocrine tumor was co-localized with islet amyloid polypeptide in their secretary granules.     

Chronic overproduction of islet amyloid polypeptide/amylin in transgenic mice: lysosomal localization of human islet amyloid polypeptide and lack of marked hyperglycaemia or hyperinsulinaemia

Summary Type 2 (non-insulin-dependent) diabetes mellitus is characterised by hyperglycaemia, peripheral insulin resistance, impaired insulin secretion and pancreatic islet amyloid formation. The major constituent of islet amyloid is islet amyloid polypeptide (amylin). Islet amyloid polypeptide is synthesized by islet beta cells and co-secreted with insulin. The ability of islet amyloid polypeptide to form amyloid fibrils is related to its species-specific amino acid sequence. Islet amyloid associated with diabetes is only found in man, monkeys, cats and racoons. Pharmacological doses of islet amyloid polypeptide have been shown to inhibit insulin secretion as well as insulin action on peripheral tissues (insulin resistance). To examine the role of islet amyloid polypeptide in the pathogenesis of Type 2 diabetes, we have generated transgenic mice with the gene encoding either human islet amyloid polypeptide (which can form amyloid) or rat islet amyloid polypeptide, under control of an insulin promoter. Transgenic islet amyloid polypeptide mRNA was detected in the pancreas in all transgenic mice. Plasma islet amyloid polypeptide levels were significantly elevated (up to 15-fold) in three out of five transgenic lines, but elevated glucose levels, hyperinsulinaemia and obesity were not observed. This suggests that insulin resistance is not induced by chronic hypersecretion of islet amyloid polypeptide. Islet amyloid polypeptide immunoreactivity was localized to beta-cell secretory granules in all mice. Islet amyloid polypeptide immunoreactivity in beta-cell lysosomes was seen only in mice with the human islet amyloid polypeptide gene, as in human beta cells, and might represent an initial step in intracellular formation of amyloid fibrils. These transgenic mice provide a unique model with which to examine the physiological function of islet amyloid polypeptide and to study intracellular and extracellular handling of human islet amyloid polypeptide in pancreatic islets.     

Parallel changes of proinsulin and islet amyloid polypeptide in glucose intolerance

Elevated proinsulin secretion and islet amyloid deposition are both features of Type 2 diabetes but their relationship to beta-cell dysfunction is unknown. To determine if islet amyloid polypeptide (IAPP) secretion is disproportionate with other beta-cell products at any stage of glucose intolerance, 116 subjects were studied. Non-diabetic subjects with equivalent body mass index (BMI) were assigned to three groups, (i) normal fasting glucose, fpg<5.5 mmol l(-1); (ii) intermediate fasting glucose, fpg> or =5.5<6.15 mmol l(-1); (iii) impaired fasting glucose (IFG), fpg> or =6.1<7.0 mmol l(-1). Diabetic subjects were divided according to therapy (9 diet, 19 tablet, and 11 insulin). IAPP, C-peptide and proinsulin were measured fasting and at the end of a 1-h glucose infusion. Fasting C-peptide, IAPP and proinsulin were significantly elevated in the IFG group compared with the other non-diabetic groups (P<0.02); fasting IAPP/C-peptide and proinsulin/C-peptide were 1-2% in all non-diabetic groups. Fasting and 1-h proinsulin and proinsulin/C-peptide were higher in diabetic compared with non-diabetic subjects (P<0.01). IAPP and IAPP/C-peptide in diabetic groups were similar to that in non-diabetic subjects but reduced in the insulin-treated group (P<0.01). Proinsulin was disproportionately increased compared with C-peptide and IAPP in Type 2 diabetes particularly in severe beta-cell failure implying more than one concurrent beta-cell pathology.     

Translational control of glucose-induced islet amyloid polypeptide production in pancreatic islets

Dysfunctional islet amyloid polypeptide (IAPP) biosynthesis and/or processing are thought contribute to formation of islet amyloid in type 2 diabetes. However, it is unclear how normal pro-IAPP biosynthesis and processing are regulated to be able to define such dysfunction. Here, it was found that acute exposure to high glucose concentrations coordinately regulated the biosynthesis of pro-IAPP, proinsulin, and its proprotein convertase PC1/3 in normal isolated rat islets, without affecting their respective mRNA levels. Pro-7B2 biosynthesis, like that of pro-PC2, did not appreciably change, but this was likely due to a much higher expression in pancreatic α-cells masking glucose regulation of their biosynthesis in β-cells. Biosynthesis of pro-SAAS, the putative PC1/3 chaperone, was unaffected by glucose, consistent with its scarce expression in β-cells. We conclude that translational control of pro-IAPP biosynthesis, in parallel to the pro-PC1/3, pro-PC2, and pro-7B2 proprotein-processing endopeptidases/chaperones, is the predominate mechanism to produce IAPP in islet β-cells.     

Exendin-4 increases islet amyloid deposition but offsets the resultant beta cell toxicity in human islet amyloid polypeptide transgenic mouse islets

Aims/hypothesis  

In type 2 diabetes, aggregation of islet amyloid polypeptide (IAPP) into amyloid is associated with beta cell loss. As IAPP is co-secreted with insulin, we hypothesised that IAPP secretion is necessary for amyloid formation and that treatments that increase insulin (and IAPP) secretion would thereby increase amyloid formation and toxicity. We also hypothesised that the unique properties of the glucagon-like peptide-1 (GLP-1) receptor agonist exendin-4 to maintain or increase beta cell mass would offset the amyloid-induced toxicity.     

Spontaneous diabetes mellitus in transgenic mice expressing human islet amyloid polypeptide.

The islet in non-insulin-dependent diabetes mellitus (NIDDM) is characterized by loss of beta cells and large local deposits of amyloid derived from the 37-amino acid protein, islet amyloid polypeptide (IAPP). We have hypothesized that IAPP amyloid forms intracellularly causing beta-cell destruction under conditions of high rates of expression. To test this we developed a homozygous transgenic mouse model with high rates of expression of human IAPP. Male transgenic mice spontaneously developed diabetes mellitus by 8 weeks of age, which was associated with selective beta-cell death and impaired insulin secretion. Small intra- and extracellular amorphous IAPP aggregates were present in islets of transgenic mice during the development of diabetes mellitus. However, IAPP derived amyloid deposits were found in only a minority of islets at approximately 20 weeks of age, notably after development of diabetes mellitus in male transgenic mice. Approximately 20% of female transgenic mice spontaneously developed diabetes mellitus at 30+ weeks of age, when beta-cell degeneration and both amorphous and amyloid deposits of IAPP were present. We conclude that overexpression of human IAPP causes beta-cell death, impaired insulin secretion, and diabetes mellitus. Large deposits of IAPP derived amyloid do not appear to be important in this cytotoxicity, but early, small amorphous intra- and extracellular aggregates of human IAPP were consistently present at the time of beta-cell death and therefore may be the most cytotoxic form of IAPP.     

Activation of peroxisome proliferator-activated receptor-gamma by rosiglitazone protects human islet cells against human islet amyloid polypeptide toxicity by a phosphatidylinositol 3'-kinase-dependent pathway

BACKGROUND: Type 2 diabetes mellitus (T2DM) is characterized by a deficit in beta-cell mass, increased beta-cell apoptosis, and islet amyloid derived from islet amyloid polypeptide (IAPP). Human IAPP (h-IAPP) applied to beta-cells forms toxic oligomers that induce apoptosis. Thiazolidinediones, ligands of peroxisome proliferator-activated receptor-gamma (PPAR-gamma), can delay the onset of T2DM. OBJECTIVE: We questioned whether activation of endogenous PPAR-gamma in human islets by rosiglitazone (RSG) inhibits h-IAPP-induced islet cell death and, if so, by which mechanism. METHODS AND RESULTS: Vehicle or h-IAPP was applied to human islets with or without RSG (10 and 50 microM) for 48 h. A 2-fold increase in the number of terminal deoxynucleotidyl transferase-mediated deoxy-UTP nick end labeling-positive nuclei was detected in h-IAPP-treated human islets (P < 0.001). RSG (10 and 50 microM) prevented h-IAPP-induced apoptosis in human islets (P < 0.001). Thioflavin T binding assays confirmed that this effect was not mediated by interference with h-IAPP oligomerization. Expression of dominant negative PPAR-gamma in human islets prevented the protective effect of RSG. RSG activation of PPAR-gamma resulted in downstream activation of the serine/threonine protein kinase Akt, an outcome that was inhibited by a specific phosphatidylinositol 3-kinase inhibitor, which ablated RSG protection against h-IAPP-induced islet cell apoptosis. CONCLUSION: We conclude that in human islets, activation of PPAR-gamma inhibits h-IAPP-induced islet cell apoptosis, and this action is at least in part mediated through activation of the phosphatidylinositol 3'-kinase-Akt cascade. If this action is present in vivo, then thiazolidinediones have the potential to decrease beta-cell apoptosis in T2DM and reduce loss of beta-cell mass.     

Extra-pancreatic expression of the rat islet amyloid polypeptide (amylin) gene.

Messenger RNA for rat islet amyloid polypeptide (IAPP) has been identified not only in the pancreas but also, in lesser amounts, in preparations from the stomach and dorsal root ganglia. In the stomach, insulin mRNA was not detectable, ruling out possible contamination by pancreatic tissue. Because IAPP and calcitonin gene-related peptide (CGRP) are related and CGRP is present in both stomach and dorsal root ganglia, it was possible that 'IAPP' signals were in fact due to cross-hybridization with CGRP mRNA. A second IAPP probe was constructed which does not cross-react. This probe also detected mRNA in both tissues, confirming the expression of IAPP in both tissues. The regional distribution of IAPP mRNA in the stomach did not parallel that of gastrin mRNA. IAPP mRNA was present in the antrum, centrum and pylorus and, like gastrin, the highest amounts were in the pylorus. However, the ratio between the pylorus and centrum was 3.6:1 for IAPP and 156:1 for gastrin. The effects of dietary manipulation were determined; a period of 48 h of starvation reduced pancreatic IAPP mRNA by approximately 60%, whereas in the stomach there was no significant reduction. If the action of IAPP was hormonal, pancreas and stomach would not be acting in concert. A paracrine role for gastric IAPP therefore seems more likely.     

Amyloidogenic hexapeptide fragment of medin: homology to functional islet amyloid polypeptide fragments

Medin is the main constituent of aortic medial amyloid that occurs in virtually all individuals older than sixty. It is derived from a proteolytic fragment of lactadherin, a mammary epithelial cell expressed glycoprotein that is secreted as part of the milk fat globule membrane. It was previously demonstrated that an octapeptide fragment of medin (NH₂-NFGSVQFV-COOH) forms typical well-ordered amyloid fibrils. To obtain further insights into the molecular determinants that mediate this process by such a short peptide fragment, we examined the amyloidogenic potential of its truncated forms and analogues. Our results clearly indicated that a truncated fragment of medin, the hexapeptide, NFGSVQ can form typical amyloid fibrils. A shorter pentapeptide fragment, NFGSV, self-assembled into a gel structure that exhibited a network of fibrous structures. The amyloid forming NFGSVQ hexapeptide is noticeably similar to the short amyloidogenic peptide fragments of the islet amyloid polypeptide (IAPP), NFGAIL and NFLVH. Moreover, the substitution of the phenylalanine residue with either alanine or isoleucine significantly reduced the amyloidogenic potential of the peptide fragment. Taken together, the results are consistent with the assumed role of stacking interactions in the self-assembly processes that lead to the formation of amyloid fibrils. The results are discussed in the context of models for the mechanism of fibril formation and ways to design inhibitors.     

Islet amyloid polypeptide (IAPP) and pancreatic islet amyloid deposition in diabetic and non-diabetic patients.

Twenty pancreata of non-diabetic patients and 17 pancreata of diabetic patients, including two patients with insulin-dependent diabetes mellitus, were immunohistochemically studied using antiserum against human islet amyloid polypeptide (IAPP). The islet beta cells in non-diabetic patients were immunoreactive for both IAPP and insulin. Amyloid deposition immunoreactive for IAPP was detected in six of 20 pancreata of non-diabetic patients. The plasma glucose level of three of these six patients was elevated to more than 200 mg/dl, and that of the other three ranged from 143 to 162 mg/dl; all six were receiving intravenous hyper-alimentation and had no history of diabetes prior to treatment. Amyloid deposition was present in all patients with non-insulin-dependent diabetes mellitus (NIDDM). The deposition was absent in the pancreata of two secondary diabetic patients, one of whom had received steroid hormone for bronchial asthma and the other of whom had liver cirrhosis with hepatocellular carcinoma; deposition was also absent in the pancreas of a patient with impaired glucose tolerance diagnosed on a 75-g oral glucose load. Heterogeneous expression of immunoreactivities of beta cells for insulin and for IAPP was present, suggesting independently regulated production and secretion of the peptides. Immunoreactivity of beta cells was more sensitively decreased for IAPP than for insulin in the islets of NIDDM patients. The decreased immunoreactivity for IAPP suggested an initial stage of disturbed beta-cell function, even if the immunoreactivity for insulin was apparently intact or the amyloid deposition in the islets was insignificant. The degree of amyloid deposition immunoreactivity for IAPP did not necessarily reflect the severity of diabetes mellitus. Amyloid deposits were seen at the narrow spaces beneath the insular capsule of connective tissues and the perivascular region or, in some cases, occupying the whole of the islet. The diabetogenic role of IAPP is unclear, but the deposition might be an accelerating factor which disturbs beta-cell function.     

The islet amyloid polypeptide gene and non-insulin-dependent diabetes mellitus in south Indians.

Islet amyloid polypeptide (IAPP), otherwise called amylin, is the monomeric component of islet amyloid. Deposition of this amyloid is a characteristic feature of non-insulin-dependent diabetes mellitus in humans and may play a role in the pathogenesis of the disease. As such, abnormalities in the structure or expression of the IAPP gene might contribute to the inheritance of this condition. The IAPP gene was studied in a well-characterised population of 62 unrelated Dravidian subjects with non-insulin-dependent diabetes mellitus and 56 normal Dravidian controls, using a restriction fragment length polymorphism generated by PvuII digestion. Genotype and allele frequencies did not differ between diabetic subjects and controls. Taken together with recent findings in Europid and other racial groups, an abnormality of the IAPP gene is highly unlikely to represent a major gene for the development of non-insulin-dependent diabetes mellitus.