Islet Amyloid Polypeptide Levels Research Articles

Okinawa-Based Nordic Diet Decreases Plasma Levels of IAPP and IgA against IAPP Oligomers in Type 2 Diabetes Patients.

Pancreas-derived islet amyloid polypeptide (IAPP) aggregates and deposits in the pancreas and periphery of Type 2 Diabetes (T2D) patients, contributing to diabetic complications. The excess IAPP can be removed by autoantibodies, and increased levels of immunoglobulin (Ig) G against IAPP have been reported in T2D patients. However, whether other Ig classes are also affected and if the levels can be managed is less known. This pre-post study examines IgA levels against IAPP oligomers (IAPPO-IgA) in T2D patients and assesses the impact of the Okinawa-based Nordic (O-BN) diet-a low-carbohydrate, high-fiber diet-on these levels after following the diet for 3 months. IAPP, IAPPO-IgA, and total IgA levels were measured in plasma and fecal samples from n = 30 T2D patients collected at baseline, after 3 months of diet, and after additional 4 months of unrestricted diets (a clinical follow-up). The IAPP and IAPPO-IgA levels were significantly lower after 3 months, with the latter also being significantly reduced at the clinical follow-up. The reduction in plasma IAPP and IAPPO-IgA levels correlated with reductions in plasma levels of metabolic and inflammatory markers. Hence, following the O-BN diet for at least 3 months is sufficient to reduce circulating IAPP and IAPPO-IgA levels, which may be principal in managing T2D.

Contraction of human brain vascular pericytes in response to islet amyloid polypeptide is reversed by pramlintide

The islet amyloid polypeptide (IAPP), a pancreas-produced peptide, has beneficial functions in its monomeric form. However, IAPP aggregates, related to type 2 diabetes mellitus (T2DM), are toxic not only for the pancreas, but also for the brain. In the latter, IAPP is often found in vessels, where it is highly toxic for pericytes, mural cells that have contractile properties and regulate capillary blood flow. In the current study, we use a microvasculature model, where human brain vascular pericytes (HBVP) are co-cultured together with human cerebral microvascular endothelial cells, to demonstrate that IAPP oligomers (oIAPP) alter the morphology and contractility of HBVP. Contraction and relaxation of HBVP was verified using the vasoconstrictor sphingosine-1-phosphate (S1P) and vasodilator Y27632, where the former increased, and the latter decreased, the number of HBVP with round morphology. Increased number of round HBVP was also seen after oIAPP stimulation, and the effect was reverted by the IAPP analogue pramlintide, Y27632, and the myosin inhibitor blebbistatin. Inhibition of the IAPP receptor with the antagonist AC187 only reverted IAPP effects partially. Finally, we demonstrate by immunostaining of human brain tissue against laminin that individuals with high amount of brain IAPP levels show significantly lower capillary diameter and altered mural cell morphology compared to individuals with low brain IAPP levels. These results indicate that HBVP, in an in vitro model of microvasculature, respond morphologically to vasoconstrictors, dilators, and myosin inhibitors. They also suggest that oIAPP induces contraction of these mural cells and that pramlintide can reverse such contraction.

Plasma IAPP-Autoantibody Levels in Alzheimer's Disease Patients Are Affected by APOE4 Status.

Pancreas-derived islet amyloid polypeptide (IAPP) crosses the blood-brain barrier and co-deposits with amyloid beta (Aβ) in brains of type 2 diabetes (T2D) and Alzheimer's disease (AD) patients. Depositions might be related to the circulating IAPP levels, but it warrants further investigation. Autoantibodies recognizing toxic IAPP oligomers (IAPPO) but not monomers (IAPPM) or fibrils have been found in T2D, but studies on AD are lacking. In this study, we have analyzed plasma from two cohorts and found that levels of neither immunoglobulin (Ig) M, nor IgG or IgA against IAPPM or IAPPO were altered in AD patients compared with controls. However, our results show significantly lower IAPPO-IgA levels in apolipoprotein E (APOE) 4 carriers compared with non-carriers in an allele dose-dependent manner, and the decrease is linked to the AD pathology. Furthermore, plasma IAPP-Ig levels, especially IAPP-IgA, correlated with cognitive decline, C-reactive protein, cerebrospinal fluid Aβ and tau, neurofibrillary tangles, and brain IAPP exclusively in APOE4 non-carriers. We speculate that the reduction in IAPPO-IgA levels may be caused by increased plasma IAPPO levels or masked epitopes in APOE4 carriers and propose that IgA and APOE4 status play a specific role in clearance of circulatory IAPPO, which may influence the amount of IAPP deposition in the AD brain.

123-OR: Deletion of Both Pcsk1 And Pcsk2 in Beta Cells: Lack of Mature Insulin Drives Beta-Cell Expansion and Dysfunction, but Not Severe Diabetes in Mice

Proinsulin (PI) is processed to mature insulin by prohormone convertases 1/3 (Pcsk1) and 2 (Pcsk2). In individuals with T1D and T2D, there is an increase in the circulating PI:insulin ratio. We hypothesized that β-cell Pcsk1 and Pcsk2 deletion would result in β-cell dysfunction, loss of insulin production, and marked hyperglycemia. Single Pcsk1flox/flox Ins1cre/+ (Pcsk1βKO), Pcsk2flox/flox Ins1cre/+ (Pcsk2βKO), and double Pcsk1flox/flox Pcsk2flox/flox Ins1cre/+ (DPCβKO) β-cell prohormone convertase knockout mice were generated (with respective Pcsk1+/+ Pcsk2+/+ Ins1cre/+ controls) and monitored until 30 weeks old. Pcsk2βKO mice displayed no glycemic phenotype, while Pcsk1βKO mice displayed mild hyperglycemia and impaired glucose tolerance by 26 weeks of age. DPCβKO mice displayed mild hyperglycemia (10.1±1.6 vs. 12.3±2.1 mM; p=0.006) and marked glucose intolerance by 10 weeks of age (AUC: 418±135 vs. 1485±360; p<0.0001). No animals displayed obesity relative to controls. Insulin+ pancreas area was doubled in DPCβKO male mice (p=0.0004) and DPCβKO islets showed early glucose-induced Ca2+ influx and loss of oscillatory Ca2+ flux. Pcsk2βKO islets had unaltered mature insulin, while Pcsk1βKO islets had reduced mature insulin. DPCβKO islets contained no detectable mature insulin by western blot. In contrast, Pcsk2βKO islets had markedly reduced mature islet amyloid polypeptide (IAPP), while Pcsk1βKO islets contained normal mature IAPP levels. Our results suggest that complete loss of β-cell prohormone processing, including PI processing, can drive β-cell dysfunction and expansion, but only mild diabetes and glucose intolerance. Although Pcsk2 deletion in β cells does not impact glycemia or PI processing, it is required for normal proIAPP processing. In total, our data support the idea that altered β-cell prohormone processing does not impact obesity but can contribute to the pathogenesis of diabetes via β-cell dysfunction. Disclosure A. Taylor: None. Y. Chen: None. D. Pasula: None. D. S. Luciani: None. B. Verchere: Advisory Panel; Self; Integrated Nanotherapeutics Inc., Sirona Biochem, Stock/Shareholder; Self; Integrated Nanotherapeutics Inc. Funding Canadian Institutes of Health Research

Dietary Supplementation with Curcumin Reduce Circulating Levels of Glycogen Synthase Kinase-3β and Islet Amyloid Polypeptide in Adults with High Risk of Type 2 Diabetes and Alzheimer's Disease.

Dietary supplementation with curcumin has been previously reported to have beneficial effects in people with insulin resistance, type 2 diabetes (T2D) and Alzheimer’s disease (AD). This study investigated the effects of dietary supplementation with curcumin on key peptides implicated in insulin resistance in individuals with high risk of developing T2D. Plasma samples from participants recruited for a randomised controlled trial with curcumin (180 mg/day) for 12 weeks were analysed for circulating glycogen synthase kinase-3 β (GSK-3β) and islet amyloid polypeptide (IAPP). Outcome measures were determined using ELISA kits. The homeostasis model for assessment of insulin resistance (HOMA-IR) was measured as parameters of glycaemic control. Curcumin supplementation significantly reduced circulating GSK-3β (−2.4 ± 0.4 ng/mL vs. −0.3 ± 0.6, p = 0.0068) and IAPP (−2.0 ± 0.7 ng/mL vs. 0.4 ± 0.6, p = 0.0163) levels compared with the placebo group. Curcumin supplementation significantly reduced insulin resistance (−0.3 ± 0.1 vs. 0.01 ± 0.05, p = 0.0142) compared with placebo group. Dietary supplementation with curcumin reduced circulating levels of IAPP and GSK-3β, thus suggesting a novel mechanism through which curcumin could potentially be used for alleviating insulin resistance related markers for reducing the risk of T2D and AD.

Levels of retinal IAPP are altered in Alzheimer's disease patients and correlate with vascular changes and hippocampal IAPP levels.

Islet amyloid polypeptide (IAPP) forms toxic aggregates in the brain of patients with Alzheimer's disease (AD). Whether IAPP also affects the retina in these patients is still unknown. Levels of IAPP in soluble and insoluble homogenate fractions of retina and hippocampus from AD patients and nondemented controls were analyzed using ELISA. Number of pericytes and vessel length were determined by analysis of immunostained retina and hippocampus. Insoluble retinal fractions of AD patients contained lower levels of unmodified IAPP, whereas soluble retinal fractions contained increased levels of the same. Total IAPP levels and pericyte numbers in retina mirrored corresponding variables in the hippocampus. Moreover, levels of total unmodified IAPP correlated negatively with the vessel length both in retina and hippocampus across the group and positively with pericyte numbers in retina in AD patients. Our studies indicate that changes in brain IAPP are reflected by corresponding levels in the retina. Our results also suggest modification of IAPP as an important event implicated in vascular changes associated with AD.

High Plasma Levels of Islet Amyloid Polypeptide in Young with New-Onset of Type 1 Diabetes Mellitus

Aims/HypothesisIslet amyloid polypeptide (IAPP) is a beta cell hormone secreted together with insulin upon glucose stimulation. IAPP participates in normal glucose regulation, but IAPP is also known for its ability to misfold and form islet amyloid. Amyloid fibrils form through smaller cell toxic intermediates and deposited amyloid disrupts normal islet architecture. Even though IAPP and amyloid formation are much discussed in type 2 diabetes, our aim was to study the significance of IAPP in type 1 diabetes.ResultsPlasma IAPP levels in children and adolescents with newly diagnosed type 1 diabetes (n = 224) were analysed and concentrations exceeding 100 pmol/L (127.2 – 888.7 pmol/L) were found in 11% (25/224). The IAPP increase did not correlate with C-peptide levels.Conclusions/InterpretationPlasma levels of IAPP and insulin deviate in a subpopulation of young with newly-diagnosed type 1 diabetes. The determined elevated levels of IAPP might increase the risk for IAPP misfolding and formation of cell toxic amyloid in beta cells. This finding add IAPP-aggregation to the list over putative pathological factors causing type 1 diabetes.

Lack of islet amyloid polypeptide/amylin-immunoreactivity in urine collected from healthy volunteers after ingestion of a carbohydrate-rich meal.

Islet amyloid polypeptide (IAPP), or amylin, is synthesized by beta cells in the islets of Langerhans of the pancreas. Plasma IAPP levels are highly elevated in patients with advanced renal failure. To investigate the involvement of the kidney in the clearance of IAPP, the response of plasma and urinary IAPP to a carbohydrate-rich meal was investigated in 14 healthy volunteers. Although plasma IAPP levels increased severalfold after the meal, no IAPP-immunoreactivity was detected in the urine samples up to 4 hours after the meal. This might be due to the fact that urinary IAPP levels are under the detection limit of the assay or, assuming the presence of IAPP in the primary urine, immunoreactive IAPP molecules may be processed by renal mechanisms in such a way that they are no longer recognized by the antibodies used in the radioimmunoassay. Processed IAPP molecules may be reabsorbed in the proximal tubules of the kidney and/or excreted.

Differential lipid profile and hormonal response in type 2 diabetes by exogenous insulin aspart versus the insulin secretagogue repaglinide, at the same glycemic control

Our aim was to study, at the same glycemic control, how treatment with either the insulin secretagogue repaglinide or exogenous insulin aspart affects endogenous insulin secretion, plasma insulin and IAPP (islet amyloid polypeptide) levels, GH-IGF (growth hormone-insulin-like growth factor) axis and plasma lipoprotein concentrations in patients with type 2 diabetes. Five patients, age 65.0+/-4.1 years (mean+/-SE), body weight 82.5+/-5.0 kg, BMI (body mass index) 27.7+/-1.5 kg/m(2) were treated for 10 weeks with repaglinide or insulin aspart in a randomized, cross-over study. At the end of each treatment a 24-h metabolic profile was performed. Blood glucose, C-peptide, free human insulin, free total (human and analogue) insulin, proinsulin, IAPP, IGF-I, IGFBP-1 (IGF binding protein-1), GHBP (growth hormone binding protein) and plasma lipoprotein concentrations were measured. Similar 24-h blood glucose profiles were obtained with repaglinide and insulin aspart treatment. During the repaglinide treatment, the meal related peaks of C-peptide and free human insulin were about twofold higher than during treatment with insulin aspart. Proinsulin, GHBP were higher and IAPP levels tended to be higher during repaglinide compared to insulin aspart. Postprandial plasma total cholesterol, triglycerides and apolipoprotein B concentrations were higher on repaglinide than on insulin aspart treatment. Our results show that, at the same glycemic control, treatment with exogenous insulin aspart in comparison with the insulin secretagogue repaglinide result in a lower endogenous insulin secretion, and a tendency towards a less atherogenic postprandial lipid profile.

Glucose Regulates Islet Amyloid Polypeptide Gene Transcription in a PDX1- and Calcium-dependent Manner

Islet amyloid polypeptide (IAPP) and insulin are expressed in the beta-cells of the islets of Langerhans. They are co-secreted in response to changes in glucose concentration, and their mRNA levels are also regulated by glucose. The promoters of both genes share similar cis-acting sequence elements, and both bind the homeodomain transcription factor PDX1, which plays an important role in the regulation of the insulin promoter and insulin mRNA levels by glucose. Here we examine the role of PDX1 in the regulation of the human IAPP promoter by glucose. The experiments were facilitated by the availability of a human beta-cell line (NES2Y) that lacks PDX1. NES2Y cells also lack operational K(ATP) channels, resulting in a loss of control of calcium signaling. We have previously used these cells to show that glucose regulation of the insulin gene is dependent on PDX1, but not calcium. In the mouse beta-cell line Min6, glucose (16 mm) stimulated a 3.5-4-fold increase in the activity of a -222 to +450 IAPP promoter construct compared with values observed in 0.5 mm glucose. In NES2Y cells, glucose failed to stimulate transcriptional activation of the IAPP promoter. Overexpression of PDX1 in NES2Y cells failed to reinstate glucose-responsive control of the IAPP promoter. Glucose effects on the IAPP promoter were observed only in the presence of PDX1 when normal calcium signaling was restored by overexpression of the two K(ATP) channel subunits SUR1 and Kir6.2. The importance of calcium was further emphasized by an experiment in which glucose-stimulated IAPP promoter activity was inhibited by the calcium channel blocker verapamil (50 microm). Verapamil was further shown to inhibit the stimulatory effect of glucose on IAPP mRNA levels. These results demonstrate that like the insulin promoter, glucose regulation of the IAPP promoter is dependent on the activity of PDX1, but unlike the insulin promoter, it additionally requires the activity of another, as yet uncharacterized factor(s), the activity of which is calcium-dependent.

Islet amyloid polypeptide and insulin relationship in a longitudinal study of the genetically obese (ob/ob) mouse.

Obese mice (Umeå ob/ob) and their lean litter-mates were investigated from 7 to 52 weeks of age with respect to the plasma concentration of islet amyloid polypeptide (IAPP) and insulin. Plasma levels of IAPP were highly elevated in the ob/ob mice and remained unchanged until age 33 weeks, after which a sudden significant increase occurred at age 40 weeks. The plasma concentration of insulin gradually increased from start to end and reached extremely high levels. In the lean mice, there were no age-related differences in plasma levels of IAPP and insulin, being of the same magnitude as in normal NMRI mice. The plasma IAPP/insulin molar ratio was similar in lean and obese mice until age 14 weeks. At 21 weeks, the ratio in the ob/ob mice had decreased dramatically and remained markedly (sixfold) lower than in the lean mice until the end of the study. The IAPP concentration in the pancreata of 21-week-old ob/ob mice was 25-fold higher than that in the lean mice. Immunohistochemically, a majority of the ob/ob mice displayed enlarged and more numerous pancreatic islets, compared with the lean mice, and the IAPP- and insulin-labeling intensity was equal for all animals. At the electron-microscopic level, there was an increase in the number of IAPP- and insulin-immunoreactive gold particles per whole granule area as well as per core granule area. We conclude that the dramatically increased IAPP levels in severely hyperinsulinemic ob/ob mice may be of importance for the development of insulin resistance. Further, the disproportionate secretion of IAPP and insulin in the adult obese mouse might indicate a disturbed negative feedback effect of IAPP on insulin secretory mechanisms, resulting in very high plasma insulin levels.

Sufficiency of postprandial plasma levels of islet amyloid polypeptide for suppression of feeding in rats.

Our objective was to study whether islet amyloid polypeptide (IAPP) produces satiety by an endocrine mechanism. We used a rat model to determine whether postprandial plasma levels of IAPP are comparable to those required to inhibit feeding when IAPP is administered by continuous intravenous infusion. Food intake in rats with aortic catheters increased plasma IAPP levels from a fasting level of 10.8 +/- 0.5 pM to a peak level of 19.0 +/- 1.0 pM at 2.2 +/- 0.5 h. In rats with jugular vein and aortic catheters, the threshold intravenous dose for IAPP suppression of feeding was between 1 and 3 pmol . kg-1 . min-1. The 3 pmol . kg-1 . min-1 dose decreased 4-h intake by approximately 25% by decreasing meal frequency rather than meal size. This dose increased plasma IAPP by approximately 24 pM. These results suggest that postprandial plasma levels of IAPP are not quite sufficient to independently produce satiety.

Islet Amyloid Polypeptide in Psammomys obesus (Sand Rat)

We investigated the possible relationship between islet amyloid polypeptide (IAPP) and the hyperinsulinemia and/or hyperglycemia that is seen in the desert-adapted gerbil Psammomys obesus, when the animal is transferred from a low-energy (LE) diet to a high-energy (HE) diet. The effects of vanadyl sulfate and transition from a HE to a LE diet on the diabetic state of the Psammomys were also studied. Psammomys maintained on a LE diet, showing normoinsulinemia and normoglycemia (group A), were used as controls. IAPP and insulin immunoreactivity in the islets of Langerhans was studied using the peroxidase-antiperoxidase technique and plasma levels of the two hormones were determined by radioimmunoassays. The islet immunoreactivity of both IAPP and insulin was significantly weaker in the hyperinsulinemic and hyperglycemic Psammomys (group C) compared to group A. Transfer to a LE diet resulted in complete recovery of the IAPP- and insulin-staining pattern to that seen in group A [group A--Rec (nutrition)]. The plasma IAPP levels of the group C animals were not significantly higher than in group A, while after vanadyl sulfate treatment the IAPP levels and IAPP/insulin ratios remained significantly higher [group A--Rec (vanadyl)]. At the same time the circulating levels of glucose and insulin were restored to normal. Conclusively, islet IAPP and insulin immunoreactivity disappeared and reappeared in parallel in Psammomys transferred to a HE diet and back to a LE diet. Furthermore, vanadyl sulfate treatment of the hyperinsulinemic and hyperglycemic animals normalized circulating glucose and insulin levels, but not IAPP levels, possibly due to a negative feedback effect of IAPP on insulin release.

Chronic low dose islet amyloid polypeptide infusion reduces food intake, but does not influence glucose metabolism, in unrestrained conscious rats: studies using a novel aortic catheterization technique.

Islet amyloid polypeptide (IAPP) is a 37-amino acid polypeptide coproduced with insulin in the beta-cells of the pancreatic islets. The physiological effects of IAPP have not been established. Although effects on glucose metabolism are seen only at pharmacological doses both in vitro and in vivo, effects on food intake have been shown at near-physiological concentrations. The aim of the present study was to investigate the effects of similar elevations of circulating plasma IAPP levels on glucose metabolism in rats and to evaluate the function of a novel aortic catheterization technique. In a cross-over design, two sets of experiments in which conscious unrestrained rats received chronic IAPP infusions at 0 and 2 or 0 and 7 pmol/kg min were performed. Peripheral glucose disposal was determined by means of the hyperinsulinemic euglycemic clamp technique. Chronic elevations of circulating IAPP at concentrations that reduced food intake [43.5 +/- 6.2 g (control) vs. 35.7 +/- 8.2 g (IAPP; P < 0.01) and 34.0 +/- 2.2 g (control) vs. 28.8 +/- 1.4 g (IAPP; P = 0.07) for the 7 and 2 pmol/kg x min experiments, respectively] had no effect on the glucose metabolic rate [GMR; 18.5 +/- 0.6 mmol/kg x h (control) vs. 18.7 +/- 0.9 mmol/kg x h (IAPP) and 14.4 +/- 0.7 mmol/kg x h (control) vs. 15.6 +/- 0.7 mmol/kg x h (IAPP) for the 7 and 2 pmol/kg x min experiments, respectively]. Thus, effects on glucose metabolism are unlikely to explain the anorectic effect of IAPP.

Chronic Low Dose Islet Amyloid Polypeptide Infusion Reduces Food Intake, But Does Not Influence Glucose Metabolism, in Unrestrained Conscious Rats: Studies Using a Novel Aortic Catheterization Technique

Islet amyloid polypeptide (IAPP) is a 37-amino acid polypeptide coproduced with insulin in the β-cells of the pancreatic islets. The physiological effects of IAPP have not been established. Although effects on glucose metabolism are seen only at pharmacological doses both in vitro and in vivo, effects on food intake have been shown at near-physiological concentrations. The aim of the present study was to investigate the effects of similar elevations of circulating plasma IAPP levels on glucose metabolism in rats and to evaluate the function of a novel aortic catheterization technique. In a cross-over design, two sets of experiments in which conscious unrestrained rats received chronic IAPP infusions at 0 and 2 or 0 and 7 pmol/kg·min were performed. Peripheral glucose disposal was determined by means of the hyperinsulinemic euglycemic clamp technique. Chronic elevations of circulating IAPP at concentrations that reduced food intake [43.5 ± 6.2 g (control) vs. 35.7 ± 8.2 g (IAPP; P < 0.01) and 34.0 ± 2.2 g (control) vs. 28.8 ± 1.4 g (IAPP; P = 0.07) for the 7 and 2 pmol/kg·min experiments, respectively] had no effect on the glucose metabolic rate [GMR; 18.5 ± 0.6 mmol/kg·h (control) vs. 18.7 ± 0.9 mmol/kg·h (IAPP) and 14.4 ± 0.7 mmol/kg·h (control) vs. 15.6 ± 0.7 mmol/kg·h (IAPP) for the 7 and 2 pmol/kg·min experiments, respectively]. Thus, effects on glucose metabolism are unlikely to explain the anorectic effect of IAPP.

Renal Elimination of Islet Amyloid Polypeptide

Six healthy volunteers showed significantly higher plasma islet amyloid polypeptide levels following an oral glucose tolerance test compared to fasting levels. The urine IAPP concentration before and after the OGTT was comparable to that in plasma. Reverse phase HPLC and radioimmunoassay analysis of urine samples revealed a single IAPP-immunoreactive peak. Before hemodialysis, the plasma levels of IAPP and C-peptide, but not of insulin, were significantly elevated in eight fasting patients with chronic renal failure, compared to eight healthy matched control subjects. After hemodialysis, there was a tendency for decreased IAPP levels compared to before dialysis. In summary, elevated levels of plasma IAPP were found in patients with chronic renal failure and the peptide is eliminated by hemodialysis. Furthermore, immunoreactive IAPP is normally present in the urine. These results suggest that IAPP is, at least in part, renally eliminated from the plasma by excretion (glomerular filtration and/or tubular secretion).

Pancreatic cancer in rats and hamsters does not induce IAPP-related hyperglycaemia.

Many patients with exocrine pancreatic cancer develop diabetes mellitus due to insulin resistance. This may relate to concurrent over-production of islet amyloid polypeptide (IAPP) by the pancreatic beta cells. We investigated the effects of pancreatic cancer on circulating IAPP and glucose homeostasis in azaserine-treated rats (developing acinar pancreatic tumours) and BOP-treated hamsters (developing ductular pancreatic tumours). Glucose, insulin and IAPP levels in plasma were neither affected in azaserine-only treated rats nor in animals with enhanced carcinogenesis after chronic caerulein treatment. Azaserine-treated rats on a high-fat diet had decreased insulin levels and enhanced IAPP/insulin ratios in plasma, without hyperglycaemia. All BOP-treated hamsters showed pancreatic carcinogenesis at 6 months post-treatment. Supranormal plasma glucose levels in animals on a low-fat diet were the only change observed. After a second 6-month period, subnormal plasma glucose levels, at least 4-fold decreased plasma insulin and up to 2-fold decreased plasma IAPP levels were present in all hamsters. Remarkably, both in azaserine-treated rats on high-fat and in BOP-treated hamsters, decreased insulin levels and elevated IAPP/insulin ratios are not associated with hyperglycaemia. In contrast to humans with pancreatic cancer, IAPP over-production and hyperglycaemia do not develop in rats and hamsters with (pre-)neoplastic pancreatic lesions.

Pancreatic cancer in rats and hamsters does not induce IAPP‐related hyperglycaemia

Many patients with exocrine pancreatic cancer develop diabetes mellitus due to insulin resistance. This may relate to concurrent over-production of islet amyloid polypeptide (IAPP) by the pancreatic beta cells. We investigated the effects of pancreatic cancer on circulating IAPP and glucose homeostasis in azaserine-treated rats (developing acinar pancreatic tumours) and BOP-treated hamsters (developing ductular pancreatic tumours). Glucose, insulin and IAPP levels in plasma were neither affected in azaserine-only treated rats nor in animals with enhanced carcinogenesis after chronic caerulein treatment. Azaserine-treated rats on a high-fat diet had decreased insulin levels and enhanced IAPP/insulin ratios in plasma, without hyperglycaemia. All BOP-treated hamsters showed pancreatic carcinogenesis at 6 months post-treatment. Supranormal plasma glucose levels in animals on a low-fat diet were the only change observed. After a second 6-month period, subnormal plasma glucose levels, at least 4-fold decreased plasma insulin and up to 2-fold decreased plasma IAPP levels were present in all hamsters. Remarkably, both in azaserine-treated rats on high-fat and in BOP-treated hamsters, decreased insulin levels and elevated IAPP/insulin ratios are not associated with hyperglycaemia. In contrast to humans with pancreatic cancer, IAPP over-production and hyperglycaemia do not develop in rats and hamsters with (pre-)neoplastic pancreatic lesions. Int. J. Cancer 72:637–641, 1997. © 1997 Wiley-Liss, Inc.

Islet hormone secretion in pancreatic cancer patients with diabetes.

The diabetes or impaired glucose tolerance that occurs in most patients with pancreatic cancer is characterized by profound insulin resistance. Recent evidence suggests that the diabetes may result from the presence of the tumor rather than being a predisposing factor to development of the malignancy. Some islet hormones have been shown to exhibit diabetogenic effects. To investigate the potential role of these hormones in the diabetic state associated with pancreatic cancer, we measured islet hormones during fasting in pancreatic cancer patients (n = 30), patients with other malignancies (n = 43), and healthy controls (n = 25). Preoperative pancreatic cancer patients were classified as normal glucose tolerance (NGTT), impaired glucose tolerance (IGTT), non-insulin-requiring diabetes (NIRD), and insulin-requiring diabetes (IRD). Nine pancreatic cancer patients were studied after tumor removal by subtotal pancreatectomy. Some preoperative pancreatic cancer patients (n = 19), postoperative patients (n = 9), and controls (n = 8) were also studied during hyperglycemia and following glucagon injection. Fasting plasma C-peptide was elevated in NIRD pancreatic cancer patients compared to controls. Fasting levels of islet amyloid polypeptide (IAPP), glucagon, and somatostatin were elevated in NIRD and IRD patients. IAPP and glucagon, but not somatostatin, normalized following subtotal pancreatectomy. During hyperglycemia, increases in C-peptide and IAPP were seen only in controls and in NGTT and postoperative pancreatic cancer patients. After glucagon infusion, IAPP levels increased in controls and nondiabetic cancer patients; C-peptide levels increased in controls, nondiabetic patients, and NIRD. Responses of C-peptide and IAPP to glucagon normalized after pancreatectomy. During hyperglycemia, glucagon levels fell in all groups except IGTT patients and a decrease in somatostatin concentrations was seen in controls.

Islet amyloid polypeptide (amylin) does not seem to be directly involved in the development of gestational diabetes mellitus.

In order to define the islet amyloid polypeptide (IAPP) levels in gestational diabetes mellitus (GDM) and their interrelationship with the insulin levels, we studied (1) the placental RNA from 10 women (5 with GDM and 5 normals) for IAPP expression by Northern blotting and (2) 10 women with GDM during a 100-gram oral glucose tolerance test and compared these with 11 normal women matched for obesity and age. Plasma levels of glucose, IAPP, insulin, and C peptide were determined. No IAPP expression was detected in any of the placentae after a long exposure. We could not demonstrate any differences in plasma IAPP levels (basal or stimulated) between the two groups of pregnant women. However, in women with GDM we found a lower IAPP/insulin ratio (p < 0.05) and a lower maximal IAPP/maximal insulin response ratio during the oral glucose tolerance test (p < 0.05) than in normal women. Therefore, IAPP does not appear to be directly involved in the development of GDM. The peripheral levels of IAPP relative to insulin are lower in GDM, a finding similar to that described in type 2 diabetes mellitus (non-insulin-dependent diabetes mellitus). This observation further confirms that GDM resembles the early stages of type 2 diabetes mellitus.