Amylin Deposition Research Articles

Analyzing Amylin Aggregation Inhibition Through Quantum Dot Fluorescence Imaging.

Protein aggregation is associated with various diseases caused by protein misfolding. Among them, amylin deposition is a prominent feature of type 2 diabetes. At present, the mechanism of amylin aggregation remains unclear, and this has hindered the treatment of type 2 diabetes. In this study, we analyzed the aggregation process of amylin using the quantum dot (QD) imaging method. QD fluorescence imaging revealed that in the presence of 100 μM amylin, aggregates appeared after 12 h of incubation, while a large number of aggregates formed after 24 h of incubation, with a standard deviation (SD) value of 5.435. In contrast, 50 μM amylin did not induce the formation of aggregates after 12 h of incubation, although a large number of aggregates were observed after 24 h of incubation, with an SD value of 2.883. Confocal laser microscopy observations revealed that these aggregates were deposited in three dimensions. Transmission electron microscopy revealed that amylin existed as misfolded fibrils in vitro and that QDs were uniformly bound to the amylin fibrils. In addition, using a microliter-scale high-throughput screening (MSHTS) system, we found that rosmarinic acid, a polyphenol, inhibited amylin aggregation at a half-maximal effective concentration of 852.8 μM. These results demonstrate that the MSHTS system is a powerful tool for evaluating the inhibitory activity of amylin aggregation. Our findings will contribute to the understanding of the pathogenesis of amylin-related diseases and the discovery of compounds that may be useful in the treatment and prevention of these diseases.

Metabolites from Marine Macroorganisms of the Red Sea Acting as Promoters or Inhibitors of Amylin Aggregation.

Amylin is part of the endocrine pancreatic system that contributes to glycemic control, regulating blood glucose levels. However, human amylin has a high tendency to aggregate, forming isolated amylin deposits that are observed in patients with type 2 diabetes mellitus. In search of new inhibitors of amylin aggregation, we undertook the chemical analyses of five marine macroorganisms encountered in high populations in the Red Sea and selected a panel of 10 metabolites belonging to different chemical classes to evaluate their ability to inhibit the formation of amyloid deposits in the human amylin peptide. The thioflavin T assay was used to examine the kinetics of amyloid aggregation, and atomic force microscopy was employed to conduct a thorough morphological examination of the formed fibrils. The potential ability of these compounds to interact with the backbone of peptides and compete with β-sheet formation was analyzed by quantum calculations, and the interactions with the amylin peptide were computationally examined using molecular docking. Despite their structural similarity, it could be observed that the hydrophobic and hydrogen bond interactions of pyrrolidinones 9 and 10 with the protein sheets result in one case in a stable aggregation, while in the other, they cause distortion from aggregation.

1549-P: Hyperamylinemia and Its Implications on Brain Function—Amylin Deposition and Cognitive Alterations—A Cross-Sectional Study

1549-P: Hyperamylinemia and Its Implications on Brain Function—Amylin Deposition and Cognitive Alterations—A Cross-Sectional Study

Abstract 18136: Efficacy and Safety of Catheter Ablation for Atrial Arrhythmias in Patients With Cardiac Amyloidosis - A Systematic Review and Proportional Meta-Analysis

Background Cardiac amyloidosis (CA) is a restrictive cardiomyopathy characterised by amylin deposits in the heart muscle. While the prevalence of atrial arrhythmias in CA is high, the data regarding the outcomes of catheter ablation in these patients is limited. Our current study aims to elucidate the safety & efficacy of catheter ablation for treating atrial arrhythmias in patients with CA. Methods: We conducted a comprehensive literature search across MEDLINE & Scopus from inception till May 2023 for randomized control trials & observational studies reporting catheter ablation (cryoablation or radiofrequency ablation) for the treatment of atrial arrhythmias (AAs) (atrial flutter, atrial fibrillation, atrial tachycardia) in patients with cardiac amyloidosis (transthyretin or light-chain). The primary outcomes of interest were pooled recurrence & re-ablation rates. The secondary outcome was all-cause mortality. All data was analyzed using the Hedges-Olkin random-effects model & presented as percentage proportions. Results: A total of 6 cohort studies with 154 cardiac amyloidosis patients with atrial fibrillation were included. The pooled incidence of repeat ablation was 16.4% [(6.2%, 26.7%), p=0.002)] & recurrence rate was 47.9% [(25.2%, 70.5%), p<0.001)]. The pooled incidence of all-cause mortality in these patients was 37.1% [(25.1%, 49.1%), p<0.001)]. Conclusion High rate of recurrence & need for re-ablation coupled with high mortality demands better patient selection. Prospective & randomized controlled data is needed to better study the outcomes of catheter ablation in these patients.

Skin capillary amylin deposition resembles brain amylin vasculopathy in rats

Background and purposeHuman amylin is a 37 amino-acid pancreatic peptide that forms neuro-toxic aggregates that deposit in the endothelium of brain capillaries of patients with diabetes, potentially contributing to cerebral small vessel ischemic injury. Pathogenic amylin also deposits in the capillary endothelium in other organs, including the skin. The aim of this study was to test the hypothesis that skin capillary amylin deposition correlates with cerebral small vessel amylin deposition, potentially providing a clinically useful marker of cerebral amylin deposition. MethodsImmunohistochemistry (IHC) was performed for human amylin and collagen IV in brain and skin sections of rats (age 15–16 months) with pancreatic overexpression of amyloidogenic human amylin polypeptide (HIP rats), and control rats (Wild type; WT; rats that express non-amyloidogenic rat amylin) using antibodies binding amylin (n = 5 male and 5 female rats for each group) and antibodies binding Hypoxia inducing factor (HIF)-1α and HIF-2α (n = 3 for each group). The reactive amylin-aldehyde 4-hydroxynonenal (4-HNE) adduct was measured in skin homogenates. (n = 4 for each group) ResultsBrain capillaries isolated from HIP rats had higher amylin content compared to WT rats using Western blot with anti-amylin antibody (p = 0.0010). The HIF-1α and HIF-2α immunoreactivity signals in skin from HIP and WT rats were similar (p = 0.2 for HIF-1 α, and p = 0.75 for HIF-2α). Amylin-4HNE adduct formation was higher in HIP rats compared to WT rats (p = 0.0014). There was phenotypic similarity between brain and skin capillary amylin based on co-staining for human amylin and collagen IV in both HIP and WT rats. ConclusionSkin and brain capillary amylin deposition are similar providing evidence that a skin biopsy might be providing a potential biomarker for diabetes-associated intracranial vasculopathy.

Disease-associated astrocytes and microglia markers are upregulated in mice fed high fat diet

High-fat diet (HFD) is associated with Alzheimer’s disease (AD) and type 2 diabetes risk, which share features such as insulin resistance and amylin deposition. We examined gene expression associated with astrocytes and microglia since dysfunction of these cell types is implicated in AD pathogenesis. We hypothesize gene expression changes in disease-associated astrocytes (DAA), disease-associated microglia and human Alzheimer’s microglia exist in diabetic and obese individuals before AD development. By analyzing bulk RNA-sequencing (RNA-seq) data generated from brains of mice fed HFD and humans with AD, 11 overlapping AD-associated differentially expressed genes were identified, including Kcnj2, C4b and Ddr1, which are upregulated in response to both HFD and AD. Analysis of single cell RNA-seq (scRNA-seq) data indicated C4b is astrocyte specific. Spatial transcriptomics (ST) revealed C4b colocalizes with Gfad, a known astrocyte marker, and the colocalization of C4b expressing cells with Gad2 expressing cells, i.e., GABAergic neurons, in mouse brain. There also exists a positive correlation between C4b and Gad2 expression in ST indicating a potential interaction between DAA and GABAergic neurons. These findings provide novel links between the pathogenesis of obesity, diabetes and AD and identify C4b as a potential early marker for AD in obese or diabetic individuals.

The association between renal accumulation of pancreatic amyloid-forming amylin and renal hypoxia.

Chronic kidney disease (CKD) is increasing worldwide and is associated with diabetic states (obesity, prediabetes and type-2 diabetes mellitus). The kidney is intrinsically susceptible to low oxygen (hypoxia) and renal hypoxia plays a vital role in the progression of CKD. Recent studies suggest an association between CKD and renal deposition of amyloid-forming amylin secreted from the pancreas. Renal accumulation of amyloid-forming amylin is associated with hypertension, mitochondrial dysfunction, increased production of reactive oxygen species (ROS) and activation of hypoxia signaling in the kidney. In this review we will discuss potential associations between renal amylin amyloid accumulation, hypertension, and mechanism of hypoxia-induced kidney dysfunction, including activation of hypoxia-inducible factors (HIFs) and mitochondrial dysfunction.

Aβ efflux impairment and inflammation linked to cerebrovascular accumulation of amyloid-forming amylin secreted from pancreas

Impairment of vascular pathways of cerebral β-amyloid (Aβ) elimination contributes to Alzheimer disease (AD). Vascular damage is commonly associated with diabetes. Here we show in human tissues and AD-model rats that bloodborne islet amyloid polypeptide (amylin) secreted from the pancreas perturbs cerebral Aβ clearance. Blood amylin concentrations are higher in AD than in cognitively unaffected persons. Amyloid-forming amylin accumulates in circulating monocytes and co-deposits with Aβ within the brain microvasculature, possibly involving inflammation. In rats, pancreatic expression of amyloid-forming human amylin indeed induces cerebrovascular inflammation and amylin-Aβ co-deposits. LRP1-mediated Aβ transport across the blood-brain barrier and Aβ clearance through interstitial fluid drainage along vascular walls are impaired, as indicated by Aβ deposition in perivascular spaces. At the molecular level, cerebrovascular amylin deposits alter immune and hypoxia-related brain gene expression. These converging data from humans and laboratory animals suggest that altering bloodborne amylin could potentially reduce cerebrovascular amylin deposits and Aβ pathology.

Cerebrovascular accumulation of amyloid‐forming amylin secreted from the pancreas induces brain hypoxia

AbstractBackgroundIslet amyloid polypeptide (amylin) is a β‐cell hormone co‐secreted with insulin. Histological analyses of human brains identified amylin deposits co‐localized with parenchymal and vascular β‐amyloid in humans with vascular cognitive impairment and Alzheimer’s dementia. Because circulating amyloid‐forming amylin triggers systemic hypoxia signaling, we sought to determine the relationship between circulating amylin levels and brain hypoxia markers in a transgenic rat model of amylin‐mediated neurological deficits.MethodTo assess amylin‐related brain hypoxia signaling, we performed a 16‐month longitudinal study in which rats that express amyloid‐forming human amylin in pancreatic β‐cells (HIP rats) were compared to wild type (WT) littermates that express non‐amyloidogenic rodent amylin (n=10 rats/group).ResultBlood amylin levels measured by ELISA were ∼2‐fold higher in 16‐month old HIP rats compared to WT littermates (P<0.01). The Thiovlavin T (Th T) fluorescence signal intensity in blood lysates from HIP rats increased compared to that in WT littermates indicating the presence of amyloid‐forming in the circulation in HIP rats (P<0.01). This was associated with higher amylin concentration in brain microvessel lysates (P<0.05) and amylin immunoreactivity signal intensity in brain sections. Plasma erythropoietin, a marker of systemic hypoxia was higher in HIP rats than in WT littermates (P<0.05), which correlated with brain accumulation of HIF‐2α (P<0.05) and HIF‐1α (P=0.07), and with altered mitochondrial DNA in brain tissue (P<0.05).ConclusionIncreased circulating levels of amyloid‐forming amylin promotes cerebrovascular amylin deposition leading to brain hypoxic‐ischemic injury. Future studies need to address functional effects of amylin‐induced brain hypoxia signaling in the brain.

Amyloidogenic amylin deposits on red blood cells of stroke patients

AbstractBackgroundAmylin, a 37‐residue amyloidogenic peptide, is co‐secreted with insulin by pancreatic beta‐cells (Verma et al. 2020). Vascular deposition of amylin has been noted in patients with diabetes and neurocognitive disorders (Ly et al., 2017) Emergent large vessel occlusions (ELVOs) result in severe ischemic strokes without appropriate treatment. Growth factors, including erythropoietin (EPO), are involved in post‐stroke recovery as a potential neuroprotectant target, inhibiting apoptosis and decreasing inflammation (Jerndal et al., 2010). Here, amylin accumulation in plasma, red blood cells (RBCs), and ELVOs (where available) and plasma EPO levels were compared between stroke and control patients. Due to amylin’s amyloidogenic propensity, we hypothesized that there would be an association between amylin uptake and stroke incidence.MethodA prospective registry (Blood and Clot Thrombectomy Registry and Collaboration; BACTRAC) was developed to analyze blood and thrombus directly in patients presenting with an ELVO. Total protein concentration and amylin concentrations of clot lysates, plasma, and RBC lysates were obtained via bicinchoninic acid assay (BCA) and competitive enzyme‐linked immunosorbent assay (ELISA), respectively. Plasma EPO concentrations were obtained via ELISA. An amylin uptake coefficient (the level of amylin in RBC lysates divided by the sum of amylin present in RBC lysates and plasma) was calculated to determine the degree to which circulating amylin is depositing on RBCs.ResultDue to a significant difference between control and stroke RBCs (p = 0.0012, Figure 1) in total protein concentration, all downstream analyses were normalized to respective protein concentrations. A significant difference in amylin uptake by RBCs between stroke and control patients is shown in Figure 2 (p = 0.0073). An uptake coefficient greater than 0.50 indicates uptake of amylin by RBCs. Finally, a significant difference in plasma EPO concentration was observed between stroke and control (p = 0.0017; Figure 3).ConclusionConsistent with our hypotheses, the present data indicates that amylin uptake by RBCs is significantly increased in stroke patients than in control patients. However, both groups show evidence of accumulation, as indicated by uptake coefficients greater than 0.50. Further, levels of erythropoietin are significantly increased in stroke patients. Further investigation into whether amylin may be thrombogenic is warranted.

Amylin: new insight into pathogenesis, diagnosis, and prognosis of non-insulin-dependent diabetes-mellitus-related cardiomyopathy

Abstract Co-secretion with insulin, highly amyloidogenic human amylin is considered to contribute to the initiation and progression of diabetic heart complications, despite other situations such as hypertension and atherosclerosis. In response to insulin resistance, hyperinsulinemia, and consequently hyperamylinemia, is common in prediabetic patients, where highly concentrated amylin is prone to form amylin oligomers, which further assemble into fibrils and amyloids with high β-sheet content. The infusion and deposition of oligomeric amylin in myocytes cause a series of consequences, including cytosolic Ca2+ dysregulation, calmodulin activation, myocyte hypertrophy, and ventricular stiffness, eventually leading to heart failure. In this review, we present the latest reports of amylin-related heart complications, provide new insights, and state the underlying pathogenesis, diagnosis, possible treatment, and prevention of diabetic cardiomyopathy.

Amyloid-β removal from the brain is blocked by circulating amyloid-forming amylin secreted by the pancreas.

Increasing amyloid-β (Aβ) transport from the brain provides a novel therapeutic approach for Alzheimer's disease (AD). Our team recently showed: 1, the brain microvasculature accumulates amylin, an amyloid-forming hormone secreted from the pancreas, in both familial and sporadic forms of AD; 2, amylin and Aβ often co-localize in the brain parenchyma and microvasculature; 3, cerebrovascular amylin deposition is associated with behavioral deficits in rats, independent of Aβ pathology; and 4, pancreatic expression of human amylin in APPswe/PS1dE9 (APP/PS1) rats accelerates the development of AD-like pathology. We tested the hypothesis that the removal of Aβ from the brain is in part affected by amylin deposition in the brain microvasculature. Amylin levels were measured in blood from 38 cognitively impaired and 41 cognitively unimpaired individuals. Evidence of amylin-Aβ co-localization was assessed in brain slices from 56 persons with AD and 37 cognitively unaffected individuals. To explore the potential mechanisms by which amylin might affect Aβ transport, we genetically manipulated amylin secretion in APP/PS1 and non-APP/PS1 rats. Average blood amylin levels were higher in those with dementia (DEM) or mild cognitive impairment (MCI) compared to those who were cognitively unimpaired (CU) (8.0 ± 2.2 pM vs. 4.7 ± 1.4 pM vs. 2.8 ± 0.5 pM; one-way ANOVA, P < 0.0001). In human AD brains and brains of APP/PS1 rats with pancreatic expression of amyloid-forming human amylin, Aβ accumulation within the perivascular space frequently co-localized with amylin deposits. In non-APP/PS1 rats expressing human amylin, amylin accumulated in brain capillaries which induced downregulation of the low-density lipoprotein receptor-related protein 1 (LRP1), the Aβ transport protein, and was associated with a lower plasma-to-brain Aβ ratio compared to wild type littermates (0.52 ± 0.01 vs. 0.64 ± 0.02, P = 0.0021). Systemic amylin dyshomeostasis leads to amylin accumulation in small cerebral vessels causing cerebral microvascular dysfunction and interference with vascular routes for Aβ removal from the brain. Lowering the blood amylin level in early AD could improve Aβ clearance from the brain.

Amylin-mediated regulation of LRP1 by miR-103/107 impairs β-amyloid efflux.

To determine whether systemic pancreatic amylin dyshomeostasis impairs the efflux of amyloid-β (Aβ) across the blood-brain barrier (BBB), we studied cerebral microvessels in humans and a rat model of pancreatic amylin dyshomeostasis, and evaluated the effect of human amylin in an in vitro BBB model. Brain sections from Alzheimer's Disease (AD) and cognitively unimpaired individuals were co-stained with anti-Aβ and anti-amylin antibodies. In vivo analyses of Aβ efflux across the BBB were carried out in aged rats that express amyloid-forming human amylin in pancreatic β-cells and littermates expressing non-amyloidogenic rat amylin. We also used an in vitro BBB model of Aβ transcytosis in which the endothelial cell monolayer was exposed to amylin-mediated stress to determine whether amylin stress downregulates LRP1, the Aβ efflux transporter. This allowed us to use pharmacology to rescue the endothelial LRP1 RESULT: In human AD brains, Aβ accumulation within the perivascular space frequently co-localizes with deposits of amylin in the vessel wall. In rats with pancreatic expression of amyloid-forming human amylin, the high blood levels of human amylin promote amylin deposition in brain capillaries, increase brain Aβ level, lower plasma-to-brain Aβ ratio and suppress expression of LRP1 protein. In vitro BBB model experiment revealed that amylin-induced stress downregulates LRP1 in endothelial cells through a miRNA-based translational repression mechanism. High blood human amylin levels cause cerebral microvascular dysfunction and interferes with Aβ efflux across the BBB through miRNA-mediated LRP1 downregulation. Lowering blood amylin level in early AD could improve Aβ clearance from the brain.

Amylin Dyshomeostasis Hypothesis: Small Vessel-Type Ischemic Stroke in the Setting of Type-2 Diabetes.

Recent histological analyses of human brains show that small vessel-type injuries in the setting of type-2 diabetes colocalize with deposits of amylin, an amyloid-forming hormone secreted by the pancreas. Amylin inclusions are also identified in circulating red blood cells in people with type-2 diabetes and stroke or cardiovascular disease. In laboratory models of type-2 diabetes, accumulation of aggregated amylin in blood and the cerebral microvasculature induces brain microhemorrhages and reduces cerebral blood flow leading to white matter ischemia and neurological deficits. At the cellular level, aggregated amylin causes cell membrane lipid peroxidation injury, downregulation of tight junction proteins, and activation of proinflammatory signaling pathways which, in turn, induces macrophage activation and macrophage infiltration in vascular areas positive for amylin deposition. We review each step of this cascade based on experimental and clinical evidence and propose the hypothesis that systemic amylin dyshomeostasis may underlie the disparity between glycemic control and stroke risk and may be a therapeutic target to reduce the risk of small vessel ischemic stroke in patients with type-2 diabetes.

Mixed pathologies in pancreatic \u03b2 cells from subjects with neurodegenerative diseases and their interaction with prion protein

Protein misfolding diseases refer to a variety of disorders that develop as a consequence of the misfolding of proteins in various organs. The etiologies of Parkinson’s and Alzheimer’s disease remain unclear, but it seems that type two diabetes and other prediabetic states could contribute to the appearance of the sporadic forms of these diseases. In addition to amylin deposition, other amyloidogenic proteins implicated in the pathophysiology of neurodegenerative diseases could have important roles in the pathogenesis of this disease. As we have previously demonstrated the presence of α-synuclein deposits in the pancreas of patients with synucleinopathies, as well as tau and Aβ deposits in the pancreatic tissue of Alzheimer’s disease patients, we studied the immunoreactivity of amylin, tau and α-synuclein in the pancreas of 138 subjects with neurodegenerative diseases or type two diabetes and assessed whether the pancreatic β-cells of these subjects present cooccurrence of misfolded proteins. Furthermore, we also assessed the pancreatic expression of prion protein (PrP) in these subjects and its interaction, both in the pancreas and brain, with α-synuclein, tau, Aβ and amylin. Our study shows, for the first time, that along with amylin, pancreatic α-synuclein, Aβ, PrP and tau may contribute together to the complex pathophysiology of type two diabetes and in the appearance of insulin resistance in Alzheimer’s and Parkinson’s disease. Furthermore, we show that the same mixed pathologies that are observed in the brains of patients with neurodegenerative diseases are also present outside the nervous system. Finally, we provide the first histological evidence of an interaction between PrP and Aβ, α-synuclein, amylin or tau in the pancreas and locus coeruleus. These findings will shed more light on the common pathological pathways shared by neurodegenerative diseases and type two diabetes, benefiting the exploration of common therapeutic strategies to prevent or treat these devastating amyloid diseases.

Curcumin and its analog alleviate diabetes-induced damages by regulating inflammation and oxidative stress in brain of diabetic rats

BackgroundDiabetic encephalopathy is a severe diabetes complication with cognitive dysfunction and neuropsychiatric disability. The mechanisms underlying diabetic encephalopathy is believed to be relevant with oxidative stress, vascular amylin deposition, immune receptors, inflammation, etc. This study wanted to evaluate the ability of curcumin and its analog A13 to alleviate oxidative stress and inflammation in diabetes-induced damages in brain.MethodsSixty adult male Sprague–Dawley rats were divided into 5 groups: normal control (NC) group, diabetes mellitus (DM) group, curcumin-treated diabetes mellitus (CUR) group, high dose of A13-treated diabetes mellitus (HA) group, low dose of A13-treated diabetes mellitus (LA) group. Activation of the nuclear factor kappa-B (NF-κB p65) pathway was detected by RT-qPCR, immunohistochemical (IHC) staining and Western blot; oxidative stress was detected by biochemical detection kit; brain tissue sections were stained with hematoxylin–eosin (HE) staining and Myelin staining.ResultsRT-qPCR, IHC staining and Western blot showed that curcumin and A13 treatment could inhibit the NF-κB p65 pathway. Curcumin and A13 increased the activity of superoxide dismutase and decreased the malondialdehyde level in the brain of diabetic rats. Furthermore, HE staining and Myelin staining demonstrated that the histological lesions of the brain in diabetic rats could be significantly ameliorated by curcumin and A13.ConclusionCurcumin analog A13 could alleviate the damages in the brain of diabetes rats by regulating the pathways of inflammation and oxidative stress. A13 may be a new potential therapeutic agent for diabetic encephalopathy.

Amylin deposition activates HIF1\u03b1 and 6-phosphofructo-2-kinase/fructose-2, 6-biphosphatase 3 (PFKFB3) signaling in failing hearts of non-human primates

Hyperamylinemia induces amylin aggregation and toxicity in the pancreas and contributes to the development of type-2 diabetes (T2D). Cardiac amylin deposition in patients with obesity and T2D was found to accelerate heart dysfunction. Non-human primates (NHPs) have similar genetic, metabolic, and cardiovascular processes as humans. However, the underlying mechanisms of cardiac amylin in NHPs, particularly related to the hypoxia inducible factor (HIF)1α and 6-phosphofructo-2-kinase/fructose-2,6-biphosphatase 3 (PFKFB3) signaling pathways, are unknown. Here, we demonstrate that in NHPs, amylin deposition in heart failure (HF) contributes to cardiac dysfunction via activation of HIF1α and PFKFB3 signaling. This was confirmed in two in vitro cardiomyocyte models. Furthermore, alterations of intracellular Ca2+, reactive oxygen species, mitochondrial function, and lactate levels were observed in amylin-treated cells. Our study demonstrates a pathological role for amylin in the activation of HIF1α and PFKFB3 signaling in NHPs with HF, establishing amylin as a promising target for heart disease patients.

Slowly Progressive Type 1 Diabetes Mellitus: Current Knowledge And Future Perspectives.

Slowly progressive type 1 insulin-dependent diabetes mellitus (SPIDDM), sometimes referred to as latent autoimmune diabetes in adults (LADA), is a heterogeneous disease that is often confused with type 1 and type 2 diabetes. As a result, there were few diagnostic criteria for this disorder until 2012, when the Japan Diabetes Society established criteria that could be used in clinical practice. A primary question is whether pathologic markers for type 1 or type 2 diabetes are present in the pancreas of patients with SPIDDM, because the phenotype of SPIDDM is similar to both type 1 and type 2 diabetes. Recent studies clarified pathologic findings in the pancreas of patients with SPIDDM, which included T-cell-mediated insulitis, a marker of type 1 diabetes; pseudoatrophic islets (islets specifically devoid of beta cells), another hallmark of type 1 diabetes; and a lack of amylin (ie, islet amyloid polypeptide) deposition to the islet cells, a pathologic marker of type 2 diabetes. In terms of preventing the loss of beta-cell function in patients with SPIDDM, several studies have shown that some drugs, including dipeptidyl peptidase-4 inhibitors, are effective. There is an increased need for early diagnosis of SPIDDM to preserve beta-cell function. This review presents updated findings on the pathogenesis and immunologic findings of the affected pancreas, diagnostic markers, risk factors for progression of beta-cell dysfunction, epidemiology, clinical features, diagnostic strategies, prevention strategies, and clinical options for patients with SPIDDM.

Diabetic microcirculatory disturbances and pathologic erythropoiesis are provoked by deposition of amyloid-forming amylin in red blood cells and capillaries

In the setting of type-2 diabetes, there are declines of structural stability and functionality of blood capillaries and red blood cells (RBCs), increasing the risk for microcirculatory disturbances. Correcting hyperglycemia is not entirely effective at reestablishing normal cellular metabolism and function. Therefore, identification of pathological changes occurring before the development of overt hyperglycemia may lead to novel therapeutic targets for reducing the risk of microvascular dysfunction. Here we determine whether RBC-capillary interactions are altered by prediabetic hypersecretion of amylin, an amyloid forming hormone co-synthesized with insulin, and is reversed by endothelial cell-secreted epoxyeicosatrienoic acids. In patients, we found amylin deposition in RBCs in association with type-2 diabetes, heart failure, cancer and stroke. Amylin-coated RBCs have altered shape and reduced functional (non-glycated) hemoglobin. Amylin-coated RBCs administered intravenously in control rats upregulated erythropoietin and renal arginase expression and activity. We also found that diabetic rats expressing amyloid-forming human amylin in the pancreas (the HIP rat model) have increased tissue levels of hypoxia-inducible transcription factors, compared to diabetic rats that express non-amyloid forming rat amylin (the UCD rat model). Upregulation of erythropoietin correlated with lower hematocrit in the HIP model indicating pathologic erythropoiesis. In the HIP model, pharmacological upregulation of endogenous epoxyeicosatrienoic acids protected the renal microvasculature against amylin deposition and also reduced renal accumulation of HIFs. Thus, prediabetes induces dysregulation of amylin homeostasis and promotes amylin deposition in RBCs and the microvasculature altering RBC-capillary interaction leading to activation of hypoxia signaling pathways and pathologic erythropoiesis. Hence, dysregulation of amylin homeostasis could be a therapeutic target for ameliorating diabetic vascular complications.

Amylin as a potential link between type 2 diabetes and alzheimer disease.

Alzheimer disease (AD) is the leading cause of dementia, and although its etiology remains unclear, it seems that type 2 diabetes mellitus (T2DM) and other prediabetic states of insulin resistance could contribute to the appearance of sporadic AD. As such, we have assessed whether tau and β-amyloid (Aβ) deposits might be present in pancreatic tissue of subjects with AD, and whether amylin, an amyloidogenic protein deposited in the pancreas of T2DM patients, might accumulate in the brain of AD patients. We studied pancreatic and brain tissue from 48 individuals with no neuropathological alterations and from 87 subjects diagnosed with AD. We examined Aβ and tau accumulation in the pancreas as well as that of amylin in the brain. Moreover, we performed proximity ligation assays to ascertain whether tau and/or Aβ interact with amylin in either the pancreas or brain of these subjects. Cytoplasmic tau and Aβ protein deposits were detected in pancreatic β cells of subjects with AD as well as in subjects with a normal neuropathological examination but with a history of T2DM and in a small cohort of control subjects without T2DM. Furthermore, we found amylin deposits in the brain of these subjects, providing histological evidence that amylin can interact with Aβ and tau in both the pancreas and hippocampus. The presence of both tau and Aβ inclusions in pancreatic β cells, and of amylin deposits in the brain, provides new evidence of a potential overlap in the mechanisms underlying the pathogenesis of T2DM and AD. ANN NEUROL 2019;86:539-551.