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Islet amyloidosis in a child with type 1 diabetes.

ABSTRACT: Histopathology based studies of the pancreas obtained from organ donors are increasing our awareness of islet phenotypic heterogeneity during development and aging, as well as in settings of type 1 diabetes, type 2 diabetes, monogenic diabetes or other forms of this metabolic disease. Islet amyloidosis represents a histopathological feature classically ascribed to patients with type 2 diabetes. Herein, the occurrence of islet amyloidosis and its severity are reported in a child with type 1 diabetes along with histological comparisons of islet amyloidosis in two young adults with recent-onset type 1 diabetes. Islet amyloidosis was infrequent yet widely distributed throughout the pancreas in the child with type 1 diabetes and both adults with type 1 diabetes, with no such pathology seen in matched control donors. Analysis of these cases add to the increasing appreciation of islet heterogeneity in children and young adults with type 1 diabetes. Such knowledge also supports a notion that multiple pathophysiological mechanisms underlie the loss of functional ?-cell mass in the spectrum of clinical phenotypes in patients with type 1 diabetes.

SUBMITTER: Beery ML

PROVIDER: S-EPMC6548483 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Islet amyloidosis in a child with type 1 diabetes.

Beery Maria L ML Jacobsen Laura M LM Atkinson Mark A MA Butler Alexandra E AE Campbell-Thompson Martha M

Islets 20190514 2

Histopathology based studies of the pancreas obtained from organ donors are increasing our awareness of islet phenotypic heterogeneity during development and aging, as well as in settings of type 1 diabetes, type 2 diabetes, monogenic diabetes or other forms of this metabolic disease. Islet amyloidosis represents a histopathological feature classically ascribed to patients with type 2 diabetes. Herein, the occurrence of islet amyloidosis and its severity are reported in a child with type 1 diabe ...[more]

PMID: 31084520

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Project description:Aims/hypothesisSphingolipids play important roles in beta cell physiology, by regulating proinsulin folding and insulin secretion and in controlling apoptosis, as studied in animal models and cell cultures. Here we investigate whether sphingolipid metabolism may contribute to the pathogenesis of human type 1 diabetes and whether increasing the levels of the sphingolipid sulfatide would prevent models of diabetes in NOD mice.MethodsWe examined the amount and distribution of sulfatide in human pancreatic islets by immunohistochemistry, immunofluorescence and electron microscopy. Transcriptional analysis was used to evaluate expression of sphingolipid-related genes in isolated human islets. Genome-wide association studies (GWAS) and a T cell proliferation assay were used to identify type 1 diabetes related polymorphisms and test how these affect cellular islet autoimmunity. Finally, we treated NOD mice with fenofibrate, a known activator of sulfatide biosynthesis, to evaluate the effect on experimental autoimmune diabetes development.ResultsWe found reduced amounts of sulfatide, 23% of the levels in control participants, in pancreatic islets of individuals with newly diagnosed type 1 diabetes, which were associated with reduced expression of enzymes involved in sphingolipid metabolism. Next, we discovered eight gene polymorphisms (ORMDL3, SPHK2, B4GALNT1, SLC1A5, GALC, PPARD, PPARG and B4GALT1) involved in sphingolipid metabolism that contribute to the genetic predisposition to type 1 diabetes. These gene polymorphisms correlated with the degree of cellular islet autoimmunity in a cohort of individuals with type 1 diabetes. Finally, using fenofibrate, which activates sulfatide biosynthesis, we completely prevented diabetes in NOD mice and even reversed the disease in half of otherwise diabetic animals.Conclusions/interpretationThese results indicate that islet sphingolipid metabolism is abnormal in type 1 diabetes and suggest that modulation may represent a novel therapeutic approach.Data availabilityThe RNA expression data is available online at https://www.dropbox.com/s/93mk5tzl5fdyo6b/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%2C%20RNA%20expression.xlsx?dl=0 . A list of SNPs identified is available at https://www.dropbox.com/s/yfojma9xanpp2ju/Abnormal%20islet%20sphingolipid%20metabolism%20in%20type%201%20diabetes%20SNP.xlsx?dl=0 .

Dataset Information

Islet amyloidosis in a child with type 1 diabetes.

Publications

Islet amyloidosis in a child with type 1 diabetes.

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