Alström syndrome: an ultra-rare monogenic disorder as a model for insulin resistance, type 2 diabetes mellitus and obesity

Endocrine ◽  
2021 ◽  
Author(s):  
Francesca Dassie ◽  
Francesca Favaretto ◽  
Silvia Bettini ◽  
Matteo Parolin ◽  
Marina Valenti ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Monogenic Disorder ◽  
Alström Syndrome ◽  
Alstrom Syndrome

scholarly journals Genomic knockout of alms1 in zebrafish recapitulates Alström syndrome and provides insight into metabolic phenotypes

2018 ◽  
Author(s):  
Jessica E. Nesmith ◽  
Timothy L. Hostelley ◽  
Carmen C. Leitch ◽  
Maggie S. Matern ◽  
Saumil Sethna ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Single Gene ◽  
Loss Of Function ◽  
Β Cells ◽  
Zebrafish Model ◽  
Alström Syndrome ◽  
Alstrom Syndrome

SCIENTIFIC ABSTRACTAlström syndrome is an autosomal recessive obesity ciliopathy caused by loss-of-function mutations in the ALMS1 gene. In addition to multi-organ dysfunction, such as cardiomyopathy, retinal degeneration, and renal dysfunction, the disorder is characterized by high rates of obesity, insulin resistance and early onset type 2 diabetes mellitus (T2DM). To investigate mechanisms linking disease phenotypes we generated a loss-of-function deletion of alms1 in the zebrafish using CRISPR/Cas9. We demonstrate conserved phenotypic effects including cardiac defects, retinal degeneration, and metabolic deficits that included propensity for obesity and fatty livers in addition to hyperinsulinemia and glucose response defects. Gene expression changes in β-cells isolated from alms1−/− mutants revealed changes consistent with insulin hyper-secretion and glucose sensing failure, which were also identified in cultured murine β-cells lacking Alms1. These data present a zebrafish model to assess etiology and new secretory pathway defects underlying Alström syndrome-associated metabolic phenotypes. Given the hyperinsulinemia and reduced glucose sensitivity in these animals we also propose the alms1 loss-of-function mutant as a monogenic model for studying T2DM phenotypes.AUTHOR SUMMARYThese data comprise a thorough characterization of a zebrafish model of Alström syndrome, a human obesity syndrome caused by loss-of-function deletions in a single gene, ALMS1. The high rates of obesity and insulin resistance found in these patients suggest this disorder as a single-gene model for Type 2 Diabetes Mellitus (T2DM), a disorder caused by a variety of environmental and genetic factors in the general population. We identify a propensity for obesity, excess lipid storage, loss of β-cells in islets, and hyperinsulinemia in larval and adult stages of zebrafish alms1 mutants. We isolated β-cells from the alms1 mutants and compared the gene expression profiles from RNASeq datasets to identify molecular pathways that may contribute to the loss of β-cells and hyperinsulinemia. The increase in genes implicated in generalized pancreatic secretion, insulin secretion, and glucose transport suggest potential β-cell exhaustion as a source of β-cell loss and excess larval insulin. We propose this mutant as a new genetic tool for understanding the metabolic failures found in Type 2 Diabetes Mellitus.

Trabecular bone score and insulin resistance in type 2 diabetes mellitus

2020 ◽  
Author(s):  
Ponce Maria Hayon ◽  
Laguna Mª del Carmen Serrano ◽  
Perez Maria Dolores Aviles ◽  
Beatriz Garcia Fontana ◽  
Sheila Gonzalez Salvatierra ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Trabecular Bone ◽  
Trabecular Bone Score

1463-P: Relationship between Hepatic and Adipose Tissue Insulin Resistance with Liver Fibrosis in Patients with Type 2 Diabetes Mellitus (T2DM) and Nonalcoholic Fatty Liver Disease (NAFLD)

Diabetes ◽  
2020 ◽  
Vol 69 (Supplement 1) ◽  
pp. 1463-P
Author(s):  
SRILAXMI KALAVALAPALLI ◽  
ROMINA LOMONACO ◽  
EDDISON GODINEZ ◽  
NADA FANOUS ◽  
LAZARO J. TEJERA ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Adipose Tissue ◽  
Liver Disease ◽  
Liver Fibrosis ◽  
Fatty Liver Disease ◽  
Nonalcoholic Fatty Liver

Echinops Spp. Polysaccharide B Ameliorates Metabolic Abnormalities in a Rat Model of Type 2 Diabetes Mellitus

2020 ◽  
Vol 19 (1) ◽  
pp. 106-114
Author(s):  
Guang Hao ◽  
Xiaoyu Ma ◽  
Mengru Jiang ◽  
Zhenzhen Gao ◽  
Ying Yang
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Insulin Secretion ◽  
Insulin Receptor ◽  
Skeletal Muscles ◽  
Insulin Receptor Substrate ◽  
Sprague Dawley

This study examined the in vivo effects of Echinops spp. polysaccharide B on type 2 diabetes mellitus in Sprague-Dawley rats. We constructed a type 2 diabetes mellitus Sprague-Dawley rat models by feeding a high-fat and high-sugar diet plus intraperitoneal injection of a small dose of streptozotocin. Using this diabetic rat model, different doses of Echinops polysaccharide B were administered orally for seven weeks. Groups receiving Xiaoke pill and metformin served as positive controls. The results showed that Echinops polysaccharide B treatment normalized the weight and blood sugar levels in the type 2 diabetes mellitus rats, increased muscle and liver glycogen content, improved glucose tolerance, increased insulin secretion, and reduced glucagon and insulin resistance indices. More importantly, Echinops polysaccharide B treatment upregulated the expression of insulin receptor in the liver, skeletal muscles, and pancreas, and significantly improved the expression levels of insulin receptor substrate-2 protein in the liver and pancreas, as well as it increased insulin receptor substrate-1 expression in skeletal muscles. These two proteins play crucial roles in increasing insulin secretion and in controlling type 2 diabetes mellitus. The findings of the present study suggest that Echinops polysaccharide B could improve the status of diabetes in type 2 diabetes mellitus rats, which may be achieved by improving insulin resistance. Our study provides a new insight into the development of a natural drug for the control of type 2 diabetes mellitus.

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