Genetic predisposition for beta cell fragility underlies type 1 and type 2 diabetes

Abstract The purpose of this review is to provide a view of the future of genomics and other omics approaches in defining the genetic contribution to all stages of risk of type 1 diabetes and the functional impact and clinical implementations of the associated variants. From the recognition nearly 50 years ago that genetics (in the form of HLA) distinguishes risk of type 1 diabetes from type 2 diabetes, advances in technology and sample acquisition through collaboration have identified over 60 loci harbouring SNPs associated with type 1 diabetes risk. Coupled with HLA region genes, these variants account for the majority of the genetic risk (~50% of the total risk); however, relatively few variants are located in coding regions of genes exerting a predicted protein change. The vast majority of genetic risk in type 1 diabetes appears to be attributed to regions of the genome involved in gene regulation, but the target effectors of those genetic variants are not readily identifiable. Although past genetic studies clearly implicated immune-relevant cell types involved in risk, the target organ (the beta cell) was left untouched. Through emergent technologies, using combinations of genetics, gene expression, epigenetics, chromosome conformation and gene editing, novel landscapes of how SNPs regulate genes have emerged. Furthermore, both the immune system and the beta cell and their biological pathways have been implicated in a context-specific manner. The use of variants from immune and beta cell studies distinguish type 1 diabetes from type 2 diabetes and, when they are combined in a genetic risk score, open new avenues for prediction and treatment.

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Oral administration of bacterial Beta cell expansion factor A (BefA) alleviates diabetes in mice with Type 1 and Type 2 diabetes

10.1101/2021.10.22.465460 ◽

2021 ◽

Author(s):

Huan Wang ◽

Jing Wei ◽

Hong Hu ◽

Fuyin Le ◽

Heng Wu ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Beta Cell ◽

Cell Expansion ◽

Dependent Manner ◽

Expansion Factor ◽

Concentration Dependent Manner ◽

Protective Function

Diabetes mellitus (DM) is a group of metabolic diseases, which is of urgent need to develop new therapeutic DM oral drugs with less side effects and sound therapeutic efficacy. In this study, a Beta cell expansion factor A (BefA) production strain of Escherichia Coli BL21-pet 28C-BefA was constructed, and the anti-diabetes effect of BefAwas evaluated using type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) mice models. The T1DM mice results indicated that BefA significantly reduced the blood glucose level, exerted protective function of islet β cell morphology, down-regulated the TLR-4, p-NFκB/NFκB, Bax/Bcl-2 expressions and the secretion level of IL-1β, TNF-α, increased the expression of PDX-1 protein and insulin secretion in a concentration-dependent manner, and restored the disturbed microbial diversity to normal level. Similar with the T1DM mice, BefA obviously increased islet β cells, reduced inflammatory reaction and apoptosis in T2DM mice, and also improved liver lipid metabolism by down-regulating the expression of CEBP-α, ACC, Fasn and inhibiting the synthesis of triglyceride and induce Cpt-1, Hmgcs2, Pparα in a concentration-dependent manner. In the present study, we verified therapeutic effect and potential mechanisms of BefA in mammal for the first time, providing basic data for its clinical application.

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Glycated albumin to glycated hemoglobin ratio reflects postprandial glucose excursion and relates to beta cell function in both type 1 and type 2 diabetes

Diabetology International ◽

10.1007/s13340-011-0035-x ◽

2011 ◽

Vol 2 (3) ◽

pp. 146-153 ◽

Cited By ~ 31

Author(s):

Yoshifumi Saisho ◽

Kumiko Tanaka ◽

Takayuki Abe ◽

Akira Shimada ◽

Toshihide Kawai ◽

...

Keyword(s):

Type 2 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Glycated Hemoglobin ◽

Glycated Albumin ◽

Postprandial Glucose ◽

Postprandial Glucose Excursion

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Diabetic ketoacidosis: a challenging diabetes phenotype

Endocrinology Diabetes and Metabolism Case Reports ◽

10.1530/edm-16-0109 ◽

2017 ◽

Vol 2017 ◽

Cited By ~ 2

Author(s):

Cliona Small ◽

Aoife M Egan ◽

El Muntasir Elhadi ◽

Michael W O’Reilly ◽

Aine Cunningham ◽

...

Keyword(s):

Insulin Resistance ◽

Type 2 Diabetes ◽

Beta Cell ◽

Beta Cell Function ◽

Cell Function ◽

Islet Autoimmunity ◽

Acute Setting ◽

History Of

Summary We describe three patients presenting with diabetic ketoacidosis secondary to ketosis prone type 2, rather than type 1 diabetes. All patients were treated according to a standard DKA protocol, but were subsequently able to come off insulin therapy while maintaining good glycaemic control. Ketosis-prone type 2 diabetes (KPD) presenting with DKA has not been described previously in Irish patients. The absence of islet autoimmunity and evidence of endogenous beta cell function after resolution of DKA are well-established markers of KPD, but are not readily available in the acute setting. Although not emphasised in any current guidelines, we have found that a strong family history of type 2 diabetes and the presence of cutaneous markers of insulin resistance are strongly suggestive of KPD. These could be emphasised in future clinical practice guidelines. Learning points: Even in white patients, DKA is not synonymous with type 1 diabetes and autoimmune beta cell failure. KPD needs to be considered in all patients presenting with DKA, even though it will not influence their initial treatment. Aside from markers of endogenous beta cell function and islet autoimmunity, which in any case are unlikely to be immediately available to clinicians, consideration of family history of type 2 diabetes and cutaneous markers of insulin resistance might help to identify those with KPD and are more readily apparent in the acute setting, though not emphasised in guidelines. Consideration of KPD should never alter the management of the acute severe metabolic derangement of DKA, and phasing out of insulin therapy requires frequent attendance and meticulous and cautious surveillance by a team of experienced diabetes care providers.

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