miR-181d promotes pancreatic beta cell dysfunction by targeting IRS2 in gestational diabetes mellitus

Hypothesis: Gestational diabetes mellitus (GDM) is a disorder of glucose metabolism during pregnancy characterized by pancreatic beta cell dysfunction and greater insulin resistance, but it is unclear whether dysfunction exists before pregnancy. The disposition index (DI) is a physiologic measure of beta cell compensation for insulin resistance strongly predictive of future diabetes. This prospective study evaluates whether a clinical approximation of DI before pregnancy is associated with risk of GDM. Methods: This analysis included 696 women (45% black, 55% white) enrolled in the CARDIA Study, a U.S. multi-center prospective cohort of young adults aged 18-30 at baseline (1985-86) who gave birth at least once during 30 years of follow up, reported GDM status and had fasting glucose and insulin measured before one or more post-baseline births. DI was defined as HOMA-B divided by HOMA-IR using standard formulas. Multinomial logistic regression models estimated odds ratios (OR) and 95%CI for GDM among pre-pregnancy DI tertiles (low, moderate, high) and fully adjusted for time to birth, race, age, parity, BMI, lifestyle behaviors and family history of diabetes, and also stratified by pre-pregnancy BMI. Results: 9% of women reported GDM (64/696) for 794 births. 55% of GDM and 30% of non-GDM were categorized as low DI. Low pre-pregnancy DI compared to moderate DI was associated with higher fully adjusted odds of GDM (OR=2.71, 95%CI:1.37-5.35) in the entire sample. In models stratified by pre-pregnancy BMI, low DI was associated with 4-fold higher odds of GDM among Overweight/Obese (OR=4.22, 95%CI: 1.35-13.91) and somewhat attenuated higher odds of GDM among Normal BMI (OR=1.94, 95%CI: 0.78–4.86); Table 1. Only family history of diabetes was strongly associated with GDM independent of DI. Conclusions: Inadequate beta cell compensation is present before pregnancy and discriminates greatest risk of GDM among high BMI, and may identify higher risk among women of normal BMI.

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433 NEW TRANSGENIC PIG DIABETES MODEL EXPRESSING THE MUTANT Insulinc93S FOR THE STUDY OF THE PANCREATIC BETA CELL DYSFUNCTION

Reproduction Fertility and Development ◽

10.1071/rdv22n1ab433 ◽

2010 ◽

Vol 22 (1) ◽

pp. 373

Author(s):

S. Renner ◽

N. Klymiuk ◽

A. Wuensch ◽

B. Kessler ◽

M. Kurome ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Beta Cell ◽

Point Mutation ◽

Genetic Background ◽

Mutant Mouse ◽

Pancreatic Beta Cell ◽

Beta Cell Dysfunction ◽

Transgenic Pig ◽

Cell Dysfunction

We previously established a mutant mouse line showing diabetes which was caused by a point mutation in the Insulin 2 (Ins2) gene. The point mutation leads to the amino acid exchange C95S and the loss of the A6-A11 intrachain disulfide bond of insulin. Male heterozygous Ins2C95S mutant mice develop progressive diabetes mellitus with strong reduction of the total pancreatic islet volume and the total beta cell volume together with severe alterations of the beta cell structure. As pigs share many anatomical and physiological characteristics with humans, we aimed to establish a transgenic pig model expressing the mutant insulin by additive gene transfer for the subsequent study of beta cell dysfunction in diabetes mellitus. The transgene consisted of German Landrace insulin sequences including 1.3 kb of the insulin promoter and 1 kb insulin gene sequences with the 3 exons and the T to A (C93S) point mutation in exon 3 analogous to the mutant mouse insulin. A floxed neomycin resistance gene at the 3′ end of the transgene was used as a selection marker. After successful transfection of male fetal fibroblasts of both the German Landrace and the Schwaebisch- Haellisch pig breeds, pooled transgenic fibroblasts were used for somatic cell nuclear transfer (SCNT). Five hundred three reconstructed pig embryos were generated and endoscopically transferred to 5 synchronized recipients. One pregnancy with German Landrace genetic background and one pregnancy with Schwaebisch-Haellisch genetic background of the cloned embryos developed to term, which gave rise to 3 living offspring from each of the 2 pregnancies; 5 of the 6 piglets were transgenic. Southern blot analysis showed different transgene signal patterns in all animals examined. Transgenic pigs of both litters revealed unaltered fasting blood glucose levels up to an age of 8 months. However, disturbed intravenous glucose tolerance and reduced insulin secretion were detected in 1 transgenic pig of the first litter at 8 months of age. The area under the glucose curve of this transgenic pig was 75% larger (22 136 v. 12617) and the area under the insulin curve 53% smaller (1250 v. 2670) compared with the control. Ongoing analyses comprise glucose tolerance tests in the second litter as well as pathohistologic analysis of the pancreata of both litters. Cells from suitable transgenic founders will be used for recloning to establish a new transgenic pig model expressing the mutant InsulinC93S for an in-depth study of pancreatic beta cell dysfunction in diabetes mellitus. Supported by the Deutsche Forschungsgemeinschaft (GRK1029).

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In vitro effect of DDE exposure on the regulation of B-TC-6 pancreatic Beta Cell insulin secretion: a potential role in Beta Cell dysfunction and Type 2 Diabetes Mellitus

Toxicology Mechanisms and Methods ◽

10.1080/15376516.2021.1950251 ◽

2021 ◽

pp. 1-25

Author(s):

Antonio B. Ward ◽

Mary B. Dail ◽

Janice E. Chambers

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Beta Cell ◽

Potential Role ◽

Pancreatic Beta Cell ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

Vitro Effect

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Endoplasmic Reticulum Stress and Insulin Biosynthesis: A Review

Experimental Diabetes Research ◽

10.1155/2012/509437 ◽

2012 ◽

Vol 2012 ◽

pp. 1-7 ◽

Cited By ~ 28

Author(s):

Mi-Kyung Kim ◽

Hye-Soon Kim ◽

In-Kyu Lee ◽

Keun-Gyu Park

Keyword(s):

Diabetes Mellitus ◽

Endoplasmic Reticulum ◽

Beta Cell ◽

Er Stress ◽

Pancreatic Beta Cells ◽

Pancreatic Beta Cell ◽

Insulin Biosynthesis ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

The Relationship

Insulin resistance and pancreatic beta cell dysfunction are major contributors to the pathogenesis of diabetes. Various conditions play a role in the pathogenesis of pancreatic beta cell dysfunction and are correlated with endoplasmic reticulum (ER) stress. Pancreatic beta cells are susceptible to ER stress. Many studies have shown that increased ER stress induces pancreatic beta cell dysfunction and diabetes mellitus using genetic models of ER stress and by various stimuli. There are many reports indicating that ER stress plays an important role in the impairment of insulin biosynthesis, suggesting that reduction of ER stress could be a therapeutic target for diabetes. In this paper, we reviewed the relationship between ER stress and diabetes and how ER stress controls insulin biosynthesis.

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Autoimmunity to insulin, beta cell dysfunction, and development of insulin-dependent diabetes mellitus

Diabetes ◽

10.2337/diabetes.35.2.139 ◽

1986 ◽

Vol 35 (2) ◽

pp. 139-142 ◽

Cited By ~ 32

Author(s):

S. Srikanta ◽

A. T. Ricker ◽

D. K. McCulloch ◽

J. S. Soeldner ◽

G. S. Eisenbarth ◽

...

Keyword(s):

Diabetes Mellitus ◽

Beta Cell ◽

Insulin Dependent Diabetes Mellitus ◽

Insulin Dependent Diabetes ◽

Dependent Diabetes Mellitus ◽

Beta Cell Dysfunction ◽

Cell Dysfunction ◽

Insulin Dependent

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Genetic variants associated with beta-cell function and insulin sensitivity potentially influence bile acid metabolites and gestational diabetes mellitus in a Chinese population

BMJ Open Diabetes Research & Care ◽

10.1136/bmjdrc-2021-002287 ◽

2021 ◽

Vol 9 (1) ◽

pp. e002287

Author(s):

Qiulun Zhou ◽

Ying Wang ◽

Yuqin Gu ◽

Jing Li ◽

Hui Wang ◽

...

Keyword(s):

Diabetes Mellitus ◽

Gestational Diabetes ◽

Gestational Diabetes Mellitus ◽

Beta Cell ◽

Genetic Variants ◽

Cell Function ◽

Chinese Women ◽

Risk Scores ◽

Nucleotide Polymorphisms ◽

Mediation Analyses

IntroductionTo investigate associations between genetic variants related to beta-cell (BC) dysfunction or insulin resistance (IR) in type 2 diabetes (T2D) and bile acids (BAs), as well as the risk of gestational diabetes mellitus (GDM).Research design and methodsWe organized a case-control study of 230 women with GDM and 217 without GDM nested in a large prospective cohort of 22 302 Chinese women in Tianjin, China. Two weighted genetic risk scores (GRSs), namely BC-GRS and IR-GRS, were established by combining 39 and 23 single nucleotide polymorphisms known to be associated with BC dysfunction and IR, respectively. Regression and mediation analyses were performed to evaluate the relationship of GRSs with BAs and GDM.ResultsWe found that the BC-GRS was inversely associated with taurodeoxycholic acid (TDCA) after adjustment for confounders (Beta (SE)=−0.177 (0.048); p=2.66×10−4). The BC-GRS was also associated with the risk of GDM (OR (95% CI): 1.40 (1.10 to 1.77); p=0.005), but not mediated by TDCA. Compared with individuals in the low tertile of BC-GRS, the OR for GDM was 2.25 (95% CI 1.26 to 4.01) in the high tertile. An interaction effect of IR-GRS with taurochenodeoxycholic acid (TCDCA) on the risk of GDM was evidenced (p=0.005). Women with high IR-GRS and low concentration of TCDCA had a markedly higher OR of 14.39 (95% CI 1.59 to 130.16; p=0.018), compared with those with low IR-GRS and high TCDCA.ConclusionsGenetic variants related to BC dysfunction and IR in T2D potentially influence BAs at early pregnancy and the development of GDM. The identification of both modifiable and non-modifiable risk factors may facilitate the identification of high-risk individuals to prevent GDM.

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