Original Data

Endoplasmic Reticulum Stress Caused by Overexpression of Islet-Specific Glucose-6-Phosphatase Catalytic Subunit-Related Protein in Pancreatic Beta-Cells

Afshin Shameli, Jun Yamanouchi, Shari Thiessen, Pere Santamaria

Abstract

The high rate of protein synthesis in β-cells renders them susceptible to endoplasmic reticulum (ER) stress, a condition that can be aggravated by additional imbalances in ER homeostasis and could potentially contribute to the pathogenesis of type-1 and type-2 diabetes. Islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP) is an ER-resident protein that is specifically expressed in pancreatic β-cells and is a major target of diabetogenic CD8⁺ T cell responses in non-obese diabetic (NOD) mice. We produced transgenic mice expressing human IGRP (hIGRP) under the control of rat insulin promoter (RIP) to study epitopes in hIGRP capable of driving diabetogenic human leukocyte antigen (HLA)-restricted CD8⁺ T-cell responses in hIGRP/HLA transgenic NOD mice. Surprisingly, we found that 3 out of 14 lines expressing RIP-hIGRP in a non-T1D-prone genetic background developed a form of early-onset diabetes that was dissociated from autoimmune inflammation of pancreatic islets. We show that diabetes in these 3 lines resulted from increased rates of β-cell death because of ER stress. We hypothesize that IGRP compounds the viability of β-cells undergoing ER stress by generating unfolded proteins in the ER lumen, and that IGRP's location in the ER accounts, in part, for its exquisite immunogenicity in T1D-prone genetic backgrounds.

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Bis(quercetinato)oxovanadium IV Reverses Metabolic Changes in Streptozotocin-Induced Diabetic Mice

Ruchi Shukla¹, Subhash Padhye², Manisha Modak³, Saroj S. Ghaskadbi³, Ramesh R. Bhonde¹

Abstract

Organic vanadium compounds offer several advantages in the treatment of diabetes, yet they are impractical to use because of known side effects. In order to ameliorate the side effects of vanadium, we conjugated it with quercetin to form bis(quercetinato)oxovanadium IV (BQOV). This study evaluates the effect of BQOV treatment on carbohydrate metabolism and overall oxidative stress in streptozotocin-induced (STZ) diabetic mice. Administration of BQOV orally to diabetic mice for 3 weeks led to a reduction of blood glucose levels and the animals exhibited normal glucose tolerance at the end of the study period. The increase in glucose uptake by skeletal muscle and liver as well as the normalization of mRNA levels of G-6-Pase and glucokinase in the liver after BQOV treatment pointed to improvements in carbohydrate metabolism. The analysis of the antioxidant status of serum, liver and pancreas revealed reduced oxidative stress in BQOV-treated animals compared to untreated diabetic controls. Serum analyses for kidney and liver function showed that BQOV treatment provoked total protection of the kidney and partial protection of the liver from diabetogenic insults. The number of insulin-positive cells and the amount of pancreatic insulin in treated mice (1.2038 ± 0.34 ng/mg tissue) did not account for pancreatic regeneration but suggested an insulin-mimetic action on the part of BQOV. Moreover, administration of BQOV for 3 weeks did not show any visible side-effects. This data indicate that BQOV is a safe and potent agent for diabetes treatment, because it is able to improve carbohydrate metabolism and to reduce overall oxidative stress.

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Improved Monitoring of the Hyperglycemic State in Type 1 Diabetes Patients by Use of the Glycoalbumin/HbA1c Ratio

Takatoshi Imai, Yoichi Oikawa, Akira Shimada

Abstract

AIM: Generally, the level of glycoalbumin (GA) is approximately 3 times higher than that of HbA1c. However, in type 1 diabetic patients, we often find an even higher GA/HbA1c ratio of nearly 3.5. Therefore, this study was performed to examine the significance of a higher GA/HbA1c ratio. METHODS: 17 type 1 diabetic patients were enrolled in part 1 of the study and divided into two groups, one with a higher and the other with a lower GA/HbA1c ratio. In both groups, the correlation between GA or HbA1c level and each "4-point" capillary glucose level was analyzed. 80 type 1 diabetic patients were enrolled in part 2 of the study and the relationship between mean GA/HbA1c ratio in the past year and degree of diabetic retinopathy was analyzed. RESULTS: In part 1 of the study, we found positive correlations between GA and bedtime capillary glucose levels and between HbA1c and bedtime capillary glucose levels in the higher GA/HbA1c group (r = 0.86, p = 0.023; r = 0.95, p = 0.012, respectively), but not in the lower GA/HbA1c group. In part 2 of the study, a significant positive correlation between GA/HbA1c ratio and severity of retinopathy could be observed (r = 0.269, p = 0.017). CONCLUSIONS: A higher GA/HbA1c ratio may reflect a postprandial hyperglycemic state and simultaneous monitoring of GA and HbA1c may improve the management of diabetic patients.

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Association of Resistin Gene 3'-Untranslated Region EX4-44G-->A Polymorphism with Obesity- and Insulin-Related Phenotypes in Turkish Type 2 Diabetes Patients

Belgin Susleyici Duman¹, Penbe Cagatay², Husrev Hatemi³, Melek Ozturk⁴

Abstract

Resistin, an adipocyte-secreted hormone, has been associated with obesity, insulin resistance and type 2 diabetes mellitus (T2DM) in some, but not all, rodent models. In humans, the exact function of resistin is unkown. Because 3'-untranslated region (3'-UTR) single nucleotide substitutions (SNPs) have been shown to affect gene expression, we examined the EX4-44G-->A SNP in the 3'-UTR of exon 3 within the resistin gene. The objective of this study was to investigate, for the first time in a Turkish study group, whether the 3'-UTR EX4-44G-->A variation in the resistin gene influences the development of T2DM, obesity and insulin-related phenotypes. We analyzed the genotype frequencies of the EX4-44G-->A polymorphism of the resistin gene in 116 type 2 diabetic and 102 normal subjects. Serum lipids, obesity-related and insulin-related phenotypes were analyzed. No significant difference for genotypic frequencies were observed for the BseRI restriction site in type 2 diabetic patients as compared to controls. Waist-to-hip ratio, BMI, body fat and apoAI levels were found to be affected by resistin genotype. In the control group, BMI (p < 0.01), HIS (p < 0.05) and BF (p < 0.05) levels were found to be elevated, whereas HOMA β-cell index (p < 0.01) and apo AI (p < 0.05) levels were found to be decreased in GG genotype carriers. In the diabetic group, the GG genotype carriers were found to have higher BMI levels (p < 0.001), waist-to-hip ratio (p < 0.05), body fat (p < 0.01), HOMA (p < 0.001) and fasting insulin (p < 0.05), but lower HbA1c levels in comparison to GC + AA carriers. These data suggest that, in the Turkish study group, the EX4-44G-->A polymorphism of the resistin gene is associated with insulin and obesity-related phenotypes.

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