Perinatal exposure to high dietary advanced glycation end products in transgenic NOD8.3 mice leads to pancreatic beta cell dysfunction

Abstract

The contribution of environmental factors to pancreatic islet damage in type 1 diabetes remains poorly understood. In this study, we crossed mice susceptible to type 1 diabetes, where parental male (CD8+ T cells specific for IGRP206-214; NOD8.3) and female (NOD/ShiLt) mice were randomized to a diet either low or high in AGE content and maintained on this diet throughout pregnancy and lactation. After weaning, NOD8.3+ female offspring were identified and maintained on the same parental feeding regimen for until day 28 of life. A low AGE diet, from conception to early postnatal life, decreased circulating AGE concentrations in the female offspring when compared to a high AGE diet. Insulin, proinsulin and glucagon secretion were greater in islets isolated from offspring in the low AGE diet group, which was akin to age matched non-diabetic C57BL/6 mice. Pancreatic islet expression of Ins2 gene was also higher in offspring from the low AGE diet group. Islet expression of glucagon, AGEs and the AGE receptor RAGE, were each reduced in low AGE fed offspring. Islet immune cell infiltration was also decreased in offspring exposed to a low AGE diet. Within pancreatic lymph nodes and spleen, the proportions of CD4+ and CD8+ T cells did not differ between groups. There were no significant changes in body weight, fasting glucose or glycemic hormones. This study demonstrates that reducing exposure to dietary AGEs throughout gestation, lactation and early postnatal life may benefit pancreatic islet secretion and immune infiltration in the type 1 diabetic susceptible mouse strain, NOD8.3.

Dietary advanced glycation end‐products: Perspectives linking food processing with health implications

“…In cell cultures, several food‐derived AGEs were shown to activate inflammatory responses via a RAGE‐dependent pathway (Somoza et al., 2005; Van der Lugt et al., 2018; Zill et al., 2003; Zill, Günther, Erbersdobler, Fölsch, & Faist, 2001). In rodent models, high‐dAGE diets deteriorated pathogenesis mediated by RAGE that are associated with diabetes (Borg et al., 2018; Lin et al., 2003), nephropathies (Yeh, Yang, Pai, Wu, & Chen, 2017), vascular dysfunction (Tikellis et al., 2008), nonalcoholic steatohepatitis (Leung et al., 2016), and Alzheimer's disease (Lubitz et al., 2016). Feeding rats with diets containing bread crust or coffee beverage upregulated the expression level of HMGB1 (ligand of RAGE) in the lungs.…”

Dietary gluten and type 1 diabetes

“…For example, cereal products that are baked at high temperatures contain advanced glycation end products that have been suggested as a risk factor for type 1 diabetes 1314. Grains also contain several other components generally considered harmful to health but that have not yet been studied in relation to type 1 diabetes, such as mycotoxins, heavy metals, and remnants of pesticides and fertilisers 1516…”

Novel role of AGE-R1/OST48 in the metabolome and proteome promoting ER stress in the kidney and liver

“…There have been previous studies where AGEs have been shown to impair insulin secretion 70,250 although it is unclear as to the role that OST48 plays in beta cells. However, we have identified that OST48 is expressed in beta cells 251 . In addition, further investigation would be required to elucidate why these apparent improvements in insulin secretion seen in diabetic OST48 mice did not translate to improved longterm clinical markers of glycaemic control.…”