Spontaneous glucose intolerance in the progeny of low dose streptozotocin-induced diabetic mice

Abstract

Summary. Multiple low doses of streptozotocin (LDS) induce low-incidence diabetes mellitus in Balb/cHan and high-incidence diabetes in CD-1 mice. We studied offspring of diabetic parents in both strains. Group 1 consisted of litters from control mice with no streptozotocin treatment. Group 2 litters had an LDS diabetic mother and a control father, group 3 litters had control mother with LDS diabetic father, and group 4 litters had both, LDS diabetic mother and father. Diabetes was induced by 5 x 40 mg streptozotocin per kg on five consecutive days. Progeny of diabetic mothers showed a state of reduced glucose tolerance associated with reduced glucose disappearance during intravenous glucose tolerance test and increased insulin secretion of isolated islets of Langerhans. These metabolic abnormalities predominated in the male litters of both strains of mice. Amniotic insulin was increased ~n diabetic mothers during pregnancy. No histologic abnormalities were observed in group 2 progeny. Pancreases in male offspring of LDS diabetic CD-1 fathers (group 3) were studied for insulitis. Insulitis was found in 40 % of mice with normal glucose tolerance. A single subdiabetogenic dose of streptozotocin (40 mg/kg) induced insulitis in 90 % of pancreases accompanied by reduced insulin release of isolated islets. By contrast, male Balb/cHan progeny of diabetic fathers failed to develop insulitis. In conclusion, we found (1) parental LDS diabetes was transmitted more often to male offspring, (2) maternal LDS diabetes was associated with hyperinsulin secretion and glucose intolerance in the offspring and (3) paternal LDS diabetes was accompanied by insulitis and insulin secretion deficiency in CD-1 progeny.

Mother or Father: Who Is in the Front Line? Mechanisms Underlying the Non-Genomic Transmission of Obesity/Diabetes via the Maternal or the Paternal Line

“…Offspring metabolic phenotype can also be affected by paternal diabetes. Paternal low-dose STZ-induced diabetes in mice was accompanied by insulitis and insulin secretion deficiency in their F1 offspring [107]. Paternal T2D alone (i.e., without associated obesity) impairs early development of endocrine pancreas and adult tolerance du glucose in rat F1 offspring.…”

Paternally induced transgenerational inheritance of susceptibility to diabetes in mammals

“…Paternal effects avoid such an issue because fathers contribute little more than sperm to offspring. A small number of paternal effects have been documented in the literature up to now (3,4,9,10). Premating fasting of male mice has been found to affect blood glucose concentrations in offspring (9).…”

“…Premating fasting of male mice has been found to affect blood glucose concentrations in offspring (9). Paternal low-dose streptozotocin (STZ)-induced diabetes is accompanied by insulitis and insulin secretion deficiency in mouse offspring (10). A chronic high-fat diet (HFD) in male rats influences pancreatic islet biology in female offspring (3), and a low-protein diet in male mice results in elevated hepatic expression of lipid biosynthetic genes in offspring (4).…”

Paternal chronic colitis causes epigenetic inheritance of susceptibility to colitis

“…Moreover, this study provides a list of candidate genes that may contribute to a better understanding of epigenetically modulated pathways during or after chronic intestinal inflammation. As such, our study adds to a growing body of literature 29 38 39 40 42 43 44 45 46 47 48 49 50 51 52 53 , which suggests that paternal lifestyle and pathological conditions (e.g. chronic inflammation) can affect spermatogenesis and can induce intergenerational transmission of epigenetic marks modulating offspring’s metabolism, but also contributing to risk for disease.…”

“…Similarly, a paternal low-protein diet can affect offspring metabolism by increasing expression of many hepatic genes involved in lipid and cholesterol biosynthesis, which correlated with aberrant cytosine methylation in offspring of males fed with a low-protein diet 30 . In addition, paternally inherited effects were linked to obesity 38 39 40 41 , diabetes 29 42 , glucose metabolism 43 , hepatic wound healing 44 , behavioral and stress responses 45 46 47 48 49 50 and toxin-inherited effects 51 52 53 . These studies suggest that the paternal lifestyle permanently influenced by certain environmental factors can affect spermatogenesis and can induce inter-generational transmission of epigenetic marks modulating offspring’s metabolism, contributing to disease risk.…”