Temporal characterization of β cell-adaptive and -maladaptive mechanisms during chronic high-fat feeding in C57BL/6NTac mice

Abstract

The onset of type 2 diabetes is characterized by transition from successful to failed insulin secretory compensation to obesity-related insulin resistance and dysmetabolism. Energy-rich diets in rodents are commonly studied models of compensatory increases in both insulin secretion and β cell mass. However, the mechanisms of these adaptive responses are incompletely understood, and it is also unclear why these responses eventually fail. We measured the temporal trends of glucose homeostasis, insulin secretion, β cell morphometry, and islet gene expression in C57BL/6NTac mice fed a 60% high-fat diet (HFD) or control diet for up to 16 weeks. A 2-fold increased hyperinsulinemia was maintained for the first 4 weeks of HFD feeding and then further increased through 16 weeks. β cell mass increased progressively starting at 4 weeks, principally through nonproliferative growth. Insulin sensitivity was not significantly perturbed until 11 weeks of HFD feeding. Over the first 8 weeks, we observed two distinct waves of increased expression of β cell functional and prodifferentiation genes. This was followed by activation of the unfolded protein response at 8 weeks and overt β cell endoplasmic reticulum stress at 12-16 weeks. In summary, β cell adaptation to an HFD in C57BL/6NTac mice entails early insulin hypersecretion and a robust growth phase along with hyperexpression of related genes that begin well before the onset of observed insulin resistance. However, continued HFD exposure results in cessation of gene hyperexpression, β cell functional failure, and endoplasmic reticulum stress. These data point to a complex but not sustainable integration of β cell-adaptive responses to nutrient overabundance, obesity development, and insulin resistance.

Maternal N-Acetyl Cysteine Intake Improved Glucose Tolerance in Obese Mice Offspring

“…As expected [20], islet hypertrophy developed due to this chronic hyperinsulinemia, as found in HFD-fed male mice, and normalized in offspring of NAC-treated mice which had improved insulin sensitivity. The expansion of β-cell might be attributed not only to islet hypertrophy, but also to neogenesis of islets, leading to an increase in their number, as found in HFD-fed male mice and as also reported previously [21]. Such an increase in islet number was not detected either in HFD-fed female mice or in male offspring of NAC-treated mice, which had a better sensitivity to insulin.…”

“…Sci. 2020, 21,1981 14 of 21 been anesthetized by ketamine+xylazine as required, and all efforts were made to minimize suffering. Animal House operates in compliance with the rules and guidelines of the Israel Council for Research in Animals, based on the US NIH Guide for the Care and Use of Laboratory Animals.…”

Adipose tissue macrophages orchestrate β cell adaptation in obesity through secreting miRNA-containing extracellular vesicles

“…A major piece of evidence for this new role of obese ATM EVs in regulating β cell functions comes from the reconstitution of obese ATMs-secreted EVs in vivo by intravenous injection into the recipients starting HFD feeding. In line with previous findings(14,47), in contrast to the prolonged obesity-induced expansions of proinflammatory M1 macrophages and beta cell populations, 4 weeks HFD feeding led to modest growth rates of β cell mass and proinflammatory M1 ATM population. After elevating the level of obese ATM EVs by multiple intravenous injections, HFD recipient mice had less glucose-stimulated insulin secretion and insulin levels at feeding condition, while the supplementation of obese ATM EVs led to more proliferating ki67+ β cells.…”

β Cell dysfunction during progression of metabolic syndrome to type 2 diabetes

“…In humans, similar compensatory increases in augmented insulin secretion have been reported in obese, nondiabetic patients and individuals with prediabetes (36,37). In addition to elevated insulin secretion, a study of HFD-fed C57BL/6NTac (B6N) mice demonstrated hyperexpression of genes known to promote β cell function and differentiation, including many key β cell transcriptional factors (11). The same study identified the transient upregulation of UPR genes to protect against decompensating ER stress responses.…”

“…Metabolic syndrome presents a set of unique stressors to the β cell, including elevated glucose, increased free fatty acids, and inflammation (11)(12)(13). In this adverse environment, β cells initially mount a compensatory response to ramp up β cell functional capacity and insulin secretion to meet the elevated metabolic demand.…”