Biphasic decline of β‐cell function with age in euglycemic nonobese diabetic mice parallels diabetes onset

Abstract

A gradual decline in insulin response is known to precede the onset of type 1 diabetes (T1D). To track age-related changes in the β-cell function of non-obese diabetic (NOD) mice, the most commonly used animal model for T1D, and to establish differences between those who do and do not become hyperglycemic, we performed a long-term longitudinal oral glucose tolerance test (OGTT) study (10–42 weeks) in combination with immunofluorescence imaging of islet morphology and cell proliferation. We observed a clear biphasic decline in insulin secretion (AUC0–30min) even in euglycemic animals. A first phase (10–28 weeks) consisted of a relatively rapid decline and paralleled diabetes development in the same cohort of animals. This was followed by a second phase (29–42 weeks) during which insulin secretion declined much slower while no additional animals became diabetic. Blood glucose profiles showed a corresponding, but less pronounced change: the area under the concentration curve (AUC0–150min) increased with age, and fit with a bilinear model indicated a rate-change in the trendline around 28 weeks. In control NOD scids, no such changes were observed. Islet morphology also changed with age as islets become surrounded by mononuclear infiltrates, and, in all mice, islets with immune cell infiltration around them showed increased β-cell proliferation. In conclusion, insulin secretion declines in a biphasic manner in all NOD mice. This trend, as well as increased β-cell proliferation, is present even in the NODs that never become diabetic, whereas, it is absent in control NOD scid mice.

Feasibility of Localized Metabolomics in the Study of Pancreatic Islets and Diabetes

“…This involved collection of a large number of samples (collected at 6, 11, 16, 21, and 26 weeks of age from mice whose glycemia was monitored and retrospectively designated as T1D progressors or non-progressors depending on whether they became hyperglycemic or not by the end of the study). Diabetes onset in these NOD mice was typical and similar to what we have obtained previously [33,34], starting around 12 weeks of age with approximately 60% of females and 30% of males becoming diabetic by week 26 (Figure S2A). At the end of the study (week 26 of age), representative samples from 3F + 3M non-progressors (control) and 4F + 4M T1D progressors were subjected to global metabolomics, which identified and quantified a large number of metabolites (676 and 706 in blood and feces, respectively).…”

Effect of Arginase-1 Inhibition on the Incidence of Autoimmune Diabetes in NOD Mice

“…Female NOD mice are used extensively as a model for human autoimmune T1D [12][13][14][15][16][17]. Numerous studies have shown that under specific-pathogen-free conditions typically 70-90% of female NOD mice develop diabetes spontaneously by 45 weeks of age [9,11]. Consistent with this, we found an 80% diabetes incidence rate in a population of 126 female NOD mice aged up to 43 weeks (Figure 1).…”

Harnessing Immune Cells to Enhance β-Cell Mass in Type 1 Diabetes

“…In addition, injection of total SPLs obtained from new-onset diabetic NOD mice showed attenuated levels of α-cell proliferation 3 weeks after transfer when compared to β-cell proliferation (figure 3B). A similar finding was reported by Cechin et al 27. Together, these data suggest that immune cell-derived soluble factors provide preferential stimulatory effects favoring β cells.…”