Hyper-Variability in Circulating Insulin, High Fat Feeding Outcomes, and Effects of Reducing Ins2 Dosage in Male Ins1-Null Mice in a Specific Pathogen-Free Facility

Abstract

Insulin is an essential hormone with key roles in energy homeostasis and body composition. Mice and rats, unlike other mammals, have two insulin genes: the rodent-specific Ins1 gene and the ancestral Ins2 gene. The relationships between insulin gene dosage and obesity has previously been explored in male and female Ins2-/- mice with full or reduced Ins1 dosage, as well as in female Ins1-/- mice with full or partial Ins2 dosage. We report herein unexpected hyper-variability in Ins1-null male mice, with respect to their circulating insulin levels and to the physiological effects of modulating Ins2 gene dosage. Two large cohorts of Ins1-/-:Ins2+/- mice and their Ins1-/-:Ins2+/+ littermates were fed chow diet or high fat diet (HFD) from weaning, and housed in specific pathogen-free conditions. Cohort A and cohort B were studied one year apart. Contrary to female mice from the same litters, inactivating one Ins2 allele on the complete Ins1-null background did not consistently cause a reduction of circulating insulin in male mice, on either diet. In cohort A, all HFD-fed males showed an equivalent degree of insulin hypersecretion and weight gain, regardless of Ins2 dosage. In cohort B the effects of HFD appeared generally diminished, and cohort B Ins1-/-:Ins2+/- males showed decreased insulin levels and body mass compared to Ins1-/-:Ins2+/+ littermates, on both diets. Although experimental conditions were consistent between cohorts, we found that HFD-fed Ins1-/-:Ins2+/- mice with lower insulin levels had increased corticosterone. Collectively, these observations highlight the phenotypic characteristics that change in association with differences in circulating insulin and Ins2 gene dosage, particularly in male mice.

Early beta cell dysfunction vs insulin hypersecretion as the primary event in the pathogenesis of dysglycaemia

“…Figure 4 illustrates the phenotypic differences in mice fed an HFD compared with their littermate controls on a moderate-fat diet. Only mice that were null for Ins1 developed the expected phenotype of obesity, hyperinsulinaemia and insulin resistance; however, these mice did not develop diabetes as may have been expected [59,60] (Fig. 4a, b).…”

Pro-angiogenic Role of Insulin: From Physiology to Pathology

“…Thus, a rodent specific Ins1 gene that likely arose from the transposition of a reverse-transcribed, partially processed mRNA of the ancestral Ins2 have been found (Soares et al, 1985). Both genes reside in different chromosomes with differential translational rates and protein function, as showed in Ins1 or Ins2 deficient mice (see details in Templeman et al, 2016). For instance, Ins1 +/− : Ins2 −/− male mice, but not female littermates, were completely protected against diet-induced obesity (Mehran et al, 2012).…”

“…For instance, Ins1 +/− : Ins2 −/− male mice, but not female littermates, were completely protected against diet-induced obesity (Mehran et al, 2012). In a converse genetic manipulation, Ins1 −/− : Ins2 +/− female mice (Templeman et al, 2015), but not male littermates (Templeman et al, 2016), also prevented obesity. Then, an intricate mechanism of regulation and compensation between each of those genes were present in Ins1 or Ins2 deficient male and female mice.…”

“…In general, insulin binds to the insulin receptor (IR), which has at least two isoforms. The first IR isoform lacks exon 11 (exon 11-, IR-A), while the second isoform includes this exon (exon +, IR-B) (see details in Templeman et al, 2016). Insulin can also activate the family of insulin-like growth factor receptors (IGF-IR), which in turn can form homodimers or heterodimers with either IR-A or IR-B (Guzmán-Gutiérrez et al, 2011; Hale and Coward, 2013).…”

Hepatic gene expression variations in response to high-fat diet-induced impaired glucose tolerance using RNAseq analysis in collaborative cross mouse population

“…Focusing on the females-only group, Ins2 expression during health was very slight and closer to zero, supporting the aforementioned hypothesis of compensatory mechanisms of the liver during diabetes, which are apparently specific for females. And indeed, referring to the literature, we realize that normally mice and rats express two non-allelic insulin genes, Ins1 and Ins2, located on different chromosomes (19 and 7, respectively), mediating different metabolic pathways in female and males (Templeman et al 2016). It is important to mention that peripheral interactions of leptin-Insulin pathways are known to play a central role in energy homeostasis and therefore are investigated as therapeutic agents for diabetes.…”