Low VIP Hormone May Contribute to Early CF-related Diabetes

Reduced levels of the VIP hormone in the pancreas due to low nerve supply may contribute to the development of early diabetes in people with cystic fibrosis (CF), a study in mice suggests.

The study, “VIP reduction in the pancreas of F508del homozygous CF mice and early signs of Cystic Fibrosis Related Diabetes (CFRD),” was published in the Journal of Cystic Fibrosis.

A unique type of diabetes — referred to as cystic fibrosis-related diabetes (CFRD) — is a common complication for people with CF, especially as they age. CFRD is characterized by decreased production of insulin, a hormone secreted by the pancreas that lowers glucose in the bloodstream.

VIP (vasoactive intestinal peptide) is a hormone known to modulate insulin secretion in the presence of glucose. VIP is produced in the nervous system and acts as a signaling molecule between nerve cells (neurotransmitter). It also is found in the respiratory, digestive, reproductive, and cardiovascular systems.

VIP also has anti-inflammatory and immunomodulatory properties, and plays a crucial role in maintaining clean airways.

Recently, researchers at Dalhousie University in Canada demonstrated VIP was 50% lower in the lungs, sweat glands, and small intestines of mice that carry the F508del-CFTR mutation, which is the most common mutation found in people with CF. This mutation results in the production of a defective CFTR protein and is the underlying cause of CF.

That study found VIP deficiency originated from a reduction in nerve supply (innervation) starting at a young age before signs of CF-like disease were seen.

In this study, the same team examined whether there were VIP changes in the pancreas, affected by nerve supply, at different stages of CF in the same mouse model to “determine whether changes in VIP levels would contribute to CFRD development,” the team wrote.

Based on their previous work, these mice showed minimal disease by eight weeks of age, whereas 17-week-old mice display well-developed CF-like disease.

The first series of experiments showed, compared to healthy control mice of the same age, VIP was 51.2 % lower in 8-week-old CF mice and 51.3% lower in  the same animals at 17 weeks, in tissue isolated from the endocrine pancreas. That part of the pancreas secretes insulin along with glucagon, a hormone that increases glucose in the bloodstream, in opposition to insulin.

Likewise, in the part of the pancreas that secretes digestive enzymes, known as the exocrine pancreas, VIP was lower by 44.5% in 8-week-old CF mice and 55.1% decreased at week 17-.

“All together, these data show that the amount of VIP is strongly reduced in the pancreas of CF mice at both early and late stages of disease progression,” the researchers wrote.

Next, the team found that endocrine and exocrine pancreas tissue from control mice had strong nerve supply. In contrast, nerve supply was 58.8% reduced in endocrine tissue of 8-week-old mice and 49.4% lower at 17 weeks of age. Nerve supply also was decreased in exocrine tissue of CF mice of both ages, a reduction statistically significant at 17 weeks.

Consistently, insulin production was significantly lower in both young and older CF mice compared to controls. In younger CF mice, insulin production was significantly reduced by 35%, whereas older mice showed a 38.7% decrease. These results were confirmed using an alternate method to measure the insulin protein.

People with type 2 diabetes have higher levels of glucagon production. In the same way, this study showed strong glucagon production in pancreas tissue from both 8- and 17-week-old CF mice.

Finally, assessing the effect of altered insulin and glucagon production, the team found significantly higher levels of glucose in the bloodstream of CF mice (210 mg per deciliter) compared to controls (141 mg per deciliter).

“Our results show a reduction in insulin and an upregulation of glucagon in the pancreas of CF mice, indicating that a CFRD phenotype [characteristic] can develop at an early stage (as early as 8-week-old) of disease progression,” the scientists wrote.

“We propose that low level of VIP, due to reduced innervation of the CF pancreas and starting at an early disease stage, contributes to changes in insulin and glucagon secretion that can lead to CFRD development,” they added.