Metabolic phenotype in Darier disease: a cross-sectional clinical study

Abstract

Background: Human data supporting a role for endoplasmic reticulum (ER) stress and calcium dyshomeostasis in diabetes is scarce. Darier disease (DD) is a hereditary skin disease caused by mutations in the ATP2A2 gene encoding the sarcoendoplasmic-reticulum ATPase 2 (SERCA2) calcium pump, which causes calcium dyshomeostasis and ER stress. We hypothesize that DD patients have a diabetes-like metabolic phenotype and the objective of this study was to examine the association between DD with impaired glucose tolerance and diabetes. Methods: Cross-sectional clinical study on 25 DD patients and 25 matched controls. Metabolic status was assessed primarily by fasting blood glucose, oral glucose tolerance test, HOMA2-%S (insulin resistence) and HOMA2-%B (beta cell function). Results: DD subjects showed normal oral glucose tolerance test and HOMA2-%S, while fasting blood glucose was lower and c-peptide as well as HOMA2-%B was higher. Conclusion: Increased HOMA2-%B values are indicative of increased basal insulin secretion which is a type of beta cell dysfunction associated to diabetes development. These results supports a role of ER stress in diabetes pathophysiology and contribute to the understanding of DD as a multi-organ syndrome.

SERCA2 regulates proinsulin processing and processing enzyme maturation in the pancreatic β cell

“…Consistent with this observation, in individuals with Darier White disease, a rare genetic icthyosis disorder resulting from SERCA2 haploinsufficiency, lesion keratinocytes exhibit ER retention of cadherin, a transmembrane protein located at the plasma membrane that typically requires trafficking to the membrane (Celli et al ., 2012). Only one group has examined proinsulin to insulin ratios in individuals with Darier White; they described a non-significant trend towards increased ratios in a small cohort of affected individuals compared to matched controls (Ahanian et al, 2020). This same group found that individuals with Darier White have an increased relative risk of developing T1D (Cederlöf et al, 2019).…”

Patients with Darier Disease Exhibit Cognitive Impairment while Patients with Hailey-Hailey Disease Do Not: An Experimental, Matched Case-control Study

“…In medical literature, HHD has not been found to be associated with extradermal symptoms, while, as previously noted, there is strong evidence for a direct link between DD and psychiatric and intellectual disabilities. Our group has recently published reports shedding further light on DD as a multi-organ disease, showing associations with type 1 diabetes and pancreatic beta-cell dysfunction, as well as heart failure ( 47 – 49 ).…”

Molecular Pathogenesis and Complications Associated with Keratosis Follicularis: A Clinical Review

“…12 Moreover, in the recent cross-sectional clinical study of metabolic phenotype of DD, it has been found that DD patients have lower fasting glucose level and higher c-peptide and HOMA2-%beta compared to their matched control group. 33 This indicates that DD patients have a higher secretory capacity of islet cells and a higher basal insulin level. The authors emphasize that increased basal insulin is associated with worse control of glucose, and with time, may lead to type 2 diabetes.…”

“…The authors emphasize that increased basal insulin is associated with worse control of glucose, and with time, may lead to type 2 diabetes. 33 The relationship between glucose metabolism and DD may be due to the fact that among different SERCA isoforms, SERCA2b is most abundantly expressed in pancreatic beta-cells. 14 It has been shown that the loss of SERCA2b due to mutations in ATP2A2, as seen in individuals with DD, leads to secretory dysfunction, and defect in proliferation and survival of beta-cells.…”