Loss of carbonic anhydrase XII function in individuals with elevated sweat chloride concentration and pulmonary airway disease.

Elevated sweat chloride levels, failure to thrive (FTT), and lung disease are characteristic features of cystic fibrosis (CF, OMIM #219700). Here we describe variants in CA12 encoding carbonic anhydrase XII in two pedigrees exhibiting CF-like phenotypes. Exome sequencing of a white American adult diagnosed with CF due to elevated sweat chloride, recurrent hyponatremia, infantile FTT and lung disease identified deleterious variants in each CA12 gene: c.908-1 G>A in a splice acceptor and a novel frameshift insertion c.859_860insACCT. In an unrelated consanguineous Omani family, two children with elevated sweat chloride, infantile FTT, and recurrent hyponatremia were homozygous for a novel missense variant (p.His121Gln). Deleterious CFTR variants were absent in both pedigrees. CA XII protein was localized apically in human bronchiolar epithelia and basolaterally in the reabsorptive duct of human sweat glands. Respiratory epithelial cell RNA from the adult proband revealed only aberrant CA12 transcripts and in vitro analysis showed greatly reduced CA XII protein. Studies of ion transport across respiratory epithelial cells in vivo and in culture revealed intact CFTR-mediated chloride transport in the adult proband. CA XII protein bearing either p.His121Gln or a previously identified p.Glu143Lys missense variant localized to the basolateral membranes of polarized Madin-Darby canine kidney (MDCK) cells, but enzyme activity was severely diminished when assayed at physiologic concentrations of extracellular chloride. Our findings indicate that loss of CA XII function should be considered in individuals without CFTR mutations who exhibit CF-like features in the sweat gland and lung.

Use of Continuous Glucose Monitoring to Facilitate Perioperative Glycemic Management: A Case Report.

Perioperative glycemic management remains an important variable in a host of postoperative outcomes, including wound infection, reoperation, and death. Patients with diabetes mellitus are increasingly utilizing continuous glucose monitors to assist with glycemic management; the ability to harness the intensive monitoring capabilities of continuous glucose monitoring (CGM) technology perioperatively presents a promising opportunity to improve patient outcomes. Here, we assessed the accuracy of CGM compared to capillary point-of-care and arterial blood analysis in 2 cases where CGM was utilized as an adjunct method of perioperative glucose monitoring.

Communication frequency between visits is associated with improved glycemic control in pediatric diabetes.

OBJECTIVES: Children with diabetes are advised to see their diabetes team every 3 months, with interim communication to address insulin dose adjustments. Despite increasing digital accessibility, there is limited data on whether provider-patient communication frequency is associated with glycemic control in pediatric diabetes. We assessed patterns of communication between diabetes clinic visits and whether communication frequency via electronic messaging (EM) and telephone was associated with glycemic control in pediatric diabetes. METHODS: Retrospective chart review of 267 children with type 1 (T1DM) and type 2 diabetes (T2DM) over a 1-year period (July 2018-June 2019) at an urban academic pediatric diabetes center. Association between frequency of communication (via EM and telephone) and HbA1c was analyzed using regression analysis. RESULTS: Of 267 participants, 224 (84%) had T1DM, 43 (16%) had T2DM, mean age 11.6 years (SD 4), mean duration of diabetes 3.5 years (SD 3.4), and mean HbA1c 73.8 ± 23 mmol/mol (8.9 ± 2.2%). Most participants (82%) communicated with their diabetes team at least once per year, with a mean number of overall communications of 10.3 ± 13.6 times. Communications were via EM (48%), phone (40%), or both (53%). Participants with more frequent communication had lower HbA1c values (p=0.007), even when controlling for age, sex, provider, and number of clinic visits per year. We determined that a threshold of three communications per year was associated with a lower HbA1c (p=0.006). CONCLUSIONS: More frequent communication with the diabetes team between visits is associated with improved glycemic control. Initiatives to contact diabetes patients between clinic visits may impact their overall glycemic control.

Genetic modifiers of cystic fibrosis-related diabetes.

Diabetes is a common age-dependent complication of cystic fibrosis (CF) that is strongly influenced by modifier genes. We conducted a genome-wide association study in 3,059 individuals with CF (644 with CF-related diabetes [CFRD]) and identified single nucleotide polymorphisms (SNPs) within and 5' to the SLC26A9 gene that associated with CFRD (hazard ratio [HR] 1.38; P = 3.6 × 10(-8)). Replication was demonstrated in 694 individuals (124 with CFRD) (HR, 1.47; P = 0.007), with combined analysis significant at P = 9.8 × 10(-10). SLC26A9 is an epithelial chloride/bicarbonate channel that can interact with the CF transmembrane regulator (CFTR), the protein mutated in CF. We also hypothesized that common SNPs associated with type 2 diabetes also might affect risk for CFRD. A previous association of CFRD with SNPs in TCF7L2 was replicated in this study (P = 0.004; combined analysis P = 3.8 × 10(-6)), and type 2 diabetes SNPs at or near CDKAL1, CDKN2A/B, and IGF2BP2 were associated with CFRD (P < 0.004). These five loci accounted for 8.3% of the phenotypic variance in CFRD onset and had a combined population-attributable risk of 68%. Diabetes is a highly prevalent complication of CF, for which susceptibility is determined in part by variants at SLC26A9 (which mediates processes proximate to the CF disease-causing gene) and at four susceptibility loci for type 2 diabetes in the general population.