Long-term complications in youth-onset type 2 diabetes

BACKGROUND: The prevalence of type 2 diabetes in youth is increasing, but little is known regarding the occurrence of related complications as these youths transition to adulthood. METHODS: We previously conducted a multicenter clinical trial (from 2004 to 2011) to evaluate the effects of one of three treatments (metformin, metformin plus rosiglitazone, or metformin plus an intensive lifestyle intervention) on the time to loss of glycemic control in participants who had onset of type 2 diabetes in youth. After completion of the trial, participants were transitioned to metformin with or without insulin and were enrolled in an observational follow-up study (performed from 2011 to 2020), which was conducted in two phases; the results of this follow-up study are reported here. Assessments for diabetic kidney disease, hypertension, dyslipidemia, and nerve disease were performed annually, and assessments for retinal disease were performed twice. Complications related to diabetes identified outside the study were confirmed and adjudicated. RESULTS: At the end of the second phase of the follow-up study (January 2020), the mean (±SD) age of the 500 participants who were included in the analyses was 26.4±2.8 years, and the mean time since the diagnosis of diabetes was 13.3±1.8 years. The cumulative incidence of hypertension was 67.5%, the incidence of dyslipidemia was 51.6%, the incidence of diabetic kidney disease was 54.8%, and the incidence of nerve disease was 32.4%. The prevalence of retinal disease, including more advanced stages, was 13.7% in the period from 2010 to 2011 and 51.0% in the period from 2017 to 2018. At least one complication occurred in 60.1% of the participants, and at least two complications occurred in 28.4%. Risk factors for the development of complications included minority race or ethnic group, hyperglycemia, hypertension, and dyslipidemia. No adverse events were recorded during follow-up. CONCLUSIONS: Among participants who had onset of type 2 diabetes in youth, the risk of complications, including microvascular complications, increased steadily over time and affected most participants by the time of young adulthood. Complications were more common among participants of minority race and ethnic group and among those with hyperglycemia, hypertension, and dyslipidemia. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; ClinicalTrials.gov numbers, NCT01364350 and NCT02310724.)

A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes

dentification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 x 10(-8)) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.Peer reviewe

Reproducibility of in-home CFRD screening using continuous glucose monitoring and mixed meal tolerance test

Background: Cystic fibrosis related diabetes (CFRD) is associated with insulin-remediable pulmonary decline, so early detection is critical. Continuous glucose monitors (CGM) have shown promise in screening but are not recommended by clinical practice guidelines. Little is known about the reproducibility of CGM results for a given patient. Methods: Twenty non-insulin treated adults and adolescents with CF placed an in-home CGM and wore it for two 14-day periods. Participants underwent a mixed meal tolerance test (MMTT) on day 5 of each 14-day period. Glycemic data from CGM 1 and CGM 2 were compared regarding published thresholds to define abnormality: percent time >140 mg/dL of ≥4.5%, percent time >140 mg/dL of >17.5%, and percent time >180 mg/dL of >3.4%. Results of the repeat MMTT were compared for peak glucose and 2-hour glucose thresholds: >140 mg/dL, >180 mg/dL, and >200 mg/dL. Results: For percent time >140 mg/dL of ≥ 4.5%, five of 20 subjects had conflicting results between CGM 1 and CGM 2. For percent time >140 mg/dL of >17.5% and >180 mg/dL of >3.4%, only one of 20 subjects had conflicting results between CGM 1 and CGM 2. On the MMTT, few participants had a 2-hour glucose >140 mg/dL. Peak glucose >140 mg/dL, 180 mg/dL, and 200 mg/dL were more common, with 10–37% of participants demonstrating disagreement between CGM 1 and CGM 2. Conclusions: Repeated in-home CGM acquisitions show reasonable reproducibility regarding the more stringent thresholds for time >140 mg/dL and >180 mg/dL. More data is needed to determine thresholds for abnormal mixed meal tolerance tests in CFRD screening

The human Kv1.1 channel is palmitoylated, modulating voltage sensing: Identification of a palmitoylation consensus sequence

Voltage-dependent K(+) channels rely on precise dynamic protein interactions with surrounding plasma membrane lipids to facilitate complex processes such as voltage sensing and channel gating. Many transmembrane-spanning proteins use palmitoylation to facilitate dynamic membrane interactions. Herein, we demonstrate that the human Kv1.1 ion channel is palmitoylated in the cytosolic portion of the S(2)-S(3) linker domain at residue C243. Through heterologous expression of the human Kv1.1 protein in Sf9 cells, covalent radiolabeling with [(3)H]palmitate, chemical stability studies of the [(3)H]-palmitoylated protein, and site-directed mutagenesis, C243 was identified as the predominant site of palmitoylation. The functional sequelae of palmitoylation were examined by analysis of whole cell currents from WT and mutant channels, which identified a 20-mV leftward shift in the current-voltage relationship when palmitoylation at C243 (but not with other cysteine deletions) is prevented by site-directed mutagenesis, implicating a role for palmitoylated C243 in modulating voltage sensing through protein-membrane interactions. Database searches identified an amino acid palmitoylation consensus motif (ACP/RSKT) that is present in multiple other members of the Shaker subfamily of K(+) channels and in several other unrelated regulatory proteins (e.g., CD36, nitric oxide synthase type 2, and the mannose-6 phosphate receptor) that are known to be palmitoylated by thioester linkages at the predicted consensus site cysteine residue. Collectively, these results (i) identify palmitoylation as a mechanism for K(+) channel interactions with plasma membrane lipids contributing to electric field-induced conformational alterations, and ii) define an amino acid consensus sequence for protein palmitoylation