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Author(s): R. Valentini (corresponding author) [1]; G. Matteucci [1]; A. J. Dolman [2]; E.-D. Schulze [3, 4]; C. Rebmann [3, 4]; E. J. Moors [2]; A. Granier [5]; P. Gross [...]

Aims/hypothesis. Glutamic acid decarhoxylase autoantibodies (GADA) are the most frequent beta-cell-specific autoantibodies in type 1 diabetes and in latent autoimmune diabetes in adults (LADA). The autoimmune attack on pancreatic islet cells is associated with a T helper 1 cell (Th1) response, mainly represented by IgG1-subclass in humans. It has been proposed that the presence of IgG4 may he associated with a Th2 response. The aim of our study was to compare the GADA IgG-subclass distribution between adult patients with type 1 diabetes and LADA. Methods. Patients with type 1 diabetes (n=45) and patients with LADA (n=60) were included. Radioimmunoprecipitation assay with IgG-subclass specific Sepharose (IgG1, IgG2, IgG3 and IgG4) was used to precipitate the antibody/antigen-complex. Results. We only detected IgG4-subclass of GADA in subjects with LADA (26.7%; p<0.001). IgG1 was the most common GADA-subclass in both groups, however IgG1 as the solely expressed subclass was more common among type 1 diabetic patients (77.8%; p<0.05). The rank order of the frequencies of IgG-subclasses in type 1 diabetes was IgG1>IgG3>IgG2>IgG4 and in LADA patients IgG 1>IgG4>IgG2>IgG3. Conclusions/interpretation. The difference in GADA IgG-subclasses could indicate a different immune response, possibly an altered balance between Th1 and Th2 cytokine profile in pancreatic islets. This difference could contribute to the slower rate of beta cell destruction in LADA patients, as reflected by a higher C-peptide level at clinical onset. [ABSTRACT FROM AUTHOR]

Intraosseous (IO) access is normally reserved for emergencies and critical care conditions when venous cannulation is not possible. Nonetheless, we present a case of IO insertion to a 56-year-old man, tetraplegic for many years due to progressive spinal muscular atrophy and with refractory suffering. The IO access was used for palliative sedation with propofol in a home care setting. The patient died after 11 days of palliative care, of which the last 4 days were with palliative sedation using an IO cannula as a vascular access. No complications were noted from this route of administration. We advocate the use of IO access in the palliative care of terminal ill patients when a venous cannulation is not possible.

Background: Several sequence variants are known to have effects on serum levels of non-high-density lipoprotein (HDL) cholesterol that alter the risk of coronary artery disease., Methods: We sequenced the genomes of 2636 Icelanders and found variants that we then imputed into the genomes of approximately 398,000 Icelanders. We tested for association between these imputed variants and non-HDL cholesterol levels in 119,146 samples. We then performed replication testing in two populations of European descent. We assessed the effects of an implicated loss-of-function variant on the risk of coronary artery disease in 42,524 case patients and 249,414 controls from five European ancestry populations. An augmented set of genomes was screened for additional loss-of-function variants in a target gene. We evaluated the effect of an implicated variant on protein stability., Results: We found a rare noncoding 12-base-pair (bp) deletion (del12) in intron 4 of ASGR1, which encodes a subunit of the asialoglycoprotein receptor, a lectin that plays a role in the homeostasis of circulating glycoproteins. The del12 mutation activates a cryptic splice site, leading to a frameshift mutation and a premature stop codon that renders a truncated protein prone to degradation. Heterozygous carriers of the mutation (1 in 120 persons in our study population) had a lower level of non-HDL cholesterol than noncarriers, a difference of 15.3 mg per deciliter (0.40 mmol per liter) (P=1.0×10(-16)), and a lower risk of coronary artery disease (by 34%; 95% confidence interval, 21 to 45; P=4.0×10(-6)). In a larger set of sequenced samples from Icelanders, we found another loss-of-function ASGR1 variant (p.W158X, carried by 1 in 1850 persons) that was also associated with lower levels of non-HDL cholesterol (P=1.8×10(-3))., Conclusions: ASGR1 haploinsufficiency was associated with reduced levels of non-HDL cholesterol and a reduced risk of coronary artery disease. (Funded by the National Institutes of Health and others.).

Objectives: The optimal treatment of latent autoimmune diabetes in adults (LADA) is not established. We explored whether early insulin treatment, which has shown beneficial effects in rodents and in human pilot studies, would result in better preservation of β-cell function or metabolic control, compared with conventional treatment., Subjects and Methods: Glucagon-stimulated C-peptide and HbAlc were evaluated at baseline and after 12, 24 and 36 months in 37 patients recently diagnosed with diabetes, aged ≥ 30 years, non-insulin-requiring and GADAb and/or ICA positive. Twenty patients received early insulin and 17 received conventional treatment (diet ± oral hypoglycaemic agents (OHA), metformin, some and/or sulfonylurea) and insulin when necessary., Results: Level of metabolic control, HbAlc, was preserved in the early insulin treated, while it significantly deteriorated in the conventionally treated. There was no significant difference between the groups in C-peptide after 12, 24 or 36 months, or in the decline of C-peptide. Only baseline C-peptide predicted a C-peptide of ≥ 0.5 nmol/l at 36 months. Gender, body mass index, antibody titres or HbAlc did not influence the levels of C-peptide or HbAlc at baseline or end-of-study, or the decline in C-peptide. Among the diet ± OHA-treated, 5/17 (30%) developed insulin dependency during the follow-up. No major hypoglycaemic events occurred., Conclusions: Early insulin treatment in LADA leads to better preservation of metabolic control and was safe. Superior preservation of C-peptide could not be significantly demonstrated. Only baseline level of C-peptide significantly influenced C-peptide level after 3 years. Further studies exploring the best treatment in LADA are warranted.