Iatrogenic hypoglycaemia following glucose-insulin infusions for the treatment of hyperkalaemia.

OBJECTIVES: To study the incidence of, and risk factors for, iatrogenic hypoglycaemia following GwI infusion in our institution. CONTEXT: Hyperkalaemia is a life-threatening biochemical abnormality. Glucose-with-insulin (GwI) infusions form standard management, but risk iatrogenic hypoglycaemia (glucose ≤ 3.9 mmol/L). Recently updated UK guidelines include an additional glucose infusion in patients with pretreatment capillary blood glucose (CBG) < 7.0 mmol/L. DESIGN: Retrospective analysis of outcomes for GwI infusions prescribed for hyperkalaemia from 1 January to 28 February 2019, extracted from the Newcastle upon Tyne Hospitals NHS Foundation Trust electronic platform (eRecord). PARTICIPANTS: 132 patients received 228 GwI infusions for hyperkalaemia. MAIN OUTCOME MEASURES: Incidence, severity and time to onset of hypoglycaemia. RESULTS: Hypoglycaemia incidence was 11.8%. At least 1 hypoglycaemic episode occurred in 18.2% of patients with 6.8% having at least 1 episode of severe hypoglycaemia (< 3.0 mmol/L). Most episodes (77.8%) occurred within 3 h of treatment. Lower pretreatment CBG (5.9 mmol/L [4.1 mmol/L-11.2 mmol/L], versus 7.6 mmol/L [3.7 mmol/L-31.3 mmol/L], P = .000) was associated with hypoglycaemia risk. A diagnosis of type 2 diabetes and treatment for hyperkalaemia within the previous 24 h were negatively associated. CONCLUSIONS: Within our inpatient population, around 1 in 8 GwI infusions delivered as treatment for hyperkalaemia resulted in iatrogenic hypoglycaemia. Higher pretreatment CBG and a diagnosis of type 2 diabetes were protective, irrespective of renal function. Our findings support the immediate change to current management, either with additional glucose infusions or by using glucose-only infusions in patients without diabetes. These approaches should be compared via a prospective randomized study.

Correction: A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965.

Since the publication of this paper the authors noticed an error in the listed authors, where Alexandros Siskos was listed as Alexandros Sitkos. This has now been corrected.

A case of malignant hyperlactaemic acidosis appearing upon treatment with the mono-carboxylase transporter 1 inhibitor AZD3965.

A 47-year-old man with metastatic melanoma presented with refractory hyperlactaemic acidosis following the first dose of the mono-carboxylase transporter 1 inhibitor AZD3965 within a "first time in man" clinical trial. The mechanism of the agent and the temporal relationship suggested that this event was potentially drug related and recruitment was suspended. However, urinary metabolomics showed extensive abnormalities even prior to drug administration, leading to investigations for an underlying metabolic disorder. The lack of clinical symptoms from the elevated lactate and low blood glucose suggested a diagnosis of "hyper-Warburgism", where the high tumour burden was associated with extensive glucose uptake and lactate efflux from malignant cells, and the subsequent impact on blood biochemistry. This was supported by an FDG-PET scan showing extensive glucose uptake in numerous metastases and lack of uptake in the brain. A review of the literature showed 16 case reports of "hyper-Warburgism" in non-haematological malignancies, none of them with melanoma, with most associated with a poor outcome. The patient was treated symptomatically, but died 2 months later. The development of AZD3965 continues with the exclusion of patients with elevated plasma lactate at screening added to the protocol as a safety measure.Trial identification number ClinicalTrials.Gov. NCT01791595.

Protocol for a systematic review and individual patient data meta-analysis of prognostic factors of foot ulceration in people with diabetes: the international research collaboration for the prediction of diabetic foot ulcerations (PODUS).

BACKGROUND: Diabetes-related lower limb amputations are associated with considerable morbidity and mortality and are usually preceded by foot ulceration. The available systematic reviews of aggregate data are compromised because the primary studies report both adjusted and unadjusted estimates. As adjusted meta-analyses of aggregate data can be challenging, the best way to standardise the analytical approach is to conduct a meta-analysis based on individual patient data (IPD).There are however many challenges and fundamental methodological omissions are common; protocols are rare and the assessment of the risk of bias arising from the conduct of individual studies is frequently not performed, largely because of the absence of widely agreed criteria for assessing the risk of bias in this type of review. In this protocol we propose key methodological approaches to underpin our IPD systematic review of prognostic factors of foot ulceration in diabetes.Review questions;1. What are the most highly prognostic factors for foot ulceration (i.e. symptoms, signs, diagnostic tests) in people with diabetes?2. Can the data from each study be adjusted for a consistent set of adjustment factors?3. Does the model accuracy change when patient populations are stratified according to demographic and/or clinical characteristics? METHODS: MEDLINE and EMBASE databases from their inception until early 2012 were searched and the corresponding authors of all eligible primary studies invited to contribute their raw data. We developed relevant quality assurance items likely to identify occasions when study validity may have been compromised from several sources. A confidentiality agreement, arrangements for communication and reporting as well as ethical and governance considerations are explained.We have agreement from the corresponding authors of all studies which meet the eligibility criteria and they collectively possess data from more than 17000 patients. We propose, as a provisional analysis plan, to use a multi-level mixed model, using "study" as one of the levels. Such a model can also allow for the within-patient clustering that occurs if a patient contributes data from both feet, although to aid interpretation, we prefer to use patients rather than feet as the unit of analysis. We intend to only attempt this analysis if the results of the investigation of heterogeneity do not rule it out and the model diagnostics are acceptable. DISCUSSION: This review is central to the development of a global evidence-based strategy for the risk assessment of the foot in patients with diabetes, ensuring future recommendations are valid and can reliably inform international clinical guidelines.

Anti-neutrophil cytoplasmic antibody (ANCA) associated small-vessel vasculitis in a patient with diabetic nephropathy and autoimmune polyendocrinopathy syndrome (APS) Type 2: a case report.

We present a 42-year-old woman with pre-existing autoimmune polyendocrinopathy syndrome (APS) Type 2 and chronic kidney disease due to Type 1 diabetic nephropathy, who developed a rapid deterioration in renal function due to perinuclear anti-neutrophil cytoplasmic antibody (pANCA)-associated vasculitis. Although possibly a chance occurrence, ANCA have been detected more frequently in patients with a history of certain autoimmune diseases. Such an association may simply reflect an underlying tendency to immune system dysfunction in these patients and the finding of positive ANCA serology does not reliably herald the development of ANCA-associated vasculitis. However, our case illustrates that positive ANCA serology in such circumstances is not always a benign phenomenon and should still be interpreted within the clinical context. Moreover, clinicians managing patients with pre-existing autoimmune disease should maintain a low threshold for appropriate assessment should such patients develop evidence suggestive of vasculitis.

Randomized 52-week Phase 2 Trial of Albiglutide Versus Placebo in Adult Patients With Newly Diagnosed Type 1 Diabetes.

CONTEXT: GLP-1 receptor agonists are an established therapy in patients with type 2 diabetes; however, their role in type 1 diabetes remains to be determined. OBJECTIVE: Determine efficacy and safety of once-weekly albiglutide 30 mg (up-titration to 50 mg at week 6) versus placebo together with insulin in patients with new-onset type 1 diabetes and residual insulin production. DESIGN: 52-week, randomized, phase 2 study (NCT02284009). METHODS: A prespecified Bayesian approach, incorporating placebo data from a prior study, allowed for 3:1 (albiglutide:placebo) randomization. The primary endpoint was 52-week change from baseline in mixed meal tolerance test (MMTT) stimulated 2-h plasma C-peptide area under the curve (AUC). Secondary endpoints included metabolic measures and pharmacokinetics of albiglutide. RESULTS: 12/17 (70.6%, placebo) and 40/50 (80.0%, albiglutide) patients completed the study. Within our study, mean (standard deviation) change from baseline to week 52 in MMTT-stimulated 2-h plasma C-peptide AUC was -0.16 nmol/L (0.366) with placebo and -0.13 nmol/L (0.244) with albiglutide. For the primary Bayesian analysis (including prior study data) the posterior treatment difference (95% credible interval) was estimated at 0.12 nmol/L (0-0.24); the probability of a difference ≥0.2 nmol/L between treatments was low (0.097). A transient significant difference in maximum C-peptide was seen at week 28. Otherwise, no significant secondary endpoint differences were noted. On-therapy adverse events were reported in 82.0% (albiglutide) and 76.5% (placebo) of patients. CONCLUSION: In newly diagnosed patients with type 1 diabetes, albiglutide 30 to 50 mg weekly for 1 year had no appreciable effect on preserving residual ß-cell function versus placebo.

Metabolic and immune effects of immunotherapy with proinsulin peptide in human new-onset type 1 diabetes.

Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4(DRB1*0401)-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated ß cell-specific CD8 T cells, and favorable ß cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in ß cell function, and is associated with antigen-specific and nonspecific immune modulation.

Successful prospective prediction of type 1 diabetes in schoolchildren through multiple defined autoantibodies: an 8-year follow-up of the Washington State Diabetes Prediction Study.

OBJECTIVE: Almost 90% of type 1 diabetes appears in individuals without a close family history. We sought to evaluate the best current predictive strategy, multiple defined autoantibodies, in a long-term prospective study in the general population. RESEARCH DESIGN AND METHODS: Autoantibodies to pancreatic islets (islet cell antibodies [ICAs]) and defined autoantibodies (d-aab) to human GAD, IA2/ICA512, and insulin were tested in 4,505 Washington schoolchildren. Eight years later, 3,000 (67%) subjects were recontacted, including 97% of subjects with any test >99th percentile. RESULTS: Six subjects developed diabetes (median interval 2.8 years), all from among the 12 individuals with multiple d-aab, representing 50% positive predictive value (95% CI 25-75%) and 100% sensitivity (58-100%). Among the others, diabetes occurred in 0 of 6 with one d-aab plus ICA, 0 of 26 with ICA only, 0 of 7 with one d-aab equaling the 99th percentile and another d-aab equaling the 97.5th percentile, 0 of 86 with one d-aab, and 0 of 2,863 with no d-aab or ICA. Adjusted for verification bias, multiple d-aab were 99.9% specific (99.86-99.93%). At this age, new d-aab seldom appeared. Once present, d-aab usually persisted regardless of disease progression, although less so for insulin autoantibodies. Insulin secretion by sequential glucose tolerance testing remained normal in four multiple d-aab subjects not developing diabetes. Of children developing diabetes, five of six (83%) would be included if HLA-DQ genotyping preceded antibody testing, but HLA-DQ did not explain outcomes among high-risk subjects, even when considered along with other genetic markers. CONCLUSIONS: Multiple d-aab were established by age 14 years and prospectively identified all schoolchildren who developed type 1 diabetes within 8 years.

Dendritic cell-based proliferative assays of peripheral T cell responses to tetanus toxoid.

Antigen-specific proliferative responses of peripheral blood T cells are widely used in humans to study the T cell compartment. However, responses to autoantigens are often weak and poorly reproducible. Here we show, using a test recall antigen (tetanus toxoid), that absolute levels of proliferation, minimally detectable antigen doses, and/or ability to detect statistically significant responses can be enhanced using in vitro-generated autologous dendritic cells as antigen presenting cells.

Humoral and cellular immune responses to proinsulin in adults with newly diagnosed type 1 diabetes.

BACKGROUND: Type 1 diabetes (T1D) is an autoimmune disease characterized by immunity against pancreatic islet-derived proteins. The object of this study was to measure antibody and T-cell responses against proinsulin (PI), an islet-derived protein, and to map its dominant T-cell epitopes. METHODS: Antibody responses to proinsulin, insulin, glutamic acid decarboxylase (GAD), protein tyrosine phosphatase IA-2 and islet-cell antigen were measured in 116 newly diagnosed diabetic subjects aged 16 to 40 years. T-cell proliferative responses to proinsulin and proinsulin peptides were measured in 33 of these diabetic subjects and in 21 healthy control subjects. RESULTS: 22% of diabetic subjects but no control subjects expressed antibodies to proinsulin. A strong correlation existed between antibody levels to proinsulin and insulin within diabetic subjects. Similar proportions of diabetic (12%) and healthy (9.5%) subjects displayed T-cell responses to proinsulin. There was no correlation between antibody and T-cell responses to proinsulin within subjects. Amino acid region 56 to 72 was identified as the major T-cell epitope of proinsulin, though significant responses to region 14 to 37 were also present. CONCLUSION: Elevated proinsulin autoantibodies in diabetic subjects confirm proinsulin is an important autoantigen in type 1 diabetes. Though elevated cellular immunity to proinsulin protein was not detected, two dominant T-cell epitopes of proinsulin were identified that span the C-peptide and insulin junctions. Immunity to proinsulin was lower than that reported for childhood-onset type 1 diabetes and we propose that, like insulin, proinsulin may be targeted less frequently in adulthood.

Dendritic cell-based assays, but not mannosylation of antigen, improves detection of T-cell responses to proinsulin in type 1 diabetes.

In vitro detection of T-cell responses to autoantigens in type 1 diabetes is recognized as being technically challenging. We aimed to accurately measure cellular responses to proinsulin in patients with diabetes, and speculated that presentation of antigen by dendritic cells (DCs) would enhance the sensitivity of the peripheral blood assay. Antigen was mannosylated to facilitate uptake through DC surface mannose receptors to further improve the assay. Whole proinsulin, as well as mannosylated peptides of proinsulin, were combined with peripheral T cells and autologous immature DCs in a proliferative assay in a panel of newly diagnosed type 1 diabetic patients. The DC-based assay detected responses to proinsulin in five of 15 diabetic patients compared to one of 15 diabetic patients detected using the standard mononuclear cell assay. When the results of all patients were combined, the DC assay, but not the mononuclear cell assay, had a proinsulin response that was significantly higher than background (P < 0.001). The DC assay was, however, associated with high autologous mixed lymphocyte reactions that possibly masked responses in individual patients. Mannosylated antigen was taken up in larger quantities than non-mannosylated antigen, but not presented any more powerfully. Our data suggest that autologous DC-based assays are more powerful than standard peripheral blood mononuclear cell assays. However, they are compromised by high autologous mixed lymphocyte reactions and this requires addressing before they can be used as a routine readout of in vitro peripheral T-cell responses.