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.

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.

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 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.

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.