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Aims/hypothesisIt is unclear whether type 1 diabetes is a single disease or if endotypes exist. Our aim was to use a unique collection of pancreas samples recovered soon after disease onset to resolve this issue.MethodsImmunohistological analysis was used to determine the distribution of proinsulin and insulin in the islets of pancreas samples recovered soon after type 1 diabetes onset (<2 years) from young people diagnosed at age <7 years, 7–12 years and ≥13 years. The patterns were correlated with the insulitis profiles in the inflamed islets of the same groups of individuals. C-peptide levels and the proinsulin:C-peptide ratio were measured in the circulation of a cohort of living patients with longer duration of disease but who were diagnosed in these same age ranges.ResultsDistinct patterns of proinsulin localisation were seen in the islets of people with recent-onset type 1 diabetes, which differed markedly between children diagnosed at <7 years and those diagnosed at ≥13 years. Proinsulin processing was aberrant in most residual insulin-containing islets of the younger group but this was much less evident in the group ≥13 years (p < 0.0001). Among all individuals (including children in the middle [7–12 years] range) aberrant proinsulin processing correlated with the assigned immune cell profiles defined by analysis of the lymphocyte composition of islet infiltrates. C-peptide levels were much lower in individuals diagnosed at <7 years than in those diagnosed at ≥13 years (median <3 pmol/l, IQR <3 to <3 vs 34.5 pmol/l, IQR <3–151; p < 0.0001), while the median proinsulin:C-peptide ratio was increased in those with age of onset <7 years compared with people diagnosed aged ≥13 years (0.18, IQR 0.10–0.31) vs 0.01, IQR 0.009–0.10 pmol/l; p < 0.0001).Conclusions/interpretationAmong those with type 1 diabetes diagnosed under the age of 30 years, there are histologically distinct endotypes that correlate with age at diagnosis. Recognition of such differences should inform the design of future immunotherapeutic interventions designed to arrest disease progression.

A female in her 60s was admitted via the emergency department following a respiratory collapse at home. She was profoundly hypoxic and hypertensive. For 1 week prior, she had been self-administering subcutaneous (SC) low molecular weight heparin (LMWH) for a small postoperative pulmonary embolism (PE) and reported worsening, self-resolving episodes of breathlessness 1 hour post-injection. Repeat imaging revealed a new small PE and blood tests showed a significant platelet drop. Her heparin-induced thrombocytopaenia (HIT) antibody test was positive. A diagnosis of HIT-associated anaphylactoid reaction was made. She was switched to a direct oral anticoagulant and fully recovered. This condition is well described, often presenting with profound respiratory compromise that can be misdiagnosed as ‘massive PE’. A key differentiation is that there is often hypertension instead of hypotension. This case, however, is unusual as it was triggered by SC LMWH not intravenous heparin as previously described in the literature.