OBJECTIVERelative contributions of reversible β-cell dysfunction and true decrease in β-cell mass in type 2 diabetes remain unclear. Definitive rodent lineage-tracing studies have identified β-cell dedifferentiation and subsequent reprogramming to α-cell fate as a novel mechanism underlying β-cell failure. The aim was to determine whether phenotypes of β-cell dedifferentiation and plasticity are present in human diabetes.RESEARCH DESIGN AND METHODSImmunofluorescence colocalization studies using classical endocrine and mesenchymal phenotypic markers were undertaken using pancreatic sections and isolated islets from three individuals with diabetes and five nondiabetic control subjects.RESULTSIntraislet cytoplasmic coexpression of insulin and vimentin, insulin and glucagon, and vimentin and glucagon were demonstrated in all cases. These phenotypes were not present in nondiabetic control subjects.CONCLUSIONSCoexpression of mesenchymal and α-cell phenotypic markers in human diabetic islet β-cells has been confirmed, providing circumstantial evidence for β-cell dedifferentiation and possible reprogramming to α-cells in clinical diabetes.

We have investigated the contributions of dose per unit area and area of application to the degree of sensitivity induced by dinitrochlorobenzene (DNCB). Subjects sensitized with 35.4 micrograms/cm2 showed equal sensitization whether the total dose was 250 micrograms applied to 7.1 cm2 or 62.5 micrograms applied to 1.8 cm2. Three groups of subjects were sensitized with 16.4 micrograms/cm2 applied as 56 micrograms on 3.5 cm2, 116 micrograms on 7.1 cm2 or 232 micrograms on 14.2 cm2. Although the total dose changed by a factor of four, the proportions of subjects sensitized were comparable (66, 50 and 55% respectively), and their degrees of reactivity were similar. This contrasts with previous findings that when the area of sensitization was fixed and the concentration was increased over a similar range, highly significant increases in the proportion of sensitized subjects and degree of reactivity occurred.

In a double-blind controlled study of patients with pustular psoriasis of palms and soles who were allocated at random to etretinate or placebo, we found that etretinate improved the condition as assessed by pustule count and overall clinical response. Side-effects occurred but were accepted by the patients in the short-term. The clinical usefulness of etretinate in this condition will depend on time to relapse, and whether this can be prevented or postponed by continuous treatment. Toxicity in the long-term will also be important.

SUMMARYWe examined theeflfecis ofa small itiitial sensitizing dose of antigen (dinitrochlorobenzene, DNCB) on the subscqucnl response to a second, defined sensitizing stimulus. The second stimulus was actually the regimen of four doses of DNCB (3-125,6-25,12'5, and 25 /jg; total 46-9 fig) normally used as the elicitation challenge. In two separate experiments Band 18 control subjects received an initial 'challenge' with the four doses to induce sensitivity, and 4 weeks later their responses were determined with a second, elicitation challenge. Two groups of 12 and 15 experimental subjeets received an inital dose predicted to induce clinically detectable sensitivity in 50% or 25%, respectively. Four weeks later, their responsiveness was determined with quantitative challenge and the subjects who gave no response received a further challenge 4 weeks later. Their responses, eompared with those from the control subjects, were augmented, indicating thai sub-clinical priming of the immune system had indeed occurred.

Twenty patients with palmoplantar pustular psoriasis were treated initially for 4 weeks with 70 mg etretinate daily. This led to clinical improvement and a significant fall in pustule count. The patients were then allocated randomly to 30 mg etretinate daily or placebo for a further 12 weeks. There was a rapid deterioration in the clinical condition and a rise in pustule count in the placebo group. The etretinate-treated group still showed clinical improvement and a significantly lower pustule count after 12 weeks. Clinical side-effects were few and adverse effects on liver function and serum lipids were not found.