Summary. QT intervals were measured over RR intervals ranging from 500 ms to 1000 ms in 13 normal male subjects, 13 male diabetic subjects without and 13 with autonomic neuropathy. There was a close linear relationship between QT and RR in all subjects. The slope of the regression line was significantly greater in the autonomic neuropathy group than the normal group. Thirty-two male diabetic subjects with varying degrees of autonomic dysfunction had repeat QT measurements 3 (range 2-6) years later. QT and QTC lengthened significantly at the second visit, unrelated to age or time between recordings, but which corresponded with changes in autonomic function. Of 71 male diabetic subjects under 60 years followed for 3 years, 13 had died, 8 unexpectedly. Of those with autonomic neuropathy, QT and QTC were significantly longer in those who subsequently died, despite similar ages and duration of diabetes. We conclude that QT/RR interval relationships are altered in diabetic autonomic neuropathy, and that changes in QT length with time parallel changese in autonomic function. There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.Key words: Diabetes mellitus, autonomic neuropathy, QT interval, sudden death, autonomic function tests.Diabetic subjects with clinical features of autonomic neuropathy may die suddenly and unexpectedly, but the mechanisms have not been elucidated [1]. There has been considerable recent interest in the relationship between QT interval length, diabetes mellitus and sudden death, with evidence to suggest that where diabetic autonomic neuropathy co-exists the QT interval is prolonged [2][3][4][5][6]. It has been speculated that this could provide a possible explanation for the unexpected deaths [2,3,6], based on observations of the long QT syndrome and the sudden infant death syndrome [7]. To date, however, no firm evidence has been produced directly linking QT interval lengthening and sudden deaths in diabetic subjects.This study was designed to try to throw further light on the possible mechanisms and the relationships between QT interval length and unexpected deaths by addressing three related questions. Firstly, is there good evidence of altered QT interval in diabetic autonomic neuropathy? We have previously shown that in the steady state there are small alterations in QT length associated with autonomic impairment [4]. We wanted to see whether QT/RR interval relationships were also altered in this group. Secondly, does QT interval lengthen with time during the progress of diabetes, and if so is this related to worsening autonomic function? Thirdly, was there a longer QT interval in those diabetic patients who had subsequently died, some suddenly and unexpectedly, when compared with those diabetic subjects who survived? Patients and methods PatientsWe studied different groups in the three parts of the study. By their very nature the studies were retrospective as the QT measurements were taken from 24 h ECG tapes that ha...

There is net outward flow of fatty acids from adipose tissue in the fasted state but net inward flow and storage in the postprandial state. We investigated how this is regulated. Arteriovenous differences were measured across a subcutaneous adipose depot in six normal subjects before and for 5 h after a meal containing 80 g fat and 80 g carbohydrate. In five further experiments, insulin was infused at 40 mU.m-2.min-1 from 30 min after the meal, clamping the plasma glucose. Net transcapillary fatty acid flow changed from negative (outward flow from tissue to capillaries) in the postabsorptive state to consistently positive (net inward flow, implying fat storage) after the meal despite continued net efflux of fatty acids into venous blood. In the "clamped" experiments (with additional insulin), net fatty acid efflux in the venous blood was suppressed and positive transcapillary flux (storage) was more marked. Regulation of fatty acid flow appeared to depend on coordinated changes in hormone-sensitive lipase (HSL) and lipoprotein lipase (LPL) action and fatty acid esterification. Additional insulin caused no further suppression of HSL or activation of LPL but markedly stimulated fatty acid retention (presumed to represent esterification). In the absence of additional insulin, a high proportion of the fatty acids liberated by LPL are released into the venous plasma in both postabsorptive and postprandial states. We hypothesize that this "loss" of fatty acids is necessary to give precise control to the pathway of fat storage.

A prospective study was carried out to determine the prevalence of autonomic dysfunction in patients with lymphoma, and to assess the effect on this of chemotherapy. Twenty consecutive patients presenting with Hodgkin's disease, high-grade non-Hodgkin's lymphoma, or low-grade non-Hodgkin's lymphoma were studied. All had advanced disease, requiring combination chemotherapy which included the use of vinca alkaloids. Clinical assessment and standard cardiovascular autonomic function tests were carried out prior to and following completion of chemotherapy. Although no patients had clinical evidence of autonomic neuropathy at presentation, 16 (80%) had abnormal cardiovascular autonomic function tests. There was no correlation with the presence or absence of mediastinal disease. There was significant improvement in autonomic scores with treatment despite the use of drugs of known neurological toxicity. Some patients showed residual abnormalities of autonomic function despite disease resolution. We suggest that subclinical autonomic dysfunction is common in patients with lymphoma, and probably represents a paraneoplastic syndrome--the pathogenesis and prevalence of which deserve further study. This phenomenon may predispose patients with lymphoma to develop gastrointestinal and genitourinary dysfunction, or postural hypotension, and should be considered during the evaluation of the neurotoxicity of chemotherapy regimens.

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In diabetic subjects, polyol pathway activity might inhibit neutrophil function and cause nerve damage. The effects of ponalrestat, an aldose reductase inhibitor, were assessed on neutrophil intracellular killing of Escherichia coli and on autonomic function in diabetic subjects in a randomized double-blind, placebo-controlled, crossover trial. We studied 31 diabetic subjects with autonomic dysfunction and 21 age- and sex-matched control subjects. During two 12-wk treatment periods, the diabetic subjects took either 600 mg of ponalrestat or matching placebo once daily. Neutrophil killing of E. coli was measured by a microbiological assay technique. Kmax by neutrophils from the diabetic subjects was lower than in the control group (Kmax of diabetic subjects 54.5 +/- 26.4 vs. control subjects 67.3 +/- 16.3, P = 0.045). Ponalrestat significantly increased bacterial killing in the diabetic subjects (Kmax of ponalrestat 75.1 +/- 16.5 vs. placebo 58.2 +/- 20.8, P = 0.003) so that there was no longer any significant difference in Kmax between the control subjects and the diabetic subjects on active treatment. Ponalrestat had no significant effect on a range of standard cardiovascular autonomic nerve function tests. We conclude that neutrophil killing of E. coli is impaired in diabetic subjects with autonomic dysfunction. This is restored to normal by ponalrestat.