The stimulation of insulin secretion in non-insulin-dependent diabetic patients by amino acids and gliclazide in the basal and hyperglycemic state.

Sulfonylureas stimulate insulin secretion as their predominant contribution toward decreasing blood glucose in diabetic patients. We studied eight gliclazide-treated, non-insulin-dependent diabetic patients on two occasions with a protocol of basal observation for 30 minutes, a 60-minute infusion of randomized leucine or arginine, and a further 90-minute hyperglycemic clamp. Basal glucose was the same on both occasions (mean, 7.82 mmol/L for leucine v 7.79 for arginine, P = NS), and glucose levels declined to 7.50 and 7.25 mmol/L, respectively, by 30 minutes. After leucine infusion, the decline of glucose continued, but stabilized or reversed with arginine such that by the end of the infusions, glucose levels were 6.63 +/- 0.69 mmol/L for leucine and 7.62 +/- 0.67 for arginine (P < .02). Arginine caused a sharp increase in insulin secretion (from 17.8 mU/L to 43.8 mU/L in 6 minutes) at the onset of the infusion, and thereafter insulin secretion was not significantly different throughout either the amino acid or hyperglycemic clamp periods (mean, 42.1 v 44.7 mU/L, respectively, P = NS). By contrast, the leucine infusion caused little acute change in secretion, but augmented it with time from the basal period (17.2 mU/L) to the end of the infusion (29.4 mU/L). During the hyperglycemic clamp period, there was significant further augmentation of insulin secretion, increasing to 81.6 +/- 16 mU/L at the end of the study. Leucine significantly augmented insulin secretion compared with arginine (81.6 +/- 16 v 54.0 +/- 8.4 mU/L, respectively, P < .002). These data suggest that leucine is a better priming agent for sulfonylurea than arginine. Additive effects on insulin secretion may allow the use of combinations of branched chain amino acids (BCAAs) and sulfonylureas to augment insulin secretion in the presence of hyperglycemia.

Regulation of fatty acid movement in human adipose tissue in the postabsorptive-to-postprandial transition.

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.

Subclinical autonomic dysfunction in patients with Hodgkin's disease and non-Hodgkin's lymphoma.

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.

Effects of ponalrestat, an aldose reductase inhibitor, on neutrophil killing of Escherichia coli and autonomic function in patients with diabetes mellitus.

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.

Hand skin blood flow in diabetic patients with autonomic neuropathy and microangiopathy.

OBJECTIVE: To determine whether changes in hand skin blood flow in diabetic men could be demonstrated with liquid crystal contact thermography and to assess the relative effects of autonomic neuropathy and microangiopathy on these changes. RESEARCH DESIGN AND METHODS: Thirty-four diabetic and 12 age-matched nondiabetic men comprised the study. The diabetic men were categorized according to standard cardiovascular autonomic function tests and the presence or absence of background or proliferative retinopathy and/or proteinuria. Bilateral hand thermograms were measured at rest and after immersion of the right hand in ice-cold water. RESULTS: Diabetic men with definite or severe autonomic neuropathy (n = 13) had a high frequency of anisothermal baseline thermograms (77 vs. 25% in nondiabetic subjects, P less than 0.05). After ice-cold water immersion, right-hand recovery was abnormally slow (514 +/- 157 arbitrary U, area under the curve) compared with nondiabetic men (685 +/- 135 arbitrary U, P less than 0.01). Diabetic men with proliferative retinopathy (n = 8) all had definite or severe autonomic neuropathy and showed the same abnormalities. Diabetic men with nor or early autonomic changes showed normal thermographic patterns. CONCLUSIONS: These results are consistent with increased palmar arteriovenous shunt blood flow or capillary closure in the hands of diabetic patients with definite or severe autonomic neuropathy. They indicate that thermoregulatory reflex changes in hand skin blood flow are controlled by the autonomic nervous system. It is possible, however, that diabetic microangiopathy, associated with the presence of proliferative retinopathy, also independently affects hand skin blood flow.

Autonomic neuropathy, QT interval lengthening, and unexpected deaths in male diabetic patients.

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 changes in autonomic function. There may be an association between QT interval prolongation and the risk of dying unexpectedly in diabetic autonomic neuropathy.