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.

Renal responses to nifedipine and captopril in hypertensive insulin-dependent diabetic men: a randomized cross-over study.

The effects of nifedipine retard and captopril on renal haemodynamic parameters have been examined in a double blind randomised cross-over trial in 10 insulin-dependent diabetic males with hypertension (systolic pressure > 150 mmHg or diastolic pressure > 90 mmHg). The acute renal haemodynamic response to nifedipine retard 20 mg and captopril 25 mg was monitored at the start of therapy and again after 8 weeks treatment with nifedipine retard 20 mg b.d. and captopril 25 mg b.d. Blood pressure fell from 148/97 +/- 4/2 (SEM) during the run-in phase to 135/87 +/- 4/1.5 on nifedipine retard and to 131/83 +/- 5/1 on captopril. There was no difference between the initial renal response to the two agents; an increase in renal plasma flow and a non-significant decline in glomerular filtration rate resulted in similar decreases in filtration fraction. After 8 weeks therapy, neither drug had a significant effect on urinary albumin excretion. Baseline renal function did not differ and no acute changes in renal haemodynamics were seen after nifedipine. Following captopril there was no acute change in systemic blood pressure but RPF rose from 572 +/- 41 to 638 +/- 42 ml/min per 1.73 m2 (P < 0.05) and filtration fraction fell from 0.21 to 0.16 (P < 0.02). This sustained acute response of the renal circulation to angiotensin-converting enzyme (ACE) inhibition after chronic therapy may be relevant to the apparent renal protection afforded by ACE inhibitors in experimental nephropathies.

Factors influencing oral carriage of yeasts among individuals with diabetes mellitus.

A total of 439 individuals with diabetes mellitus were examined for carriage of yeasts by the oral rinse and palatal swab techniques. Eighteen genetic or environment variables were assessed for their contribution to carriage of yeasts. The factor contributing to palatal and oral carriage of yeasts among individuals with insulin dependent diabetes mellitus (IDDM) was age (P < 0.01). The factor contributing to palatal carriage of yeasts among individuals with non-insulin dependent diabetes mellitus (NIDDM) was poor glycaemic control (glycosuria P < 0.01); carriage in the oral cavity as a whole was influenced additionally by non-secretion of ABH blood group antigens (P < 0.05). Introduction of a denture altered the above risk factors. For individuals with IDDM, oral carriage was associated with the presence of retinopathy (P < 0.05); palatal carriage was influenced by poor glycaemic control (HbA1P < 0.01, plasma glucose levels P < 0.05) and age (P < 0.05). For those with NIDDM, palatal carriage was associated with continuous presence of the denture in the mouth (P < 0.01); oral carriage was associated with plasma glucose levels (P < 0.05).

Neutrophil count and activation in vascular disease.

An elevated peripheral leucocyte count is associated with an increased risk of myocardial infarction and progression of coronary artery disease. The aim of this study was to determine neutrophil count and activation, measured as an increase in plasma neutrophil elastase, in patients with stable ischaemic heart disease, insulin-dependent diabetes mellitus and essential hypertension compared with a comparable group of control subjects. Neutrophil count and neutrophil elastase were raised significantly for patients with ischaemic heart disease (p less than 0.005; p less than 0.002), diabetes mellitus (p less than 0.001; p less than 0.01) and hypertension (p less than 0.05; p less than 0.0001) respectively compared to the control subjects. Neutrophil elastase did not correlate with subject age or leucocyte count. This study confirms the association between leucocyte count and vascular disease, and is consistent with neutrophil activation contributing to the progression of vascular disease.

Regulation of ANP secretion in insulin-dependent diabetes mellitus and the influence of autonomic neuropathy.

In order to determine the effect of diabetic autonomic neuropathy (DAN) on the atrial natriuretic peptide (ANP) response to dynamic stimuli, we studied the ANP response to 60 degrees head-up and 60 degrees leg-up tilt in diabetic subjects with (DAN + ve, n = 8) and without (DAN - ve, n = 8) evidence of autonomic neuropathy and seven matched non-diabetic controls. Mean baseline plasma ANP concentrations were similar in all three groups. Head-up tilt was associated with a fall in plasma ANP in all seven healthy controls (21.8 (16.8-30.7) to 16.8 (7.1-29.1), P = 0.06, mean (range)), seven of the eight DAN - ve (16.9 (6.5-33.7) to 8.5 (3.0-21.1), P = 0.015) and all eight DAN + ve subjects (27.3 (8.5-101.5) to 15.4 (1.0-67.6), P = 0.044). Leg-up tilt caused a rise in plasma ANP in six of the seven healthy controls (17.6 (7.5-27.9) to 22.4 (15.2-48.1), P = 0.041), six of the eight DAN - ve (12.5 (7.8-27.8) to 15.5 (7.3-31.3), P = 0.054) and seven of the eight DAN + ve subjects (18.2 (2.8-55.1) to 25.1 (4.5-92.8), P = 0.013). There was no significant difference in the fall in plasma ANP during head-up tilt or in the rise in plasma ANP during leg-up tilt between the three groups. We conclude that the regulation of ANP secretion is normal in diabetes mellitus, and is unaffected by the presence of autonomic neuropathy.

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.

A double-blind crossover study of oral xamoterol in postural hypotension due to diabetic autonomic neuropathy.

Recent reports have suggested that xamoterol, a beta 1 adrenoceptor partial agonist with 43% intrinsic sympathomimetic activity improves symptomatic postural hypotension in patients with primary autonomic failure. To evaluate the use of xamoterol in eleven insulin dependent patients with diabetes mellitus who had postural hypotension (over 20 mmHg systolic blood pressure) secondary to autonomic neuropathy, we performed a double-blind, randomized, placebo controlled crossover study with xamoterol (200 mg bd orally) for 1 month. Treatment with xamoterol raised supine systolic blood pressure by 11 mmHg but a reduced standing systolic blood pressure by 11 mmHg with an increase in the standing-supine systolic blood pressure difference. No significant differences were observed in symptom score, HbA1 or plasma glucose. We conclude that oral xamoterol raises supine systolic blood pressure but paradoxically lowers standing systolic blood pressure further in insulin dependent diabetes mellitus. Xamoterol is unlikely to be of value in the management of postural hypotension in diabetic patients with autonomic neuropathy.

Alterations in monocyte receptor function in type 1 diabetic patients with ketoacidosis.

The level of expression of three monocyte cell surface receptors was studied in seven patients with Type 1 (insulin-dependent) diabetes admitted to hospital with ketoacidosis. After recovery of metabolic control the monocyte carbohydrate-binding ('lectin-like') receptors that recognize bacterial cell wall sugars and receptors for complement components were reduced in the patients compared with normal control subjects. This was in contrast to the expression of the receptor for the Fc portion of immunoglobulin which remained unaltered. Compared with the control subjects the level of 'lectin-like' receptors was reduced by 22.8 +/- 6.5% (p less than 0.05) on admission to hospital and 12.1 +/- 1.7% (p less than 0.001) 6 weeks later when metabolic control had been established. The expression of complement receptors was 33.8 +/- 8.1% (p less than 0.01) lower than normal subjects when the diabetic patients suffered from ketoacidosis and 8.6 +/- 1.6% (p less than 0.01) lower than control subjects when patients had recovered metabolic control. The increased susceptibility to infection seen in diabetic patients, and the high incidence of infection in patients with ketoacidosis, may be partially the result of these changes in monocyte recognition mechanisms.

Chronic atrophic oral candidiasis among patients with diabetes mellitus--role of secretor status.

Non-diabetic individuals who are non-secretors of blood group antigens are prone to superficial infections by Candida albicans. In this study, 216 patients with diabetes mellitus who were denture wearers were examined for the presence or absence of denture stomatitis. There was an overall trend for non-secretors to be prone to denture stomatitis compared with secretors. Stepwise linear discriminant analysis was used to dissect the contribution of secretor status and other variables to the development of the disease. Secretor status was found to be a contributory factor among patients with non-insulin dependent diabetes but not among those with insulin-dependent diabetes. The possible reasons for this are discussed.

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.

The natural history and associations of microalbuminuria in type 2 diabetes during the first year after diagnosis.

The prevalence of microalbuminuria was assessed in 149 consecutive, newly-diagnosed and untreated patients with Type 2 diabetes, 129 of whom were followed up for 1 year, with at least three urine specimens being obtained during this period. At initial presentation, 39 (26%) patients had a urinary albumin to creatinine ratio (ACR) of greater than 2.5 mg mmol-1 and compared with patients who had a normal ACR, they were older (64 (11) (SD) vs 58 (11) yr, p less than 0.002), with higher random blood glucose (14.4 (4.5) vs 12.3 (4.4) mmol l-1, p less than 0.02) and glycosylated haemoglobin (13.0 (3.1) vs 11.3 (2.7)%, p less than 0.01) concentrations. An elevated ACR was also associated with a higher systolic blood pressure (149 (22) vs 140 (22), p less than 0.05) and the presence of macrovascular disease, particularly peripheral vascular disease (p less than 0.001), with this association persisting after adjustment for the effect of age. Ten patients reverted to normal albumin excretion on improving blood glucose control, this group having a significantly higher glycosylated haemoglobin concentration at initial presentation than the group with a persistently elevated ACR (14.4 (2.5) vs 12.0 (3.0)%, p less than 0.05). The 21 (16%) patients with a persistently elevated ACR from diagnosis of Type 2 diabetes were older than those with normal albumin excretion throughout (64 (7) vs 58 (10) yr, p less than 0.02) and it is probable that these patients have abnormal albumin excretion secondary to established renal pathology.

Vagus nerve morphology in diabetic gastropathy.

Two patients were treated with gastroenterostomy and vagotomy for intractable vomiting due to diabetic gastropathy. A morphometric examination of nerve fibres and capillaries in their resected abdominal vagi was performed and the results were compared with findings from two diabetic and two non-diabetic patients undergoing gastroenterostomy and vagotomy for duodenal ulceration. All four diabetic patients had pathological changes of a similar character: reduced myelinated fibre density, degeneration and regeneration of unmyelinated fibres, and capillary basement membrane thickening. Abnormalities were more pronounced in the two diabetic patients with gastropathy but intact and regenerating nerve fibres were still present. The findings support the view that vagal neuropathy could be a causal factor in diabetic gastropathy but imply that severe gastropathy with vomiting is not simply a consequence of autovagotomy. The morphological observations indicated that structural changes can occur in the autonomic nerves of diabetic patients who do not develop autonomic symptoms or have easily detectable abnormal autonomic physiology.

Association of painful and painless diabetic polyneuropathy with different patterns of nerve fiber degeneration and regeneration.

We evaluated neuropathological abnormalities in sural nerve biopsies from 6 nondiabetic control subjects and 16 age-matched diabetic patients with different syndromes of sensory polyneuropathy (6 with chronic painful neuropathy [CPN], 4 with newly presenting painful neuropathy [NPN], and 6 with painless neuropathy associated with recurrent neurotrophic foot ulcers [RFU]). Although all but one of the evaluated features of myelinated and unmyelinated fiber pathology could be found in every diabetic patient, certain myelinated fiber abnormalities were associated with the clinical characteristics of the neuropathy. Thus, myelinated fiber density was severely reduced, "empty" Schwann tubes (an index of myelinated fiber degeneration) were increased, and early regeneration (bands of Büngner [BB], nonmyelinated axons) was pronounced in the RFU group. Progression from BB to regenerating myelinated fiber cluster (myelination and maturation) was more successful in patients with CPN and NPN than in those with RFU, and the finding of fibers with disproportionately large Schwann cells (cytoplasm and myelin) relative to axon caliber was exclusive to patients with neuropathic pain. We concluded that 1) unequal rates of successful fiber regeneration may underlie the apparent difference in the extent of myelinated fiber loss between painful and painless diabetic polyneuropathy; 2) myelinated and unmyelinated fiber degeneration and regeneration per se are probably not the cause of neuropathic pain in diabetic polyneuropathy, because each occurred in patients with RFU; and 3) axonal atrophy may be involved in neuropathic pain generation.

Relationship of endoneurial capillary abnormalities to type and severity of diabetic polyneuropathy.

Endoneurial capillary abnormalities have been assessed quantitatively in sural nerve biopsies from diabetic patients with different syndromes of sensory polyneuropathy: chronic painful neuropathy, newly presenting painful neuropathy, and painless neuropathy associated with neurotrophic foot ulceration. Comparisons were made with age-matched nondiabetic control subjects. The diabetic groups showed no abnormality in capillary density or mean endoneurial area per fascicle. Compared with control subjects, all diabetic patients had an increase in mean capillary diameter, capillary wall thickness, and outer tunic (basement membrane and pericytes) thickness. The increase in wall thickness was most pronounced in patients with painless neuropathy (200%) and less marked in similar patients with painful neuropathy (100%). The pericyte volume fraction of the outer tunic was reduced in all diabetic patients, implying that basement membrane hypertrophy and reduplication were responsible for outer tunic thickening. There was evidence of endothelial cell hyperplasia rather than hypertrophy. There was a correlation between the degree of basement membrane thickening and the severity of myelinated fiber abnormality assessed neurophysiologically and morphologically. This study shows a link between the degree of endoneurial capillary basement membrane thickening, the type of neuropathology, and the clinical expression of neuropathy in diabetes mellitus.

Comparison of intramuscular glucagon and intravenous dextrose in the treatment of hypoglycaemic coma in an accident and emergency department.

Hypoglycaemia remains a serious and much feared complication of insulin therapy. In this study, patients attending an accident and emergency department in hypoglycaemic coma were randomized to treatment with either intravenous dextrose (25g) or intramuscular glucagon (1mg), administered into the right thigh. Restoration of normal conscious level was slower after glucagon than dextrose (9.0 vs 3.0 min, P less than 0.01), although the average duration of hypoglycaemic coma was 120 min. Two patients in the glucagon-treated group, who failed to show satisfactory recovery after 15 min, required additional treatment with intravenous dextrose. On questioning following recovery, all except two patients reported loss of awareness of the onset of hypoglycaemia Intramuscular glucagon is valuable in the treatment of severe hypoglycaemia outwith hospital and, although the slightly slower and less predictable recovery may appear to make it a less attractive option than intravenous dextrose in the accident and emergency department, this must be balanced against the advantages of ease of administration and a lower incidence of serious adverse effects.

Blood glucose control determines the renal haemodynamic response to angiotensin converting enzyme inhibition in type 1 diabetes.

Elevation of glomerular filtration rate (GFR) is a feature of diabetes mellitus in humans and in animal models. Angiotensin II has been implicated as a mediator of GFR in diabetes. The acute effect of inhibition of angiotensin converting enzyme with captopril on renal haemodynamic and endocrine parameters was therefore studied in 14 normotensive male Type 1 diabetic patients, and the responses compared with those in five normal male control subjects. Following captopril 12.5 mg orally the diabetic patients exhibited an acute fall in GFR from 122 +/- 3.8 to 113 +/- 4.5 ml min-1 1.73-m-2 (p less than 0.02) and a rise in renal plasma flow (RPF) from 670 +/- 57 to 797 +/- 46 ml min-1 1.73-m-2 (p less than 0.01) which resulted in a fall in filtration. This did not occur in normal control subjects. Natriuresis occurred only in normal control subjects. There was no change in urinary excretion of PGE2 or kallikrein in either group but excretion of 6-keto-PGF1 alpha fell in the diabetic patients. There was a significant correlation between glycosylated haemoglobin and baseline RPF (rs = -0.79, p less than 0.001) and filtration fraction (rs = 0.83, p less than 0.001) that persisted when the change in these variables following captopril was analysed. Our results are compatible with the response to ACE inhibition in diabetic patients being secondary to inhibition of angiotensin II and suggest that this response may be related to blood glucose control.

Relationship between urinary excretion of sodium and dopamine in type 1 diabetic patients with an without microalbuminuria.

The relationship between urinary sodium and dopamine excretion was investigated in 40 normal males and in 48 normotensive, Type 1 diabetic males, 11 with microalbuminuria and 37 with normal albumin excretion. In all three groups a significant correlation was demonstrated and the regression lines were similar. Thus, no evidence was found that a defect in dopamine mobilization contributes to the early renal pathophysiological changes of Type 1 diabetes.

Vasopressin secretion in diabetic subjects with and without autonomic neuropathy: responses to osmotic and postural stimulation.

1. The release of arginine vasopressin (AVP) after an osmotic stimulus and head-up tilt was assessed in diabetic subjects with and without autonomic neuropathy. 2. Six diabetic subjects with (DAN +ve) and five without (DAN -ve) evidence of autonomic neuropathy and five normal subjects were infused with 5% (w/v) NaCl at a rate of 0.05 ml min-1 kg-1 body weight for 120 min. Blood pressure, heart rate and plasma AVP were measured over this period. 3. Seven DAN +ve, six DAN -ve and six normal subjects were tilted head-up to 45 degrees for 120 min. Blood pressure, heart rate and plasma AVP were measured during the study. 4. Infusion of 5% (w/v) NaCl produced appropriate rises in plasma osmolality and plasma AVP levels which did not differ between the three groups, confirming the normal osmotic release of AVP in the diabetic subjects. 5. During head-up tilt, there were no differences in AVP responses between the three groups, despite a major hypotensive stimulus in the DAN +ve group. 6. We conclude that osmotic release of AVP is normal in diabetes, but that cardiovascular release of AVP is impaired in diabetic subjects with cardiovascular reflex evidence of autonomic neuropathy, reflecting an afferent defect.

A trial of the calcium antagonist felodipine in hypertensive type 2 diabetic patients.

Although calcium antagonists may impair insulin release in vitro, clinical studies have produced conflicting results. Felodipine is a highly selective dihydropyridine calcium antagonist effective in the treatment of hypertension. The efficacy of felodipine was assessed in a double-blind randomized placebo cross-over study of 21 Type 2 diabetic patients with primary hypertension, 13 men and 8 women, with an age of 61 (range 46-73) years. Thirteen were controlled on oral hypoglycaemic therapy and 8 on diet alone. Mean (SD) blood pressure (mmHg) was 176(20)/102(8) after a 2-4 week placebo run-in period, 169(21)/101(8) during the subsequent placebo period compared with 151(15)/88(9) after 4 weeks felodipine therapy (p less than 0.001). Nineteen patients required 5 mg twice daily and 2 patients 10 mg twice daily to achieve a target diastolic pressure of 95 mmHg. Side-effects seen with felodipine included ankle oedema, facial flushing, headache, and dizziness. During oral glucose tolerance tests performed after the felodipine and placebo phases, mean (SD) fasting blood glucose was 9.5(3.1) and 9.0(3.0) mmol l-1, respectively (NS), and the 90 min (peak) blood glucose was 19.1(4.8) and 18.1(4.8) mmol l-1, respectively (NS). Glycosylated haemoglobin and fructosamine concentrations likewise showed no significant changes.