J. Cabezas-Cerrato

A preventative foot care programme for people with diabetes with different stages of neuropathy.

The aim of this study was to assess the efficacy of a preventative foot care programme, applied in a normal outpatient setting to decrease the incidence of foot ulcers in people with diabetes diagnosed as having neuropathy by neuropathy disability score (NDS), in relation to the severity of neuropathy based on the vibration perception threshold (VPT). A structured continuous preventative foot care programme was designed to ensure proper footwear, walking foot hygiene, callus care, nailcutting, water temperature checks, use of warming devices, bathroom surgery, foot care products and self-inspection. Continual foot-care education and treatment, including podiatry, were available. Evaluation was at least every 6 months. Diabetic patients (n=308) with neuropathy (NDS > or =6), 72.3+/-10.7 years old, 45% men, 10.9+/-8.8 years duration of diabetes, and HbA(1c) 6.5+/-1.3%, without a history of foot lesions were recruited over 3 years and followed-up for 4.6 (3-6) years. A low risk group (n=124) had a VPT<25 V while 184 had a VPT > or =25 V (high risk). In all 220 patients (71%) complied with the programme, compliance being 76 and 68% in low and high risk groups. The low risk group developed nine ulcers in nine patients, and the high risk group 24 ulcers in 19 patients. Of these eight and 19 ulcers, respectively, were in the non-compliant patient group, giving relative risk of 22 and eight compared with people attending the programme. Thus compliance with a preventative foot programme reduces the incidence of foot ulceration in people with diabetes with neuropathy. This decrease is relatively greater in patients with less severity of neuropathy. The simple design should be widely generalisable.

Depending on the Stimulus, Central Serotoninergic Activation by Fenfluramine Blocks or Does not Alter Growth Hormone Secretion in Man

The role of serotonin (5-HT) in the hypothalamic regulation of human growth hormone (GH) was reassessed through the use of fenfluramine, which selectively releases 5-HT from presynaptic terminals. Oral administration of L-dopa plus propranolol induced a potent and sustained GH release in the subjects tested (26 +/- 6 ng/ml). The administration of fenfluramine (20 mg i.v. as bolus plus 20 mg/30 min i.v.) completely suppressed the L-dopa-induced GH secretion (2 +/- 09.5 ng/ml). On the other hand, when arginine (30 g/30 min i.v.) was used as a GH stimulant of medium intensity (12.7 +/- 2.8 ng/ml), fenfluramine at the same dose was not able to alter the pattern of pituitary secretion (11.5 +/- 4.2 ng/ml). Fenfluramine alone induced a slight nonsignificant decrease in GH values with a parallel and significant increase in prolactin (PRL) secretion in accordance with the proposed serotoninergic activity of the drug. Rat PRL secretion by pituitaries incubated in vitro was inhibited by dopamine. Fenfluramine added to the system did not counteract the dopaminergic reduction of PRL release, making unlikely the possibility of an antagonism at the dopaminergic receptor as mechanism of action of fenfluramine on PRL secretion. In conclusion, depending on the stimulus under study, serotoninergic activation by fenfluramine either inhibits or does not alter GH secretion in man. No proof of a serotoninergic stimulatory component on GH regulation has been detected in this study. Fenfluramine is a valuable tool in neuroendocrinological studies, dealing with serotoninergic mechanisms.

CARDIAC AUTONOMIC NEUROPATHY, ESTIMATED CARDIOVASCULAR RISK, AND CIRCADIAN BLOOD PRESSURE PATTERN IN DIABETES MELLITUS

This study was designed to investigate potential factors involved in the disruption of the circadian blood pressure (BP) pattern in diabetes mellitus, as well as the relation between BP, cardiac autonomic neuropathy, and estimated cardiovascular risk. We studied 101 diabetic patients (58% with type 2 diabetes; 59% men), age 21–65 yrs, evaluated by 48 h BP monitoring. We performed three autonomic tests in a single session: deep breathing, Valsalva maneuver, and standing up from a seated position. Patients were classified according to the number of abnormal tests and their 10 yr risk of coronary heart disease or stroke. The prevalence of non-dipping 24 h patterning ranged from 47.6% in type 1 to 42.4% in type 2 diabetes. The awake/asleep ratio of systolic BP (SBP) was comparable between patients with or without abnormal autonomic tests. Pulse pressure (PP) was significantly higher in patients with ≥1 abnormal autonomic test (p < 0.001). Ambulatory SBP was significantly elevated in the group with higher risk of coronary heart disease (p < 0.001). Patients with higher stroke-risk had higher SBP but lower diastolic BP, and thus an elevated ambulatory PP by 9 mmHg, compared to those with lower risk (p < 0.001). Cardiac autonomic neuropathy is not the main causal-factor for the non-dipper BP pattern in diabetes mellitus. The most significant finding from this study is the high ambulatory PP found in patients with either cardiac autonomic dysfunction or high risk for coronary heart disease or stroke. After correcting for age, this elevated PP level emerged as the main cardiovascular risk factor in diabetes mellitus.

Aminoguanidine inhibits protein browning without extensive Amadori carbonyl blocking

It has been proposed that aminoguanidine reacts extensively with Amadori carbonyl groups of glycated proteins thus blocking them and inhibiting the further reactions which lead to browning and fluorescence development. We have glycated bovine serum albumin in the presence of 1, 5, 10 and 25 mM aminoguanidine and measured fluorescence development at 440 nm upon excitation at 370 nm, free (unblocked) Amadori groups as fructosamine with a colorimetric assay and furosine by HPLC, as an index of total Amadori products. Aminoguandine significantly inhibited fluorescence development at all the tested concentrations (31%, 65%, 69% and 82% inhibitions, respectively) (P < 0.001). Blocking of Amadori groups was demonstrated by decreased fructosamine and unchanged furosine yields but only at the higher concentrations and to a very limited extent (13% and 27% blocking, respectively) (P < 0.01). Incubation of Aminoguanidine with albumin produced the appearance of 320 nm absorbing yellow chromophores, quite increased in the presence of glucose. These results suggest that Aminoguanidine is able to block Amadori groups, as previously hypothesized, but question the importance of this mechanism as an explanation of its capacity to inhibit browning. Scavenging of glucose seems to have no impact on glycation as seen by unchanged furosine yields.

Influence of moderate physical exercise on insulin-mediated and non—insulin-mediated glucose uptake in healthy subjects

To establish the relative importance of insulin sensitivity and glucose effectiveness during exercise using Bergmans minimal model, 12 nontrained healthy subjects were studied at rest and during 95 minutes of moderate exercise (50% maximum oxygen consumption [VO2max]). Each subject underwent two frequently sampled intravenous glucose tolerance tests (FSIGTs) for 90 minutes, at rest (FSIGTr) and during exercise (FSIGTe). Plasma glucose, insulin, and C-peptide were determined. Insulin sensitivity (S(I)), glucose effectiveness at basal insulin (S(G)), insulin action [X(t)], and first-phase (phi1) and second-phase (phi2) beta-cell responsiveness to glucose were estimated using both minimal models of glucose disposal (MMg) and insulin kinetics (MMi). Glucose effectiveness at zero insulin (GEZI), glucose tolerance index (K(G)), and the area under the insulin curve (AUC(0-90)) were also calculated. Intravenous glucose tolerance improved significantly during physical exercise. During exercise, S(I) (FSIGTr v FSIGTe: 8.5 +/- 1.0 v 25.5 +/- 7.2 x 10(-5) x min(-1) [pmol x L(-1)]-1, P < .01), S(G) (0.195 +/- 0.03 v 0.283 +/- 0.03 x 10(-1) x min(-1), P < .05), and GEZI (0.190 +/- 0.03 v 0.269 +/- 0.04 x 10(-1) x min(-1), P < .05) increased; however, no changes in phi1 and phi2 were found. Despite a significant decrease in the insulin response to glucose (AUC0-90, 21,000 +/- 2,008 v 14,340 +/- 2,596 pmol x L(-1) x min, P < .01), insulin action [X(t)] was significantly higher during the FSIGTe. These results show that physical exercise improves mainly insulin sensitivity, and to a lesser degree, glucose effectiveness. During exercise, the insulin response to glucose was lower than at rest, but beta-cell responsiveness to glucose did not change.

Influence of sodium valproate on late follicular phase pulsatile LH secretion in normal women

objective To study whether modulation of the GABAergic system (with sodium valproate) affects pulsatile LH secretion in the late follicular phase of normal women

Both a reduced acute insulin response to glucose and lower glucose effectiveness are responsible for the worsening of intravenous glucose tolerance in healthy subjects independently of the degree of obesity

The effects of the acute insulin response to glucose (AIRg), insulin sensitivity (SI), and glucose effectiveness at zero insulin (GEZI) on intravenous glucose tolerance were studied in 94 non elderly healthy subjects with a wide range of body mass index (BMI). Conrads coefficient of glucose assimilation (KG) was calculated between 10 and 19 minutes of an intravenous glucose tolerance test. Both SI and GEZI were estimated using Bergmans minimal model. AIRg was calculated as the area under the insulin curve above basal between 0 and 10 minutes, and the suprabasal insulin effect was determined by the product of SI x AIRg. Stepwise multiple regression showed that the combined effect of SI x AIRg and GEZI explained 67% of the KG index variance. Division of the sample into tertiles according to KG shows that subjects with the lowest KG (KG < 1.32 min[-1]) had the lowest AIRg (2,832 +/- 1,362 v 6,510 +/- 4,410 [pmol x L(-1)] min, P = .0005), the lowest GEZI (0.092 +/- 0.06 v 0.179 +/- 0.09 min(-1), P = .0004), and the lowest SI x AIRg (0.014 +/- 0.008 v 0.022 +/- 0.01 min(-1), P = .00001), and were the oldest (41 +/- 10 v 31 +/- 10 years, P = .002) compared with subjects with the highest KG (KG > 1.8 min[-1]). However, no differences in SI (4.86 +/- 4.6 v 6.5 +/- 3.7 min(-1) [pmol x L(-1)],(-1) NS) or BMI (29.6 +/- 5.0 v 26.6 +/- 5.9 kg x m(-2), NS) were observed. These results did not vary when lean and obese subjects were analyzed separately. Age correlated significantly only with SI x AIRg. In conclusion, although the main factors that determine intravenous glucose tolerance are the suprabasal insulin effect and GEZI, worsening of the KG index depends on inadequate insulin secretion for the degree of insulin sensitivity and lower non-insulin-mediated glucose uptake. Age seems to be another factor in the worsening of intravenous glucose tolerance through a lower suprabasal insulin effect.

Non-insulin-mediated glucose uptake in several insulin-resistant states in the postabsortive period

The aim of our work was to study non-insulin-mediated glucose uptake (NIMGU), in the postabsorptive state, in several pathologies characterized by peripheral insulin resistance, namely, obesity (n = 10), NIDDM (n = 7), acromegaly (n = 7) and Cushings disease (n = 6). These groups were compared with a group of 16 healthy subjects. To estimate peripheral insulin sensitivity (SI) and glucose effectiveness (SG), we used the minimal model of glucose metabolism. Although all of these pathologies showed severe insulin resistance (control: 6.44 +/- 2.63, obesity: 2.84 +/- 1.57, NIDDM: 1.71 +/- 0.77, acromegaly: 1.88 +/- 1.23, Cushings disease: 1.87 +/- 0.66 x 10(-4) min-1 (microU/ml)-1, P < 0.01), fasting insulin-mediated glucose uptake (IMGU) did not differ significantly among the five groups, because reactive hyperinsulinaemia was present in all of these states. The contribution of NIMGU to whole-body glucose uptake did not differ significantly among the five groups (control: 77 +/- 8%; obesity: 77 +/- 9%; acromegaly: 82 +/- 8%; Cushings disease: 83 +/- 8%; NIDDM: 84 +/- 7%). In conclusion, our data show that, in the postabsorptive period, non-insulin mediated glucose uptake is a major determinant of glucose disposal and is similar in the different pathologies studied; on the other hand, although absolute rates of basal insulin-mediated glucose uptake are reduced in insulin-resistant states, they did not achieve statistical value compared with control subjects because of compensatory hyperinsulinaemia.

Insulin sensitivity, glucose effectiveness, and insulin secretion in nondiabetic offspring of patients with non—insulin-dependent diabetes mellitus: A cross-sectional study☆

To evaluate the factors that determine the worsening of intravenous glucose tolerance in subjects at high risk for developing non-insulin-dependent diabetes mellitus (NIDDM), 15 glucose-tolerant offspring of NIDDM patients and 21 control subjects were studied. Each subject underwent a frequently sampled intravenous glucose tolerance (FSIGT) test. The intravenous glucose tolerance index (K(G) index) was calculated between minutes 10 and 40 of a FSIGT test. Insulin sensitivity (S(I)), glucose effectiveness at zero insulin (GEZI), and first- and second-phase insulin responsiveness (phi1 and phi2) were estimated using glucose and insulin kinetic minimal models. The acute insulin response to glucose (AIRg) was calculated as the area under the insulin curve above the basal level between 0 and 10 minutes, and the suprabasal insulin effect was determined by the product of S(I) times AIRg. Offspring had a lower S(I) than control subjects (14.1 +/- 7.5 v 9.25 +/- 4.20 x 10(-5) x min(-1)(pmol x L(-1))(-1), P < .01), and their AIRg was similar (3,284 +/- 2,280 v 3,105 +/- 1,499 pmol x L(-1), NS). Sample division according to the median K(G) value showed that control subjects with low tolerance had a lower AIRg (4,417 +/- 2,531 v 2,043 +/- 1,068 pmol x L(-1), P < .05) and a lower suprabasal insulin effect (0.057 +/- 0.03 v 0.023 +/- 0.009 min(-1), P < .05) than control subjects with high tolerance. Offspring with low tolerance had a lower AIRg (2,574 +/- 1,197 v 3,707 +/- 1,656 pmol x L(-1), P < .05) and a lower GEZI (0.101 +/- 0.05 v 0.212 +/- 0.08 x 10(-1) x min(-1), P < .05) than offspring with high tolerance. Offspring with high and low tolerance showed lower phi1 (375 +/- 155 v 272 +/- 181 v 698 +/- 336 (pmol x L(-1))min(mmol x L(-1)), NS) than control subjects with high tolerance. In conclusion, our data suggest that decreases in GEZI and AIRg are the main factors responsible for the worsening of intravenous glucose tolerance in the offspring of NIDDM patients.

Influence of sodium valproate on medium‐late luteal phase pulsatile LH secretion in normal women

OBJECTIVE It is not known whether gamma‐aminobutyric acid (GABA) is involved in control of pulsatile LH secretion in human beings. Previous work by our group has shown that manipulation of the GABAergic system with sodium valproate does not affect pulsatile LH secretion in normal women in the late follicular phase. However, it has been suggested that steroid levels are critical for the influence of GABA upon hormone secretion; in particular, progesterone has been said to enhance inhibition by GABA. In this work we studied the effect of sodium valproate on pulsatile LH secretion in medium‐late luteal phase of normal women.