Luciano Scionti

Meticulous Prevention of Hypoglycemia Normalizes the Glycemic Thresholds and Magnitude of Most of Neuroendocrine Responses to, Symptoms of, and Cognitive Function During Hypoglycemia in Intensively Treated Patients With Short-Term IDDM

To test the hypothesis that hypoglycemia unawareness is largely secondary to recurrent therapeutic hypoglycemia in IDDM, we assessed neuroendocrine and symptom responses and cognitive function in 8 patients with short-term IDDM (7 yr) and hypoglycemia unawareness. Patients were assessed during a stepped hypoglycemic clamp, before and after 2 wk and 3 mo of meticulous prevention of hypoglycemia, which resulted in a decreased frequency of hypoglycemia (0.49 ± 0.05 to 0.045 ± 0.03 episodes/patient-day) and an increase in HbA1c (5.8 ± 0.3 to 6.9 ± 0.2%) (P < 0.05). We also studied 12 nondiabetic volunteer subjects. At baseline, lower than normal symptom and neuroendocrine responses occurred at lower than normal plasma glucose, and cognitive function deteriorated only marginally during hypoglycemia. After 2 wk of hypoglycemia prevention, the magnitude of symptom and neuroendocrine responses (with the exception of glucagon and norepinephrine) nearly normalized, and cognitive function deteriorated at the same glycemic threshold and to the same extent as in nondiabetic volunteer subjects. At 3 mo, the glycemic thresholds of symptom and neuroendocrine responses normalized, and surprisingly, some of the responses of glucagon recovered. We concluded that hypoglycemia unawareness in IDDM is largely reversible and that intensive insulin therapy and a program of intensive education may substantially prevent hypoglycemia and at the same time maintain the glycemic targets of intensive insulin therapy, at least in patients with IDDM of short duration.

Better long-term glycaemic control with the basal insulin glargine as compared with NPH in patients with Type 1 diabetes mellitus given meal-time lispro insulin

Background  Glargine is a long‐acting insulin analogue potentially more suitable than NPH insulin in intensive treatment of Type 1 diabetes mellitus (T1 DM), but no study has proven superiority. The aim of this study was to test superiority of glargine on long‐term blood glucose (BG) as well as on responses to hypoglycaemia vs. NPH.

Contribution of Autonomic Neuropathy to Reduced Plasma Adrenaline Responses to Hypoglycemia in IDDM: Evidence for a Nonselective Defect

To determine the contribution of clinically overt diabetic autonomic neuropathy (DAN) to reduced plasma adrenaline responses to hypoglycemia in IDDM and to establish its selectivity for hypoglycemia, we studied 17 IDDM patients (7 without DAN [DAN−] and 10 with DAN [DAN+]), of whom 5 had and 5 did not have postural hypotension (DAN+PH+ and DAN+PH−, respectively), and 8 nondiabetic subjects on 2 different occasions, i.e., clamped hypoglycemia (steps from 5.0 to 2.2 mmol/l plasma glucose) and 30-min steady-state exercise at 55% VO2max. Recent antecedent hypoglycemia was meticulously prevented before the studies to exclude hypoglycemia as a cause of reduced responses of adrenaline to hypoglycemia. In DAN− patients, maximal responses of adrenaline to hypoglycemia were reduced (2.44 ± 0.58 nmol/l vs. 4.9 ± 0.54 nmol/l in nondiabetic patients) (P < 0.05). In DAN+, adrenaline responses initiated at a lower plasma glucose and were lower than in DAN− (DAN+PH−, 1.06 ± 0.38 nmol/l; DAN+PH+, 0.84 ± 0.27 nmol/l; P < 0.001, but NS between PH− and PH+). In response to exercise, adrenaline increased less in DAN− (0.89 ±0.11 nmol/l) patients than in nondiabetic subjects (1.19 ± 0.14 nmol/l; NS) and only to 0.36 ± 0.07 nmol/l in DAN+PH− and 0.23 ± 0.09 nmol/l in DAN+PH+ (P < 0.001 vs. DAN− and nondiabetic subjects). These results were confirmed when nondiabetic and DAN− subjects repeated the exercise at 60 watts (35 and 41% of Vo2max, respectively), i.e., at the same absolute workload of DAN+ patients. Thus, DAN (both PH+ and PH−) contributes to reduced responses of adrenaline to hypoglycemia independently of recent antecedent hypoglycemia. The adrenaline defect in DAN is not selective for hypoglycemia.

Cardiovascular response to exercise in diabetic patients: influence of autonomic neuropathy of different severity

SummaryWe investigated cardiovascular function and plasma catecholamine response during incremental exercise and recovery in diabetic patients with (DAN+) and without autonomic neuropathy (DAN−). The former group was divided according to the presence of parasympathetic (DAN+PH−) or associated parasympathetic and sympathetic (DAN+PH+) damage to the autonomic nervous system. A group of healthy volunteers was studied as a control group. All the patients and control subjects underwent a submaximal or symptom-limited incremental exercise test using a cycle-ergometer. Air flow and respiratory gas fractions were sampled at the level of the mouth allowing a breath-by-breath analysis of oxygen consumption (VO2). Heart rate and systolic blood pressure were recorded and venous blood samples were obtained from the patients at rest and during each minute of exercise and recovery to measure norepinephrine and epinephrine plasma levels. Haemodynamic parameters and plasma catecholamines were computed at rest and at 25, 50, 75 and 100% of the peak VO2 (VO2 max). The breath-by-breath relationships among VO2, heart rate and VO2/heart rate against work were assessed during exercise for patients and control subjects. While VO2 max in absolute values was not significantly different among the diabetic groups, VO2 max was much less in diabetic patients than in control subjects (p<0.01). During exercise the rate of heart rate, systolic blood pressure, norepinephrine and epinephrine increase was different among the diabetic groups, being significantly blunted in DAN+PH+. The VO2/work relationship of the three diabetic groups was similar but markedly reduced in respect to that of control subjects (p<0.001). The relationship between oxygen pulse (VO2/heart rate) and work showed no differences among the diabetic groups, whereas its slope was significantly steeper in control subjects (p<0.01 vs DAN−; p<0.05 vs DAN+PH− and DAN+PH+). In conclusion during incremental exercise both DAN+PH− and DAN+PH+ exhibit abnormal heart rate, systolic blood pressure and catecholamine responses which, however, appear clearly distinct between the two groups of DAN+. In DAN+ the VO2 increment is reduced during exercise. Since DAN−show the same impairment, this particular finding seems most likely to be influenced by factors (i.e.: diabetic cardiomyopathy) other than overt autonomic neuropathy.

Two-step autologous grafting using HYAFF scaffolds in treating difficult diabetic foot ulcers: results of a multicenter, randomized controlled clinical trial with long-term follow-up

This study evaluated the efficacy and tolerability of an autologous tissue-engineered graft—a 2-step HYAFF autograft—in the treatment of diabetic foot ulcers compared with standard care. In all, 180 patients with dorsal or plantar diabetic foot ulcers (unhealed for ≥1 month) were randomized to receive Hyalograft-3D autograft first and then Laserskin autograft after 2 weeks (n = 90; treatment group) or nonadherent paraffin gauze (n = 90; control group). Efficacy and adverse events were assessed weekly for 12 weeks, at 20 weeks, and at 18 months. The primary efficacy outcome was complete ulcer healing at 12 weeks. Wound debridement, adequate pressure relief, and infection control were provided to both groups. At 12 weeks, complete ulcer healing was similar in both groups (24% of treated vs 21% controls). A 50% reduction in ulcer area was achieved significantly faster in the treatment group (mean 40 vs 50 days; P = .018). Weekly percentage ulcer reduction was consistently higher in the treatment group. At 20 weeks, ulcer healing was achieved in 50% of the treated group as compared with 43% of controls. Dorsal ulcers had a 2.17-fold better chance of wound healing per unit time following autograft treatment (P = .047). In a subgroup with hard-to-heal ulcers, there was a 3.65-fold better chance of wound healing following autograft treatment of dorsal ulcers ( P = .035). Adverse events were similar in both groups. The study results demonstrated the potential of this bioengineered substitutes to manage hard-to-heal dorsal foot ulcers.

Mechanisms of Arterial Hypotension After Therapeutic Dose of Subcutaneous Insulin in Diabetic Autonomic Neuropathy

To assess whether a therapeutic, subcutaneous injection of insulin exerts hemodynamic effects in subjects with IDDM, 0.2 U/kg regular insulin was injected subcutaneously in 17 IDDM subjects: 6 without autonomic neuropathy, 7 with autonomic neuropathy and othostatic hypotension, and 4 with autonomic neuropathy but without orthostatic hypotension. Plasma glucose was maintained at ∼8.5 mM throughout the studies. Mean blood pressure, plasma norepinephrine concentration, forearm vascular resistances, and calf venous volume were measured before and 120 min after subcutaneous insulin, in the supine position and 5 min after standing. Supine plasma volume ([125I]albumin and [131I]albumin) was measured before and after subcutaneous injection of insulin. In all three groups, subcutaneous insulin activated the sympathetic nervous system (∼30% increase in norepinephrine concentration). In subjects with IDDM but without autonomic neuropathy, standing forearm vascular resistance increased ∼70% less after subcutaneous insulin, but supine or standing mean blood pressure did not decrease. In contrast, in subjects with IDDM with autonomic neuropathy and orthostatic hypotension, subcutaneous insulin decreased supine mean blood pressure (from 99 ± 3 to 94 ± 5 mmHg) and exaggerated the standing decrement in mean blood pressure (24 ± 3 vs. 19 ± 2 mmHg) (P < 0.05). This was associated with a decrease in forearm vascular resistance. Similarly, in subjects with IDDM with autonomic neuropathy without orthostatic hypotension, subcutaneously injected insulin decreased supine mean blood pressure (from 95 ± 2 to 89 ± 2 mmHg) and standing mean blood pressure by 8 ± 1 mmHg (P < 0.05). Calf venous volume was not affected by subcutaneous insulin in any of the three groups. Plasma volume did not change after subcutaneous insulin in subjects with IDDM without autonomic neuropathy, whereas it decreased in those with autonomic neuropathy and orthostatic hypotension from 1.692 ± 0.069 to 1.610 ± 0.064 L/m2, without orthostatic hypotension from 1.631 ± 0.027 to 1.593 ± 0.024 L/m2 P < 0.05). No hemodynamic effects were observed when subjects with IDDM were restudied in a control experiment where placebo (distilled water), not insulin, was injected subcutaneously. In conclusion, therapeutic doses of subcutaneous insulin activate the sympathetic nervous system; decrease blood pressure in subjects with IDDM with autonomic neuropathy, but not in those without, primarily by decreasing arterial vascular resistances and plasma volume; and have no effects of capacitance vessels. Thus, in subjects with IDDM without autonomic neuropathy, greater activation of sympathetic nervous system after subcutaneous injection of insulin prevents orthostatic hypotension. In contrast, in subjects with IDDM with autonomic neuropathy, the sympathetic nervous system failure unmasks the inhibition of sympathetic vasoconstriction by insulin, and blood pressure decreases, in part possibly because of insulin-induced decrease in plasma volume.

Neurohumoral control of gallbladder motility in healthy subjects and diabetic patients with or without autonomic neuropathy

Patients affected by diabetes mellitus are reported to have an increased incidence of gallbladder abnormalities. The pathophysiologic mechanisms for this phenomenon are unclear. In the present study ultrasonography was used to determine gallbladder emptying in response to a meal or separate cephalic or hormonal stimulation in 21 diabetic patients and 10 healthy subjects. Gallbladder emptying and refilling after a meal were similar in diabetic patients and healthy subjects. When diabetics were divided according to the presence or absence of cardiac autonomic neuropathy (AN), a significant reduction of gallbladder emptying in response to cephalic stimulation was found in diabetics with AN (P<0.01 in comparison with diabetics without AN or healthy subjects). A dose-response curve of gallbladder emptying in response cerulein, a cholecystokinin analog, at concentrations of 0.25, 1, and 4 μg/kg/min was evaluated. No differences of gallbladder emptying were found in the three groups of subjects, indicating that gallbladder sensitivity to hormonal stimulation is not changed in diabetic patients with or without AN. Diabetic patients with AN have a significant reduction of gastric acid output and pancreatic polypeptide (PP) secretion in response to cephalic stimulation (P<0.05 in comparison with diabetic patients without AN or healthy subjects). Cerulein-induced PP secretion was similar in all three groups of subjects (P>0.05). This study indicates that in diabetic patients with AN, gallbladder emptying as well as gastric acid and PP secretions induced by neural stimulation are markedly reduced in comparison to diabetics without AN.

HbA1 in Subjects with Abnormal Glucose Tolerance but Normal Fasting Plasma Glucose

HbA1(a+b+c)(HbA1) was determined chromatographically in 107 subjects with normal fasting plasma glucose (FPG) and 112 patients with overt diabetes. Subjects with normal FPG were divided into two groups based on their response to two oral glucose tolerance tests (OGTTs), at an interval of 2 mo. In 40 subjects with normal OGTT (group I), HbA1 ranged from 5.2% to 7.2%, while in 67 subjects with abnormal OGTT (group II), it ranged from 6.3% to 9.6%. HbA1 levels were significantly higher in group II than in group I (7.7 ± 0.09% versus 6.4 ± 0.08%, mean ± SEM, P < 0.0005), but 14 subjects of group II had HbA1 levels less than 7.2%. No correlation was found between HbA1 and FPG, OGTT peak, and curve area in either group. However, the correlation became significant in all 107 subjects with normal FPG (groups I + II). In patients with overt diabetes, HbA1 ranged from 6.3% to 18% (11.9 ± 0.22%) and correlated with FPG (r = 0.78, P < 0.0005). The traditional OGTT seems more sensitive than the HbA1 measurement in detecting subjects with reduced carbohydrate tolerance. HbA1 level, on the other hand, is known to be a more specific indicator of structural abnormalities following long-term hyperglycemia. Thus HbA1 determination might be a helpful test along with OGTT to improve both selection and follow-up of subjects with true borderline diabetes.

Effect of erythromycin on gallbladder emptying in diabetic patients with and without autonomic neuropathy and high levels of motilin.

A reduction of gallbladder emptying in response to neural or hormonal stimulation has been reported in patients with diabetes mellitus. Decreased gallbladder emptying may be a key factor in the pathogenesis of gallbladder stones. Few drugs, if any, are able to stimulate gallbladder emptying. However, in a previous study we demonstrated that erythromycin, a macrolide antibiotic, stimulates gallbladder emptying and motilin release in healthy human subjects by an atropine-sensitive pathway. Therefore, the present study was designed to evaluate the effect of erythromycin on gallbladder emptying and motilin release in diabetic patients with or without cardiac autonomic neuropathy (AN). Thirteen diabetic patients, six with AN, and 10 healthy subjects were enrolled in the study protocol. Gallbladder emptying was determined by sonography after ingestion of a standard meal and during infusion of erythromycin alone or together with 6 μg/kg/hr atropine. We found that 100 mg/hr erythromycin caused a significant reduction in gallbladder volume in both healthy subjects and diabetic patients. The ejection fraction (mean ±se) of 45.3±8.2% and 37.3±5.0% was similar. The presence of AN had no influence on gallbladder emptying induced by erythromycin. Basal motilin plasma levels were 111.5±14.5 pmol/liter in diabetic patients and 63.3 ±6.0 pmol/liter in healthy subjects (P<0.01). However, patients with AN had higher (130.0 ±11.9 pmol/liter) motilin plasma levels than patients without (74.0±9.4 pmol/liter,P<0.01). Erythromycin administration caused an approximately twofold increase in plasma motilin concentrations in healthy subject and patients withou AN, but did not stimulate motilin release in neuropathic patients. A negative correlation (r=−0.75,P<0.01) was found between basal plasma levels of motilin and peak of gallbladder emptying induced by erythromycin. Atropine completely inhibited the effects of erythromycin on gallbladder emptying and motilin release (P<0.001 by ANOVA). A negative correlation (r=−0.52,P<0.05) was also found between plasma glucose concentrations and peak of gallbladder emptying. Present results demonstrate that erythromycin could be used for treating alterations of gallbladder emptying in diabetic patients with or without AN.

Frequency-modulated electromagnetic neural stimulation enhances cutaneous microvascular flow in patients with diabetic neuropathy

AIM The aim of this study was to investigate the effects of frequency modulated electromagnetic neural stimulation (FREMS), a recently developed safe and effective treatment of painful diabetic neuropathy, on cutaneous microvascular function. METHODS Thirty-one patients with painful neuropathy were enrolled in a randomised, double-blind, crossover FREMS vs. placebo study; each received two series of 10 treatments of either FREMS or placebo in random sequence within no more than 3 weeks. Patients were studied at baseline, end of FREMS and placebo series, and after 4 months of follow-up. Cutaneous blood flow was measured by laser doppler flowmetry and partial tissue tension of oxygen (TcPO2) and carbonic anhydride (TcPCO2) by oxymetry at the lower extremities in basal resting conditions and as incremental response after thermal stimulation. RESULTS Crossover analysis showed no consistent differences between FREMS and placebo. After 4-month follow-up, a 52% increase of cutaneous blood flow was observed in resting conditions (P=.0086 vs. baseline), while no differences were observed as incremental flow after warming; compared with baseline, no significant differences were observed for TcPO2 and TcPCO2, both in resting conditions and as incremental response to warm. CONCLUSION These results indicate that 10 treatments with FREMS may induce an enhancement of microvascular blood flow measurable at 4 months of follow-up. The findings of this study will need to be confirmed in a larger, adequately powered study (ClinicalTrial.gov Id: NCT00337324).