Paolo Bottini

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.

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.

Autonomic Neuropathy Increases the Risk of Obstructive Sleep Apnea in Obese Diabetics

Background: Nonobese diabetics with diabetic autonomic neuropathy (DAN) show an elevated prevalence of obstructive sleep apnea-hypopnea (OSAH). Objective: It was the aim of this study to assess if the presence of DAN could further increase the risk of developing OSAH in obese diabetics. Methods: Eighteen obese diabetic patients, 8 with DAN [age 57 ± 5 years, body mass index (BMI) 35 ± 4] and 10 without DAN (age 56 ± 8 years, BMI 37 ± 5), were recruited. Ten age-matched obese subjects were studied as controls (age 53 ± 12 years, BMI 34 ± 3). All subjects underwent a cardiorespiratory sleep study in the in-hospital sleep laboratory to obtain the apnea-hypopnea index (AHI) and oxygen desaturation indices. Results: Diabetics with DAN (Ob-DAN+) had a higher AHI than diabetics without DAN (Ob-DAN–) and controls, amounting to 39.5 ± 13 versus 15.8 ± 12 (p < 0.01) and 19.3 ± 21 (p < 0.05), respectively. A moderate-to-severe OSAH (AHI ≧15) occurred in all Ob-DAN+ and only in 4 Ob-DAN– and 4 control patients. Moreover, the indices reflecting the impairment of oxygen saturation (SaO2) during sleep such as the mean lowest SaO2 and sleep time with a SaO2 <90% were more severely affected in Ob-DAN+ patients compared with the other groups and were associated with longer obstructive respiratory events. Conclusions: Apneas-hypopneas are more frequent and last longer in Ob-DAN+ than in other obese subjects, with or without diabetes.

Long-Term Intensive Therapy of IDDM Patients With Clinically Overt Autonomic Neuropathy: Effects on Hypoglycemia Awareness and Counterregulation

To test the hypothesis that hypoglycemia unawareness and impaired counterregulation are reversible after meticulous prevention of hypoglycemia in IDDM patients with diabetic autonomic neuropathy (DAN), 21 patients (8 without DAN [DAN−]; 13 with DAN [DAN+]; of the latter, 7 had orthostatic hypotension [DAN+PH+] and 6 did not [DAN+PH−]) and 15 nondiabetic subjects were studied during stepped hypoglycemia (plateau plasma glucose decrements from 5.0 to 2.2 mmol/l) before and 6 months after prevention of hypoglycemia (intensive therapy). After 6 months, frequency of mild hypoglycemia decreased from ∼20 to ∼2 episodes/patient-month while HbA1c increased from 6.2 ± 0.3 to 6.9 ± 0.2% (P < 0.05). Responses of adrenaline improved more in DAN− patients (from 1.17 ± 0.12 to 2.4 ± 0.22 nmol/l) than in DAN+PH− (from 0.75 ± 0.25 to 1.56 ± 0.23 nmol/l) and DAN+PH+ patients (from 0.80 ± 0.24 to 1.15 ± 0.27 nmol/l, P < 0.05) but remained lower than in nondiabetic subjects (4.9 ± 0.37 nmol/1, P < 0.05), whereas glycemic thresholds normalized only in DAN−, not DAN+. Autonomic symptoms of hypoglycemia improved but remained lower in DAN− (6.2 ± 0.6) than in nondiabetic subjects (8.1 ± 1.1) and lower in DAN+PH+ (4 ± 0.8) than in DAN+PH− subjects (5.1 ± 0.8, P < 0.05), whereas neuroglycopenic symptoms normalized (NS). Cognitive function deteriorated less before than after prevention of hypoglycemia (P < 0.05). Thus, intensive therapy with emphasis on preventing hypoglycemia reverses hypoglycemia unawareness in DAN+ patients despite marginal improvement of adrenaline responses, results in low frequency of hypoglycemia despite impaired counterregulation, and maintains HbA1c in the range of intensive therapy. We conclude that DAN, long IDDM duration per se, and antecedent recent hypoglycemia contribute to different extents to impaired adrenaline responses and hypoglycemia unawareness.

Sleep Apnea Syndrome in Endocrine Diseases

It is increasingly recognized that sleep-disordered breathing (SDB) – from snoring to apnea-hypopnea syndrome (SAHS) – can affect patients with various endocrine diseases (ED). Different mechanisms are implied in SDB, promoting either central or, more frequently, obstructive apnea in different ED. In the past, acromegaly and hypothyroidism were first associated with both central and obstructive SAHS. Today, great attention is placed on the complex cause-effect relationship between diabetes mellitus and obstructive SAHS (and vice versa). Symptoms and signs of SAHS may complicate the clinical course of these diseases and should be promptly suspected to detect and possibly treat the accompanying SDB.

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.

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.

Effects of CPAP on systemic hypertension in OSAH: a monocentric, observational, cohort study.

BACKGROUND Obstructive sleep apnea-hypopnea (OSAH) is a risk factor for development of systemic arterial hypertension (SAH) and can worse the control of established SAH. We investigated the effects of long-term continuous positive airway pressure (CPAP) treatment in controlling and preventing SAH in a large cohort of subjects referred for sleep study for suspected OSAH. METHODS In 495 subjects of whom 422 with OSAH and 73 without OSAH, the clinical history was obtained, arterial blood pressure was measured and the current anti-hypertensive drugs was recorded at diagnosis and/or at CPAP start. Subjects were interviewed after a follow-up period of (mean ± SD) 3.4 ± 2.2 yr (range 1-8 yr) and divided in patients with moderate-to-severe OSAH (n = 125) who referred to use CPAP regularly for at least 4 h every night (group 1), with moderate-to-severe OSAH (n = 70) who refused or abandoned the CPAP treatment after few weeks (group 2), with mild OSAH (n = 227) with no CPAP indication (group 3) and simple snorers or normals (n = 73) (group 4). For each group clinical status, BMI, and changes in SAH therapy and occurrence of SAH were assessed at the follow-up. RESULTS At the follow-up, a higher risk of increasing treatment for SAH was found for group 2 and group 3 versus group 1 (OR = 5, 95%CI 1-20, p < 0.01 and OR = 3, 95%CI 1-10, p < 0.05), respectively. The occurrence of SAH was lower (p < 0.001) in the group 1 (1.9%), vs group 2 (35.9%), 3 (21.1%) and 4 (18.6%). CONCLUSIONS In moderate-to-severe OSAH patients, long-term CPAP treatment significantly reduces the development of SAH and, in those with SAH at baseline, the need of anti-hypertensive drugs.

Blunted epinephrine response following exercise in autonomic neuropathy

Dear Sir, With interest we read that Bottini et al. [1] claim that the epinephrine response following exercise is blunted in diabetic patients with autonomic neuropathy featuring postural hypotension (DAN§ This might well be true; however, the workloadma x (% of predicted), the VO2max (% of predicted), and the maximal heart rate during exercise were lower in this group of patients (DAN+PH +) than in other groups. Hence, it is difficult to exclude a lower degree of sympathetic stimulation during exercise in DAN+PH + patients than in other subjects. Neverthe-