Insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus: evidence for an intrinsic effect of insulin on the central nervous system.

Evidence for an intrinsic effect of insulin on the central nervous system is accumulating. To test the hypothesis that insulin per se may modulate neuroendocrine counterregulation, hypoglycemia perception, and cerebral function in insulin-dependent diabetes mellitus, we examined 27 patients without any sign of classical autonomic neuropathy or evidence of so-called hypoglycemia unawareness. We used the hyperinsulinemic (0.67 vs. 2.00 mU/kg.min), stepped hypoglycemic (5.6/3.5/2.4/2.0 mmol/L) clamp technique to assess the patient's awareness of and response to equivalent hypoglycemic stimuli under different degrees of physiological hyperinsulinemia (approximately 270 vs. approximately 810 pmol/L) after an overnight euglycemic clamp (5.6 mmol/L). Simultaneously, the patient's cerebral function was assessed from his electrophysiological activity and neuropsychological skills. Higher degrees of physiological hyperinsulinemia caused enhanced neuroendocrine response (adrenaline, P < 0.05; noradrenaline, P < 0.03; GH, P < 0.02; beta-endorphin, P < 0.03; ACTH, P = 0.12; cortisol, P = 0.06; PRL, P = 0.08) and symptom awareness (total symptoms, P < 0.04; autonomic symptoms, P < 0.02; neuroglycopenia symptoms, P < 0.05; sweating, P < 0.05; heart pounding, P < 0.02; trembling, P < 0.01; lack of concentration, P < 0.02) to occur. Deteriorations of electrophysiological activity (middle latency auditory-evoked potentials, P < 0.04; Pa peak latencies, P < 0.05; Pa-V interpeak latencies, P = 0.08) and neuropsychological skills (Stroop test, P < 0.05; trail making, P = 0.12) were more pronounced the higher the insulin level, but at similar blood glucose concentrations. We conclude that insulin-associated modulation of neuroendocrine counterregulation, hypoglycemia perception, and cerebral function may occur in insulin-dependent diabetes mellitus, which indicates an intrinsic effect of insulin on the human brain.

Improvement of impaired counterregulatory hormone response and symptom perception by short-term avoidance of hypoglycemia in IDDM.

OBJECTIVE: To test the hypothesis that impaired counterregulatory hormone response and symptom perception, induced by recurrent hypoglycemic episodes over 2 days, may be improved by short-term (2-day) avoidance of hypoglycemia. RESEARCH AND DESIGN: We examined two groups of insulin-dependent diabetes mellitus (IDDM) patients (n = 16), none of whom exhibited signs of peripheral or autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed applying stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol/l, at which the patients' awareness of and responses to hypoglycemia were evaluated. In the intervention group (n = 11), three short-term hypoglycemic ( < 2.2 mmol/l) episodes (days 1-3) preceded the first clamp study (day 4), whereas the second clamp study (day 6) followed a 2-day interval of strict avoidance of hypoglycemia. A control group (n = 5) was introduced to detect adaptation effects caused by the study procedure per se. RESULTS: This short-term avoidance of hypoglycemia caused improvement of the impaired counterregulatory hormone response during insulin-induced hypoglycemia involving adrenaline (P < 0.05), adrenocorticotrophic hormone (P < 0.03), and cortisol (P < 0.05). Improvement of hypoglycemia symptom awareness encompassed overall symptom perception (multiple analysis of variance, P < 0.04) and the automatic symptoms of heart pounding (P < 0.05) and sweating (P < 0.05). CONCLUSIONS: The previously reported compromised neuroendocrine counterregulation and symptom awareness, occurring as a consequence of repetitive hypoglycemic episodes over 2 days, may be improved by a single 2-day interval of strict avoidance of hypoglycemia

Young hospital doctors after night duty: their task-specific cognitive status and emotional condition.

Sleep deprivation is an unpleasant burden of young hospital doctors during their medical training. It may disrupt the balance between coping strategies available to them and the professional demands encountered. Impaired medical care offered by sleep-deprived juniors may be a consequence. Valid research work on this subject is rare and surprisingly contradictory. Therefore, we evaluated the task-specific cognitive status and emotional condition of 40 young hospital doctors (27 men and 13 women, 29.9 +/- 2.9 years of age) at the University of Tuebingen, all of whom were in the beginning of their academic career. Subjects were tested twice acting as their own control, once at 8.00 am after a night off duty (OD) (at least 6 hours of uninterrupted sleep), and once at a similar time after a night on call (OC) being in the hospital for 24 hours. Standardized and reliable psychometric tests thought to represent daily routine medical function were performed. On-call activities were recorded by means of a sleep diary, whereas a questionnaire interrogated aspects of private and professional life. Neuropsychological function deteriorated significantly: number connection test (per cent of norms +/- SD, 103.2 +/- 9.8 OC vs 107.8 +/- 10.5 OD, F = 27.7, P < 0.001), things-to-do list (correct items +/- SD, 6.7 +/- 1.2 OC vs 7.4 +/- 1.5 OD, F = 12.7, P < 0.01), Vienna reaction timer (per cent of norms +/- SD, 95.6 +/- 9.0 OC vs 97.7 +/- 10.4 OD, F = 4.8, P < 0.05), Stroop test (T-values +/- SD, 59.7 +/- 6.3 OC vs 64.6 +/- 7.1 OD, F = 37.1, P < 0.001), ECG test (correct responses +/- SD, 38.3 +/- 7.3 OC vs 43.4 +/- 6.5 OD, F = 45.2, P < 0.001) and status of mood (T-value +/- SD, 60.3 +/- 9.0 OC vs 54.0 +/- 6.6 OD, F = 19.6, P < 0.001). Cognitive function and mood status of young hospital doctors after a night on call decrease considerably. In view of the special vulnerability of medical trainees to occupational stress all efforts are warranted to reduce sleep deprivation in the medical profession.

Acute and chronic effects on cholesterol biosynthesis of LDL-apheresis with or without concomitant HMG-CoA reductase inhibitor therapy.

To determine the acute and long-term effects of low density lipoprotein (LDL) reduction on cholesterol biosynthesis, we studied changes in the cholesterol precursors mevalonic acid (MVA) and lathosterol in patients with heterozygous familial hypercholesterolemia undergoing LDL-apheresis. Long-term LDL-apheresis in eight patients resulted in slight but insignificant increases in plasma MVA levels and lathosterol/cholesterol (L/C) ratios over 18 months. In short-term studies, six patients not on drugs and six patients treated with lovastatin or pravastatin had blood taken immediately before and after LDL-apheresis, and afterwards on days 1, 2, 3, 5, and 7. Plasma L/C ratios and MVA concentration did not change significantly on the first day after LDL-apheresis in those not on statin therapy (1.11 +/- 0.08 vs. 1.40 +/- 0.18, and 9.2 +/- 1.3 vs. 9.1 +/- 0.6 ng/ml, respectively) but increased in the statin-treated group (from 0.78 +/- 0.09 to 1.55 +/- 0.21, P = 0.003 and from 5.0 +/- 0.7 to 11.0 +/- 1.6 ng/ml, P = 0.008, respectively). There was no clear correlation between the changes in either of these precursors and the extent of reduction of total cholesterol by LDL-apheresis, but there was a strong inverse correlation with the post-apheresis LDL-cholesterol level (r = -0.77, P = 0.002 for L/C ratio; r = -0.75, P = 0.003 for MVA). Post-apheresis changes in L/C ratio and MVA were mutually correlated (r = 0.68. P = 0.01). We conclude that LDL-apheresis stimulates cholesterol biosynthesis transiently despite concomitant therapy with an HMG-CoA reductase inhibitor, the degree of stimulation being inversely related to the level to which the LDL-cholesterol was reduced.

Recovery of hypoglycaemia-associated compromised cerebral function after a short interval of euglycaemia in insulin-dependent diabetic patients.

To test the hypothesis that compromised cerebral function, induced by recurrent hypoglycaemic episodes, may recover after a short interval of euglycaemia, we examined electrophysiological activity and symptom awareness during two sequential euglycaemic-hypoglycaemic clamp studies in 11 insulin-dependent diabetic patients without any signs of peripheral or autonomic neuropathy. Neurophysiological testing and evaluation of hypoglycaemic symptoms were performed at stable glycaemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol/l. The first clamp study was preceded by 3 short-term hypoglycaemic episodes, whereas the second clamp study followed a 2 day interval of strict euglycaemia. The latter caused a recovery of electrophysiological activity, which was demonstrated by recovery of delays of the middle latency auditory evoked potentials (latency shift of the P(a) component, MANOVA, P < 0.01). Reversal of hypoglycaemic symptom unawareness involved the overall symptom perception (MANOVA, P < 0.04), as well as the autonomic symptoms of heart pounding (P < 0.05) and sweating (P < 0.05). We conclude that the previously reported impaired cerebral function, occurring as a consequence of repetitive hypoglycaemic episodes, may recover after a single euglycaemic interval.

Hypothalamic-pituitary activation does not differ during human and porcine insulin-induced hypoglycemia in insulin-dependent diabetes mellitus.

Although pituitary hormones play only a minor role in acute hormonal counterregulation during insulin-induced hypoglycemia, their concomitant secretion with the profound sympathoadrenal response provides an indicator of hypothalamic-pituitary activation. The release of different amounts of beta-endorphin, growth hormone, and adrenocorticotropin during human (HI) and porcine (PI) insulin-induced hypoglycemia would serve as a pointer to a different insulin species effect on hypothalamic-pituitary response. We performed a controlled, double-blind study with randomization to either HI or PI to compare insulin effects during developing and established hypoglycemia. The glucose clamp technique was used to lower the blood glucose concentration stepwise (3.3, 2.2, 1.7 mmol/l) over similar periods in ten patients with insulin-dependent diabetes mellitus. beta-endorphin, growth hormone, and adrenocorticotropin levels were determined by radioimmunoassay from arterialized blood at the above plateaus. A different action of HI or PI on peripheral glucose metabolism was not found. Pituitary hormones increased significantly during hypoglycemia (analysis of variance for hypoglycemic effects: beta-endorphin, P < 0.02; growth hormone, P < 0.04; adrenocorticotropin, P < 0.05). No insulin species effect was detected. Hypothalamic-pituitary activation during insulin-induced hypoglycemia is independent of the insulin species used, which supports earlier observations of an identical sympathoadrenal response during HI- and PI-induced hypoglycemia.

Neurophysiological impairments in IDDM patients during euglycemia and hypoglycemia.

OBJECTIVE: To test the hypothesis that latencies of evoked potentials in IDDM patients are delayed compared with healthy control subjects during euglycemia, and that insulin-induced hypoglycemia causes further latency delays of evoked potentials to occur. RESEARCH DESIGN AND METHODS: We recruited 23 IDDM patients (27.9 +/- 1.6 yr of age, HbA1c 6.7 +/- 0.3%, without sensory or autonomic neuropathy) and 26 unequivocally healthy subjects who were carefully matched for sex, age, and body mass index to serve as the control group (18 men and 8 women, 28.4 +/- 1.6 yr of age, 22.6 +/- 0.7 kg/m2), for a controlled, prospective study. Sequential euglycemic-hypoglycemic clamps were performed with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' and healthy control subjects' neurophysiological functions were evaluated. The methodological armamentarium included the measurement of brainstem auditory, middle-latency auditory, and somatosensory evoked potentials that assessed conduction velocity in corresponding neural structures and information processing in the midbrain and auditory cortex. RESULTS: Multiple analysis of variance revealed a significant overall difference of brainstem auditory evoked potential latencies during euglycemia between the study group and healthy control group (F = 3.41, P < 0.03), which was mainly attributable to latency delays of wave III (F = 6.60, P < 0.02), V (F = 9.19, P < 0.01), and interpeak latency I-V (F = 2.82, P < 0.07). Repeated analysis of variance measures detected a significant latency delay of the major wave Pa of the middle-latency auditory evoked potentials during hypoglycemia (F = 4.4, P < 0.02), which rapidly returned to normal after reinstitution of euglycemia. CONCLUSIONS: In IDDM patients, chronic, structural CNS changes already appear at the brainstem level during euglycemia. Functional, reversible CNS changes, however, seem to emerge during acute deviation from glucose homeostasis in more rostral brain regions.

Compromised hormonal counterregulation, symptom awareness, and neurophysiological function after recurrent short-term episodes of insulin-induced hypoglycemia in IDDM patients.

To test the hypothesis that recurrent short-term hypoglycemic episodes may impair hormonal counterregulation, symptom awareness, and neurophysiological function during subsequent hypoglycemia, we examined two groups of IDDM patients (n = 18), neither of whom exhibited signs of autonomic neuropathy. Two sequential euglycemic-hypoglycemic clamp studies were performed three days apart with stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM, at which the patients' awareness of and response to hypoglycemia was evaluated. In the intervention group (n = 11), three short-term hypoglycemic episodes preceded the second clamp study. Counterregulatory hormones increased significantly during hypoglycemia, but adrenaline (P < 0.03), cortisol (P < 0.01), and ACTH (albeit not significant) showed a blunted response after repetitive hypoglycemic events. In this group, the perception of hypoglycemic symptoms was significantly reduced and was most evident for the autonomic symptoms of sweating (P < 0.05), heart pounding (P < 0.01), and warmness (P < 0.03). The deterioration of neurophysiological function, as assessed from the middle latency auditory evoked potentials, was more pronounced in the intervention group (latency shift of the Pa component, P < 0.05). These data suggest that alterations of neuroendocrine counterregulation, symptom perception, and certain aspects of cerebral function may occur as a consequence of recurrent short-term hypoglycemic episodes. These adaptation phenomena may contribute to the increased incidence of severe hypoglycemia in IDDM patients on intensive insulin therapy.

Hormonal counterregulation, symptom awareness, and neurophysiological function in type 1 diabetes during insulin-induced hypoglycaemia.

To evaluate a putative differential impact of human (HI) and porcine (PI) insulin on human brain function we examined 10 Type 1 (insulin-dependent) diabetic patients without any signs of sensory or autonomic neuropathy. The glucose clamp technique was applied to achieve stable glycaemic plateaus of 5.6, 3.3, 2.2, and 1.7 mmol l-1 on two occasions with randomized and blinded allocation of either HI or PI. At each of the plateaus, symptom awareness, hormonal counterregulation, and neurophysiological functions (primary sensory information processing of the auditory and somatosensory system) were recorded. The effect of both types of insulin on glucose metabolism and counterregulatory hormone response was almost identical. Catecholamines increased (adrenaline p less than 0.05; noradrenaline p less than 0.02) during hypoglycaemia, independent of the type of insulin being used. Symptom awareness increased significantly during the fall of blood glucose concentration. This effect was more pronounced (total symptom score 26 vs 2, p less than 0.05) with PI, but only during developing hypoglycaemia (3.3 mmol l-1-plateau). For brainstem auditory evoked potentials and somatosensory evoked potentials, all individual and averaged latencies and corresponding amplitudes were within the normal range. No effect of insulin type or blood glucose concentration on neurophysiological measures could be detected. Our results suggest a differential impact of HI and PI on human brain function with regard to symptom awareness, but not hormonal counterregulation. This direct effect of insulin on central nervous function does not involve the afferent transmission in the auditory and somatosensory system.

Catecholamine response during human and pork insulin-induced hypoglycemia in IDDM patients.

OBJECTIVE: To evaluate the catecholamine response during human and pork insulin-induced hypoglycemia. RESEARCH DESIGN AND METHODS: Ten insulin-dependent diabetes mellitus (IDDM) patients without any signs of autonomic neuropathy received either human or pork insulin in a randomized crossover fashion on 2 nonconsecutive days. The glucose clamp technique was applied to achieve stable glycemic plateaus of 5.6, 3.3, 2.2, and 1.7 mM. RESULTS: The effect of both types of insulin on glucose metabolism and circulating catecholamines was almost identical. There was a sharp rise of both epinephrine (P less than 0.05) and norepinephrine (P less than 0.02) during hypoglycemia, which did not depend on the type of insulin applicated. Symptom awareness increased significantly during the decrease of blood glucose concentration. Only during developing hypoglycemia (3.3-mM plateau), was this effect more pronounced (cumulative symptom score 2 vs. 26, P less than 0.05) with pork insulin. CONCLUSIONS: AN attenuated catecholamine secretion seems not to be the putative mechanism of a reduced awareness of human insulin-induced hypoglycemia.

Cognitive and psychomotor function during severe insulin-induced hypoglycaemia in insulin-dependent diabetic patients.

Cognitive and psychomotor function, hormonal counterregulation and symptom awareness during severe insulin-induced hypoglycaemia were evaluated in 10 insulin-dependent diabetic patients. The glucose-clamp technique (Biostator) was applied to achieve a stable hypoglycaemic (39 +/- 2 mg/dl) plateau. A battery of 7 neuropsychological tests and a standardized questionnaire assessing hypoglycaemia symptoms were administered during euglycaemia and hypoglycaemia. There was a significant increase in counterregulatory hormone response (cortisol, growth hormone, p less than 0.05). Every patient experienced symptoms during severe hypoglycaemia. Four patients, however, were not aware of this threatening metabolic state. There was a significant performance decrement in all but two neuropsychological tests (Aiming Center I, Aiming Center II, Line Tracing Errors, Reaction Time, p less than 0.01; Digit Symbol, p less than 0.05). Performance of simple motor tasks as well as cognitive tasks requiring complex discrimination deteriorated similarly. Furthermore, the patients' general well-being (subjective condition) worsened considerably. In conclusion, a significant impairment of neuropsychological functions emerged during severe hypoglycaemia in insulin-dependent diabetes mellitus, even in the face of adequate hormonal counterregulation, and did not always coincide with an appropriate patient awareness of the actual metabolic state.

Analysis of polyunsaturated fatty acids in blood serum after fish oil administration.

Free and total fatty acids in the blood serum of patients with hyperlipoproteinemia have been analysed as their methyl esters by capillary gas chromatography using an FFAP column. In one-step reactions the free fatty acids in serum react with methanol-acetyl chloride (50:1, v/v) at 25 degrees C, the total fatty acids (free plus esterified) are transesterified with methanol-toluene-acetyl chloride (8:2:1, v/v) at 100 degrees C. The quantification of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) is based on an internal standard (13,16,19-docosatrienoic acid) and on calibration standards. Under normal diet the concentrations of EPA and DHA are as follows (mean +/- S.D., n = 27): free EPA, 0.2 +/- 0.1 mg/dl; free DHA, 0.6 +/- 0.2 mg/dl; total EPA, 3.6 +/- 2.1 mg/dl; total DHA 11.4 +/- 3.1 mg/dl. Under a fish oil intake of 9 g per day, free and total EPA concentrations rise by ca. five- to six-fold, and free and total DHA concentrations by ca. two-fold.

Different awareness of hypoglycaemia induced by human or purified pork insulin in type I diabetic patients.

Recently, there have been reports on a diminished awareness of hypoglycaemia after a switch from purified pork insulin (PPI) to human insulin (HI) in insulin-dependent diabetes mellitus (IDDM). To clarify this phenomenon we investigated nine IDDM patients without signs of autonomic neuropathy. After an overnight euglycaemic clamp, blood glucose was lowered to hypoglycaemic levels by means of an artificial pancreas (Biostator) on 2 days. Insulin was used in a double-blind, randomized, cross-over fashion, either PPI or HI. The symptomatology and the hormonal counterregulation of developing hypoglycaemia was recorded. Venous concentrations of free insulin, cortisol, glucagon, growth hormone and the prevailing blood glucose were similar under both insulins. Eight out of nine IDDM patients felt more symptoms and at a higher blood glucose concentration under PPI than under HI. The first symptom of developing hypoglycaemia appeared at a mean blood glucose concentration of 61.1 +/- 5.4 mg.dl-1 under PPI and 44.4 +/- 5.3 mg.dl-1 under HI respectively (P less than 0.05). We conclude that HI may cause symptoms of hypoglycaemia to appear later and with a lesser number in comparison to PPI.

Influence of breakfasts with different nutrient contents on glucose, C peptide, insulin, glucagon, triglycerides, and GIP in non-insulin-dependent diabetics.

To examine the influence of coingestion of fat and protein in a mixed meal on carbohydrate metabolism, subjects with non-insulin-dependent diabetes mellitus (NIDDM) received three different breakfasts varying in the amount of fat and protein (group 1) or only in the amount of fat (group 2). Compared with the changes after a standard breakfast, insulin increased after the protein-rich meal and decreased after the fat-rich meal in group 1. Glucose and gastric inhibitory polypeptide (GIP) remained constant. In contrast, only GIP showed a significant increase after a high-fat meal in group 2. Thus, in NIDDM subjects, glucose and insulin responses to different mixed meals do not appear to be exclusively mediated by GIP. Protein was confirmed as a potent stimulator of insulin secretion. Other factors, such as an altered beta-cell response in diabetics to GIP or other incretions, must be considered to explain the reported results.

[Abscess of the thyroid gland caused by Salmonella enteritidis in immunosuppressive treatment of generalized myasthenia gravis with thymoma]. / Schilddrüsenabszess durch Salmonella enteritidis unter immunsuppressiver Behandlung einer generalisierten Myasthenia gravis mit Thymom.

We report the case of a 69-year old male caucasian patient who developed a lateral neck tumor while under immunosuppression with azathioprine. The tumor was diagnosed finally as an abscess caused by Salmonella enteritidis after isolation of the agent from blood, tumor biopsy and feces. This extremely rare manifestation of an infection by Salmonella enteritidis is considered as a complication of immunosuppressive therapy.

Symptoms of hypoglycemia--a comparison between porcine and human insulin.

For more than 2 years now it has been controversially debated whether awareness of hypoglycemia is reduced when type I diabetic patients are switched from porcine to human insulin. In order to address this question, we studied nine C-peptide negative diabetics (age 27.6 years, Broca index 106%, duration of diabetes 5.7 years, HbA1, 8.8%) in comparison with eight healthy volunteers (age 22.4 years, Broca index 104%). Following euglycemic monitoring overnight, a controlled hypoglycemia was induced by altering the algorithms of the Biostator. This was done in a double-blind, cross-over fashion using porcine or human insulin on 2 nonconsecutive days. There were no differences between the results obtained with respect to the time course of the study, blood glucose, amount of insulin infused, and concentration of venous free insulin achieved. Of the nine diabetics, eight were aware of hypoglycemia at a higher blood glucose level under porcine insulin. The first symptom of hypoglycemia was perceived at a mean blood glucose level of 61.1 +/- 5.4 mg/dl under porcine insulin and of 44.4 +/- 5.3 mg/dl under human insulin (P less than or equal to 0.05). Thirty symptoms were noted under porcine insulin exclusively or preferentially as opposed to only eight which were observed exclusively or preferentially under human insulin. The healthy volunteers evidenced fewer symptoms at lower blood glucose concentrations than the diabetics. The clear difference between human and porcine insulin could not unequivocally be reproduced in this group.(ABSTRACT TRUNCATED AT 250 WORDS)

Exercise and insulin requirements.

In order to facilitate the management of sports and work for insulin injecting diabetic patients we analyzed 6 different situations: 1) In the morning before injecting insulin stepwise increasing bicycle ergometry until exhaustion with a duration of less than one half hour may be performed without previous reduction of insulin or additional oral carbohydrates. Maximal work load can thus be determined with ECG monitoring. After insulin injection we advise our patients to estimate their reaction by calculating with exercise units. One exercise unit equals 20 minutes of half maximal exercise or one hour of 30% maximal exercise. 2) Performing one exercise unit the diabetic will have to anticipate a blood glucose reduction of -60 mg/dl. In order to maintain normal blood glucose levels he will have to reduce the regular insulin bolus 3) in the morning by -3,3 IU or 4) by -1.7 IU in the evening or he should 5) take +12 g of oral glucose (quickly absorbable carbohydrates). 6) A reduction of basal rate (CSII) or NPH insulin (ICT) is not advisable for exercise up to 3 hours. On the basis of these mean values every diabetic patient has to monitor blood glucose during exercise and adapt the measures to his individual reactions.

Cognitive and psychomotor function during hypoglycemia: a comparison between porcine and human insulin.

After an overnight euglycemic clamp, blood glucose levels were precisely lowered on two nonconsecutive mornings via a glucose-controlled insulin infusion system (GCIIS, Biostator) using either purified porcine insulin (PPI) or human insulin (HI). Two cognitive and psychomotor tests were significantly different in 8 type-I diabetic subjects and 8 healthy volunteers at four timepoints, when mean blood glucose concentrations (BGCs) were 100, 65, 50, and 40 mg/dl. Also, a significant difference (p = 0.005) could be found between the mean of all reaction time testing (RTT) values under HI as compared with the mean of all RTT values under PPI. Lowering the BGC resulted in a significant increase in the reaction time (p = 0.012). These effects were not dependent on the type of insulin being used nor were they typical of a particular study group.