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Biomedical subjects

C G Fanelli

Publications and source records attributed to C G Fanelli.

At least 19 recordsLinked to original sources
PubMed2002

Rate of fall of blood glucose and physiological responses of counterregulatory hormones, clinical symptoms and cognitive function to hypoglycaemia in Type I diabetes mellitus in the postprandial state.

AIMS/HYPOTHESIS: The aim of this study was to establish the effect of a rate of decreasing plasma glucose concentrations on responses to hypoglycaemia, i.e. release of counterregulatory hormones, perception of symptoms, deterioration of cognitive function, and rates of forearm noradrenaline spillover, in the postprandial condition and in the sitting position. METHODS: We studied 11 subjects with Type I (insulin-dependent) diabetes mellitus, twice during clamped insulin-induced hypoglycaemia (2.4 mmol/l) after eating in the sitting position. On one occasion, plasma glucose was decreased at the rate of 0.1+/-0.003 mmol x min(-1) x l(-1) (fast fall), on the other at the rate of 0.03+/-0.001 mmol x min(-1) x l(-1) (slow fall). Subjects underwent a control euglycaemic clamp study as well. RESULTS: In response to fast-fall as compared to slow-fall hypoglycaemia, which was about 30 min longer, cognitive tasks were performed as follows: Trail-Making B, PASAT 2 s, Digit Vigilance Test and Verbal Memory deteriorated more, adrenaline increased less (2.8+/-0.5 vs 3.5+/-0.7 nmol/l, p=0.03), forearm noradrenaline spillover was greater (6.5+/-1.0 vs 5.2+/-0.4 pmol x min(-1) x 100 ml(-1), p=0.04), and symptoms were no different. After recovery from hypoglycaemia, cognitive function was still deteriorated compared to the baseline with no difference between fast and slow-fall hypoglycaemia. The evident response of glucagon to postprandial hypoglycaemia contrasted with the blunted or absent response in the fasting state. CONCLUSION/INTERPRETATION: In the postprandial condition and sitting position, fast-fall hypoglycaemia is more dangerous than slow-fall, because it deteriorates cognitive function more, and activates responses of counterregulatory hormones less than slow-fall hypoglycaemia.

Adult↗
PubMed2001

Blood-to-brain glucose transport, cerebral glucose metabolism, and cerebral blood flow are not increased after hypoglycemia.

Recent antecedent hypoglycemia has been found to shift glycemic thresholds for autonomic (including adrenomedullary epinephrine), symptomatic, and other responses to subsequent hypoglycemia to lower plasma glucose concentrations. This change in threshold is the basis of the clinical syndromes of hypoglycemia unawareness and, in part, defective glucose counterregulation and the unifying concept of hypoglycemia-associated autonomic failure in type 1 diabetes. We tested in healthy young adults the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport, a plausible mechanism of this phenomenon. Eight subjects were studied after euglycemia, and nine were studied after approximately 24 h of interprandial hypoglycemia ( approximately 55 mg/dl, approximately 3.0 mmol/l). The latter were shown to have reduced plasma epinephrine (P = 0.009), neurogenic symptoms (P = 0.009), and other responses to subsequent hypoglycemia. Global bihemispheric blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain time-activity curves-the latter determined by positron emission tomography (PET)-after intravenous injection of [1-(11)C]glucose at clamped plasma glucose concentrations of 65 mg/dl (3.6 mmol/l). For these calculations, a model was used that includes a fourth rate constant to account for egress of [(11)C] metabolites. Cerebral blood flow was measured with intravenous [(15)O]water using PET. After euglycemia and after hypoglycemia, rates of blood-to-brain glucose transport (24.6 +/- 2.3 and 22.4 +/- 2.4 micromol. 100 g(-1). min(-1), respectively), cerebral glucose metabolism (16.8 +/- 0.9 and 15.9 +/- 0.9 micromol. 100 g(-1). min(-1), respectively) and cerebral blood flow (56.8 +/- 3.9 and 53.3 +/- 4.4 ml. 100 g(-1). min(-1), respectively) were virtually identical. These data do not support the hypothesis that recent antecedent hypoglycemia increases blood-to-brain glucose transport during subsequent hypoglycemia. They do not exclude regional increments in blood-to-brain glucose transport. Alternatively, the fundamental alteration might lie beyond the blood-brain barrier.

Adult↗
PubMed1999

Physiology of glucose counterregulation to hypoglycemia.

Prevention of hypoglycemia is essential for the preservation of brain metabolism and survival of the whole body. Normally, glucose is the only substrate used by the brain to meet its metabolic requirements. Therefore, a continuous supply of circulatory glucose is a necessary prerequisite for normal cerebral metabolism. When plasma glucose concentration decreases (e.g., during prolonged fasting or after administration of glucose-lowering drugs) several physiologic responses are activated to prevent further decreases in blood glucose. The first response is known as counterregulation, a system that prevents and corrects hypoglycemia through the release of counterregulatory hormones.

Adrenal Cortex↗
PubMed1999

Hypoglycemia per se stimulates sympathetic neural as well as adrenomedullary activity, but, unlike the adrenomedullary response, the forearm sympathetic neural response is not reduced after recent hypoglycemia.

We tested the hypotheses that 1) hypoglycemia per se stimulates the sympathetic neural as well as the adrenomedullary component of the sympathochromaffin system, and 2) sympathetic neural responses to hypoglycemia, like adrenomedullary responses, are reduced after recent hypoglycemia. To this end, we studied 10 healthy young adults on 2 consecutive days on two separate occasions, on one occasion with euglycemia (5.0 mmol/l) and on the other occasion with hypoglycemia (2.8 mmol/l) from 1000 to 1200 and 1400 to 1600 on day 1 of each occasion. On day 2 of each occasion, plasma epinephrine and norepinephrine (NE) concentrations and rates of systemic NE spillover (SNESO) and forearm NE spillover (FNESO) were measured during hyperinsulinemic (12.0 pmol x kg(-1) x min(-1)) euglycemia (5.0 mmol/l) and hypoglycemia (2.8 mmol/l). Compared with values during euglycemia, plasma epinephrine and NE and rates of SNESO and FNESO all increased during hypoglycemia (P < 0.01). After day 1 hypoglycemia, there were reductions during hypoglycemia on day 2 in plasma epinephrine (2,050 +/- 500 vs. 2,960 +/- 400 pmol/l; P < 0.02), plasma NE (1.35 +/- 0.16 vs. 1.92 +/- 0.20 nmol/l; P < 0.01), and SNESO rates (5.13 +/- 0.84 vs. 6.87 +/- 0.81 nmol/min; P < 0.02). However, FNESO rates were unaltered (1.16 +/- 0.25 vs. 1.27 +/- 0.17 pmol x min(-1) x 100 ml tissue(-1). Thus we conclude that 1) hypoglycemia per se stimulates both the sympathetic neural and adrenomedullary components of the sympathochromaffin system and 2) adrenomedullary, but not forearm sympathetic neural, responses to hypoglycemia are reduced after recent hypoglycemia. The extent to which the lower plasma NE levels and reduced SNESO responses to hypoglycemia after day 1 hypoglycemia reflect reduced NE release from the adrenal medullae, sympathetic nerves other than those in the forearm, or both cannot be determined from these data.

Adrenal Medulla↗
PubMed1998

Forearm norepinephrine spillover during standing, hyperinsulinemia, and hypoglycemia.

Plasma norepinephrine (NE) concentrations are a fallible index of sympathetic neural activity because circulating NE can be derived from sympathetic nerves, the adrenal medullas, or both and because of regional differences in sympathetic neural activity. We used isotope dilution measurements of systemic and forearm NE spillover rates (SNESO and FNESO, respectively) to study the sympathochromaffin system during prolonged standing, hyperinsulinemic euglycemia, and hyperinsulinemic hypoglycemia in healthy humans. Prolonged standing led to decrements in blood pressure without increments in heart rate, the pattern of incipient vasodepressor syncope. FNESO was not increased (0.58 +/- 0.20 to 0. 50 +/- 0.21 pmol. min-1. 100 ml tissue-1), suggesting that the approximately twofold increments in plasma NE and SNESO were derived from sympathetic nerves other than those in the forearm (with a possible contribution from the adrenal medullas). Hyperinsulinemia per se (euglycemia maintained) stimulated sympathetic neural activity, as evidenced by increments in FNESO (0.57 +/- 0.11 to 1.25 +/- 0.25 pmol. min-1. 100 ml tissue-1, P < 0.05), but not adrenomedullary activity. Hypoglycemia per se stimulated adrenomedullary activity (plasma epinephrine from 190 +/- 70 to 1720 +/- 320, pmol/l, P < 0.01). Although SNESO (P < 0.05) and perhaps plasma NE (P < 0.06) were raised to a greater extent during hyperinsulinemic hypoglycemia than during hyperinsulinemic euglycemia, FNESO was not. Thus these data do not provide direct support for the concept that hypoglycemia per se also stimulates sympathetic neural activity.

Adult↗
PubMed1998

Impact of nocturnal hypoglycemia on hypoglycemic cognitive dysfunction in type 1 diabetes.

To test the hypothesis that glycemic thresholds for cognitive dysfunction during hypoglycemia, like those for autonomic and symptomatic responses, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with type 1 diabetes mellitus (T1DM), 15 patients were studied on two occasions. Cognitive functions were assessed during morning hyperinsulinemic stepped hypoglycemic clamps (85, 75, 65, 55, and 45 mg/dl steps) after, in random sequence, nocturnal (2330-0300) hypoglycemia (48 +/- 2 mg/dl) on one occasion and nocturnal euglycemia (109 +/- 1 mg/dl) on the other. Compared with nondiabetic control subjects (n = 12), patients with T1DM had absent glucagon (P = 0.0009) and reduced epinephrine (P = 0.0010), norepinephrine (P = 0.0001), and neurogenic symptom (P = 0.0480) responses to hypoglycemia; the epinephrine (P = 0.0460) and neurogenic symptom (P = 0.0480) responses were reduced further after nocturnal hypoglycemia. After nocturnal hypoglycemia, in contrast to nocturnal euglycemia, there was less deterioration of cognitive function overall (P = 0.0065) during hypoglycemia based on analysis of the sum of standardized scores (z-scores). There was relative preservation of measures of pattern recognition and memory (the delayed non-match to sample task, P = 0.0371) and of attention (the Stroop arrow-word task, P = 0.0395), but not of measures of information processing (the paced serial addition task) or declarative memory (the delayed paragraph recall task), after nocturnal hypoglycemia. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, like those for autonomic and symptomatic responses to hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia in patients with T1DM.

Adult↗
PubMed1998

Blood-to-brain glucose transport and cerebral glucose metabolism are not reduced in poorly controlled type 1 diabetes.

To test the hypothesis that blood-to-brain glucose transport is reduced in poorly controlled type 1 diabetes, we studied seven patients with a mean (+/- SD) HbA1c level of 10.1 +/- 1.2% and nine nondiabetic subjects during hyperinsulinemic, mildly hypoglycemic (approximately 3.6 mmol/l, approximately 65 mg/dl) glucose clamps. Blood-to-brain glucose transport and cerebral glucose metabolism were calculated from rate constants derived from blood and brain time-activity curves--the latter determined by positron emission tomography (PET)--after intravenous injection of [1-(11)C]glucose using a model that includes a fourth rate constant to account for regional egress of 11C metabolites. Cerebral blood flow and cerebral blood volume were determined with intravenous H2(15)O and inhaled C(15)O, respectively, also by PET. At plateau plasma glucose concentrations of 3.6 +/- 0.0 and 3.7 +/- 0.1 mmol/l, rates of blood-to-brain glucose transport were similar in the two groups (23.7 +/- 2.2 and 21.6 +/- 2.9 micromol x 100 g(-1) x min(-1), P = 0.569, in the control subjects and the patients, respectively). There were also no differences in the rates of cerebral glucose metabolism (16.8 +/- 0.8 and 16.3 +/- 1.2 micromol x 100 g(-1) x min(-1), P = 0.693, respectively). Plasma epinephrine (1,380 +/- 340 vs. 450 +/- 170 pmol/l, P = 0.0440) and glucagon (26 +/- 5 vs. 12 +/- 1 pmol/l, P = 0.0300) responses to mild hypoglycemia were reduced in the patients with type 1 diabetes. We conclude that neither blood-to-brain glucose transport nor cerebral glucose metabolism is measurably reduced in people with poorly controlled type 1 diabetes.

Adult↗
PubMed1998

Brief twice-weekly episodes of hypoglycemia reduce detection of clinical hypoglycemia in type 1 diabetes mellitus.

We tested the hypothesis that as few as two weekly brief episodes of superimposed hypoglycemia (i.e., doubling the average frequency of symptomatic hypoglycemia) would reduce physiological and behavioral defenses against developing hypoglycemia and reduce detection of clinical hypoglycemia in patients with type 1 diabetes mellitus (T1DM). Compared with nondiabetic controls, six patients with well-controlled T1DM (HbA1c, 7.5 +/- 0.7% [mean +/- SD]) exhibited absent glucagon responses and reduced epinephrine (P = 0.0027), norepinephrine (P = 0.0007), pancreatic polypeptide (P = 0.0030), and neurogenic symptom (P = 0.0451) responses to hypoglycemia as expected. In these patients, 2 h of induced hypoglycemia (50 mg/dl, 2.8 mmol/l) twice weekly for 1 month, compared in a random-sequence crossover design with an otherwise identical 2 h of induced hyperglycemia (150 mg/dl, 8.3 mmol/l) twice weekly for 1 month, further reduced the epinephrine (P = 0.0001) and pancreatic polypeptide (P = 0.0030) responses, tended to further reduce the norepinephrine and neurogenic symptom responses to hypoglycemia, and reduced cognitive dysfunction during hypoglycemia (P = 0.0271), all assessed in the investigational setting. In the clinical setting, induced hypoglycemia did not alter overall glycemic control, but did reduce the total number of symptomatic hypoglycemic episodes detected by the patients from 49 to 30 per month and lowered the mean +/- SE self-monitored blood glucose level during symptomatic hypoglycemia from 51 +/- 2 mg/dl (2.8 +/- 0.1 mmol/l) to 46 +/- 3 mg/dl (2.6 +/- 0.2 mmol/l) (P < 0.01). It also reduced the proportion of low regularly scheduled self-monitored values that were symptomatic by approximately 33%. Thus as little as doubling the frequency of symptomatic hypoglycemia further reduced both the key epinephrine response and clinical awareness of developing hypoglycemia, changes reasonably expected to increase the risk of severe iatrogenic hypoglycemia in T1DM.

Adult↗
PubMed1996

Impact of recent antecedent hypoglycemia on hypoglycemic cognitive dysfunction in nondiabetic humans.

To test the hypothesis that glycemic thresholds for hypoglycemic cognitive dysfunction, like those for neuroendocrine responses to and symptoms of hypoglycemia, shift to lower plasma glucose concentrations after recent antecedent hypoglycemia, 16 healthy young adult subjects (7 women and 9 men) were studied on two separate occasions in random sequence, once with hyperinsulinemic hypoglycemia (2.6 +/- 0.1 mmol/l, 47 +/- 1 mg/dl) and once with otherwise identical hyperinsulinemic euglycemia (4.8 +/- 0.1 mmol/l, 86 +/- 5 mg/dl) between 1430 and 1630. Neuroendocrine, symptomatic, and cognitive responses to hyperinsulinemic stepped hypoglycemic (4.7, 4.2, 3.6, 3.0, 2.8, 2.5, and 2.2 mmol/l; 85, 75, 65, 55, 50, 45, and 40 mg/dl) clamps were quantitated the following morning on both occasions. Cognitive function tests included measures of information processing (Serial Addition), attention (Stroop Arrow Word), pattern recognition and memory (Delayed Non-Match to Sample), and declarative memory (Paragraph Recall). As expected, plasma glucagon (P = 0.0094), epinephrine (P = 0.0063), and pancreatic polypeptide (P = 0.0046) responses to stepped hypoglycemia were reduced significantly, and symptomatic responses tended to be reduced after afternoon hypoglycemia. Performance on the cognitive function tests deteriorated (P < 0.0001) during stepped hypoglycemic clamps, but there were no significant overall effects of antecedent hypoglycemia on hypoglycemic cognitive dysfunction. Although deterioration was reduced (P < 0.05) from the 2.8 mmol/l (50 mg/dl) to the 2.5 mmol/l (45 mg/dl) steps on the Serial Addition and Delayed Non-Match to Sample tasks after afternoon hypoglycemia, comparable differences were not found on the Stroop Arrow Word or Paragraph Recall tasks. Thus, glycemic thresholds for hypoglycemic cognitive dysfunction, unlike those for neuroendocrine responses to and symptoms of hypoglycemia, do not seem to shift to substantially lower plasma glucose concentrations after recent antecedent hypoglycemia in nondiabetic humans.

Adolescent↗
PubMed1993

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.

Adult↗
PubMed1993

Nocturnal blood glucose control in type I diabetes mellitus.

A major problem in replacing insulin in type I diabetes mellitus is that currently no depot preparation exists that is capable of mimicking the background insulin secretion of the healthy pancreas. Because all of the currently available intermediate- or long-acting insulin preparations have a peaked-action profile, excess insulin action at midnight and insulin waning at dawn occur whenever such an insulin preparation is given at supper time. If the target fasting plasma glucose is the ambitious near-normoglycemia of intensive insulin therapy, intermediate-acting insulin at suppertime easily results in hypoglycemia in the early evening hours and hyperglycemia in the fasting state. The problems of overnight glycemia in type I diabetes are further complicated by the dawn phenomenon and the Somogyi phenomenon. The dawn phenomenon is the combination of an initial decrease in insulin requirements between approximately 2400 and approximately 0300, followed by an increase in the insulin needs between approximately 0500 and approximately 0800. The dawn phenomenon is the result of changes in hepatic (and extrahepatic) insulin sensitivity, which are best attributed to nocturnal growth hormone secretion. The dawn phenomenon is a day-to-day reproducible event that occurs in nearly all diabetic patients. Its contribution to fasting hyperglycemia correlates with diabetes duration (inversely) and the HbA1c percentage (directly). Overall, it is estimated that the specific contribution of the dawn phenomenon to fasting hyperglycemia is approximately 2 mM (approximately 35 mg/dl), but it may be much greater because of the warning of the depot-insulin preparation injected the previous evening. The Somogyi phenomenon, strictly speaking, refers to fasting hyperglycemia that occurs after inducement of nocturnal hypoglycemia by regular insulin. Because the present therapeutic regimens of NPH/Lente insulin given at suppertime cause overnight hyperinsulinemia, excessive fasting hyperglycemia rarely follows nocturnal hypoglycemia, except when excessive glucose is ingested to correct hypoglycemia. However, nocturnal hypoglycemia may easily deteriorate glycemic control later in the day, because it induces prolonged posthypoglycemic insulin resistance, which results in postbreakfast and late-morning hyperglycemia. With nocturnal insulin therapy, it is important to consider the problems of insulin pharmacokinetics, the dawn phenomenon, and the Somogyi phenomenon to prevent both nocturnal hypoglycemia and excessive fasting hyperglycemia.(ABSTRACT TRUNCATED AT 400 WORDS)

Blood Glucose↗