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.

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.

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.

Whole body, adipose tissue, and forearm norepinephrine kinetics in lean and obese women.

We evaluated whole body and regional (subcutaneous abdominal adipose tissue and forearm) norepinephrine (NE) kinetics in seven lean (body mass index 21.3 +/- 0.5 kg/m2) and six upper body obese (body mass index 36.4 +/- 0.4 kg/m2) women who were matched on fat-free mass. NE kinetics were determined by infusing [3H]NE and obtaining blood samples from a radial artery, a deep forearm vein draining mostly skeletal muscle, and an abdominal vein draining subcutaneous abdominal fat. Mean systemic NE spillover tended to be higher in obese (2.82 +/- 0.49 nmol/min) than in lean (2.53 +/- 0.40 nmol/min) subjects, but the differences were not statistically significant. Adipose tissue and forearm NE spillover rates into plasma were greater in lean (0.91 +/- 0.08 pmol. 100 g tissue-1. min-1 and 1.01 +/- 0.09 pmol. 100 ml tissue-1. min-1, respectively) than in obese (0.26 +/- 0.05 pmol. 100 g tissue-1. min-1 and 0.58 +/- 0.11 pmol. 100 ml tissue-1. min-1, respectively) subjects (P < 0.01). These results demonstrate that adipose tissue is an active site for NE metabolism in humans. Adipose tissue NE spillover is considerably lower in obese than in lean women, which may contribute to the lower rate of lipolysis per kilogram of fat mass observed in obesity.

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.

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.

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.