Hypoglycemia In Humans Research Articles

Fructose amplifies counterregulatory responses to hypoglycemia in humans.

Glucokinase (GK) is required for cellular glucose sensing, although there is a paucity of data regarding its role in the counterregulatory response to hypoglycemia in humans. Because fructose has been shown to modulate GK activity, we examined the effects of an acute infusion of fructose on hypoglycemia counterregulation in seven lean nondiabetic subjects. Using stepped hypoglycemia clamp studies (5.0, 4.4, 3.9, and 3.3 mmol/l target plasma glucose steps, 50 min each), subjects were studied on two separate occasions, without (control) or with co-infusion of fructose (1.2 mg.kg(-1).min(-1)). Fructose induced a resetting of the glycemic thresholds for secretion of epinephrine (3.8 +/- 0.1 mmol/l) and glucagon (3.9 +/- 0.2 mmol/l) to higher plasma glucose concentrations (4.0 +/- 0.1 mmol/l [P = 0.006] and 4.1 +/- 0.1 mmol/l [P = 0.03], respectively). In addition, the magnitude of increase in epinephrine and glucagon concentrations was higher after administration of fructose (48 and 39%, respectively, P < 0.05 for both). The amplification of these hormonal responses was specific because plasma norepinephrine, growth hormone, and cortisol were comparable in both sets of studies. Endogenous glucose production, measured with [3-(3)H]glucose, increased by 47% (P < 0.05) in the fructose infusion studies compared with 14% (P = NS) in the control studies. In addition, glucose uptake was more suppressed with fructose infusion (by 33%, P < 0.05). In concert with these effects of fructose on glucose kinetics, average glucose infusion rate was markedly reduced in the fructose infusion studies during the 3.9-mmol/l glucose step (4.6 +/- 0.9 vs. 7.4 +/- 1.1 micromol.kg(-1).min(-1), respectively, P = 0.03) and during the 3.3-mmol/l glucose step (0.5 +/- 0.1 vs. 5.2 +/- 1.2 micromol.kg(-1).min(-1), respectively, P < 0.001), suggesting more potent glucose counterregulation and improved recovery from hypoglycemia with fructose infusion. We conclude that infusion of a catalytic dose of fructose amplifies the counterregulatory response to hypoglycemia by both increases in hormonal activation and augmentation of glucose counterregulation in humans.

Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans

Reduced awareness of hypoglycemic symptoms and compromised hormonal counterregulation increase the risk of severe hypoglycemia in people with diabetes mellitus. Up to the present, angiotensin 1 receptor blockers, which play an important role in controlling diabetic complications, have not been known to increase the risk of hypoglycemia. Nevertheless, we observed 3 cases of diabetic patients complaining of reduced awareness of hypoglycemic symptoms while they were under treatment with losartan in our outpatients clinic. We therefore investigated the effects of losartan on symptomatic and hormonal responses to hypoglycemia in humans. We carried out a randomized, double-blind, crossover study including 16 healthy men. The subjects received losartan 50 mg/d versus placebo. Treatment periods lasted for 7 days and were followed by a stepwise hypoglycemic clamp session (4.5 to 3.8 to 3.1 to 2.4 mmol/L) with measurement of counterregulatory hormones (epinephrine, norepinephrine, adrenocorticotropin, cortisol, glucagon), symptoms, and hemodynamic parameters (blood pressure, heart rate). Losartan attenuated the hypoglycemia-induced rise in plasma epinephrine (6480 +/- 490 pmol/L versus placebo 8970 +/- 790 pmol/L; P <.001) and the rise in plasma adrenocorticotropin (21 +/- 2 pmol/L versus 26 +/- 3 pmol/L; P <.01). Losartan also reduced symptom scores during hypoglycemia (P <.05). We conclude that short-term treatment with losartan slightly attenuates symptomatic and hormonal responses to hypoglycemia. At present, for patients who are unaware of hypoglycemia and who require antihypertensive or nephroprotective treatment, we would recommend caution concerning treatment with losartan.

Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans

Losartan attenuates symptomatic and hormonal responses to hypoglycemia in humans

Ethnicity influences morphine pharmacokinetics and pharmacodynamics

Our objective was to evaluate ethnic differences in response to morphine and to determine whether any detectable differences were pharmacokinetically based. This cohort study was carried out in a teaching hospital. Sixty-six young, healthy male subjects from 3 ethnic groups (Caucasians, native Indians, and Latinos; n = 22 in each group) consented to participate. All subjects received an intravenous morphine bolus of 0.08 mg/kg followed by 0.002 mg/kg. min infused for 30 minutes. Respiratory response was evaluated with the carbon dioxide rebreathing method before and at 25, 95, 180, and 360 minutes after morphine administration. Vital signs and opioid side effects were recorded, and serial blood samples were analyzed for morphine, morphine-3-glucuronide, and morphine-6-glucuronide (M6G). All 3 groups had suppression of the ventilatory response to hypercapnia, but the degree of blunting of the ventilatory response differed among groups. Compared with Caucasians, native Indians had an additional 18% reduction in ventilatory response after morphine administration (95% confidence interval, -35% to -2%). The incidence of side effects was similar in all groups (P =.18). Caucasians had higher plasma levels of M6G than did native Indians or Latinos. M6G areas under 6-hour concentration-versus-time curve were as follows: Caucasians, 12,065 +/- 4354; native Indians, 8464 +/- 4809; and Latinos, 9156 +/- 3764 ng. min/mL (P =.03). Ethnicity influences the response to morphine. Native Indians are more susceptible to morphine depression of the ventilatory response than Caucasians, despite the higher serum M6G levels in Caucasians.

Oral Glucose Augments the Counterregulatory Hormone Response during Insulin-Induced Hypoglycemia in Humans

Oral Glucose Augments the Counterregulatory Hormone Response during Insulin-Induced Hypoglycemia in Humans

Renal substrate metabolism and gluconeogenesis during hypoglycemia in humans.

To examine the potential contribution of precursor substrates to renal gluconeogenesis during hypoglycemia, 14 healthy subjects had arterialized hand vein and renal vein (under fluoroscopy) catheterized after an overnight fast. Net renal balance of lactate, glycerol, alanine, and glutamine was determined simultaneously with systemic and renal glucose kinetics using arteriovenous concentration differences and 6-[2H2]glucose tracer dilution. Renal plasma flow was measured by para-aminohippurate clearance and was converted to blood flow using the mathematical value (1-hematocrit). Arterial and renal vein samples were obtained in the postabsorptive state and during a 180-min hyperinsulinemic period during either euglycemia or hypoglycemia. Insulin increased from 49 +/- 14 to 130 +/- 25 pmol/l (hypoglycemia) and to 102 +/- 10 pmol/l (euglycemia). Arterial blood glucose decreased from 4.5 +/-0.2 to 3.0 +/- 0.1 mmol/l during hypoglycemia but did not change during euglycemia (4.3 +/- 0.2 mmol/l). After 150 min, endogenous glucose production reached a plateau value that was higher during hypoglycemia (10.3 +/0.6 micromol x kg(-1) x min(-1)) than during euglycemia (5.73 +/-0.6 micromol x kg(-1) x min(-1), P < 0.001). Hypoglycemia was associated with a rise in renal glucose production (RGP) from 3.0 +/- 0.7 to 5.4 +/- 0.6 micromol x kg(-1) x min(-1) (P < 0.05), although glucose utilization remained the same (2.0 +/- 0.8 vs. 2.1 +/-0.6 micromol x kg(-1) x min(-1)). As a result, net renal glucose output increased from 1.0 +/- 0.3 to 3.3 +/- 0.40 micromol x kg(-1) x min(-1). Elevations in net renal uptake of lactate (2.4 +/- 0.5 to 3.5 +/- 0.7 vs. 2.8 +/- 0.4 micromol x kg(-1) x min(-1)), glycerol (0.6 +/- 0.3 to 1.3 +/- 0.5 vs. 0.4 +/- 0.2 micromol x kg(-1) x min(-1)), and glutamine (0.7 +/- 0.2 to 1.1 +/- 0.3 vs. 0.1 +/- 0.3 micromol x kg(-1) x min(-1)) during hypoglycemia versus euglycemia (P < 0.05) could account for nearly 60% of all glucose carbons released in the renal vein during hypoglycemia. Our data indicate that extraction of circulating gluconeogenic precursors by the kidney is enhanced and responsible for a substantial fraction of the compensatory rise in RGP during sustained hypoglycemia. Increased renal gluconeogenesis from circulating substrates represents an additional physiological mechanism by which the decrease in blood glucose concentration is attenuated in humans.

Hormone-independent activation of EGP during hypoglycemia is absent in type 1 diabetes mellitus.

It has been suggested that insulin-induced suppression of endogenous glucose production (EGP) may be counteracted independently of increased epinephrine (Epi) or glucagon during moderate hypoglycemia. We examined EGP in nondiabetic (n = 12) and type 1 diabetic (DM1, n = 8) subjects while lowering plasma glucose (PG) from clamped euglycemia (5.6 mmol/l) to values just above the threshold for Epi and glucagon secretion (3.9 mmol/l). Individualized doses of insulin were infused to maintain euglycemia during pancreatic clamps by use of somatostatin (250 microg/h), glucagon (1.0 ng. kg(-1). min(-1)), and growth hormone (GH) (3.0 ng. kg(-1). min(-1)) infusions without need for exogenous glucose. Then, to achieve physiological hyperinsulinemia (HIns), insulin infusions were fixed at 20% above the rate previously determined for each subject. In nondiabetic subjects, PG was reduced from 5.4 +/- 0.1 mmol/l to 3.9 +/- 0.1 mmol/l in the experimental protocol, whereas it was held constant (5. 3 +/- 0.2 mmol/l and 5.5 mmol/l) in control studies. In the latter, EGP (estimated by [3-(3)H]glucose) fell to values 40% of basal (P < 0.01). In contrast, in the experimental protocol, at comparable HIns but with PG at 3.9 +/- 0.1 mmol/l, EGP was activated to values about twofold higher than in the euglycemic control (P < 0.01). In DM1 subjects, EGP failed to increase in the face of HIns and PG = 3.9 +/- 0.1 mmol/l. The decrease from basal EGP in DM1 subjects (4.4 +/- 1.0 micromol. kg(-1). min(-1)) was nearly twofold that in nondiabetics (2.5 +/- 0.8 micromol. kg(-1). min(-1), P < 0.02). When PG was lowered further to frank hypoglycemia ( approximately 3.1 mmol/l), the failure of EGP activation in DM1 subjects was even more profound but associated with a 50% lower plasma Epi response (P < 0. 02) compared with nondiabetics. We conclude that glucagon- or epinephrine-independent activation of EGP may accompany other counterregulatory mechanisms during mild hypoglycemia in humans and is impaired or absent in DM1.

Recovery of cognitive function and mood after severe hypoglycemia in adults with insulin-treated diabetes.

Acute hypoglycemia in humans impairs cognitive functions and alters mood states. The time required for cognitive functions and moods to return to normal after an acute episode of severe hypoglycemia is unknown. Cognitive functions and moods were studied prospectively in 20 subjects with insulin-treated diabetes who had recently experienced a spontaneous episode of severe hypoglycemia ("hypo" subjects) and 20 matched control subjects with insulin-treated diabetes who had not experienced severe hypoglycemia during the preceding year. The hypo subjects had a history of a greater number of episodes of severe hypoglycemia (P = 0.000). Cognitive function tests and mood scales were administered at 1.5, 9, and 30 days after the severe hypoglycemia and at similar intervals for the control subjects. For most of the cognitive tests, no evidence of a "hangover" effect of the acute hypoglycemia on cognitive function was observed (P > 0.05). A trend was noted for levels of hedonic tone (P = 0.082) and energetic arousal (P = 0.053) to improve with time in the hypo subjects but not in the control subjects. However, the hypo subjects had chronically elevated levels of depression (P = 0.011) and anxiety (P = 0.049) and persistently performed more poorly in several cognitive tests, such as the Digit Symbol Test (P = 0.009) and the Stroop Task (P = 0.007). These results suggest that, in general, recovery from any acute cognitive decrement after severe hypoglycemia was complete by 1.5 days. The cognitive decrements and altered mood states noted in the hypo subjects may be persistent and may be a consequence of previous exposure to recurrent episodes of severe hypoglycemia.

Transcutaneous glucose measurement using near-infrared spectroscopy during hypoglycemia.

To analyze a transcutaneous near-infrared spectroscopy system as a technique for in vivo noninvasive blood glucose monitoring during euglycemia and hypoglycemia. Ten nondiabetic subjects and two patients with type 1 diabetes were examined in a total of 27 studies. In each study, the subject's plasma glucose was lowered to a hypoglycemia level (approximately 55 mg/dl) followed by recovery to a glycemic level of approximately 115 mg/dl using an intravenous infusion of insulin and 20% dextrose. Plasma glucose levels were determined at 5-min intervals by standard glucose oxidase method and simultaneously by a near-infrared spectroscopic system. The plasma glucose measured by the standard method was used to create a calibration model that could predict glucose levels from the near-infrared spectral data. The two data sets were correlated during the decline and recovery in plasma glucose, within 10 mg/dl plasma glucose ranges, and were examined using the Clarke Error Grid Analysis. Two sets of 1,704 plasma glucose determinations were examined. The near-infrared predictions during the fall and recovery in plasma glucose were highly correlated (r = 0.96 and 0.95, respectively). When analyzed during 10 mg/dl plasma glucose segments, the mean absolute difference between the near-infrared spectroscopy method and the chemometric reference ranged from 3.3 to 4.4 mg/dl in the nondiabetic subjects and from 2.6 to 3.8 mg/dl in the patients with type 1 diabetes. Using the Error Grid Analysis, 97.7% of all the near-infrared predictions were assigned to the A-zone. Our findings suggest that the near-infrared spectroscopy method can accurately predict plasma glucose levels during euglycemia and hypoglycemia in humans.

Renal glucose production during insulin-induced hypoglycemia in humans.

We investigated the effects of hypoglycemia on renal glucose production (RGP) and renal glucose uptake (RGU) using arteriovenous balance combined with tracer technique in humans. Our 14 healthy subjects had arterialized hand veins (artery) and renal veins (under fluoroscopy) catheterized after an overnight fast. Systemic and renal glucose kinetics were measured with infusion of [6-(2)H2]glucose, and renal plasma flow was measured by para-aminohippurate clearance. After a 150-min equilibration period, artery and renal vein samples were obtained between -30 and 0 min, and subjects received a 180-min peripheral insulin infusion (0.250 mU kg(-1) x min(-1)) with a variable infusion of [6-(2)H2]dextrose adjusted to maintain plasma glucose at either approximately 60 mg/dl (hypoglycemic clamp) or approximately 90 mg/dl (euglycemic clamp). Blood samples were obtained between 150 and 180 min during the study period. Insulin increased from 49 +/- 14 to 130 +/- 25 (hypoglycemia) and to 102 +/- 10 (euglycemia) pmol/l. Glucose decreased from 5.32 +/- 0.11 to 3.58 +/- 0.07 micromol/ml during hypoglycemia, but it did not change during euglycemia (5.20 +/- 0.19 vs. 5.05 +/- 0.15 micromol/ml). Endogenous glucose production decreased (9.30 +/- 0.70 vs. 5.65 +/- 0.50) during euglycemia but not during hypoglycemia (9.80 +/- 0.50 vs. 10.25 +/- 0.60 micromol x kg(-1) x min(-1)). During hypoglycemia, net renal glucose output increased from 0.54 +/- 0.30 to 2.31 +/- 0.40, RGP increased from 1.88 +/- 0.70 to 3.65 +/- 0.50 (P < 0.05), and RGU did not change (1.34 +/- 0.50 vs. 1.34 +/- 0.60 micromol x kg(-1) x min(-1)). During euglycemia, renal glucose balance switched from a net output of 0.72 +/- 0.20 to a net uptake of 1.70 +/- 0.92, RGP decreased from 2.31 +/- 0.50 to 1.20 +/- 0.58, and RGU increased from 1.59 +/- 0.50 to 2.90 +/- 0.70 micromol x kg(-1) x min(-1) (P < 0.05). During hypoglycemia, arterial glucagon increased from 105 +/- 6 to 129 +/- 8, epinephrine increased from 116 +/- 28 to 331 +/- 33, norepinephrine increased from 171 +/- 9 to 272 +/- 9 (all P < 0.05), and renal vein norepinephrine increased from 236 +/- 13 to 426 +/- 50 (P < 0.001). These data indicate that, in addition to counterregulatory hormones, activation of the autonomic nervous system during hypoglycemia stimulates glucose production by the kidney, which may represent an important additional component of the body's defense against hypoglycemia in humans.

A comparative study of glucose meter accuracy during biochemical hypoglycaemia in humans

AbstractFour glucose meters (Medi Sense Pen 2, Boehringer Mannheim Reflolux‐S and Mini‐Accutrend, and Lifescan One Touch II) were compared with laboratory glucose estimation during hypoglycaemia in human subjects. During hypoglycaemia the bias was −0.15 ± 0.6mmol/L (bias ±95% confidence interval) for the Medi Sense Pen 2, +0.2 ±0.6 mmol/L for the Reflolux‐S, −0.4 ±1.6 mmol/L for the Mini‐Accutrend, and −0.1 ±1.0 mmol/L for the One Touch II, giving limits of agreement of −0.75 to +0.45 mmol/L, −0.4 to +0.8 mmol/L, −2.0 to +1.2 mmol/L and‐1.1 to +0.9 respectively. The precision of the reference method was ±0.1 mmol/L in the hypoglycaemic range. We conclude that none of the meters assessed were as accurate as laboratory glucose estimation but that the Medi Sense Pen 2 and Reflolux‐S may be useful in clinical practice to confirm the presence of biochemical hypoglycaemia.

Counterregulatory mechanisms to insulin-induced hypoglycemia in humans: relevance to the problem of intensive treatment of IDDM.

Hypoglycemia unawareness is a condition of decreased/absent perception of specific symptoms which normally inform the subject that plasma glucose is decreasing to dangerous levels resulting in neuroglycopenia. This syndrome is frequent in IDDM. In the absence of warning symptoms, IDDM patients cannot take any measure (e.g. eating) to prevent severe neuroglycopenia (unconsciousness). Because hypoglycemia unawareness is associated with impaired glucose counterregulation, especially reduced adrenaline responses, hypoglycemia unawareness is a risky condition for severe hypoglycemia. A number of studies in animals and humans indicate that hypoglycemia unawareness is largely, if not fully, secondary to recurrent or chronic hypoglycemia. Meticulous prevention of hypoglycemia in IDDM largely recovers the symptoms of hypoglycemia and the responses of adrenaline. It is important that diabetologists and IDDM patients are familiar with the syndrome of hypoglycemia unawareness and learn how to prevent/treat it in programs of intensive therapy. Intensive therapy aiming strictly at normoglycemia may increase the frequency of hypoglycemia and hypoglycemia unawareness. On the other hand, if intensive therapy is combined with a program of prevention of hypoglycemia, the percentage of HbA1c can be maintained long-term below 7.0% (i.e. below values risky for onset/progression of complications), and at the same time the frequency of hypoglycemia is very low. Under these conditions, IDDM patients maintain the awareness of warning symptoms and adrenaline response to hypoglycemia, a vital back-up system for the safety of intensive therapy of IDDM.

Introduction and commentary to: M.I. Mityushov (1954) "Conditioned reflex secretion of insulin".

Recent research on the role of classical conditioning in homeostatic regulation (Dworkin, 1993; Siegel, Krank & Hinson, 1987) has underscored the potential importance of the work of earlier Eastern-European work on physiological conditioning. The present article is a translation and discussion of a paper on blood glucose conditioning, first published in 1954 by the Russian physiologist M.I. Mityushov. Mityushov was able to demonstrate conditioned hypoglycemia in humans and dogs after using an injection procedure as the CS and intravenous glucose as the UCS. The translation is preceded by a general introduction and followed by a reanalysis and discussion of Mityushov's results.

Sensing hypoglycemia: the ventromedial hypothalamus.

Hypoglycemia as a limiting factor in the treatment of diabetes mellitus with insulin was apparent even before the hormone was administered to patients. A passage in a biography of Banting notes: ‘The pace picked up as Banting and Best began adjusting extract . . . On December 2, 1921 . . . the injections threw the longevity dog, number 27, into repeated convulsions. . . . It finally died, killed by the extract.’ (1). It is acknowledged that the organism has an intricate control mechanism to regulate glycemic levels within a narrow range; insulin as the hypoglycemic agent, and an array of mechanisms as a control against potentially fatal hypoglycemia. The central nervous system (CNS) plays a major role in sensing glucopenia and triggering hormone release during imminent hypoglycemia (2–4). As previous studies have demonstrated, selective perfusion of the cranial arteries with glucose abrogate counterregulation elicited by insulin-induced hypoglycemia, but hepatic glucoreceptors have also been reported to sense hypoglycemia and to activate the sympathoadrenal system (5). This mechanism is regarded to be secondary to the dominant role of the CNS. Several lines of evidence localize the specific region which is responsible for activation of counterregulatory mechanisms to the ventromedial hypothalamus (VMH): focal lesioning of this region abolishes the hormonal response to systemic hypoglycemia (6) and production of local hypoglycemia by perfusion of 2-deoxy-glucose into the VMH is able to trigger the release of counterregulatory hormones despite systemic normoglycemia (7). Alternatively one may ask: when peripheral hypoglycemia is induced by insulin, does continued supply of glucose to the VMH prevent the peripheral neurohumoral counterregulatory response? This question has been studied in a recent and most remarkable piece of work in which the authors were able to demonstrate the central role of the VMH in sensing and responding to hypoglycemia (8). Indeed, they showed that in awake rats, local perfusion of glucose to the VMH by a microdialysis technique blocks counterregulation during systemic hypoglycemia (8). Most of the counterregulatory responses were abrogated. At this point it is important to note that counterregulatory mechanisms normally come into play well before hypoglycemia ensues (4), such that it may be assumed that the VMH is usually active in physiologic situations. Glucagon – an important counterregulatory hormone – is an exception since it appears to be regulated normally regardless of the state of the VMH, suggesting that ambient glucose levels directly or indirectly regulate glucagon secretion independent of the above mentioned mechanisms. Let us now turn to the pathophysiology of hypoglycemia when it arises from prolonged fasting or strenuous exercise. During these situations circulating ketone bodies and lactate levels increase severalfold. In both situations certain signs and symptoms of hypoglycemia are diminished. In experimental situations, hyperketonemia and hyperlactacidemia lowered responses to hypoglycemia in humans (9–11). One of these studies reported that lactate infusions protect cerebral function during hypoglycemia suggesting a potential therapeutic application of lactate during hypoglycemia in patients with insulin overdosage (11). Another important finding of these studies is that, during glucopenia, ketone bodies and lactate can serve as an immediate energy substitute to the CNS. Future studies will reveal whether – similar to glucose – local infusion of ketone bodies and lactate to the VMH will abrogate the hormonal response to hypoglycemia. Moreover, the sensing at the molecular level of hypoglycemia and/or adequate alternative energy supplies to the brain remain to be investigated.

Importance of Catecholamines in Defense against Insulin Hypoglycemia in Humans

Publisher Summary The several differences in the counterregulatory mechanisms observed between the acute and the clinical model of hypoglycemia suggest that, in the clinical model, the secretion of epinephrine may play a much important counterregulatory role as compared with that envisaged on the basis of the acute hypoglycemia model. In this chapter, the contribution of the adrenergic mechanisms to counterregulation in an experimental model of prolonged hypoglycemia closely mimicking the clinical situation is reviewed. For this purpose, the pancreatic-adrenocortical-pituitary clamp, a technique that allows examining the role of a single counterregulatory hormone without confounding changes in the plasma concentrations of other hormones, is used. Catecholamines are found to contribute to human glucose counterregulation because an early phase of hypoglycemia throughout; they exert effects both at the liver and at the muscle level; their counterregulatory effects are not compensated by other hormones, in particular glucagon; thus, the failure of catecholamines to exert their effects in hypoglycemia, such as during α , β pharmacological blockade, results in severe hypoglycemia, despite increase in other counterregulatory hormones. Finally, catecholamines largely work during counterregulation via indirect mechanisms such as stimulation of lipolysis, which enhances gluconeogenesis and hepatic glucose production, and suppress oxidation and utilization of glucose.

Cognitive function during insulin-induced hypoglycemia in humans: short-term cerebral adaptation does not occur

Cognitive function during insulin-induced hypoglycemia in humans: short-term cerebral adaptation does not occur

Visual information processing during controlled hypoglycaemia in humans.

A general impairment of cognitive performance occurs during acute insulin-induced hypoglycaemia, but little objective evidence is available for disruption of more specific cognitive processes. The effect of controlled hypoglycaemia on the early stages of visual information processing and contrast sensitivity was examined in a homogeneous group of 20 nondiabetic human subjects. Hypoglycaemia caused a significant disruption in general cognitive performance as assessed by a digit symbol task (P < 0.001) and the trail making B task (P < 0.05). Hypoglycaemia also produced a highly significant deterioration in performance on all of the visual information processing tasks, namely inspection time (IT) (P = 0.01), visual change detection (VCD) (P < 0.005) and visual movement detection (VMD) (P < 0.005). A significant deterioration in contrast sensitivity was observed during hypoglycaemia (P < 0.005). In contrast, no significant effect of hypoglycaemia was demonstrated on standard clinical measures of visual acuity or stereoscopic vision. Thus, although hypoglycaemia caused no detectable deterioration in visual acuity as measured by Snellen-type tests, a marked deterioration occurred in the speed of visual information processing and in contrast sensitivity. As many decisions are made under conditions of limited perceptual time and low visual contrast (e.g. when driving), the disruptive effect of moderate insulin-induced hypoglycaemia on visual perception will have important practical implications in diabetic humans exposed to this metabolic stress. The present results are congruent with other evidence which shows that the early stages of visual information processing are susceptible to deterioration by general cerebral insults.

Autonomic Mediation of Glucagon Secretion During Insulin-Induced Hypoglycemia in Rhesus Monkeys

Autonomic activation mediates the majority of the increase of glucagon secretion during insulin-induced hypoglycemia in several species including dogs, mice, and rats. However, the role of the autonomic nervous system to increase glucagon during hypoglycemia in humans remains controversial, and investigations in nonhuman primates have not been previously conducted. The autonomic contribution to glucagon secretion during hypoglycemia in a nonhuman primate was examined by two independent pharmacological approaches. Glucagon responses to clamped insulin-induced hypoglycemia were compared in conscious rhesus monkeys in the presence or absence of ganglionic blockade with trimethaphan, or during combined muscarinic and adrenergic receptor blockade with atropine, propranolol, and tolazoline. Insulin-induced hypoglycemia (plasma glucose = 1.9 +/- 0.1 mmol/l) activated parasympathetic nerves to the pancreas as assessed by increased plasma pancreatic polypeptide (PP) levels (delta = 135.0 +/- 36.8 pmol/l, P < 0.01), produced sympathoadrenal activation as assessed by elevations of plasma epinephrine (EPI) (delta = 22.3 +/- 2.95 nmol/l, P < 0.0005) and norepinephrine (NE) (delta = 3.72 +/- 0.77 mmol/l, P < 0.0025) and increased plasma immunoreactive glucagon (IRG) (delta = 920 +/- 294 ng/l, P < 0.025). Nicotinic ganglionic blockade with trimethaphan prevented parasympathetic (deltaPP = 16.5 +/- 16.3 pmol/l, P < 0.01 vs. control) and sympathoadrenal (deltaEPI = 1.52 +/- 0.98 nmol/l; deltaNE = -0.62 +/- 0.24 mmol/l, both P < 0.0025 vs. control) activation during hypoglycemia and inhibited the IRG response by 70% (delta = 278 +/- 67 ng/l, P < 0.025 vs. control). Combined muscarinic and adrenergic receptor blockade reduced parasympathetic activation (deltaPP = 48.3 +/- 16.3 pmol/l, P < 0.01 vs. control) and inhibited the IRG response by a similar degree to ganglionic blockade (deltaIRG = 284 +/- 60 ng/l, P < 0.025 vs. control). These results demonstrate by two independent pharmacological approaches that autonomic activation makes a substantial contribution to increased glucagon secretion during hypoglycemia of approximately 2.0 mmol/l in a species of nonhuman primate.

Different effects of the serotonergic agonists buspirone and sumatriptan on the posterior pituitary hormonal responses to hypoglycemia in humans

The responses of serum oxytocin (OT) and vasopressin (AVP) to the serotonergic HT1A agonist buspirone (15 mg p.o.) or the HTD1 agonist sumatriptan (6 mg injected subcutaneously) were evaluated in 7 normal men either in basal conditions or during an insulin (0.15 iu/kg as an i.v. bolus) tolerance test (ITT). Neither buspirone nor sumatriptan administration modified the basal secretion of AVP and OT. Stimulation of 5HT-1D receptors with sumatriptan was unable to change neither AVP nor OT response to insulin-induced hypoglycemia. On the other hand, the pretreatment with the 5HT1A agonist buspirone significantly enhanced the OT response during hypoglycemia, without modifying the AVP rise. The results of this study suggest that serotonergic 5HT1A receptors may interact with hypoglycemia in the stimulation of OT, but not AVP secretion.

Atropine Inhibits the Increase in Gastric Emptying During Hypoglycemia in Humans

To study the effect of a cholinergic muscarinic blockade on the gastric emptying rate during insulin-induced hypoglycemia in healthy subjects. In eight healthy subjects, the rate of gastric emptying of an isotope-labeled meal was assessed by a scintigraphic technique during normoglycemia and hypoglycemia with simultaneous infusion of either atropine or saline. Blood glucose concentrations were controlled by an insulin-glucose clamp. The median time for emptying 50% of the liquid phase from the stomach (T50) was 24.9 min (range 13.9-120.0) during normoglycemia compared with 8.1 min (range 3.6-16.5) during hypoglycemia without atropine infusion (P = 0.0005). The T50 for the solid phase was 26.8 min (range 9.7-74.0) and 43.1 min (range 29-57.8), respectively (P = 0.007). During hypoglycemia with atropine infusion, T50 was 40.7 min (range 10.0-120.0) for the liquid phase and 111.4 min (range 38.9-120.0) for the solid phase, not statistically different from normoglycemic examinations. Cholinergic muscarinic blockade with atropine inhibits the increase in gastric emptying during hypoglycemia. Vagal activity seems to be an important determinant of gastric emptying during hypoglycemia.