Hormonal response to insulin-induced hypoglycemia in patients with Shy-Drager syndrome

We examined the response of plasma glucose concentration and glucose counterregulatory factors (eg, glucagon, epinephrine, growth hormone, cortisol, and norepinephrine) to insulin-induced hypoglycemia in four patients with Shy-Drager syndrome and in five control subjects to determine if glucose counterregulation occurred in the patients with sympathetic and parasympathetic nervous system defects. The recovery of plasma glucose from hypoglycemia in a slower phase in the patients appeared to be almost similar to that in the control subjects, along with the absence of an initial rapid recovery phase; that is, there was no significant difference in the plasma glucose levels observed at any point between the patients and the control subjects. Although the insulin-induced hypoglycemia in the control subjects provoked a rapid release of epinephrine, followed by an increase in the plasma glucagon, growth hormone, and cortisol levels, it did not cause a significant increase in any of the glucose counterregulatory factors in the patients. Our findings that the restoration of normoglycemia after insulin-induced hypoglycemia occurred despite no significant increase in the counterregulatory hormonal factors suggest that other glucose counterregulatory mechanisms (eg, increased glucose release from the liver by the intrinsic effect of hypoglycemia on the liver) than the hormonal glucose counterregulatory factors might play an important role in the recovery of plasma glucose from insulin-induced hypoglycemia in a state of chronic deficiency of hormonal factors.     

Responses of catecholamines and other counterregulatory hormones to insulin-induced hypoglycemia in totally pancreatectomized patients

Responses of glucagon, catecholamines, and other counterregulatory hormones to insulin-induced hypoglycemia were evaluated in five totally pancreatectomized patients and six normal subjects. In pancreatectomized patients, plasma glucagon, probably of gastric origin, did not change significantly during hypoglycemia. The responses of epinephrine and norepinephrine were delayed but adequate compared with those in normal subjects. The responses of cortisol and GH were almost as great as those in normal subjects. However, plasma glucose levels did not recover from hypoglycemia normally in these patients. These results suggest that glucagon responses are essential to recover from hypoglycemia and that neither epinephrine nor norepinephrine plays a crucial role in the recovery from acute insulin-induced hypoglycemia in totally pancreatectomized patients.     

Insulin counterregulatory hormones are ineffective in neonatal hyperinsulinemic hypoglycemia.

Insulin counterregulatory hormones play a major role in the maintenance of glucose homeostasis. To evaluate the hypothesis that the reported imprecise control of glucose production by insulin is mirrored by a corresponding lack of response to the various insulin counterregulatory hormones, 30 spontaneously delivered mixed-breed term lambs weighing 4.9 +/- 0.5 kg (mean +/- SD) were studied at 5.0 +/- 0.7 days after birth following administration of 100 microCi D-[6-(3)H2]glucose in 0.9% NaCl by the primed-constant infusion technique to measure glucose kinetics. Infusion of 2.0 mU kg(-1) x min(-1) insulin produced hyperinsulinemic hypoglycemia and was combined with 1.0 mg x kg(-1) x min(-1) somatostatin (SRIF) to block insulin, glucagon, and growth hormone release. Infusion of 2 ng x mg(-1) x min(-1) glucagon or 10 microg x kg(-1) x h(-1) growth hormone with SRIF and insulin isolated the glucagon or growth hormone effect, respectively. The addition of metyrapone blocked cortisol release. Controls received only the isotope. In toto, the data can be interpreted to suggest that insulin has a greater effect on glucose uptake than on glucose production, and that neither glucagon, growth hormone, nor cortisol appreciably influenced the endogenous glucose production rate (Rp) during hyperinsulinemic hypoglycemia. The imprecise effect of these insulin counterregulatory hormones on neonatal glucose production mirrors the previously documented imprecise control by insulin.     

Differential effects of insulin-induced hypoglycaemia on the plasma branched-chain and non-branched-chain amino acid concentrations in humans.

In order to determine plasma amino acid concentrations during a prolonged but moderate insulin-induced hypoglycaemia, six healthy volunteers received a constant subcutaneous insulin infusion (15 mU.m-2.min-1) over a 12 hour period. The plasma glucose concentrations decreased from 4.72 +/- 0.11 to 2.83 +/- 0.07 mM at 600 minutes and then remained stable over the last 120 minutes. Plasma counterregulatory hormones (glucagon, epinephrine, growth hormone and cortisol) increased significantly between 120 and 180 minutes. The plasma concentration of all the amino acids paralleled the decrease in plasma glucose. The branched chain amino acids decreased to a greater extent in the first part of the study (0-360 min) in comparison to the essential non-branched chain aminoacids (p < 0.01), then increased significantly with a peak at 600 minutes (p < 0.05 vs 360 min) despite stable hyperinsulinaemia. These results suggests that during prolonged but moderate hypoglycaemia the counterregulatory hormones are able to antagonize partially the effects of insulin on protein metabolism, analogous to their well-known anti-insulin effects on glucose and fatty acid metabolism.     

Effect of short-term glucose control on glycemic thresholds for epinephrine and hypoglycemic symptoms.

Hypoglycemia is the principal barrier to achieving target glucose goals in type 2 diabetes. The effect of short-term improvement in glycemic control on plasma glucose thresholds for symptomatic and hormonal responses to hypoglycemia in type 2 diabetes is not known. We hypothesized that the thresholds for these events would be increased by 1 wk of improved glycemic control in elderly patients with type 2 diabetes. Ten elderly patients with type 2 diabetes were admitted for an 8-d inpatient protocol. All subjects underwent insulin-induced hypoglycemia on days 2 (preglucose control) and 8 (postglucose control). Between days 2 and 8, subjects received intensive diabetes management to improve their glycemic control. Timed blood glucose profiles were obtained daily during the week before and during admission. Plasma glucose, counterregulatory hormones, and hypoglycemic symptoms were assessed at baseline and every 10 min during the hypoglycemic studies. Mean blood glucose concentrations were significantly reduced by intensive diabetes management from 9.8 +/- 3.7 mmol/liter to 7.7 +/- 3.3 mmol/liter (P < 0.001). The plasma glucose threshold for epinephrine release during insulin-induced hypoglycemia was significantly increased by intensive management from a glucose concentration of 3.7 +/- 0.5 mmol/liter at baseline to 3.1 +/- 0.3 mmol/liter after intensive management (P < 0.05). The plasma glucose threshold for hypoglycemic symptoms was also increased by intensive therapy from a glucose concentration of 5.3 +/- 1.2 to 3.3 +/- 0.6 mmol/liter (P = 0.003). These rapid changes may increase the risk for severe hypoglycemia in type 2 diabetes and limit the ability of physicians to rapidly correct hyperglycemia in elderly type 2 diabetes patients.     

Physiological concentrations of insulin augment pancreatic cancer cell proliferation and glucose utilization by activating MAP kinase, PI3 kinase and enhancing GLUT-1 expression

Pancreatic carcinoma is characterized by poor prognosis and lack of response to conventional therapy for reasons that are not clear. Because of the structural relationship between the exocrine and endocrine pancreas and high concentrations of islet hormones bathing pancreatic tissue, we hypothesized that pancreatic cancer cell proliferation and glucose utilization are regulated by pancreatic islet hormones, particularly insulin. Based on this, the effect of islet hormones on pancreatic cancer cells in vitro was investigated. Five pancreatic cancer cell lines, CD11, CD18, HPAF, PANC-1, and MiaPaCa2 were used to investigate the effect of islet hormones on cell proliferation, glucose utilization, and GLUT-1 expression. Insulin, but not somatostatin and glucagon, induced pancreatic cancer cell growth in a concentration- and time-dependent manner. At concentrations within the range of those in the intrapancreatic vasculature, insulin (10(-10)-10(-8) mol/L) markedly increased [3H]-thymidine incorporation. Insulin significantly enhanced glucose utilization of pancreatic cancer cells before it enhanced cell proliferation. The MAPK kinase inhibitor PD 098059 abolished insulin-stimulated DNA synthesis and partially reduced insulin-stimulated glucose uptake. In contrast, the PI3 kinase inhibitor wortmannin substantially inhibited insulin-induced glucose uptake and partially blocked thymidine incorporation. Furthermore, after 24-hour treatment with insulin, GLUT-I expression in pancreatic cancer cells was markedly increased, indicating that insulin enhances glucose utilization partly through increasing glucose transport. These findings suggest that insulin stimulates proliferation and glucose utilization in pancreatic cancer cells by two distinct pathways. Insulin augments DNA synthesis mainly by MAP kinase activation and glucose uptake mainly by PI3 kinase activation and enhancement of GLUT-I expression. High intrapancreatic concentrations of insulin are likely to play an important role in stimulating pancreatic cancer growth indirectly by increasing substrate availability as well as by direct action as a trophic factor.     

Glucose counterregulation in Type 2 diabetes mellitus.

Glucose counterregulatory failure and hypoglycaemia unawareness frequently complicate treatment of Type 1 diabetes mellitus, especially when aiming for intensive metabolic control. Since tight metabolic control reduces microvascular long-term complications in Type 2 diabetes mellitus, the integrity of glucose counterregulation in Type 2 diabetic patients is important. Using a Medline search, we identified 12 studies in which counterregulatory responses to insulin-induced hypoglycaemia were compared between Type 2 diabetic patients and appropriate controls. A review of these studies showed that some patients with Type 2 diabetes mellitus develop mild counterregulatory dysfunction and reduced awareness of insulin-induced hypoglycaemia. Some studies suggested an association between counterregulatory impairment and intensity of metabolic control. We speculate that the relatively low frequency of (severe) hypoglycaemic events in Type 2 diabetes may explain why glucose counterregulation remains unaffected in most patients. We hypothesize that residual beta-cell reserve and insulin resistance provide protection against severe hypoglycaemia and limit impaired counterregulation. Diabet. Med. 18, 519-527 (2001)     

Counterregulatory response to insulin-induced hypoglycemia in trained and nontrained humans

The aim of the present series of experiments was to investigate the hormonal counterregulatory response to insulin-induced hypoglycemia in trained and nontrained healthy individuals. Five endurance athletes and six controls were administered intravenous insulin infusion at a rate of 0.15 U/kg/h until plasma glucose reached 50 mg/dL. The mean duration of the infusion in the trained and nontrained subjects corresponded to 18.6 and 26.3 minutes (P less than .01), suggesting that the former were characterized by an increased insulin sensitivity. Plasma glucose levels were similar in the two groups at the end of the insulin infusion, as well as during the postinfusion recovery period. Forty-five minutes after the end of the infusion, plasma glucose levels were not significantly different from the preinfusion levels in the two groups. During this period of glycemia recovery, the increases in plasma glucagon, epinephrine, norepinephrine, and growth hormone were at least 50% lower in the trained than in the nontrained subjects. The increase in heart rate and oxygen uptake during the same period of time was significantly higher in the trained subjects. To determine whether this reduced hormonal response to hypoglycemia was due to reduced insulin levels or to an increased sensitivity to counterregulatory hormones, we investigated the effect of epinephrine on plasma glucose in two other groups of trained and nontrained subjects. In response to a constant epinephrine infusion of 0.01 or 0.1 micrograms/kg fat-free mass (FFM)/min, plasma glucose levels increased similarly in the two groups. In conclusion, these results indicate that trained subjects are characterized by a normal recovery from hypoglycemia despite a reduced response of counterregulatory factors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Aggravation of hypoglycemia in insulinoma patients by the long-acting somatostatin analogue octreotide (Sandostatin)

Recently somatostatin analogues were successfully used to control insulin-induced hypoglycemia in patients with insulinoma. We observed a transient decrease in glucose levels and symptomatic hypoglycemia after administration of the long-acting somatostatin-analogue octreotide (Sandostatin) in two insulinoma patients. We studied the acute effects of octreotide (administered before breakfast) on blood glucose and gluco-regulatory hormones in these patients. In one patient, we studied the effects of glucagon replacement and changing the time of breakfast (relative to octreotide administration) on octreotide-associated changes in blood glucose and glucoregulatory hormones. Compared with control levels, octreotide therapy reduced insulin levels. During hypoglycemia glucagon and growth hormone levels were suppressed, but cortisol levels appropriately increased. The increase in catecholamine levels was normal in one patient, but markedly attenuated in the other. A transient decrease in serum glucose after octreotide was absent after glucagon replacement, but present when breakfast was taken before administration of octreotide. We conclude that in patients with insulinoma, octreotide therapy may be associated with clinically important hypoglycemia, during which counterregulatory hormone secretion may be attenuated.     

Effect of acute and recurrent hypoglycemia on changes in brain glycogen concentration

Our objective was to evaluate whether excessive brain glycogen deposition might follow episodes of acute hypoglycemia (AH) and thus play a role in the hypoglycemia-associated autonomic failure seen in diabetic patients receiving intensive insulin treatment. We determined brain glucose and glycogen recovery kinetics after AH and recurrent hypoglycemia (RH), an established animal model of counterregulatory failure. A single bout of insulin-induced AH or RH for 3 consecutive days was used to deplete brain glucose and glycogen stores in rats. After microwave fixation and glycogen extraction, regional recovery kinetics in the brain was determined using a biochemical assay. Both AH and RH treatments reduced glycogen levels in the cerebellum, cortex, and hypothalamus from control levels of 7.78 +/- 0.55, 5.4 +/- 0.38, and 4.45 +/- 0.37 micromol/g, respectively, to approximately 50% corresponding to a net glycogen utilization rate between 0.6 and 1.2 micromol/g.h. After hypoglycemia, glycogen levels returned to baseline within 6 h in both the AH and the RH group. However, recovery of brain glycogen tended to be faster in rats exposed to RH. This effect followed more rapid recovery of brain glucose levels in the RH group, despite similar blood glucose levels in both groups. There was no statistically significant increase above baseline glycogen levels in either group. In particular, brain glycogen was not increased 24 h after the last of recurrent episodes of hypoglycemia, when a significant counterregulatory defect could be documented during a hyperinsulinemic hypoglycemic clamp study. We conclude that glycogen supercompensation is not a major contributory factor to the pathogenesis of hypoglycemia-associated autonomic failure.     

Primary role of glucagon release in the effect of beta-endorphin on glucose homeostasis in normal man

The present study aimed at evaluating the effect of human beta-endorphin on pancreatic hormone levels and on glucose metabolism in normal subjects. Infusion of 143 nmol/h beta-endorphin in 7 subjects caused a significant rise in plasma glucose concentrations (+ 1.7 +/- 0.3 mmol/l) which was preceded by a significant increase in peripheral plasma glucagon levels (+ 44 +/- 13 ng/l). No changes occurred in the plasma concentrations of insulin and catecholamines (adrenaline and noradrenaline). The influence of beta-endorphin per se on glucose homeostasis was studied in 7 other subjects using the euglycaemic clamp technique in which the endocrine pancreatic function was fixed at its basal level with somatostatin together with replacement of basal insulin and glucagon by the exogenous infusion of these hormones. In this new metabolic conditions, beta-endorphin failed to have significant influences on the various parameters of tracer-estimated glucose metabolism (production, utilization, and clearance) and on the plasma levels of the gluconeogenic precursors (glycerol and alanine). Moreover, the levels of pancreatic and counterregulatory hormones (cortisol and catecholamines) were not different between beta-endorphin and control studies. We conclude that the naturally occurring opioid peptide beta-endorphin produced an hyperglycaemic effect in man which appears to be mediated by glucagon. The opioid seems to have no direct effect on glucose metabolism. These results suggest that the metabolic effects of beta-endorphin in normal man are secondary to its impact on pancreatic hormone secretion and not a consequence of a direct modulation of glucose metabolism.     

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.     

Recurrent hypoglycemia increases hypothalamic glucose phosphorylation activity in rats

The mechanisms underpinning impaired defensive counterregulatory responses to hypoglycemia that develop in some people with diabetes who suffer recurrent episodes of hypoglycemia are unknown. Previous work examining whether this is a consequence of increased glucose delivery to the hypothalamus, postulated to be the major hypoglycemia-sensing region, has been inconclusive. Here, we hypothesized instead that increased hypothalamic glucose phosphorylation, the first committed intracellular step in glucose metabolism, might develop following exposure to hypoglycemia. We anticipated that this adaptation might tend to preserve glucose flux during hypoglycemia, thus reducing detection of a falling glucose. We first validated a model of recurrent hypoglycemia in chronically catheterized (right jugular vein) rats receiving daily injections of insulin. We confirmed that this model of recurrent insulin-induced hypoglycemia results in impaired counterregulation, with responses of the key counterregulatory hormone, epinephrine, being suppressed significantly and progressively from the first day to the fourth day of insulin-induced hypoglycemia. In another cohort, we investigated the changes in brain glucose phosphorylation activity over 4 days of recurrent insulin-induced hypoglycemia. In keeping with our hypothesis, we found that recurrent hypoglycemia markedly and significantly increased hypothalamic glucose phosphorylation activity in a day-dependent fashion, with day 4 values 2.8 ± 0.6-fold higher than day 1 (P < .05), whereas there was no change in glucose phosphorylation activity in brain stem and frontal cortex. These findings suggest that the hypothalamus may adapt to recurrent hypoglycemia by increasing glucose phosphorylation; and we speculate that this metabolic adaptation may contribute, at least partly, to hypoglycemia-induced counterregulatory failure.     

Opiate modulation of glucose turnover in dogs

We examined the effect of opiate infusion and of opiate blockage on glucose turnover in the basal state, using isotope dilution techniques in trained conscious dogs (n = 5). After a primed-continuous infusion of 3-3H glucose to steady state specific activity (90 minutes), infusion of one of the following was given: D-met2 pro5 enkephalinamide (DMPE), a potent morphine-like opiate, 0.5 mus g/kg/min; naloxone, an opiate antagonist, 1.25 mg followed by 10 mus g/min; or saline control. Infusion of DMPE led to a fall in glucose from 92 +/- 3 to 87 +/- 3 mg/dL by 60 minutes (P less than 0.05), associated with a rise in glucose utilization (Rd) from 3.0 +/- 0.4 to 3.9 +/- 0.6 mg/kg/min by 30 minutes (P less than 0.05); a transient rise in glucose production (Ra; from 3.2 +/- 0.4 to 4.3 +/- 0.4 mg/kg/min; P less than 0.05). Changes in counterregulatory hormones did not account for these findings; insulin was unchanged during all infusions; glucagon showed small late rises at 75 minutes during both DMPE and naloxone infusion; cortisol rose by 30 and 15 minutes, respectively, of DMPE and naloxone infusion; epinephrine rose transiently after 5 minutes of naloxone but was unchanged during DMPE, and norepinephrine was unchanged throughout. Saline infusion had no effects on any of these indices. We conclude that a potent opiate with morphine-like effects (DMPE) can lower glucose in dogs by enhancing peripheral glucose utilization independently of hormonal changes.     

Beta blockade and diabetes mellitus: effect of oxprenolol and metoprolol on the metabolic, cardiovascular, and hormonal response to insulin-induced hypoglycemia in normal subjects

In a double-blind randomized study, the effect of the acute administration of a single oral dose of oxprenolol, a nonselective beta-blocker, and of metoprolol, a beta 1 selective blocker, on insulin-induced hypoglycemia was tested in seven normal subjects. Neither of the drugs potentiated the hypoglycemic effect of insulin. The recovery from hypoglycemia was delayed by both blocking agents only in the late phases of the experimental observation. This effect could not be accounted for by suppression of release of the counterregulatory hormones glucagon or cortisol, but may be mediated by the inhibition of NEFA and gluconeogenic-substrate release in response to hypoglycemia. Both drugs blocked the hypoglycemia-induced tachycardia. Only oxprenolol raised diastolic blood pressure during hypoglycemia. Symptoms of hypoglycemia were not masked by either blocking agent, and sweating was enhanced and prolonged by both drugs. Thus, no clear-cut differences in the glycemic response to insulin-induced hypoglycemia were found between metoprolol and oxprenolol, but the drugs differed in their influence upon the blood pressure response to insulin-induced hypoglycemia.     

Counterregulation of insulin-induced hypoglycaemia in primary hypothyroidism

Hypothyroidism has been alleged to modulate insulin action and influence the secretion of growth hormone and catecholamines. We recently investigated the influence of hypothyroidism on glucose counter-regulatory capacity and the hormonal responses to insulin-induced hypoglycaemia in 6 patients with primary hypothyroidism (age 32-52 years, TSH-values 66-200 mU/l). Hypoglycaemia was induced in the hypothyroid state and again when the subjects were euthyroid. After an overnight fast a constant rate infusion of insulin (2.4 U/h) was given for 4 h. Glucose was measured every 15 min and insulin. C-peptide, glucagon, epinephrine, norepinephrine, growth hormone and cortisol every 30 min for 5 h. During insulin infusion somewhat higher concentrations of the hormone were obtained in the hypothyroid state and simultaneously glucose levels were 0.5 mmol/l lower. As expected, basal norepinephrine levels were higher in hypothyroidism. However, no increase in circulating norepinephrine during hypoglycaemia was registered in the two experiments. The responses of counterregulatory hormones showed an enhanced response of cortisol, similar responses of growth hormone and epinephrine while the glucagon response was paradoxically impaired. Our findings suggest that hypothyroidism alters insulin metabolism, and that the glucagon response to hypoglycaemia is impaired in this condition.     

Counterregulatory hormonal responses to hypoglycaemia in Type 1 (insulin-dependent) diabetes: evidence for diminished hypothalamic-pituitary hormonal secretion

Summary Acute insulin-induced hypoglycaemia in humans provokes autonomic neural activation and counterregulatory hormonal secretion mediated in part via hypothalamic stimulation. Many patients with Type 1 (insulin-dependent) diabetes have acquired deficiencies of counterregulatory hormonal release following hypoglycaemia. To study the integrity of the hypothalamic-pituitary and the sympatho-adrenal systems, the responses of pituitary hormones, beta-endorphin, glucagon and adrenaline to acute insulin-induced hypoglycaemia (0.2 units/kg) were examined in 16 patients with Type 1 diabetes who did not have autonomic neuropathy. To examine the effect of duration of diabetes these patients were subdivided into two groups (Group 1: 8 patients < 5 years duration; Group 2 8 patients>15 years duration) and were compared with 8 normal volunteers (Group 3). The severity and time of onset of hypoglycaemia were similar in all 3 groups, but mean blood glucose recovery was slower in the diabetic groups (p<0.01). The mean responses of glucagon, adrenaline, adrenocorticotrophic hormone, prolactin and beta-endorphin were similar in all 3 groups, but the mean responses of growth hormone were lower in both diabetic groups than in the normal group (p<0.05). The mean increments of glucagon and adrenaline in the diabetic groups were lower than the normal group, but these differences did not achieve significance; glucagon secretion was preserved in several diabetic patients irrespective of duration of disease. Various hormonal responses to hypoglycaemia were absent or diminished in individual diabetic patients, and multiple hormonal deficiencies could be implicated in delaying blood glucose recovery. The demonstration of subnormal secretion of adrenaline and pituitary hormones following hypoglycaemia in individual patients supports the concept that central (hypothalamic) activation of counterregulation may be diminished in Type 1 diabetes.     

Antecedent adrenaline attenuates the responsiveness to but not the release of counterregulatory hormones during subsequent hypoglycemia

Hypoglycemia unawareness is thought to be the consequence of recurrent hypoglycemia, yet the underlying mechanism is still incompletely understood. The aim of the present study was to determine the role of antecedent elevated adrenaline in the pathogenesis of hypoglycemia unawareness. Sixteen healthy volunteers (eight of either sex) participated in two experiments, performed in random order and at least 3 wk apart. During the morning, three consecutive doses of 0.04, 0.06, and 0.08 microg.kg(-1).min(-1) of adrenaline or matching placebo (normal saline) were infused for the total duration of 1 h. Three hours later, a hyperinsulinemic (360 pmol.m(-2).min(-1)) two-step hypoglycemic (5.0-3.5-2.5 mmol.liter(-1)) clamp study was performed. During hypoglycemia, hypoglycemic symptoms, counterregulatory hormones, cardiovascular responses, and cognitive function were monitored. Hypoglycemia induced similar responses of autonomic and neuroglycopenic symptoms, counterregulatory hormones, and lengthening in reaction time on the choice reaction time task, irrespective of antecedent infusions. However, prior adrenaline was associated with higher exogenous glucose requirements at hypoglycemic nadir (10.1 +/- 1.3 vs. 7.3 +/- 1.3 micromol.kg(-1).min(-1), P = 0.017), an attenuated hypoglycemia-induced fall in blood pressure (mean arterial pressure, -13 +/- 2 vs. -8 +/- 2 mm Hg, P = 0.006), and preserved cognitive function as assessed by the symbol digit test during hypoglycemia, when compared with prior placebo. We conclude that elevated adrenaline attenuates the responsiveness to, but not the release of counterregulatory hormones during subsequent hypoglycemia. As such, adrenaline's role in the development of hypoglycemia unawareness is limited.     

In vivo glucose utilization in rat tissues during the three phases of starvation

Three phases of starvation have been described from changes in protein and lipid utilization in birds and mammals. In the present study, tissue glucose utilization was measured in vivo during these three phases, using a 2-deoxy-[1-3H]glucose technique in the anesthetized rat. According to this technique, the term glucose utilization therefore refers to transport and phosphorylation of glucose in tissues, ie, whatever is the fate of glucose. Whole-body glucose turnover rate, which was determined by a continuous infusion of [3-3H]glucose, decreased by 40% during the first two days of starvation (phase 1); it did not change thereafter, neither in the protein-sparing phase 2 nor in phase 3, which is marked by an increase in net protein breakdown. Two days of starvation caused a marked decrease in the glucose utilization in skeletal muscles; this decrease was higher in oxidative muscles (65% in diaphragm, 66% in soleus) than in glycolytic muscles (31% in extensor digitorum longus, 34% in epitrochlearis). Glucose utilization also decreased in heart atria (75%), heart ventricles (93%), and white adipose tissue (54%); by contrast, there was a two-fold increase in glucose utilization in brown adipose tissue and no change in brain and skin. No variations were observed in glucose utilization in any of the tissues from phase 1 to phase 2. However, phase 3 was marked by a decrease in glucose utilization in extensor digitorum longus (45%), brown adipose tissue (76%), brain (29%), and skin (40%), whereas there was a 2.3- and 3.4-fold increase in glucose utilization in diaphragm and heart ventricles, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)     

Influence of duration of hypoglycemia on the hormonal counterregulatory response in normal subjects

Glucagon and epinephrine are the most important short term glucose counterregulatory hormones. The epinephrine response in patients with insulin-dependent diabetes mellitus is related to the level of glycemic control, but little is known about the factors influencing counterregulation in normal subjects. We, therefore, conducted hyperinsulinemic glucose clamp studies to examine the counterregulatory response to recurrent and prolonged mild hypoglycemia in normal women. Blood glucose was clamped for 20 min at 3.5 mmol/L. Thereafter, the subjects had their blood glucose maintained at 2.8 mmol/L for 90 min and on another occasion lowered to 2.8 mmol/L and raised to 3.5 mmol/L twice during the 90-min period. Continuous hypoglycemia produced augmented plasma glucagon, cortisol, and pancreatic polypeptide responses (all P less than 0.05) compared to these responses to recurrent hypoglycemia. Plasma GH increased, but the magnitude of the response was not altered by the duration of hypoglycemia. During the recurrent hypoglycemia study plasma epinephrine levels rose and fell in parallel with the fluctuations in blood glucose. The mean peak increase was similar [1.37 +/- 0.25 (+/- SE) nmol/L] to that during the continuous study (1.76 +/- 0.23 nmol/L). There was no change in plasma glucagon levels in response to hypoglycemia of less than 15-min duration. We conclude that 1) the duration of hypoglycemia influences the counterregulatory response, and 2) epinephrine release is under precise control and responds rapidly to fluctuations in blood glucose.