Effect Of Insulin-induced Hypoglycaemia Research Articles

Insulin-induced hypoglycaemia suppresses pulsatile luteinising hormone secretion and arcuate Kiss1 cell activation in female mice.

Stress suppresses pulsatile luteinising hormone (LH) secretion in a variety of species, although the mechanism underlying this inhibition of reproductive function remains unclear. Metabolic stress, particularly hypoglycaemia, is a clinically-relevant stress type that is modelled with bolus insulin injection (insulin-induced hypoglycaemia). The present study utilised ovariectomised C57BL/6 mice to test the hypothesis that acute hypoglycaemia suppresses pulsatile LH secretion via central mechanisms. Pulsatile LH secretion was measured in 90-minute sampling periods immediately prior to and following i.p. injection of saline or insulin. The secretion of LH was not altered over time in fed animals or acutely fasted (5hours) animals following an i.p. saline injection. By contrast, insulin elicited a robust suppression of pulsatile LH secretion in fasted animals, preventing LH pulses in five of six mice. To identify the neuroendocrine site of impairment, a kisspeptin challenge was performed in saline or insulin pre-treated animals in a cross-over design. LH secretion in response to exogenous kisspeptin was not different between animals pre-treated with saline or insulin, indicating normal gonadotrophin-releasing hormone cell and pituitary responses during acute hypoglycaemia. Based on this finding, the effect of insulin-induced hypoglycaemia on arcuate kisspeptin (Kiss1) cell function was determined using c-Fos as a marker of neuronal activation. Insulin caused a significant suppression in the percentage of Kiss1 cells in the arcuate nucleus that contained c-Fos compared to saline-injected controls. Taken together, these data support the hypothesis that insulin-induced hypoglycaemia suppresses pulsatile LH secretion in the female mouse via predominantly central mechanisms, which culminates in the suppression of the arcuate Kiss1 population.

The Effect of Insulin-induced Hypoglycaemia on Gut-derived Glucagon Secretion (Px-Hypo)

The Effect of Insulin-induced Hypoglycaemia on Gut-derived Glucagon Secretion (Px-Hypo)

Effect of insulin-induced hypoglycaemia on the peripheral nervous system: focus on adaptive mechanisms, pathogenesis and histopathological changes.

Insulin-induced hypoglycaemia (IIH) is a common acute side effect in type 1 and type 2 diabetic patients, especially during intensive insulin therapy. The peripheral nervous system (PNS) depends on glucose as its primary energy source during normoglycaemia and, consequently, it may be particularly susceptible to IIH damage. Possible mechanisms for adaption of the PNS to IIH include increased glucose uptake, utilisation of alternative energy substrates and the use of Schwann cell glycogen as a local glucose reserve. However, these potential adaptive mechanisms become insufficient when the hypoglycaemic state exceeds a certain level of severity and duration, resulting in a sensory-motor neuropathy with associated skeletal muscle atrophy. Large myelinated motor fibres appear to be particularly vulnerable. Thus, although the PNS is not an obligate glucose consumer, as is the brain, it appears to be more prone to IIH than the central nervous system when hypoglycaemia is not severe (blood glucose level ≤ 2 mm), possibly reflecting a preferential protection of the brain during periods of inadequate glucose availability. With a primary focus on evidence from experimental animal studies investigating nondiabetic IIH, the present review discusses the effect of IIH on the PNS with a focus on adaptive mechanisms, pathogenesis and histological changes.

Effect of insulin-induced hypoglycaemia on secretion patterns and rates of corticotrophin-releasing hormone, arginine vasopressin and adrenocorticotrophin in horses.

To study the effect of hypoglycaemia on secretion rates of corticotrophin-releasing hormone (CRH), arginine vasopressin (AVP) and ACTH in a non-ruminant species, a non-surgical method was used to collect pituitary venous (PitVen) blood every 0.5 or 1 min from seven horses before and after insulin administration (0.4 U/kg i.v.). To assess the effect of PitVen cannulation on results, peripheral hormones were also measured before and after insulin in five horses without PitVen cannulae. Insulin administration lowered plasma glucose in all horses (P < 0.0001; paired t-test). Cortisol concentrations, which were similar in horses with and without PitVen cannulae before insulin, rose significantly after insulin administration in both groups. Most horses showed discomfort as glucose fell. When data from horses with and without PitVen cannulae were pooled, the peak fractional change in cortisol (Spearman's rank correlation coefficient (rs) = -0.94, P < 0.001) and the severity of hypoglycaemic symptoms (rs = -0.61, P < 0.02) were inversely ranked with the glucose nadir. In horses with PitVen cannulae, insulin administration increased secretion rates of ACTH (P < 0.0001), AVP (P < 0.0001) and CRH (P < 0.02). Increments in ACTH (rs = -0.96, P < 0.005) and CRH (rs = -0.81, P < 0.05), but not in AVP, measured during the second half-hour after insulin (i.e. the peak response), were inversely ranked with the glucose nadir. Moreover, ACTH increments were positively ranked with those in CRH (rs = 0.81, P < 0.05), but not in AVP. Nevertheless, in individual horses, minute-to-minute AVP and ACTH concentrations in PitVen blood were always correlated, whereas minute-to-minute CRH and ACTH concentrations were correlated only when glucose dropped below 3.4 mmol/l. In less hypoglycaemic horses, ACTH secretion rose despite little or no change in CRH. We suggest that in horses AVP is the primary acute signal for ACTH release both before and during hypoglycaemia; however, the increasing magnitude of ACTH increments induced by greater degrees of hypoglycaemia is determined largely by selective CRH release, which then augments corticotroph responses to AVP.

The Effect of Insulin-Induced Hypoglycaemia on Factor VIII: C Concentrations and Thrombin Activity in Subjects with Type 1 (Insulin-Dependent) Diabetes

The effect of insulin-induced hypoglycaemia on plasma coagulant activity was studied in 11 subjects with well-controlled, uncomplicated type 1 diabetes. Thrombin generation was determined in plasma by a computer ex-vivo assisted chromogenic method and by the activated partial thromboplastin time (APTT). In addition, factor VIII:C, thrombin-antithrombin III (TAT) complex and fibrinopeptide A (FPA) levels were measured. Hypoglycaemia induced a rise in mean (SD) factor VIII:C concentrations from a baseline level of 1.13 (0.32) IU/ml to a peak 15 min after onset of symptoms and they remained increased at 90 min [1.54 (0.57) and 1.5 (0.54) IU/ml, p < 0.001 respectively]. A corresponding reduction in time to generate 50% maximal thrombin activity occurred from a pre-insulin value of 56 (6) s to a minimum reading of 46 (7) s at 15 min (p < 0.001) and remained low at 90 min [48 (6) s, p < 0.001]. APTT shortened from 43.3 (4.8) s to 40.1 (4.6) s at 30 min (p < 0.001) but did not fall below the normal range (37.6-42.7 s) and no significant changes in TAT or FPA levels were noted. Factor VIII:C correlated inversely with time to generate 50% maximal thrombin activity and APTT (r = -0.580, p < 0.001; r = -0.673, p < 0.001, n = 66, respectively). The results show that the rise in plasma factor VIII:C levels induced by hypoglycaemia is accompanied by accelerated rates of generation of thrombin in contact-activated plasma, though concentrations of FPA and TAT remain unchanged, although TAT complexes are not a sensitive marker of in vivo thrombin generation.

Serum beta-endorphin in non-dialysed and haemodialysed patients with chronic renal failure

Endogenous opioid peptides play an important role in the pathogenesis of uraemic syndrome. The effect of insulin-induced hypoglycaemia on serum beta-endorphin (BE) concentration was studied in 27 uraemic patients and in 14 healthy subjects. Despite elevated basal BE level, that correlated positively with serum creatinine, uraemic patients showed a normal BE secretory pattern. No differences were found between uraemic patients on conservative and those on haemodialysis treatment. The influence of haemodialysis treatment on BE secretion requires further investigations.

Hypoglycaemia increases the gastric emptying rate in patients with type 1 diabetes mellitus.

The effect of insulin-induced hypoglycaemia on the gastric emptying rate was studied in eight patients with Type 1 diabetes mellitus of short duration (1-5 years). Gastric emptying was studied using a scintigraphic technique. All patients were studied twice, both during euglycaemia and insulin-induced hypoglycaemia. The blood glucose concentration was adjusted with an insulin-glucose clamp technique. All patients were examined in a standardized way, undergoing the first examination during euglycaemia, with a blood glucose concentration of 4-7 mmol l-1, and the second during hypoglycaemia, with a mean blood glucose concentration of 1.9 +/- 0.3 mmol l-1 at the time of starting the gastric emptying study. During hypoglycaemia both the liquid and the solid gastric emptying rates were significantly increased compared to the rate during euglycaemia. The time to empty 50% of the radioactivity from the stomach for liquid was 48.5 +/- 9.8 min during euglycaemia, compared to 27.6 +/- 20.2 min during hypoglycaemia, p < 0.001. The time to empty 50% of the radioactivity from the stomach for solid food was 48.7 +/- 10.3 min and 23.2 +/- 15.9 min, respectively, p < 0.001. In conclusion, it appears that insulin-induced hypoglycaemia increases the gastric emptying rate in patients with Type 1 diabetes mellitus.

Effect of Insulin‐induced Hypoglycaemia on Absorption of Unmodified Insulin after Subcutaneous or Intramuscular Injection

The effect of insulin-induced hypoglycaemia on the absorption of iodine-125 labelled unmodified insulin (10 U) from thigh after subcutaneous or intramuscular injection was studied in eight immobilized, supine, normal subjects. Ultrasonic determination of the subcutaneous thickness was used to accurately localize the site for insulin injection. Insulin absorption was studied twice during hypoglycaemia or normoglycaemia in random order. Insulin absorption was similar after subcutaneous and intramuscular injections (residual activity at 5 h: SC 59.3 +/- 5.0 (+/- SE) %; IM 55.2 +/- 3.7%). Hypoglycaemia did not change the disappearance rate of iodine-125 insulin after either subcutaneous (55.0 +/- 4.4%) or intramuscular injection (52.6 +/- 5.7%), despite a plasma glucose nadir of 1.7 +/- 0.2 mmol I-1. In a controlled study under standardized conditions hypoglycaemia has no effect on insulin absorption rate.(ABSTRACT TRUNCATED AT 250 WORDS)

Insulin‐induced Hypoglycaemia and Absorption of Injected Insulin in Diabetic Patients

The effect of insulin-induced hypoglycaemia (soluble insulin 1 mU kg-1 min-1 IV) on the absorption of 125I-labelled soluble insulin (10 U SC) from thigh was studied in 10 insulin-treated Type 1 diabetic patients on a test and a control day. Disappearance of 125I was followed by external gamma counting. Adipose tissue blood flow was measured concomitantly using the 133Xe-clearance technique. Arterial plasma levels of glucose, insulin, adrenaline and noradrenaline were determined intermittently. Hypoglycaemia occurred at a glucose level of 2.2 +/- 0.1 (+/- SE) mmol l-1 after 58 +/- 6 min. Peak levels of adrenaline (6.44 +/- 1.62 nmol l-1) and noradrenaline (2.29 +/- 0.39 nmol l-1) were found 10 min later. During the 30-min period after onset of hypoglycaemia, adipose tissue blood flow increased 132 +/- 45% (p less than 0.05) but the disappearance rate of 125I-insulin was unchanged. Thus, insulin absorption was unaltered in connection with hypoglycaemia in Type 1 diabetic patients, in contrast to the depression previously reported in healthy subjects, despite similar increases in adipose tissue blood flow.

The effect of insulin-induced hypoglycaemia on gastrointestinal motility in man

The effect of insulin-induced hypoglycaemia on gastro-jejunal motility was studied in five, healthy, male subjects using tethered, pressure sensitive, radiotelemetry capsules. Thirty minutes after the intravenous injection of soluble insulin (0.15 unit/kg body weight), a significant reduction in blood glucose concentration (control: 5.26 +/- 0.19 SEM mmol/l; insulin: 1.48 +/- 0.44 mmol/l; P less than 0.001) was associated with a rise in heart rate (mean peak rise 29 +/- 8 beats/min, P less than 0.05), systolic arterial blood pressure (mean peak rise 28 +/- 4 mmHg, P less than 0.01) and plasma pancreatic polypeptide concentration (control: 20 +/- 7 pmol/l; insulin: 287 +/- 66 pmol/l; P less than 0.01). These events coincided with a short period of jejunal motor activity, which was not associated with gastric motor activity nor with raised plasma motilin concentrations. During the control study, there were no changes in blood glucose concentration, heart rate, arterial blood pressure or plasma pancreatic polypeptide concentrations, and there was no jejunal motor activity. The interval between successive gastric migrating motor complexes (MMC) was not significantly different in the insulin and control studies (control: median interval 110 min, range 108-148 min; insulin: median interval 124 min, range 115-125 min), suggesting that the fasting gastrojejunal MMC and jejunal motor activity arose independently. Insulin-induced hypoglycaemia is accompanied by jejunal motor activity, which may underlie the abdominal symptoms associated with hypoglycaemia.

Cerebral blood flow increases during insulin-induced hypoglycaemia in type 1 (insulin-dependent) diabetic patients and control subjects.

The effect of insulin-induced hypoglycaemia on cerebral blood flow was examined using the intravenous xenon-clearance technique in 9 patients with Type 1 (insulin-dependent) diabetes (aged 20 to 43 years) and 9 age-matched control subjects before, during and after hypoglycaemia. Cerebral blood flow rose in both groups. The mean basal cerebral flood flow values were not significantly different and during hypoglycaemia mean cerebral blood flow increased by 17% (p = 0.008) in the diabetic patients and by 21% (p = 0.0003) in the control subjects. The results suggest that in young diabetic patients without autonomic neuropathy or microangiopathy cerebral vessels dilate normally in response to hypoglycaemia. The physiological importance of an increase in cerebral blood flow during hypoglycaemia is uncertain; but glucose availability is increased.

The effect of insulin-induced hypoglycaemia on serum group I pepsinogens, serum gastrin, and plasma secretin and on gastric H+ and pepsin outputs.

The effect of insulin-induced hypoglycaemia on serum group I pepsinogens (PG I), serum gastrin, and plasma secretin, and on gastric H+ and pepsin secretion was studied on 2 consecutive days in six healthy male students. The hypoglycaemia elicited a significant rise in serum PG I on both days. Furthermore, an increase in basal serum PG I was noted from the first to the second day, with a further increase the third day. Serum gastrin, which was not significantly affected, nevertheless tended to peak immediately after the nadir of the blood glucose value. Plasma secretin, on the other hand, fell significantly during gastric suction before the injection of insulin on the second day and non-significantly on the first day. A further declining tendency in plasma secretin was observed after insulin injection. Gastric H+ and pepsin outputs increased significantly on both days. There was no significant difference in gastric H+ response on the 2 days, whereas peak gastric pepsin output was significantly reduced on the second day. It is concluded that the rise in serum PG I probably reflects an increased synthesis of pepsinogens and that the fall in peak gastric pepsin output on the second day may reflect reduced storage of pepsinogens in the chief cells.

Plasma cyclic nucleotide responses to insulin-induced hypoglycaemia and methacholine in patients with hyperthyroidism.

The effect of insulin-induced hypoglycaemia and methacholine on plasma cAMP and cGMP levels was studied in normal volunteers, hyperthyroid and hypothyroid patients. A significant positive correlation existed between the maximal increase in plasma cAMP and the maximal decrease in plasma glucose in normals during insulin-induced hypoglycaemia. Therefore, the plasma cAMP response is considered to be dependent on the degree of hypoglycaemia, rather than the dose of insulin. The cAMP response to hypoglycaemia was significantly higher in hyperthyroid patient, and was lower in patients with hypothyroidism than in normals. The cAMP response of the hyperthyroid patients was normalized when their hyperthyroidism was controlled after 3 months of treatment. The plasma level of cGMP was slightly elevated during hypoglycaemia, but there was no significant difference between controls and hyperthyroid patients. The cGMP response to methacholine, which is probably mediated by cholinergic receptors, was significantly potentiated in hyperthyroid patients. The cAMP response, which is presumably dependent on endogenous catecholamines secreted during methacholine-induced hypotension, was also enhanced in hyperthyroid patients. It is likely that beta-adrenergic receptor responses and cholinergic receptor responses are both enhanced in hyperthyroidism.

Stomach motility in insulin-treated sheep.

The effect of insulin-induced hypoglycaemia on the motility of the reticulum, rumen and abomasum of sheep was investigated using small lightly inflated balloons connected to transducers and a multichannel recorder. The principle response recorded was an inhibition of reticulo-ruminal and abomasal motility, occurring in 'resting' cycles only, and not during eating or rumination. The only hypermotility recorded was that shown by the abomasum just before the onset of inhibition. Ruminating cycles were recorded as frequently during hypoglycaemia as in control periods, and showed no abnormality. The inhibition was reversed by intravenous glucose or adrenaline and by feeding or ruminating.

Rapid Re-Synthesis of Catecholamines in the Dog's Adrenal Medulla during Insulin-Induced Hypoglycaemia

The effect of insulin-induced hypoglycaemia was investigated on adrenal medullary secretion and synthesis of catecholamines in the adrenal glands of dogs. Hypoglycaemia induced increased secretion and very rapid and abundant synthesis of catecholamine in the adrenal.