Insulin-induced Hypoglycemia In Type Research Articles

Effects of Hypoglycemia on Circulating Stem and Progenitor Cells in Diabetic Patients.

Iatrogenic hypoglycemia is the most common acute diabetic complication, and it significantly increases morbidity. In people with diabetes, reduction in the levels of circulating stem and progenitor cells predicts adverse outcomes. To evaluate whether hypoglycemia in diabetes affects circulating stem cells and endothelial progenitor cells (EPCs). We performed an experimental hypoglycemia study (Study 1) and a case-control study (Study 2). Tertiary referral inpatient clinic. Type 1 diabetic patients (Study 1, n = 19); diabetic patients hospitalized for severe iatrogenic hypoglycemia, matched inpatient and outpatient controls (Study 2, n = 22/group). Type 1 diabetic patients underwent two in-hospital sessions of glucose monitoring during a breakfast meal with or without induction of hypoglycemia in random order. In Study 2, patients hospitalized for hypoglycemia and matched controls were compared. Circulating stem cells and EPCs were measured by flow cytometry based on the expression of CD34 and kinase insert domain receptor (KDR). In Study 1, the physiologic decline of CD34+KDR+ EPCs from 8 am to 2 pm was abolished by insulin-induced hypoglycemia in type 1 diabetic patients. In Study 2, diabetic patients hospitalized for severe iatrogenic hypoglycemia had significantly lower levels of CD34+ stem cells and CD34+KDR+ EPCs compared with diabetic inpatients or outpatient controls. In diabetic patients, a single mild hypoglycemic episode can compromise the physiologic EPC fluctuation, whereas severe hypoglycemia is associated with a marked reduction in stem cells and EPCs. These data provide a possible link between hypoglycemia and adverse outcomes of diabetes.

Comment on Rickels et al. Intranasal Glucagon for Treatment of Insulin-Induced Hypoglycemia in Adults With Type 1 Diabetes: A Randomized Crossover Noninferiority Study. Diabetes Care 2016;39:264–270

Rickels et al. (1) report the results of a randomized crossover noninferiority study, making the firm assertion that intranasal glucagon was highly effective in treating insulin-induced hypoglycemia in type 1 diabetes. Unfortunately, the methods described in their article fail to support such a strong claim. We have several concerns about their ambitious conclusion. First, because of the controlled and artificial environment, this was not an effectiveness but an efficacy trial. Testing effectiveness requires carrying out the comparison in a “real-world setting” of severe hypoglycemia. Second, the design of the study does not seem appropriate considering that the intention was to prove intranasal glucagon was clinically equivalent to …

Prevention of Insulin-Induced Hypoglycemia in Type 1 Diabetes with Predictive Low Glucose Management System.

Sensor-augmented pump therapy (SAPT) with algorithms to predict impending low blood glucose and suspend insulin delivery has the potential to reduce hypoglycemia exposure. The aim of this study was to determine whether predictive low glucose management (PLGM) system is effective in preventing insulin-induced hypoglycemia in controlled experiments. Two protocols were used to induce hypoglycemia in an in-clinic environment. (A) Insulin bolus: Insulin was administered as a manual bolus through the pump. (B) Increased basal insulin: Hypoglycemia was induced by increasing basal rates overnight to 180%. For both protocols, participants were randomized and studied on 2 separate days; a control day with SAPT alone and an intervention day with SAPT and PLGM activated. The predictive algorithm was programmed to suspend basal insulin infusion when sensor glucose was predicted to be <80 mg/dL in 30 min. The primary outcome was the requirement for hypoglycemia treatment (symptomatic hypoglycemia or plasma glucose <50 mg/dL) and was compared in both control and intervention arms. With insulin bolus, 24/28 participants required hypoglycemia treatment with SAPT alone compared to 5/28 participants when PLGM was activated (P ≤ 0.001). With increased basal rates, all the eight SAPT-alone participants required treatment for hypoglycemia compared to only one with SAPT and PLGM. There was no post pump-suspend hyperglycemia with insulin bolus (P = 0.4) or increased basal rates (P = 0.69) in participants with 2-h pump suspension on intervention days. SAPT with PLGM reduced the requirement for hypoglycemia treatment following insulin-induced hypoglycemia in an in-clinic setting.

Effect of the amino acid alanine on glucagon secretion in non-diabetic and type 1 diabetic subjects during hyperinsulinaemic euglycaemia, hypoglycaemia and post-hypoglycaemic hyperglycaemia

The aim of our study was to establish whether the well-known defective or absent secretion of glucagon in type 1 diabetes in response to hypoglycaemia is selective or includes lack of responses to other stimuli, such as amino acids. Responses of glucagon to hypoglycaemia were measured in eight patients with type 1 diabetes and six non-diabetic subjects during hyperinsulinaemic (insulin infusion 0.5 mU kg(-1) min(-1)) and eu-, hypo- and hyperglycaemic clamp studies (sequential steps of plasma glucose 5.0, 2.9, 5.0, 10 mmol/l). Subjects were studied on three randomised occasions with infusion of low- or high-dose alanine, or saline. With saline, glucagon increased in hypoglycaemia in non-diabetic subjects but not in diabetic subjects. Glucagon increased further with low-dose (181 +/- 16 ng l(-1) min(-1)) and high-dose alanine (238 +/- 20 ng l(-1) min(-1)) in non-diabetic subjects, but only with high-dose alanine in diabetic subjects (area under curve 112 +/- 5 ng l(-1) min(-1)). The alanine-induced glucagon increase in diabetic subjects paralleled the spontaneous glucagon response to hypoglycaemia in non-diabetic subjects not receiving alanine. The greater responses of glucagon to hypoglycaemia with alanine infusion were offset by recovery of eu- or hyperglycaemia. In type 1 diabetes, the usually deficient responses of glucagon to hypoglycaemia may improve after increasing the concentration of plasma amino acids. Amino acid-enhanced secretion of glucagon in response to hypoglycaemia remains under physiological control since it is regulated primarily by the ambient plasma glucose concentration. These findings might be relevant to improving counter-regulatory defences against insulin-induced hypoglycaemia in type 1 diabetes.

Effects of dipeptide administration on hypoglycaemic counterregulation in type 1 diabetes

To investigate if a dipeptide made of glutamine and alanine is able to contribute to the recovery from insulin-induced hypoglycaemia in type 1 diabetes. Fifteen adult type 1 patients were randomly assigned to study group (n=7): intravenous infusion of 20 g Dipeptiven in normal saline (i.e., 8 g alanine and 13 g glutamine), or control group (n=8): same infusion, normal saline only. A 150 min gradual hypoglycaemic hyperinsulinemic clamp was administered after 2 h of infusion. Counterregularory hormones, symptoms, and cognitive function (4 choice reaction test) were regularly measured during the study. Blood glucose and glucose infusion rates were similar in the 2 groups. Circulating levels of alanine and glutamine peaked at 90 min and remained elevated throughout the test. This was associated with significant differences in: glucagonemia 107 +/- 20 vs 58 +/- 8 pg/ml, and neuroglycopenic symptoms scores: 7 +/- 3 vs 18 +/- 13, at t 150 min, in study and control group, p<0.05. Dysautonomic symptoms, cognitive tests as well as epinephrine, norepinephrine, cortisol and growth hormone were similar between groups. Intravenous infusion of a dipeptide made of alanine and glutamine is capable to reactivate glucagon secretion during insulin-induced hypoglycaemia and to reduce hypoglycaemic symptoms.

Abnormal Arginine-Vasopressin Responses to Metoclopramide and Insulin-Induced Hypoglycemia in Type I Diabetes Mellitus

Alterations in the control of arginine-vasopressin (AVP) secretion have been described in type I diabetes mellitus. In order to gain a better insight into this problem, we examined whether insulin-dependent diabetics in good metabolic conditions and without diabetic complications had an abnormal AVP responsiveness to metoclopramide (MCP), an AVP-stimulating agent with a central site of action. In addition, we tested the AVP response to insulin-induced hypoglycemia in the same subjects. Twenty insulin-dependent diabetic men without neuropathy or other diabetic complications were divided into two groups according to the duration of their illness (10 patients who had been diabetic for less than 10 years, group 1, and 10 patients who had been diabetic for more than 10 years, group 2). Eleven age- and weight-matched normal men participated as controls. All groups were tested with MCP (20 mg in an intravenous bolus) and, on a different occasion, with insulin-induced (0.15 IU/kg) hypoglycemia. Experiments started after optimization of the metabolic status of the diabetic men by 3 days of treatment with continuous subcutaneous insulin infusion. Basal concentrations of AVP were similar in all groups (diabetics of group 1: 2.2 +/- 0.2 pmol/l, mean +/- SE; group 2: 2.3 +/- 0.2 pmol/l; normal controls: 2.2 +/- 0.2 pmol/l). Administration of MCP induced a striking elevation of plasma AVP levels in the normal controls and in the diabetic subjects of groups 1 and 2. All subjects showed a mean peak response at 15 min.(ABSTRACT TRUNCATED AT 250 WORDS)

Arginine Vasopressin and Oxytocin Responses to Insulin-Induced Hypoglycemia in Type 1 (Insulin-Dependent) Diabetes*

In normal humans, arginine vasopressin and oxytocin are released acutely from the posterior pituitary gland in response to hypoglycemia, and their release may assist counterregulation. The responses of these hormones to insulin-induced hypoglycemia were measured in 16 insulin-dependent diabetic patients with no autonomic neuropathy (8 patients who had been diabetic less than 5 yr and 8 patients who had been diabetic greater than 15 yr) and in 6 normal subjects. The time of the onset of hypoglycemia and the mean blood glucose nadirs were similar in all groups, but the blood glucose recovery was delayed in the diabetic patients. In the normal subjects plasma arginine vasopressin rose from a mean basal value of 0.4 +/- 0.2 (+/- SE) pmol/L to a maximum of 1.3 +/- 0.6 pmol/L, and plasma oxytocin rose from 0.7 +/- 0.1 pmol/L to a maximum of 1.2 +/- 0.2 pmol/L 30 min after the onset of hypoglycemia. The plasma arginine vasopressin and oxytocin concentrations after hypoglycemia were significantly higher in both of the diabetic groups compared with those in the normal group. Arginine vasopressin and oxytocin rose in all control subjects after hypoglycemia. The individual hormonal profiles in the diabetic patients were variable, with an exaggerated rise of oxytocin in some diabetic patients and no rise in others. The arginine vasopressin responses were exaggerated in all of the diabetic patients. There was no correlation between the hormonal responses and the duration of diabetes. The exaggerated plasma arginine vasopressin and oxytocin responses to hypoglycemia in diabetic patients may indicate the failure of a normal inhibitory mechanism which modulates hormonal secretion or a compensatory response to impaired glucose recovery.

Effect of ?a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus

Effect of ?a-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus

Effect of alpha 2-adrenoceptor antagonist on platelet activation during insulin-induced hypoglycaemia in type 2 (non-insulin-dependent) diabetes mellitus.

The role of epinephrine in platelet activation and the effect of an alpha 2-adrenoceptor antagonist, midaglizole, during insulin-induced hypoglycaemia in Type 2 (non-insulin-dependent) diabetes mellitus were examined. The action of midaglizole as a platelet alpha 2-antagonist was confirmed by in vitro studies using platelet-rich plasma and washed platelet suspension. Hypoglycaemia was induced by a bolus injection of short-acting insulin in 24 diabetic patients. They were divided into two groups, a control group (n = 12) and an alpha 2-group (n = 12), and midaglizole was administered orally 60 min before insulin injection in the latter. Blood glucose and plasma C-peptide levels were significantly decreased (p less than 0.005) by insulin injection in both groups. Counter-regulatory hormones, including epinephrine, and arginine vasopressin were similarly increased at the hypoglycaemic nadir compared with the levels at 0 min in both groups. Plasma beta-thromboglobulin was increased at the hypoglycaemic nadir (165.5 +/- 12.6 ng/ml) compared with the level at 0 min (121.0 +/- 11.5, p less than 0.005) in the control group, whereas no significant increase was demonstrated in the alpha 2-group. These results suggest that plasma epinephrine plays an important role in platelet activation during hypoglycaemia in Type 2 diabetes mellitus, and that the platelet activation is prevented by alpha 2-adrenoceptor antagonist.

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.

Effect of aging on growth hormone, ACTH and cortisol response to insulin-induced hypoglycemia in type I diabetes.

The influence of age on plasma growth hormone (GH) response to i.v. insulin (0.2 U/kg body weight) was evaluated in clinically stable type I (insulin-dependent) diabetics divided into four age groups (range 18.80 years). ACTH and cortisol were also assayed in two groups of diabetics under and over 50 years of age. A significant reduction with aging in GH response to insulin was observed. On the contrary, the glucose fall was similar in all the groups. ACTH and cortisol responses to insulin were slightly decreased in the older diabetics. Since insulin-induced hypoglycemia was similar in all the age groups, the progressive decline with aging in the GH response to insulin may be attributed to age-related changes of the pituitary gland. The data on ACTH and cortisol are less striking. Our data, as a whole, confirm that growth hormone response to insulin-induced glucose fall is not critical in acute glucose counterregulation in insulin-dependent diabetics. In fact, in spite of a 4-fold difference in GH levels, there was no difference in the 2-h glycemic course after 0.2 U/kg of i.v. insulin between young and aged patients. When a group of 26 type I diabetics with proliferative retinopathy was compared with a group of age-matched type I diabetics without retinopathy and with 30 age-matched normal subjects (injected i.v. with 0.1 U/kg body weight of insulin), no difference was found in GH response to insulin, indicating that GH hypersecretion is not a characteristic finding of diabetic retinopathy.

Plasma beta-thromboglobulin response to insulin-induced hypoglycemia in type I diabetic patients

Plasma beta-thromboglobulin response to insulin-induced hypoglycemia in type I diabetic patients

Plasma beta-thromboglobulin response to insulin-induced hypoglycemia in type I diabetic patients.

The effect of an insulin-induced hypoglycemia was examined in 14 type I diabetic patients. After an overnight blood glucose normalization, each patient received an additional intravenous bolus of 3 U regular insulin at 0900 h (time 0). Blood glucose was continuously recorded up to 180 min. Plasma samples were assayed for beta-thromboglobulin (beta TG, ng/ml), pancreatic glucagon (pg/ml), cortisol (microgram/dl), and growth hormone (ng/ml) 30 min before the insulin stress, at time 0, at blood glucose nadir, and at 180 min. The blood glucose fell from a baseline level of 85.0 +/- 3.2 mg/dl to a nadir value of 39.2 +/- 1.9 mg/dl (P less than 0.001) reached at an average time of 41.4 +/- 4.9 min. Plasma beta TG increased significantly (P less than 0.05) during the insulin stress: 93.4 +/- 23.7 ng/ml at nadir versus 42.5 +/- 5.9 at time 0. Plasma cortisol and growth hormone were significantly increased (P less than 0.02 and P less than 0.01) at nadir compared with time 0 values. Plasma pancreatic glucagon was higher at nadir than at time 0, but the difference was not significant. The present results indicate that in vivo platelet activation can be triggered by hypoglycemic episodes in insulin-treated diabetic patients.

Insulin-induced hypoglycemia in type I diabetics.

Insulin-induced hypoglycemia in type I diabetics.

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors

Important role of adrenergic mechanisms in acute glucose counterregulation following insulin-induced hypoglycemia in type I diabetes. Evidence for an effect mediated by beta-adrenoreceptors.

During hypoglycemia induced by an i.v. insulin infusion for 60 min, rates of plasma glucose (PG) decrease and recovery, PG nadir, and plasma counter-regulatory hormone and free fatty acid responses were studied in eight type I uncomplicated diabetic subjects and eight nondiabetic subjects. Each subject was tested three times at two different rates of insulin infusion (25 and 32 mU/m2/min): (1) during infusion of saline, (2) during infusion of phentolamine + propranolol (combined alpha, beta-blockade), and (3) during infusion of propranolol alone (isolated beta-blockade) for 150 min. At the time of the studies, the diabetic subjects had been made euglycemic by an overnight i.v. insulin infusion. During infusion of insulin (25 mU/m2/min) and saline, the rates of PG decrease and recovery were slower (P less than 0.01) and PG nadir was delayed in the diabetic subjects. Moreover, their plasma glucagon response was blunted while plasma epinephrine, norepinephrine, growth hormone, and cortisol responses were similar in both groups. Infusion of insulin at 32 mU/m2/min caused larger decreases in PG than had been observed when insulin was infused at 25 mU/m2/min. Plasma glucagon responses increased in the nondiabetic subjects (P less than 0.05) but not in the diabetic subjects. However, in the diabetic subjects, plasma epinephrine increased more than in the nondiabetic subjects (P less than 0.05). There was an inverse correlation between the individual plasma epinephrine responses and the plasma glucagon responses in the diabetic subjects (r = -0.72) but not in the nondiabetic subjects. Alpha, beta-adrenergic blockade decreased the plasma glucose nadir and impaired the rate at which normoglycemia was restored in the diabetic subjects (P less than 0.005 vs. saline) but not in the nondiabetic subjects. Plasma catecholamine and growth hormone responses were increased and plasma FFA recovery was suppressed in both groups (P less than 0.05 vs. saline), while the cortisol responses were unaltered. During isolated beta-adrenergic blockade, changes in plasma glucose, counterregulatory hormones and FFA were essentially identical to those observed during combined alpha, beta-adrenergic blockade in both groups except that the augmented plasma norepinephrine responses were no longer apparent. although epinephrine is not essential for prompt restoration of normoglycemia in normal man following insulin-induced hypoglycemia, it plays a major role in glucose counterregulation in diabetics who have an impaired glucagon secretion in response to hypoglycemia. These counterregulatory effects of epinephrine are mediated by beta-adrenoreceptors.

Transport of glucose from blood to brain.

Transport of glucose from blood to brain.