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Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

ABSTRACT: Aim:Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans. Methods:This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects were exposed to a 2nd HG clamp at 2 pm and discharged home in euglycaemia. They returned the following day for a 3rd HG clamp at 8 am. Results:Twenty-two subjects were enrolled. Eighteen subjects completed the entire protocol. The epinephrine response during clamp 3 (171 ± 247 pg/mL) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (538 ± 392 pg/mL) (clamp 3 to clamp 1 NAC: P = .0013). The symptom response during clamp 3 (7 ± 5) following clamp 1 NAC infusion was lower than the response during the clamp 1 NAC infusion (16 ± 10) (clamp 3 to clamp 1 NAC: P = .0003). Nine subjects experienced rash, pruritus or nausea during NAC infusion. Conclusion:We found no difference in the hormone and symptom response to experimental hypoglycaemia measured in subjects who were administered NAC as opposed to saline the day before. This observation suggests that further development of NAC as a therapy for impaired awareness of hypoglycaemia in patients with diabetes may be unwarranted.

SUBMITTER: Moheet A

PROVIDER: S-EPMC7375074 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

Moheet Amir A Kumar Anjali A Zhang Yuan Y Eberly Lynn L Coles Lisa D LD Seaquist Elizabeth R ER

Endocrinology, diabetes & metabolism 20200515 3

<h4>Aim</h4>Administration of N-acetyl cysteine (NAC) during hypoglycaemia will preserve the counterregulatory response to subsequent hypoglycaemia in healthy humans.<h4>Methods</h4>This was a randomized double-blind cross over study where humans were given either a 60-minute infusion of NAC (150 mg/kg) followed by a 4-hour infusion of NAC (50 mg/kg) or saline starting 30 minutes before the initiation of a 2-hour hypoglycaemic (HG) clamp at 8 am. After rest at euglycaemia for ~2 hours, subjects ...[more]

PMID: 32704565

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Project description:Aims/hypothesisThe aim of this study was to determine the mechanism(s) for hypoglycaemia occurring late following oral glucose loading in patients with cystic fibrosis (CF).MethodsA 3 h 75 g OGTT was performed in 27 non-diabetic adults with CF who were classified based on this test as experiencing hypoglycaemia (glucose <3.3 mmol/l with or without symptoms or glucose <3.9 mmol/l with symptoms, n = 14) or not (n = 13). Beta cell function, incretin (glucagon-like peptide-1 [GLP-1] and glucose-dependent insulinotropic peptide [GIP]) and counterregulatory hormone responses (glucagon, catecholamines, growth hormone and cortisol) were assessed.ResultsThe two groups did not differ in age, weight or BMI. There were more male participants and individuals with pancreatic exocrine insufficiency in the hypoglycaemia group. Fasting plasma glucose did not differ between the two groups (5.3 ± 0.16 vs 5.3 ± 0.10 mmol/l). Both fasting insulin (20.7 ± 2.9 vs 36.5 ± 4.8 pmol/l; p = 0.009) and C-peptide (0.38 ± 0.03 vs 0.56 ± 0.05 nmol/l; p = 0.002) were lower in those who experienced hypoglycaemia. Following glucose ingestion, glucose concentrations were significantly lower in the hypoglycaemia group from 135 min onwards, with a nadir of 3.2 ± 0.2 vs 4.8 ± 0.3 mmol/l at 180 min (p < 0.001). The test was terminated early in three participants because of a glucose level <2.5 mmol/l. Insulin and C-peptide concentrations were also lower in the hypoglycaemia group, while incretin hormone responses were not different. Modelling demonstrated that those experiencing hypoglycaemia were more insulin sensitive (439 ± 17.3 vs 398 ± 13.1 ml min-1 m-2, p = 0.074 based on values until 120 min [n = 14]; 512 ± 18.9 vs 438 ± 15.5 ml min-1 m-2, p = 0.006 based on values until 180 min [n = 11]). In line with their better insulin sensitivity, those experiencing hypoglycaemia had lower insulin secretion rates (ISRfasting: 50.8 ± 3.2 vs 74.0 ± 5.9 pmol min-1 m-2, p = 0.002; ISROGTT: 44.9 ± 5.0 vs 63.4 ± 5.2 nmol/m2, p = 0.018) and beta cell glucose sensitivity (47.4 ± 4.5 vs 79.2 ± 7.5 pmol min-1 m-2 [mmol/l]-1, p = 0.001). Despite the difference in glucose concentrations, there were no significant increases in glucagon, noradrenaline, cortisol or growth hormone levels. Adrenaline increased by only 66% and 61% above baseline at 165 and 180 min when glucose concentrations were 3.8 ± 0.2 and 3.2 ± 0.2 mmol/l, respectively.Conclusions/interpretationHypoglycaemia occurring late during an OGTT in people with CF was not associated with the expected counterregulatory hormone response, which may be a consequence of more advanced pancreatic dysfunction/destruction.

Project description:AimWe evaluated the efficacy of a novel brain permeable "metformin-like" AMP-activated protein kinase activator, R481, in regulating glucose homeostasis.Materials and methodsWe used glucose sensing hypothalamic GT1-7 neuronal cells and pancreatic αTC1.9 α-cells to examine the effect of R481 on AMPK pathway activation and cellular metabolism. Glucose tolerance tests and hyperinsulinemic-euglycemic and hypoglycemic clamps were used in Sprague-Dawley rats to assess insulin sensitivity and hypoglycemia counterregulation, respectively.ResultsIn vitro, we demonstrate that R481 increased AMPK phosphorylation in GT1-7 and αTC1.9 cells. In Sprague-Dawley rats, R481 increased peak glucose levels during a glucose tolerance test, without altering insulin levels or glucose clearance. The effect of R481 to raise peak glucose levels was attenuated by allosteric brain permeable AMPK inhibitor SBI-0206965. This effect was also completely abolished by blockade of the autonomic nervous system using hexamethonium. During hypoglycemic clamp studies, R481 treated animals had a significantly lower glucose infusion rate compared to vehicle treated controls. Peak plasma glucagon levels were significantly higher in R481 treated rats with no change to plasma adrenaline levels. In vitro, R481 did not alter glucagon release from αTC1.9 cells, but increased glycolysis. Non brain permeable AMPK activator R419 enhanced AMPK activity in vitro in neuronal cells but did not alter glucose excursion in vivo.ConclusionsThese data demonstrate that peripheral administration of the brain permeable "metformin-like" AMPK activator R481 increases blood glucose by activation of the autonomic nervous system and amplifies the glucagon response to hypoglycemia in rats. Taken together, our data suggest that R481 amplifies the counterregulatory response to hypoglycemia by a central rather than a direct effect on the pancreatic α-cell. These data provide proof-of-concept that central AMPK could be a target for future drug development for prevention of hypoglycemia in diabetes.

Project description:Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome and acute lung injury - conditions that closely resemble the signs and symptoms of COVID-19. Few mild and transient adverse events were reported in published randomised-controlled trials, indicating that NAC may be reasonably safe. These findings suggest that NAC may complement the management of COVID-19 infection, particularly when administered intravenously within an intensive care unit (ICU) environment. Verdict Current evidence suggests that N-Acetyl Cysteine (NAC) administration may help improve outcomes in people with acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) - conditions that closely resemble the signs and symptoms of COVID-19. In this rapid review, NAC was predominately administered intravenously to patients with ARDS or ALI, who were at risk of or requiring mechanical ventilation, and were admitted to a hospital intensive care unit. Findings indicated that NAC administration may assist in improving markers of inflammation or oxidation, systemic oxygenation, the need for / duration of ventilation, rate of patient recovery and clinical improvement score. The effects of NAC on patient length of stay, CT/x-ray images, mortality rate and pulmonary complications were inconclusive. Few mild and transient adverse events were noted, indicating that NAC may be safe for use in acute respiratory distress syndrome or acute lung injury. Based on the evidence identified, and the similar symptomatic profiles of ARDS/ALI and COVID-19, the findings suggest that NAC may be used to complement the management of COVID-19 infection within an acute care setting. The safety and efficacy of orally administered NAC for the management of milder forms of COVID-19 infection within the community setting, remains uncertain. The current research evidence suggests NAC warrants further research for acute respiratory viral infections, including COVID-19.

Project description:Aim/hypothesisThe physiological counterregulatory response to hypoglycaemia is reported to be organised hierarchically, with hormone responses usually preceding symptomatic awareness and autonomic responses preceding neuroglycopenic responses. To compare thresholds for activation of these responses more accurately between people with or without type 1 diabetes, we performed a systematic review on stepped hyperinsulinaemic-hypoglycaemic glucose clamps.MethodsA literature search in PubMed and EMBASE was conducted. We included articles published between 1980 and 2018 involving hyperinsulinaemic stepped hypoglycaemic glucose clamps among people with or without type 1 diabetes. Key exclusion criteria were as follows: data were previously published; other patient population; a clamp not the primary intervention; and an inadequate clamp description. Glycaemic thresholds for counterregulatory hormone and/or symptom responses to hypoglycaemia were estimated and compared using generalised logrank test for interval-censored data, where the intervals were either extracted directly or calculated from the data provided by the study. A glycaemic threshold was defined as the glucose level at which the response exceeded the 95% CI of the mean baseline measurement or euglycaemic control clamp. Because of the use of interval-censored data, we described thresholds using median and IQR.ResultsA total of 63 articles were included, whereof 37 papers included participants with type 1 diabetes (n=559; 67.4% male sex, aged 32.7±10.2 years, BMI 23.8±1.4 kg/m2) and 51 papers included participants without diabetes (n=733; 72.4% male sex, aged 31.1±9.2 years, BMI 23.6±1.1 kg/m2). Compared with non-diabetic control individuals, in people with type 1 diabetes, the median (IQR) glycaemic thresholds for adrenaline (3.8 [3.2-4.2] vs 3.4 [2.8-3.9 mmol/l]), noradrenaline (3.2 [3.2-3.7] vs 3.0 [2.8-3.1] mmol/l), cortisol (3.5 [3.2-4.2]) vs 2.8 [2.8-3.4] mmol/l) and growth hormone (3.8 [3.3-3.8] vs. 3.2 [3.0-3.3] mmol/l) all occurred at lower glucose levels in people with diabetes than in those without diabetes (all p≤0.01). Similarly, although both autonomic (median [IQR] 3.4 [3.4-3.4] vs 3.0 [2.8-3.4] mmol/l) and neuroglycopenic (median [IQR] 3.4 [2.8-N/A] vs 3.0 [3.0-3.1] mmol/l) symptom responses were elicited at lower glucose levels in people with type 1 diabetes, the thresholds for autonomic and neuroglycopenic symptoms did not differ for each individual subgroup.Conclusions/interpretationPeople with type 1 diabetes have glycaemic thresholds for counterregulatory hormone and symptom responses at lower glucose levels than people without diabetes. Autonomic and neuroglycopenic symptoms responses are generated at about similar levels of hypoglycaemia. There was a considerable variation in the methodology of the articles and the high insulin doses in most of the clamps may affect the counterregulatory responses.FundingThis article has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement no. 777460.RegistrationThis systematic review is registered in PROSPERO (CRD42019120083).

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Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

Publications

Infusion of N-acetyl cysteine during hypoglycaemia in humans does not preserve the counterregulatory response to subsequent hypoglycaemia.

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