Basu, Ananda

New Findings What is the central question of this study? Hyperoxia blunts hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in carotid body‐resected patients; and (ii) carotid body‐resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. What is the main finding and its importance? Our data indicate that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, a relatively normal counterregulatory response to hypoglycaemia in carotid body‐resected patients highlights: (i) the potential for long‐term adaptations after carotid body resection; and (ii) the importance of redundant mechanisms in mediating hypoglycaemia counterregulation. Hyperoxia reduces hypoglycaemia counterregulation in healthy adults. We hypothesized that this effect is mediated by the carotid bodies and that: (i) hyperoxia would have no effect on hypoglycaemia counterregulation in patients with bilateral carotid body resection; and (ii) carotid body‐resected patients would exhibit an impaired counterregulatory response to hypoglycaemia. Five patients (three male and two female) with bilateral carotid body resection for glomus tumours underwent two 180 min hyperinsulinaemic, hypoglycaemic (∼3.3 mmol l−1) clamps separated by a minimum of 1 week and randomized to either normoxia (21% fractional inspired O2) or hyperoxia (100% fractional inspired O2). Ten healthy adults (seven male and three female) served as control subjects. Hypoglycaemia counterregulation in carotid body‐resected patients was not significantly altered by hyperoxia (area under the curve expressed as a percentage of the normoxic response: glucose infusion rate, 111 ± 10%; cortisol, 94 ± 6%; glucagon, 107 ± 7%; growth hormone, 92 ± 10%; adrenaline, 89 ± 26%; noradrenaline, 79 ± 15%; main effect of condition, P > 0.05). This is in contrast to previously published results from healthy adults. However, the counterregulatory responses to hypoglycaemia during normoxia were not impaired in carotid body‐resected patients when compared with control subjects (main effect of group, P > 0.05). Our data provide further corroborative evidence that the effect of hyperoxia on hypoglycaemic counterregulation is mediated by the carotid bodies. However, relatively normal counterregulatory responses to hypoglycaemia in carotid body‐resected patients highlight the importance of redundant mechanisms in mediating hypoglycaemia counterregulation.

Background and Objective: The premise of effective closed-loop insulin therapy for type 1 diabetes (T1D) relies on the accuracy of continuous interstitial fluid glucose sensing that represents the crucial afferent arm of such a system. An important determinant of sensor accuracy is the physiological time lag of glucose transport from the vascular to the interstitial space. The purpose of current studies was to determine the physiological time lag of glucose transport from the vascular to the abdominal subcutaneous interstitial space in T1D. Method: Four microdialysis catheters were inserted into the abdominal subcutaneous space in 6 T1D subjects under overnight fasted conditions. Plasma glucose was maintained at 113.7 ± 6.3 mg/dl using a continuous intravenous insulin infusion. After sequential intravenous bolus administrations of glucose isotopes, timed plasma and interstitial fluid samples were collected chronologically and analyzed for tracer enrichments. Results: We observed a median (range) time lag of tracer appearance (time to detection) into the interstitial space after intravenous bolus of 6.8 (4.8-9.8) minutes, with all participants having detectable values by 9.8 minutes. Conclusions: We conclude that in the overnight fasted state in T1D adults, the delay of glucose appearance from the vascular to the interstitial space is less than 10 minutes, thereby implying that this minimal physiological time lag should not be a major impediment to the development of an effective closed-loop control system for T1D.

This single-centre, 12-week, double-blind, placebo-controlled trial assessed how the human glucagon-like-peptide 1 analogue liraglutide impacted endothelial function in adult patients (n = 49) with type 2 diabetes and no overt cardiovascular disease. Patients were randomized to liraglutide, placebo or glimepiride. At baseline and Week 12, venous occlusion plethysmography was used to measure forearm blood flow (FBF) in response to acetylcholine (ACh) and sodium nitroprusside (SNP) before and after l-N G -monomethyl arginine (L-NMMA) infusion. At Week 12, ACh-mediated FBF increased with liraglutide and decreased with placebo; however, the between-treatment difference was not significant ( p = 0.055). Inhibition of ACh-mediated FBF after L-NMMA infusion increased with liraglutide and decreased with placebo; this between-treatment difference was also not significant ( p = 0.149). No change in FBF was observed with SNP. Liraglutide did not significantly impact endothelium-dependent vasodilation after 12 weeks; however, additional investigations looking at the effect of liraglutide on endothelial function in alternative vasculature and during the postprandial period are warranted.

Controlling meal-related glucose excursions continues to be a therapeutic challenge in diabetes mellitus. Mechanistic reasons for this need to be understood better to develop appropriate therapies. To investigate delayed gastric emptying effects on postprandial glucose turnover, insulin sensitivity, and β-cell responsivity and function, as a feasibility study prior to studying patients with type 1 diabetes, we used the triple tracer technique C-peptide and oral minimal model approach in healthy subjects. A single dose of 30 μg of pramlintide administered at the start of a mixed meal was used to delay gastric emptying rates. With delayed gastric emptying rates, peak rate of meal glucose appearance was delayed, and rate of endogenous glucose production (EGP) was lower. C-peptide and oral minimal models enabled the assessments of β-cell function, insulin sensitivity, and β-cell responsivity simultaneously. Delayed gastric emptying induced by pramlintide improved total insulin sensitivity and decreased total β-cell responsivity. However, β-cell function as measured by total disposition index did not change. The improved whole body insulin sensitivity coupled with lower rate of appearance of EGP with delayed gastric emptying provides experimental proof of the importance of evaluating pramlintide in artificial endocrine pancreas approaches to reduce postprandial blood glucose variability in patients with type 1 diabetes.

To provide an understanding of both the preclinical and clinical aspects of closed-loop artificial pancreas systems, we provide a discussion of this topic as part of this two-part Bench to Clinic narrative. Here, the Bench narrative provides an in-depth understanding of insulin-glucose-glucagon physiology in conditions that mimic the free-living situation to the extent possible in type 1 diabetes that will help refine and improve future closed-loop system algorithms. In the Clinic narrative, Doyle and colleagues compare and evaluate technology used in current closed-loop studies to gain further momentum toward outpatient trials and eventual approval for widespread use.

Muscle microvascular surface area determines substrate and hormonal exchanges between plasma and muscle interstitium. GLP-1 (glucagon-like peptide-1) regulates glucose-dependent insulin secretion and has numerous extrapancreatic effects, including a salutary vascular action. To examine whether GLP-1 recruits skeletal and cardiac muscle microvasculature in healthy humans, 26 overnight-fasted healthy adults received a systemic infusion of GLP-1 (1.2 pmol/kg of body mass per min) for 150 min. Skeletal and cardiac muscle MBV (microvascular blood volume), MFV (microvascular flow velocity) and MBF (microvascular blood flow) were determined at baseline and after 30 and 150 min. Brachial artery diameter and mean flow velocity were measured and total blood flow was calculated before and at the end of the GLP-1 infusion. GLP-1 infusion raised plasma GLP-1 concentrations to the postprandial levels and suppressed plasma glucagon concentrations with a transient increase in plasma insulin concentrations. Skeletal and cardiac muscle MBV and MBF increased significantly at both 30 and 150 min (P<0.05). MFV did not change in skeletal muscle, but decreased slightly in cardiac muscle. GLP-1 infusion significantly increased brachial artery diameter (P<0.005) and flow velocity (P=0.05) at 150 min, resulting in a significant increase in total brachial artery blood flow (P<0.005). We conclude that acute GLP-1 infusion significantly recruits skeletal and cardiac muscle microvasculature in addition to relaxing the conduit artery in healthy humans. This could contribute to increased tissue oxygen, nutrient and insulin delivery and exchange and therefore better prandial glycaemic control and tissue function in humans.

New Findings What is the central question of this study? Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor‐mediated responses in humans. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia). What is the main finding and its importance? We show that hypoglycaemia‐mediated changes in heart rate variability and baroreflex sensitivity cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors play a role in resetting the baroreflex working range during hypoglycaemia. These results provide a potential mechanism for impaired glycaemic control and increased risk of cardiac arrhythmias in patients with carotid chemoreceptor overactivity (i.e. sleep apnoea). Activation of the carotid body chemoreceptors with hypoxia alters baroreceptor‐mediated responses. We aimed to examine whether this relationship can be translated to other chemoreceptor stimuli (i.e. hypoglycaemia) by testing the following hypotheses: (i) activation of the carotid body chemoreceptors with hypoglycaemia would reduce spontaneous cardiac baroreflex sensitivity (sCBRS) in healthy humans; and (ii) desensitization of the carotid chemoreceptors with hyperoxia would restore sCBRS to baseline levels during hypoglycaemia. Ten young healthy adults completed two 180 min hyperinsulinaemic [2 mU (kg fat‐free mass)−1 min−1], hypoglycaemic (∼3.2 μmol ml−1) clamps, separated by at least 1 week and randomized to normoxia (arterial partial pressure of O2, 122 ± 10 mmHg) or hyperoxia (arterial partial pressure of O2, 424 ± 123 mmHg; to blunt activation of the carotid body glomus cells). Changes in heart rate, blood pressure, plasma catecholamines, heart rate variability (HRV) and sCBRS were assessed. During hypoglycaemia, HRV and sCBRS were reduced (P < 0.05) and the baroreflex working range was shifted to higher heart rates. When hyperoxia was superimposed on hypoglycaemia, there was a greater reduction in blood pressure and a blunted rise in heart rate when compared with normoxic conditions (P < 0.05); however, there was no detectable effect of hyperoxia on sCBRS or HRV during hypoglycaemia (P > 0.05). In summary, hypoglycaemia‐mediated changes in HRV and sCBRS cannot be attributed exclusively to the carotid chemoreceptors; however, the chemoreceptors appear to play a role in resetting the baroreflex working range during hypoglycaemia.