Carvedilol prevents counterregulatory failure and impaired hypoglycaemia awareness in non-diabetic recurrently hypoglycaemic rats

Abstract

Aims/hypothesis This study evaluates whether the non-selective β-blocker, carvedilol, can be used to prevent counterregulatory failure and the development of impaired awareness of hypoglycaemia (IAH) in recurrently hypoglycaemic rats. Methods Sprague Dawley rats were implanted with vascular catheters and intracranial guide cannulas targeting the ventromedial hypothalamus (VMH). These animals underwent either three bouts of insulin-induced hypoglycaemia or received three saline injections (control group) over 3 days. A subgroup of recurrently hypoglycaemic animals was treated with carvedilol. The next day, the animals underwent a hypoglycaemic clamp with microdialysis without carvedilol treatment to evaluate changes in central lactate and hormone levels. To assess whether carvedilol prevented IAH, we treated rats that had received repeated 2deoxyglucose (2DG) injections to impair their awareness of hypoglycaemia with carvedilol and measured food intake in response to insulin-induced hypoglycaemia as a surrogate marker for hypoglycaemia awareness. Results Compared with the control group, recurrently hypoglycaemic rats had a~1.7-fold increase in VMH lactate and this was associated with a 75% reduction in the sympathoadrenal response to hypoglycaemia. Treatment with carvedilol restored VMH lactate levels and improved the adrenaline (epinephrine) responses. In 2DG-treated rats compared with control animals receiving saline, food intake was reduced in response to hypoglycaemia and increased with carvedilol treatment. Conclusions/interpretation We conclude that carvedilol may be a useful therapy to prevent counterregulatory failure and improve IAH.

Hypoglycemia unawareness and autonomic dysfunction in diabetes: Lessons learned and roles of diabetes technologies

“…A major cause of IAH and impaired adrenomedullary responses to hypoglycemia is recurrent episodes of hypoglycemia, which (as part of a vicious cycle) perpetuate these conditions [52][53][54] . There is also evidence that IAH can be induced by sleep 55,56 , psychological stress 57 and alcohol 58 , yet there are still controversies as to whether exercise 59,60 and beta-adrenergic blockers 61,62 have detrimental or beneficial effects on hypoglycemia awareness status.…”

Metabolic effects of carvedilol through β‐arrestin proteins: investigations in a streptozotocin‐induced diabetes rat model and in C2C12 myoblasts

“…In addition, elevated lactate levels in the brain in recurrently hypoglycaemic animals were accompanied by increased mRNA expression of monocarboxylate transporter, Mct2 . Interestingly, Mct2 expression was reduced with carvedilol treatment along with the reduction in extracellular lactate levels, further suggesting an improved utilization of glucose with the drug (Farhat et al, 2019).…”

The Neuroprotective Effect of Carvedilol on Diabetic Neuropathy: An In Vitro Study

“…However, there is minimal evidence for supporting the establishment that beta-blockers can be routinely contraindicated in diabetes since they have few clinically essential effects on hypoglycemia recovery and unawareness. Symptoms such as sweating might be improved even though some hypoglycemia signs including palpitation and tremor might be blunted [ 32 – 35 ]. The reason is that sweating is a sympathetic cholinergic reaction to hypoglycemia, which cannot be repressed by beta-blockers, and cautious use of beta-blockers improves sympathoadrenal activation by hypoglycemia.…”