Glucagon-like peptide-1 and impaired counterregulatory responses to hypoglycemia in type 1 diabetes

Abstract

This letter comments on a study by Jin et al, published recently in the World Journal of Diabetes. Hypoglycemia is a significant complication of diabetes, with primary defense mechanisms involving the stimulation of glucagon secretion in α-cells and the inhibition of insulin secretion in pancreatic β-cells, which are often compromised in type 1 diabetes mellitus (T1DM) and advanced type 2 diabetes mellitus. Recurrent hypoglycemia predisposes the development of impaired hypoglycemia awareness, a condition underpinned by complex pathophysiological processes, encompassing central nervous system adaptations and several hormonal interactions, including a potential role for glucagon-like peptide-1 (GLP-1) in paracrine and endocrine vias. Experimental evidence indicates that GLP-1 may impair hypoglycemic counterregulation by disrupting the sympathoadrenal system and promoting somatostatin release in pancreatic δ-cells, which inhibits glucagon secretion from neighboring α-cells. However, current trials evaluating GLP-1 receptor agonists (GLP-1 RAs) in T1DM patients have shown promising benefits in reducing insulin requirements and body weight, without increasing the risk of hypoglycemia. Further research is essential to elucidate the specific roles of GLP-1 and GLP-1 RAs in modulating glucagon secretion and the sympathetic-adrenal reflex, and their impact on hypoglycemia unawareness in T1DM patients.

Key Words: Glucagon-like peptide 1; Type 1 diabetes mellitus; Counterregulatory hypoglycemic dysfunction; Hypoglycemia unawareness; Glucagon; Sympathoadrenal system

Core Tip: Hypoglycemia is a common and significant phenomenon in type 1 diabetes, with recurrent episodes causing progressive dysfunction in glycemic counterregulation and reduced hypoglycemia awareness. The involvement of glucagon-like peptide 1 in this impairment is under investigation, but the pathophysiology is complex and multifactorial, involving various hormones and central receptors. Notwithstanding, studies on glucagon-like peptide 1 receptor agonists in type 1 diabetes mellitus have shown promising benefits and a favorable safety profile.

TO THE EDITOR

Hypoglycemia is a systemic and challenging complication in individuals with diabetes. According to the American Diabetes Association, iatrogenic hypoglycemia encompasses all instances of abnormally low plasma glucose concentrations that expose the individual to potential harm[1]. Although a universal threshold cannot be established to represent all individuals, a plasma glucose concentration of < 70.0 mg/dL (< 3.9 mmol/L) is utilized to define hypoglycemia[2]. Glucose counterregulation is a physiological mechanism for the prevention and correction of hypoglycemia, which, in healthy individuals, typically restores normoglycemia rapidly[3].

The immediate defense against hypoglycemia involves the inhibition of insulin secretion in pancreatic β-cells, followed by the stimulation of glucagon secretion in pancreatic α-cells. In diabetic patients, the insufficiency of insulin production, whether induced by type 1 diabetes mellitus (T1DM) or advanced type 2 diabetes mellitus (T2DM)[4], compromises this mechanism. This impairment progressively arises from the lack of a responsive insulin depletion to hypoglycemia and the absence of paracrine signaling from insulin to the glucagon-secreting cells[5]. Consequently, there is an increased susceptibility to recurrent hypoglycemia, which, in turn, lowers the glycemic threshold required for the activation of counterregulatory hormonal mechanisms, thereby establishing a vicious cycle that determines the impairment of counterregulatory hypoglycemic responses[6]. Although central adaptive changes may underpin this condition[7], the complete mechanisms establishing it are not fully understood.

In addition to the intrinsic pancreatic counterregulation of hypoglycemia, the sympathetic nervous system stimulates the secretion of epinephrine from the adrenal gland, which not only induces hepatic gluconeogenesis via β2-adrenergic activation, but also produces autonomic symptoms such as hunger, palpitations, sweating, and tremors[8]. These symptoms are responsible for the symptomatic awareness of hypoglycemia before the onset of neurocognitive symptoms indicating glucose deprivation to the central nervous system (neuroglycopenia)[5]. However, prior exposure to hypoglycemia attenuates the magnitude of sympathoadrenal activity in such scenarios. Clinically, this manifests as a spectrum ranging from diminished symptomatic perception of hypoglycemia to hypoglycemia unawareness (HU), which is characterized by a complete absence of autonomic symptoms[9]. As a clinical syndrome, HU, in conjunction with compromised glycemic counterregulation, is classified as hypoglycemia-associated autonomic failure (HAAF)[9].

Several studies are underway to elucidate the mechanisms underlying HAAF, with the aim of identifying therapeutic targets that could prevent or potentially disrupt the progression of this condition. Researchers demonstrate that attenuated responses of growth hormone and/or cortisol may be more prevalent in patients with counterregulatory impairment compared to the general population, although the causal relationship remains uncertain[10,11]. An experimental study by Lontchi-Yimagou et al[12] demonstrated that increased epinephrine responses are intricated on HAAF pathogenesis in non-diabetic subjects, even in the absence of prior hypoglycemia episodes. In diabetic rats, the administration of carvedilol, a third-generation β-blocker, was shown to enhance both sympathoadrenal response and hypoglycemia awareness (HA), as reported by Farhat et al[13]. However, no direct impact on glucagon or insulin levels was detected.

In contrast, glucagon-like peptide-1 (GLP-1), an incretin hormone produced in the intestinal epithelial L-cells by differential posttranslation of the proglucagon gene[14], enhances insulin secretion, suppresses glucagon release, and induces satiety, primarily by a glucose-dependent mechanism[15]. In 2002, Nauck et al[16] suggested that exogenous intravenous GLP-1 does not suppress glucagon levels at hypoglycemic plasma glucose concentrations in healthy individuals. However, a recent study by Jin et al[17] demonstrates that recurrent hypoglycemia in T1DM rats can exacerbate GLP-1 intestinal expression, which may be correlated to impaired counterregulatory responses by endocrine pathways. In this study, a protocol of recurrent hypoglycemic episodes was conducted in streptozotocin-induced diabetic rats, initiating on the 15^th day post-diabetes induction, and involving five hypoglycemic episodes every 3 days. The successive hypoglycemic events generated progressive attenuation of autonomic symptom-related behaviors in response to hypoglycemia, which is consistent with the spectrum of impaired counterregulation and impaired HA.

The primary result demonstrated that recurrent hypoglycemia exacerbates plasma GLP-1 levels compared to a single episode of hypoglycemia, indicating a correlation between elevated GLP-1 levels and impaired HA. Additionally, subsequent modulation of GLP-1 receptor (GLP-1R) revealed that in T1DM with impaired HA, excessive intestinal GLP-1 exacerbates the impairment of counterregulatory mechanisms, specifically affecting glucagon, adrenaline, and noradrenaline pathways[17]. These remarkable findings highlight the need for further investigation into the role of GLP-1 and GLP-1Rs in the pathogenesis of HAAF, specially in T1DM.

GLP-1 INFLUENCE ON THE MODULATION OF SYMPATHETIC-ADRENAL ACTIVATION

Hypoglycemia exerts multiple effects on the cardiovascular system, and low glucose conditions (40-70 mg/dL) induce marked impairment in endothelial function[18]. GLP-1 antioxidant properties were reported by Ceriello et al[19], whose study concludes that infusion of GLP-1 attenuates oxidative stress during hypoglycemia and hyperglycemia episodes in T1DM patients. GLP-1 receptor agonists (GLP-1 RAs) were also shown to present antioxidant properties, as supported by a meta-analysis by Bray et al[20].

In the stress response, GLP-1 also plays a role as a neurotransmitter in the modulation of autonomic function. Despite its expression being restricted to pre-proglucagon neurons, a specific group of neurons in the nucleus of the solitary tract and ventrolateral medulla of the brainstem[21], GLP-1Rs expression extends to the area postrema of the brainstem, arcuate nucleus, ventromedial hypothalamus, and paraventricular nucleus[22]. Also, GLP-1 and GLP-1R agonists can cross the blood–brain barrier[23]. GLP-1 actions comprehend not only the regulation of food intake, but also the hypothalamic-pituitary-adrenal axis function and sympathetic nervous system activation. This was similarly shown by Jessen et al[24], who found that intracerebroventricular infusion of GLP-1 resulted in robust activation of the sympathetic nervous system with increased epinephrine levels[24]. As proposed by Diz-Chaves et al[25] in an extensive review into the role of GLP-1R agonists on neural and endocrine integration, a GLP-1 neural reflex pathway, via GLP-1Rs in vagal afferent fibers located in the gastrointestinal tract, can activate neurons within the nucleus of the solitary tract, which are responsible for sympathetic activation[25]. Accordingly, the study by Jin et al[17] demonstrated that intestinal expression of GLP-1 and GLP-1R increased in T1DM mice after exposition to hypoglycemia, with higher values in those exposed to recurrent episodes[17]. As reflected by the progressive attenuation of autonomic symptoms, plasma adrenaline levels and pancreatic noradrenaline levels were significantly lower in rats exposed to recurrent hypoglycemia[17].

In rats with intact HA, the modulation of intestinal GLP-1R through GLP-1 (7-36) (an agonist) and exendin 9-39 (an antagonist) administration, respectively, leads to exacerbation and attenuation of plasma adrenaline levels, but this effect was not seen in rats with impaired HA. This implies that once counterregulatory impairment exceeds a certain threshold, GLP-1 cannot generate a proper sympathetic autonomic response during hypoglycemic episodes.

Lontchi-Yimagou et al[12] demonstrated that, like a hypoglycemic event, prior activation of adrenergic receptors through epinephrine infusion attenuates plasma epinephrine levels in subsequent hypoglycemic events[12]. Furthermore, it was observed that in non-diabetic patients, the magnitude of serum epinephrine elevation during hypoglycemia predicts susceptibility to the development of HAAF[12]. These findings support the hypotheses that: (1) Prior epinephrine exposure can impair subsequent sympathoadrenal responses; and (2) Additional factors, such as GLP-1, may influence sympathoadrenal activation and potentially contribute to the predisposition to HAAF.

ROLE OF GLP-1 IN PANCREATIC ISLET CELL REGULATION

In addition to stimulating insulin secretion and enhancing peripheral insulin sensitivity, GLP-1 RAs significantly inhibit glucagon secretion from pancreatic α-cells. Supporting this, Jin et al[17] found that rats with impaired HA had elevated serum levels of GLP-1 and decreased serum levels of glucagon, with the attenuation further exacerbated by intraperitoneal injection of GLP-1 (7-36)[17]. The exact mechanism underlying the inhibition of glucagon by GLP-1 remains uncertain.

It is unclear whether this effect is mediated primarily through direct GLP-1R signaling on α-cells or through predominant paracrine signaling from adjacent pancreatic islet cells. Transcriptomic analysis has demonstrated that GLP-1R expression is significantly higher in β-cells and δ-cells compared to α-cells[26]. Creutzfeldt et al[27] previously demonstrated the inhibitory effect of GLP-1 on glucagon secretion in established T1DM, implying that paracrine mechanisms involving pancreatic β-cells are insufficient to fully explain this phenomenon[27].

Jin et al[17] observed that in rats with impaired HA (and elevated GLP-1 levels), there was an increase in cyclic adenosine monophosphate (cAMP) levels in pancreatic δ-cells, elevated plasma somatostatin (SST) levels, and an increased SST + cell area in the pancreas, with the latter being a novel finding. Concurrently, cAMP levels in pancreatic α-cells decreased, and serum glucagon levels were reduced. Indeed, in δ-cells, GLP-1 signaling through GLP-1R stimulates the secretion of SST, which exerts a significant inhibitory effect on α-cells[28].

The inhibitory effect of SST on glucagon secretion is mediated through its binding to the SST subtype-2 receptor (SSTR2) on α-cells[29]. Utilizing an SSTR2 antagonist theoretically allows for the investigation of SST’s paracrine role in GLP-1-mediated glucagon inhibition. However, studies employing this approach have yielded inconsistent results. Some research supports the critical role of SST receptors in mediating the GLP-1 effect on attenuating α-cell activity[30-32], whereas Ramracheya et al[33] found no significant difference in glucagon expression when using an SSTR2 antagonist[33]. Collectively, the evidence suggests a complex interplay of paracrine feedback mechanisms involving GLP-1’s modulation of glucagon secretion, integrating direct GLP-1R signaling and reciprocal paracrine hormonal interactions among various pancreatic cell types.

GLP-1 AND GASTRIC EMPTYING UNDER HYPOGLYCEMIA

The modulation of gastric emptying (GE) rate directly correlates with postprandial glycemic increases, whether in healthy individuals or those with diabetes (T1DM or T2DM)[34]. Acute hyperglycemia is associated with a slowing of GE, due to the reduction of fundic tone and gastric antral contractions[35]. Conversely, acute insulin-induced hypoglycemia is known to significantly accelerate GE in healthy individuals[36,37] or those with T1DM (including those with autonomic dysfunction)[38,39], indicating its role as a counterregulatory mechanism against hypoglycemia by increasing the rate of glucose delivery to the small intestine in the postprandial period[40].

However, outside controlled environments, daily fluctuations in fasting plasma glucose do not seem to significantly influence GE in healthy individuals or those with T1DM[41]. In contrast, prolonged exposure to hyperglycemia [high glycated hemoglobin (HbA1c) levels] tends to be associated with delayed GE[41-44]. Among patients with T1DM, children and adolescents may exhibit accelerated GE[45], though delayed GE is more prevalent in adults[45,46]. To date, there is no significant evidence suggesting that variations in GE are predictive of recurrent hypoglycemia or HU in patients with diabetes. Notably, after recurrent exposure to hypoglycemia, the mechanism of GE acceleration remains unaffected as a counterregulatory agent against hypoglycemia, unlike the compromised autonomic response[47].

GLP-1 exerts an inhibitory effect on gastric motility and postprandial GE[48,49]. Additionally, as demonstrated by Plummer et al[50] in an experimental study involving healthy individuals, during insulin-induced hypoglycemia, intravenous GLP-1 significantly attenuates counterregulatory GE acceleration and glucose absorption. However, prolonged administration of GLP-1 leads to tachyphylaxis (attenuation of its inhibitory effect on gastric motility), unlike its insulinotropic effect, which remains sustained[51,52]. Conceivably, while randomized controlled trials (RCTs) evaluating the use of twice-daily exenatide, a short-acting GLP-1 RA in patients with T1DM, revealed a significant slowing of postprandial GE[53,54], once-daily liraglutide, a long-acting GLP-1 RA, does not sustain its delaying effect on GE after 24-26 weeks[55,56].

In summary, the dynamics of GE in patients with type 1 diabetes and its underlying pathophysiological bases require further experimental evaluation. Although the attenuation of postprandial GE is a well-documented effect of GLP-1 RAs, particularly short-acting ones, an RCT evaluating the use of liraglutide as an adjunct to insulin in patients with type 1 diabetes did not identify any impairment in the GE counterregulatory response to hypoglycemia[57]. GLP-1 modulation has been investigated as a glycemic management strategy in other contexts where it plays a key role. For example, GLP-1 antagonism has recently been evaluated by Craig et al[58-60] as a potential approach to prevent hypoglycemia in individuals experiencing postprandial hypoglycemia following bariatric surgery, justified by the fact that these patients exhibit significantly higher endogenous GLP-1 levels compared to those who do not experience hypoglycemia[61]. However, to date, there is no clinical evidence demonstrating that this method would benefit patients with T1DM and recurrent hypoglycemia.

CLINICAL IMPLICATIONS

GLP-1 RAs are widely recommended in the therapeutic management of T2DM, given their unequivocal benefits in preventing major adverse cardiovascular events, efficacy in HbA1c reduction, weight loss, and low risk of hypoglycemia[62]. However, the benefits and safety profile of GLP-1 RAs in T1DM patients remain less well established. For instance, in the MAG1C trial[63], the use of exenatide three times a day in patients with T1DM did not show significant glycemic control benefits (HbA1c, postprandial glycemic excursions, or glycemic variability).

In contrast, long-acting GLP-1 RAs as adjuncts to insulin therapy in T1DM appear more promising. In the ADJUNCT ONE[64] and ADJUNCT TWO[65] trials, the addition of liraglutide to insulin therapy for 26 weeks in individuals with T1DM was associated with reductions in HbA1c levels, total insulin dosage, and body weight compared to a placebo; however, higher rates of symptomatic hypoglycemia were reported. Nevertheless, a recent meta-analysis by Park et al[66], which included data from 24 trials, not only supports these therapeutic benefits, but also indicates that the odds of severe [odds ratio (OR) = 0.67; 95% confidence interval (CI): 0.43-1.04] or symptomatic hypoglycemia (OR = 0.89; 95%CI: 0.53-1.51) were not significantly elevated with GLP-1 RA adjunctive therapy.

Although Jin et al[17] suggest a correlation between GLP-1 and the exacerbation of established HU, this does not definitively indicate that GLP-1 itself is a causal factor in the development of this condition. Lontchi-Yimagou’s thorough review of the literature suggests that the onset of HAAF is linked to multiple mechanisms, including several hormones, nutrients, and central regulatory changes, rather than being attributable to a single causal pathway[67].

To date, we have identified only four RCTs investigating whether treatment with GLP-1 RAs contributes to impaired hypoglycemic counterregulation in patients with T1DM[57,68-70]. Each RCT evaluated a specific agent, including exenatide and liraglutide, with none demonstrating a worsening in counterregulatory responses to hypoglycemia. In a comparable study involving patients with T2DM conducted by Yabe et al[71], a 2-week treatment resulted in suppression of serum glucagon in both the liraglutide-treated group and the control group receiving linagliptin. However, the stepped hyperinsulinemic glucose clamp test revealed similar recovery responses to hypoglycemia across both treatment groups and between pre- and post-treatment assessments[71]. We have not identified any studies investigating the effects of GLP-1 agonists or antagonists in patients with T1DM who have established HU.

CONCLUSION

Recent evidence indicates that excessive intestinal GLP-1 may be intricated in impaired glycemic counterregulation in diabetic patients; however, the underlying mechanisms remain not fully understood. Besides cortisol, growth factors, opioid receptors, and other central regulatory factors, the range of mechanisms underlying HA and impaired hypoglycemic counterregulation include the sympathetic-adrenal reflex mediated by paracrine actions of GLP-1 and the suppression of glucagon secretion via endocrine pathways. While the safety profile of GLP-1 RAs in patients with T1DM is not well established, emerging evidence suggests no significant alteration in hypoglycemia risk or counterregulatory response impairment. Furthermore, GLP-1 RAs therapy on type 1 diabetes has been associated with a reduction in insulin dosages for glycemic control and weight loss, with the latter being beneficial in specific scenarios, but potentially unfavorable in others. Therefore, further cautious assessment of the effects of endogenous GLP-1, as well as GLP-1 RAs and antagonists, is warranted, particularly regarding their impact on hypoglycemia risk following recurrent hypoglycemic episodes or in established HU.