Patients with type 1 diabetes mellitus (T1DM) experience multiple episodes of hypoglycemia, resulting in dysfunctional counter-regulatory responses with time. The recent experimental study by Jin et al explored the role of intestinal glucagon-like peptide-1 (GLP-1) in impaired counter-regulatory responses to hypoglycemia. They identified intestinal GLP-1 along with GLP-1 receptor (GLP-1R) as the new key players linked with impaired counter-regulatory responses to hypoglycemia in type 1 diabetic mice. They also demonstrated that excessive expression of GLP-1 and GLP-1R was associated with attenuated sympathoadrenal responses and decreased glucagon secretion. The study has enormous clinical relevance as defective counter regulation and hypoglycemia unawareness negatively impacts the intensive glycemic management approach in this group of patients. However, the physiological processes must be validated in dedicated human studies to comprehensively understand the pathophysiology of this complex relationship, and to clarify the true extent of impaired hypoglycemia counter regulation by intestinal GLP-1. For now, following the results of the index study and other similar studies, GLP-1 analogues usage in T1DM must be carefully monitored, as there is an inherent risk of worsening the already impaired counter-regulatory responses in these patients. Further studies in the future could identify other key players involved in this clinically relevant interaction.

Meticulous management of blood glucose levels in diabetes is critical to prevent both microvascular and macrovascular complications[1]. Multiple large clinical trials have shown the protective effect of strict glycemic control in preventing or delaying microvascular complications[2-4]. However, intense blood glucose management increases the incidence of hypoglycemia, which becomes a limiting factor for intensifying glycemic control. Patients with type 1 diabetes mellitus (T1DM) are more prone to iatrogenic hypoglycemia in comparison to those with type 2 diabetes mellitus due to absence of the first defense mechanism (decrease in insulin secretion) against hypoglycemia in T1DM[5].

Patients with T1DM suffer an average of 1-2 episodes of hypoglycemia per week[6]. Severe hypoglycemia (requiring assistance from another individual to correct) manifests with neuroglycopenic symptoms such as confusion, drowsiness, speech difficulty, and altered behavior[7]. Further, around 6-10% of all patients with T1DM die from hypoglycemia, underlining its impact and relevance in management of these patients[8,9].

As the brain is dependent upon glucose for metabolism, the body elicits robust counter-regulatory mechanisms to normalize blood glucose levels during hypoglycemic episodes. Progressive decreases in glucose levels triggers sequential physiological and behavioral responses to counterbalance the reduced blood glucose levels. A decrease in insulin secretion (first defense mechanism) starts when plasma glucose levels fall within the physiological range (4.4-4.7 mmol/L or 80-85 mg/dL). A further fall in blood glucose levels to 3.6-3.9 mmol/L (65-70 mg/dL) causes release of counter-regulatory hormones including glucagon, epinephrine, growth hormone, and cortisol; a further reduction to 2.8-3 mmol/L (50-55 mg/dL) causes neurogenic and neuroglycopenic symptoms followed by overt brain dysfunction at a blood glucose level below 2.8 mmol/L (50 mg/dL)[10,11]. Aggressive glycemic control with subsequent recurrent episodes of hypoglycemia results in a shift of these thresholds to lower plasma glucose levels, culminating in blunted hypoglycemic responses with time[10].

In patients with T1DM, a decrease in insulin release, which is the first physiological response to hypoglycemia, is not possible due to absolute beta cell failure. The first defense mechanism against hypoglycemia is, therefore, lost. Furthermore, this is coupled with an absence of increased glucagon secretion in response to hypoglycemia, attributable to the impaired signal for glucagon secretion in those with an absent first defense mechanism[12].

Because of intrinsic absence of the first two defense mechanisms, patients with T1DM depend on sympatho-adrenal responses to counter hypoglycemia. Recurrent episodes of hypoglycemia lead to blunting of sympathetic activation and epinephrine secretion from the adrenal medulla[12,13]. An attenuated adrenomedullary response causes defective glucose counter regulation. Defective sympathetic neural activation leads to impaired awareness of hypoglycemia[14]. An impaired counter-regulatory response and hypoglycemia unawareness is associated with a six-fold increase in incidence of severe hypoglycemia in patients with T1DM[15,16]. Meticulous avoidance of hypoglycemia for 2-3 weeks recovers counter-regulatory responses to hypoglycemia[17-19].

Hölzen et al[14] have proposed the role of cerebral adaptation in the attenuated counter-regulatory response to recurrent hypoglycemia. Ma et al[13] revealed the role of neuropeptide Y (NPY), an adrenal co-transmitter, in inhibiting the counter-regulatory response by suppressing adrenal activity. Pharmacological inhibition of NPY prevents the attenuation of both tyrosine hydroxylase and epinephrine release. Therefore, therapeutic agents inhibiting peripheral NPY-dependent negative feedback are underdeveloped as a solution to impaired counter-regulatory responses in recurrent hypoglycemia.

These arguments support the critical importance of identifying the exact pathophysiological basis of dysfunctional counter regulation, which remains the major hurdle to implementation of a tight glycemic control. Despite evidence, the pathophysiology of hypoglycemic counter regulation is still not obvious. Recently, Jin et al[20] evaluated the role of intestinal glucagon-like peptide-1 (GLP-1) in hypoglycemia counter regulation in mouse models with T1DM. GLP-1 is an incretin hormone produced by L cells in the intestine, acting on GLP-1 receptors on both beta and alpha cells in the pancreas to mediate its incretin effects. This results in increased glucose dependent secretion of insulin and a simultaneous decrease in glucagon secretion. In addition, GLP-1 plays a critical role in glucose homeostasis after oral intake of nutrients, acting as an anorexic peptide and delaying gastric emptying by its effects on the brain and autonomic nervous system. However, to date, there is little evidence to suggest that this has a direct role in impairment of the counter-regulatory response to hypoglycemia.

In the recent experimental study published in the World Journal of Diabetes, Jin et al[20] highlight the significant role of intestinal GLP-1 in impairment of the hypoglycemia-induced counter-regulatory responses in T1DM mouse models created by administering streptozotocin. In their study, recurrent hypoglycemia led to increased expression of intestinal GLP-1 and its receptor. Excessive intestinal GLP-1 was strongly associated with impaired secretion of adrenaline and noradrenaline during hypoglycemia. Immunohistochemistry showed increased expression of GLP-1 receptors on delta cells in the pancreas. Elevated plasma GLP-1 levels were shown to enhance the function of pancreatic delta cells, thereby suppressing the glucagon secretion by alpha cells. Decreased foraging behavior in mice was attributed to satiety induced by increased expression of GLP-1 and GLP-1 receptors. This is in line with prior evidence which supports the satiety promoting and anorexic effects of GLP-1 in humans[21].

Jin et al[20] conducted a comprehensive basic study covering endocrine and paracrine changes in response to hypoglycemia (recurrent and single) in T1DM mouse models. The role of GLP-1 and GLP-1 receptor expression in response to different hypoglycemia settings was elucidated. One major concern for the present study is the lack of in vitro validation to provide a more detailed insight into the mechanism. However, this work does serve as preliminary evidence in support of the crucial role of GLP-1 in glucose homeostasis, and may pave the way for further in vitro studies of the intestinal GLP-1-neural reflex pathway to elucidate conclusive and robust evidence. It would be interesting to determine the effect of time of day on counter regulation mechanisms (like nocturnal hypoglycemia), which could also have been explored. Similar studies in the future in patients with T1DM and hyperinsulinemic hypoglycemia such as insulinoma could shed light on the mechanisms of this relationship.

The findings of the study make a strong case for careful monitoring of hypoglycemia in T1DM patients being treated with GLP-1 analogues and insulin, raising concerns about the safety profile in line with a previous meta-analysis by Tan et al[22]. Treatment armamentarium of type 1 diabetes consists of insulin administration, GLP-1 analogues, and Pramlintide. Insulin combats absolute beta cell failure, but does not target alpha cell dysfunction and disease progression. Pramlintide must be administered multiple times, and is associated with high risk of gastrointestinal side effects.

Of GLP-1 analogues, Liraglutide and exenatide have been studied in patients with T1DM. The published evidence suggests beneficial effects of GLP-1 analogues in reducing the dose of insulin, weight loss, and satisfactory glycemic control. GLP-1 analog therapy is an important additional therapeutic option to achieve reduced insulin doses, weight loss, and modest improvements in HbA1c. GLP-1 analogues are well tolerated without increasing the occurrence of severe hypoglycemia. GLP-1 RA therapy is more beneficial in patients with detectable C-peptide and/or who are overweight or unable to achieve glycemic goals without hypoglycemia.

The effect of GLP-1 analogues on microvascular and macrovascular complications is yet to be studied in those with T1DM. In a meta-analysis, it was concluded that despite the efficacy of the combination (insulin and GLP-1 analogues) in reducing glycosylated hemoglobin, the risk of hypoglycemia is increased, which merits attention and cautious monitoring. However, risk of severe hypoglycemia is not increased by coadministration of GLP-1 analogues in patients with T1DM. Further, in-human prospective studies with larger sample sizes are needed to clarify the intricate hormonal balance involved in glucose homeostasis in diabetics and healthy populations, and the clinical implications thereof.

The authors demonstrated the role of intestinal GLP-1 and GLP-1 receptors in hypoglycemia unawareness. The results of this study have substantial clinical relevance. This study is even more relevant in patients with T1DM treated with GLP1 analogues in addition to insulin therapy. Based on the findings thereof, it would be wise to stop GLP-1 analogues for short periods in patients with recurrent hypoglycemia, and it is logical to think that a short course of GLP1 antagonist could be used in patients suffering recurrent hypoglycemia, such as in T1DM and hyper insulinemic hypoglycemia.

Increased intestinal GLP-1 and GLP-1 receptor expression plays a key role in attenuated sympathoadrenal responses to recurrent hypoglycemia in mouse models with T1DM. Further, it promotes satiety and decreases appetite even in the presence of hypoglycemia. Similar human studies are required in the future from a clinical perspective to draw relevant conclusions and make use of this knowledge in clinical practice.