Skip to main content
Download PDF

Glucagon: a potential protective factor against peripheral nerve compromise in patients with type 2 diabetes and obesity

Diabetology & Metabolic Syndrome volume 17, Article number: 35 (2025) Cite this article

Abstract

Background

Increased glucagon levels are now recognized as a pathophysiological adaptation to counteract overnutrition in type 2 diabetes (T2D). This study aimed to elucidate the role of glucagon in peripheral nerve function in patients with T2D with different body mass indices (BMIs).

Methods

We consecutively enrolled 174 individuals with T2D and obesity (T2D/OB, BMI ≥ 28 kg/m2), and 480 individuals with T2D and nonobesity (T2D/non-OB, BMI < 28 kg/m2), all of whom underwent oral glucose tolerance tests to determine the area under the curve for glucagon (AUCgla). Electromyography was utilized to assess overall composite Z-scores for latency, amplitude, and nerve conduction velocity (NCV) across all peripheral nerves, specifically examining the median, ulnar, common peroneal, posterior tibial, superficial peroneal, and sural nerves.

Results

In the T2D/OB group, the AUCgla exhibited a significant correlation with the latency, amplitude and NCV of each peripheral nerve, as well as with the overall composite Z-scores for latency (r = –0.283, p < 0.001), amplitude (r = 0.295, p < 0.001), and NCV (r = 0.362, p < 0.001). In contrast, the T2D/non-OB group did not exhibit obvious correlations between the AUCgla and the overall composite Z-scores for latency (r = –0.088, p = 0.056), amplitude (r = 0.054, p = 0.251), and NCV (r = 0.116, p = 0.012). Furthermore, multivariate linear regression analyses indicated that elevated AUCgla was independently associated with a lower overall composite Z-score for latency (β = –0.304, t = –3.391, p = 0.001), as well as higher overall composite Z-scores for amplitude (β = 0.256, t = 2.630, p = 0.010) and NCV (β = 0.286, t = 3.503, p = 0.001), after adjusting for other clinical covariates within the T2D/OB group.

Conclusion

Increased glucagon levels may be a potential protective factor against peripheral nerve compromise in patients with T2D and obesity.

Introduction

Diabetic peripheral neuropathy (DPN) is the most common complication, with the latest national epidemiological survey indicating that up to 67.6% of patients with type 2 diabetes (T2D) experience this condition [1]. Owing to the increase in peripheral nerve dysfunction, patients with DPN experience debilitating symptoms such as pain, numbness, diminished sensation, and imbalance, which can lead to walking disabilities, falls resulting in fractures, foot ulcers, and amputations [2]. Furthermore, DPN not only poses a potential risk for cardiovascular disease and other microvascular complications in patients with T2D but also serves as a predictor of major adverse cardiovascular outcomes in these patients [3, 4]. Given the large population affected by DPN and its substantial adverse impact on individuals, it is crucial to identify risk factors and develop interventions for DPN in clinical practice.

Glucagon, which is predominantly secreted by pancreatic α-cells and is traditionally recognized as a counterregulatory hormone to insulin, extends beyond its role in glucose homeostasis to encompass the maintenance of overall energy and nutritional equilibrium [5]. In a longitudinal study involving 4,194 nondiabetic participants, Wagner et al. [6] reported that elevated postchallenge glucagon levels are associated with enhanced insulin sensitivity, which indicates a metabolically healthier phenotype. In a clinical study involving 4,937 diabetic participants, Wang et al. [7] demonstrated that elevated glucagon levels were inversely correlated with the inflammatory progression of nonalcoholic fatty liver disease (NAFLD). Thus, the potential increase in glucagon secretion by α-cells in metabolic disorders may represent a compensatory mechanism aimed at preserving metabolic homeostasis. Consequently, within the subgroup of individuals with T2D and obesity, characterized by an overnutrition status, increased glucagon levels are hypothesized to ameliorate the effects of nutrient excess and confer protection against diabetic complications, such as DPN. While basic research suggests that glucagon may confer protective effects on the nervous system [8], there is a paucity of clinical data regarding the role of glucagon in DPN among patients with T2D, particularly those with obesity.

Therefore, we conducted a clinical observational study designed to quantify plasma glucagon levels during oral glucose tolerance tests in patients with T2D, evaluating peripheral nerve function—specifically latency, amplitude, and nerve conduction velocity—using electromyography and to investigate the associations between plasma glucagon levels and peripheral nerve function indices in these patients, stratified by body mass index (BMI) status (obesity versus nonobesity).

Materials and methods

Study design and patient recruitment

The present study was approved by the Medical Ethics Committee of Nantong First People's Hospital, as indicated by reference number 2023KT228. Initiated in 2023, the study involved the recruitment of eligible patients with type 2 diabetes (T2D) from the Department of Endocrinology. The inclusion criteria were as follows: (1) a diagnosis of T2D in accordance with the 2020 Diabetes Management Guidelines issued by the American Diabetes Association [9]; (2) an age range from 20 to 75 years; and (3) full understanding of the study procedures with informed consent provided for participation. The exclusion criteria were as follows: (1) presence of autoantibodies associated with diabetes; (2) diagnosis of malignant tumors; (3) chronic viral hepatitis or liver cirrhosis; (4) cardiovascular conditions, including stroke, myocardial infarction, cardiovascular revascularization, and peripheral artery occlusion; (5) chronic kidney disease, characterized by an estimated glomerular filtration rate (eGFR) of less than 60 ml/min/1.73 m2; (6) use of glucocorticoids or sex hormone therapy; (7) administration of glucagon-like peptide-1 receptor agonists; (8) presence of anemia or deficiencies in folic acid or vitamin B12; (9) cervical and lumbar disorders; and (10) connective tissue diseases. Finally, the study enrolled a total of 654 eligible patients with T2D who had complete data. This cohort included 174 individuals with both T2D and obesity (T2D/OB, defined as a BMI ≥ 28 kg/m2) and 480 individuals with T2D and nonobesity (T2D/non-OB, defined as a BMI < 28 kg/m2), utilizing the Chinese BMI cutoff point for obesity classification [10].

Data collection

A comprehensive collection of clinical data was obtained, encompassing anthropometric and demographic parameters such as age, sex, height, weight, BMI, and systolic/diastolic blood pressure (SBP/DBP). Additionally, data on the duration of diabetes, prescribed medications (including statins and hypoglycemic agents), and biochemical markers were included.

Following an 8-h fasting period, peripheral venous blood samples were obtained to quantify the concentrations of alanine aminotransferase (ALT), albumin, triglyceride (TG), total cholesterol (TC), uric acid (UA), cystatin C (CysC), hemoglobin, glycated hemoglobin (HbA1c), glycated albumin, and fasting C-peptide. Concurrently, morning urine samples were collected to assess albumin and creatinine levels, enabling the calculation of the urinary albumin-to-creatinine ratio (ACR). Additionally, the estimated glomerular filtration rate (eGFR) was calculated via the Modification of Diet in Renal Disease (MDRD) equation [11].

Assessment of pancreatic α-cell function

A 75-g oral glucose tolerance test (OGTT) was employed to evaluate the function of pancreatic α-cells and was administered to all participants in the morning after an overnight fast. Venous blood samples were obtained at baseline (fasting) and at 30, 60, 120, and 180 min following glucose administration to concurrently quantify plasma glucagon concentrations (GLA0min, GLA30min, GLA60min, GLA120min, and GLA180min). The overall glucagon response during the OGTT was evaluated by the area under the curve for glucagon (AUCgla). Plasma glucagon was measured using a chemiluminescence immunoassay (Glucagon Kit, JINDE BIOTECH, Guangzhou, China) with the HomoG100 analyser. The kit employs a double monoclonal antibody sandwich method, achieving a detection precision bias within ± 10% and both intra-assay and interassay CVs under 10%.

Peripheral nerve function assessment

Nerve conduction studies conducted through electromyography are recognized as the most sensitive, objective, and reliable techniques for evaluating DPN and quantifying nerve function, especially in asymptomatic patients [12, 13].

We used an electromyography (MEB-9200 K, Nihon Kohden, Japan) to assess peripheral nerve function in all patients. Nerve latency, amplitude, and conduction velocity (NCV) were measured in the median (MN), ulnar (UN), common peroneal (CPN), posterior tibial (PTN), superficial peroneal (SPN), and sural (SN) nerves.

After standardizing the functional data using Z-scores, overall composite Z-scores for latency, amplitude, and nerve conduction velocity (NCV) were calculated by averaging the respective parameters across all peripheral nerves. Specifically, the composite Z-score for latency was derived by calculating the mean of the latency Z-scores across all peripheral nerves, a methodology that has been previously documented in the literature [13, 14].

In addition, we computed the composite Z-scores for motor nerves (MN, UN, CPN, and PTN) as well as the composite Z-scores for sensory nerves (MN, UN, SPN, and SN).

Statistical analysis

Statistical analyses were conducted using IBM SPSS Statistics, Version 25.0. A p value of less than 0.05 was deemed indicative of statistical significance.

Initially, descriptive statistical analyses were undertaken. Continuous data following a normal distribution are reported as the means and standard deviations, whereas nonnormally distributed continuous data are presented as medians and interquartile ranges. Categorical data are expressed as frequencies and percentages. AUCgla and other nonnormally distributed data were transformed using the natural logarithm for further analytical procedures, such as lnAUCgla.

Second, we utilized the Student's t test, the Mann–Whitney U test, and the chi-square test to assess differences in normally distributed, skewed, and categorical data, respectively, between the T2D/OB and T2D/non-OB groups.

Third, Pearson's correlation analysis was conducted to evaluate the relationships between glucagon levels (AUCgla) and peripheral nerve functional indices within the T2D/OB and T2D/non-OB groups.

Finally, multivariate linear regression analyses were employed to adjust for additional clinical variables, thereby determining whether glucagon levels (AUCgla) were independently associated with peripheral nerve function in patients with T2D.

Results

Clinical characteristics of patients

The clinical data of the enrolled patients with T2D, both overall and stratified by BMI status (T2D/OB and T2D/non-OB groups), are presented in Table 1. In comparison to the T2D/non-OB group (BMI < 28 kg/m2), the T2D/OB group (BMI ≥ 28 kg/m2) exhibited a younger age, a shorter duration of diabetes, and elevated levels of SBP, DBP, prevalence of hypertension, ALT, TG, UA, CysC, fasting C-peptide, and hemoglobin. However, no significant differences were observed between the two subgroups in terms of sex distribution, statin use, albumin levels, TC, eGFR, ACR, glycated albumin, or HbA1c. With respect to the use of hypoglycemic agents, the T2D/OB group showed a tendency to use metformin and sodium-glucose co-transporter-2 inhibitors (SGLT-2Is) more frequently, whereas insulin and dipeptidyl peptidase-4 inhibitors (DPP-4Is) were used less frequently than the T2D/non-OB group was. The use of secretagogues, thiazolidinediones (TZDs), and α-glucosidase inhibitors (AGIs) was comparable between the two subgroups. Furthermore, the T2D/OB group showed increased GLA0min, GLA30min, GLA60min, GLA120min, and GLA180min, and overall glucagon levels (AUCgla), along with significantly pronounced peripheral nerve function, as evidenced by reduced nerve latency and elevated nerve amplitude and NCV, in comparison with those of the T2D/non-OB group.

Table 1 Clinical features of the recruited patients with T2D according to BMI status
Full size table

Univariate analysis of the associations between glucagon levels and peripheral nerve functional indices

In the T2D/OB group, Pearson's correlation analysis revealed that an increased AUCgla contributed to a lower overall composite Z-score for latency (r = −0.283, p < 0.001), as well as higher overall composite Z-scores for amplitude and NCV (r = 0.295 and 0.362, respectively; p < 0.001). In contrast, the T2D/non-OB group did not exhibit obvious correlations between the AUCgla and the overall composite Z-scores for latency (r = −0.088, p = 0.056), amplitude (r = 0.054, p = 0.251), and NCV (r = 0.116, p = 0.012). The correlations between AUCgla and overall peripheral nerve functional indices in both the T2D/OB and T2D/non-OB groups are depicted in Fig. 1.

Fig. 1
figure 1

Graphical correlations between lnAUCgla and overall peripheral nerve functional indices in both the T2D/OB group (n = 174) and the T2D/non-OB group (n = 480). T2D type 2 diabetes, T2D/OB patients with T2D and obesity, T2D/non-OB patients with T2D and nonobesity, AUCgla area under the curve for glucagon, lnAUCgla natural log-transformed AUCgla, NCV nerve conduction velocity

Full size image

Given the asynchronous progression of sensory and motor nerve injuries in the limbs during T2D, we conducted an in-depth analysis of the correlation between the AUCgla and the function of all peripheral nerves (Table 2). In the T2D/OB group, an increased AUCgla generally exhibited a strong correlation with pronounced nerve function across various peripheral nerves. In contrast, these correlations were generally weak in the T2D/non-OB group. The correlations between AUCgla and functional indices of motor and sensory nerves in both the T2D/OB and T2D/non-OB groups are presented in Fig. 2.

Table 2 Pearson's correlation analysis for associations between lnAUCgla and peripheral nerve functional indices in T2D/OB group (n = 174) and T2D/non-OB group (n = 480)
Full size table
Fig. 2
figure 2

Graphical correlations between lnAUCgla and functional indices of motor and sensory nerves in both the T2D/OB group (n = 174) and the T2D/non-OB group (n = 480). T2D type 2 diabetes, T2D/OB patients with T2D and obesity, T2D/non-OB patients with T2D and nonobesity, AUCgla area under the curve for glucagon, lnAUCgla natural log-transformed AUCgla, NCV nerve conduction velocity

Full size image

Multivariate linear regression analysis of whether glucagon levels are independent indicators of peripheral nerve function

A multivariate linear regression analysis was conducted to control for a range of variables, including age, sex, BMI, blood pressure, diabetes duration, the use of statins and hypoglycemic agents, ALT, albumin, TG, TC, UA, CysC, eGFR, ACR, C-peptide, hemoglobin, glycated albumin, and HbA1c. The analysis revealed that an increase in the AUCgla was independently linked to a lower overall composite Z-score for latency (β = −0.304, t = −3.391, p = 0.001) and higher overall composite Z-scores for amplitude (β = 0.256, t = 2.630, p = 0.010) and NCV (β = 0.286, t = 3.503, p = 0.001) in the T2D/OB group, as presented in Table 3.

Table 3 Impacts of lnAUCgla on overall peripheral nerve function by multivariable linear regression analysis in the T2D/OB group (n = 174)
Full size table

Moreover, a detailed examination of the correlations between AUCgla and the functional parameters of sensory and motor nerves revealed that elevated AUCgla remained independently associated with significantly pronounced peripheral sensory and motor nerve function, as demonstrated in Tables 4 and 5.

Table 4 Impacts of lnAUCgla on motor nerve function by multivariable linear regression analysis in the T2D/OB group (n = 174)
Full size table
Table 5 Impacts of lnAUCgla on sensory nerve function by multivariable linear regression analysis in the T2D/OB group (n = 174)
Full size table

Discussion

This study potentially represents a significant investigation into elucidating the role of glucagon in diabetic complications, specifically peripheral nerve dysfunction, among patients with T2D stratified by varying nutritional statuses, namely obesity versus nonobesity. The principal findings of our study are summarized as follows: (1) Patients with T2D classified as obesity exhibited elevated overall glucagon levels, as assessed by AUCgla during the OGTT, and demonstrated more pronounced peripheral nerve function than their nonobesity counterparts did. (2) In patients with T2D and obesity, an increased AUCgla is generally well correlated with enhanced nerve function across various peripheral nerves. In contrast, those correlations were not observed in patients with T2D who were categorized as nonobesity. (3) Finally, adjusting for demographic variables, glycemic control, eGFR, and other clinical factors, an elevated AUCgla was independently associated with improved composite peripheral nerve function in patients with T2D and obesity. These associations remained statistically significant when the analysis focused specifically on sensory or motor nerve function. Consequently, elevated glucagon levels may serve as a potential protective factor against peripheral nerve impairment in individuals with T2D and obesity.

Risk factors for compromised peripheral nerve function

DPN and its associated peripheral nerve dysfunction manifest within the context of diabetes and may share common risk factors with this disease, including cardiometabolic and inflammatory factors [15]. Cardiometabolic risk factors, including insulin resistance, hyperglycemia, long-term diabetes, hypertension, and dyslipidemia, play significant roles in the development and progression of peripheral nerve dysfunction in patients with T2D [16]. The presence of inflammation can exacerbate nerve damage by promoting oxidative stress and impairing vascular function, which is essential for nerve health [17]. Moreover, the interplay between cardiometabolic and inflammatory factors can create a vicious cycle that exacerbates nerve damage. For example, insulin resistance, a hallmark of T2D, is associated with increased inflammatory cytokine production, which in turn can worsen metabolic dysregulation and contribute to further nerve injury [15]. In the present study, we observed that patients with T2D and obesity (BMI ≥ 28 kg/m2) presented more pronounced differences in peripheral nerve function than their nonobese counterparts did (BMI < 28 kg/m2). These patients were also characterized by elevated levels of C-peptide, increased hemoglobin, and notably higher glucagon levels at all time points during the oral glucose tolerance test (OGTT). Previous studies have indicated that low C-peptide levels, a lower BMI, and anaemia are associated with impaired nerve function [1, 18]. Building on previous research, our study strengthens the notion that inadequate β-cell secretion and suboptimal nutritional status are significant contributors to peripheral neuropathy. Furthermore, our findings indicate that overall glucagon levels, assessed via the AUCgla, are positively correlated with enhanced peripheral nerve function in patients with T2D and obesity. In murine models of diabetes, chronic hyperglucagonemia has been shown to partially ameliorate glucose levels and mitigate glucose intolerance [19]. Moreover, patients with prolonged T2D and diminished glucagon levels exhibit an elevated risk of developing DPN [20]. Additionally, the role of glucagon in resolving inflammation has been emphasized, particularly in experimental models of pulmonary neutrophilia, where it facilitates neutrophil apoptosis and augments the production of proresolving mediators [21]. Glucagon may enhance peripheral nerve function in T2D by addressing both glucose intolerance and inflammation, which are integral components of the underlying pathogenesis of T2D.

Clinical implications of increased glucagon adaptation

The perception of increased glucagon secretion has evolved from being solely viewed as a pathogenic response that exacerbates the progression of metabolic diseases, such as obesity, NAFLD, and T2D, to being acknowledged as a pathophysiological adaptation intended to mitigate nutrient overflow in these conditions [22]. An elevated fold change in late-phase glucagon secretion following oral glucose administration is associated with improved glucose tolerance and increased insulin sensitivity [6]. Conversely, a reduced change in late-phase glucagon secretion under similar conditions is linked to insulin resistance and an elevated risk of developing T2D [23]. Beyond its role in metabolic homeostasis, the diverse physiological actions of glucagon have been recognized for its key regulatory function in resolving inflammation, modulating cardiovascular hemodynamics, and exerting neuroprotective effects across various contexts. Glucagon may mitigate the progression of atherosclerotic plaques through its anti-inflammatory properties in a murine model of atherosclerosis [24]. It has been shown to decrease vascular resistance and induce dose-dependent relaxation of the rat thoracic aorta [25]. Additionally, glucagon has been implicated in preventing methylglyoxal-induced cytotoxicity in neuronal cell lines [8]. In contrast, mice deficient in peptides derived from the glucagon gene are prone to developing peripheral neuropathy [26], and patients with a long duration of T2D and reduced glucagon levels are associated with a high risk of DPN [20]. In the present study, in patients with T2D and obesity, higher overall glucagon levels, as measured by AUCgla, were independently associated with reduced nerve latency, as well as increased nerve amplitude and NCV. In contrast, these correlations were less pronounced in patients with T2D who were not obesity. Furthermore, when the analysis focused on sensory or motor nerves in patients with T2D and obesity, increased glucagon levels remained significantly associated with improved sensory or motor peripheral nerve function. In patients with T2D and obesity, conditions marked by overnutrition and increased glucagon levels may mitigate peripheral nerve impairment and potentially represent a compensatory adaptation to preserve peripheral nerve function in these individuals.

Mechanistic link between increased glucagon levels and pronounced peripheral nerve function

There may be potential mechanistic links between increased glucagon levels and pronounced peripheral nerve function in individuals with T2D and obesity. First, under conditions of T2D characterized by excessive nutrient stress, α-cells undergo modifications that result in increased expression of prohormone convertase 1 (PC1), leading to increased secretion of glucagon-like peptide-1 (GLP-1) [27], which subsequently serves to mitigate metabolic stress and preserve the function of peripheral nerves. Second, glucagon was found to mitigate the intracellular accumulation of advanced glycation end products, diminish the production of mitochondrial reactive oxygen species, reduce apoptosis, and decrease overall cytotoxicity, thereby promoting neurite outgrowth. These effects were documented in a model of diabetic neuropathy using neuronal cells subjected to methylglyoxal and subsequently treated with glucagon [8]. Third, addressing inflammation plays a pivotal role in the amelioration of DPN. Recent studies have underscored the role of glucagon in modulating inflammatory responses, especially in models of neutrophilic inflammation triggered by lipopolysaccharide [21]. In these scenarios, glucagon facilitates the apoptosis of neutrophils, reduces the synthesis of local proinflammatory cytokines, and increases the concentration of proresolving mediators [21]. Finally, as an energy mobilizer, glucagon facilitates the release of energy substrates, primarily glucose, from energy-storing organs such as the liver and adipose tissue, subsequently delivering these substrates to energy-consuming organs, including the nervous system. Concurrently, a moderate increase in glucose levels may enhance capillary permeability in peripheral nerves (such as the sciatic nerve), thereby offering protection against nerve impairment in patients with T2D and DPN [28].

Limitations

The present study is subject to several limitations. First, as an observational study, it does not establish a definitive causal relationship between elevated glucagon levels and enhanced peripheral nerve function in patients with T2D and obesity. Consequently, longitudinal cohort studies are needed for further elucidation. Second, the study scope was confined to T2D patients at a single center in China, thereby limiting the generalizability of the findings. Third, while a clinical correlation was identified in this study, further animal research is necessary to explore the role of glucagon in protection against DPN. Finally, the administration of hypoglycemic agents in the present study may have affected peripheral nerve function. Moreover, recruiting a substantial cohort of drug-naive patients presents a significant challenge in clinical practice.

Conclusions

In summary, increased glucagon levels were independently associated with pronounced peripheral nerve function in patients with T2D and obesity and may be a potential protective factor against peripheral nerve compromise in those patients. Future clinical treatment strategies aimed at activating glucagon signalling may subsequently alleviate peripheral nerve dysfunction in patients with T2D.

Availability of data and materials

It is reasonable to request that the principal investigators make the data available for this study.

Abbreviations

T2D:

Type 2 diabetes

DPN:

Diabetic peripheral neuropathy

BMI:

Body mass index

T2D/OB:

Patients with T2D and obesity (BMI ≥ 28 kg/m2)

T2D/non-OB:

Patients with T2D and nonobesity (BMI < 28 kg/m2)

SBP/DBP:

Systolic/diastolic blood pressure

TZDs:

Thiazolidinediones

AGIs:

α-Glucosidase inhibitors

DPP-4Is:

Dipeptidyl peptidase-4 inhibitors

SGLT-2Is:

Sodium‒glucose cotransporter 2 inhibitors

ALT:

Alanine aminotransferase

TG:

Triglyceride

TC:

Total cholesterol

UA:

Uric acid

CysC:

Cystatin C

eGFR:

Estimated glomerular filtration rate

ACR:

Urinary albumin/creatinine ratio

HbA1c:

Glycosylated hemoglobin A1c

GLA:

Glucagon

AUCgla :

Area under the curve for glucagon

lnAUCgla :

Natural log-transformed AUCgla

NCV:

Nerve conduction velocity

References

  1. Wang W, Ji Q, Ran X, Li C, Kuang H, Yu X, et al. Prevalence and risk factors of diabetic peripheral neuropathy: a population-based cross-sectional study in China. Diabetes Metab Res Rev. 2023;39(8):e3702.

    Article  CAS  PubMed  Google Scholar 

  2. Feldman EL, Callaghan BC, Pop-Busui R, Zochodne DW, Wright DE, Bennett DL, et al. Diabetic neuropathy. Nat Rev Dis Primers. 2019;5(1):41.

    Article  PubMed  Google Scholar 

  3. Brownrigg JR, de Lusignan S, McGovern A, Hughes C, Thompson MM, Ray KK, et al. Peripheral neuropathy and the risk of cardiovascular events in type 2 diabetes mellitus. Heart. 2014;100(23):1837–43.

    Article  PubMed  Google Scholar 

  4. Kim K, Lee SN, Ahn YB, Ko SH, Yun JS. Associations of polyneuropathy with risk of all-cause and cardiovascular mortality, cardiovascular disease events stratified by diabetes status. J Diabetes Investig. 2023;14(11):1279–88.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Kawamori D, Sasaki S. Newly discovered knowledge pertaining to glucagon and its clinical applications. J Diabetes Investig. 2023;14(7):829–37.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Wagner R, Hakaste LH, Ahlqvist E, Heni M, Machann J, Schick F, et al. Nonsuppressed glucagon after glucose challenge as a potential predictor for glucose tolerance. Diabetes. 2017;66(5):1373–9.

    Article  CAS  PubMed  Google Scholar 

  7. Wang Y, Lin Z, Wan H, Zhang W, Xia F, Chen Y, et al. Glucagon is associated with NAFLD inflammatory progression in type 2 diabetes, not with NAFLD fibrotic progression. Eur J Gastroenterol Hepatol. 2021;33:e818-23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Mohiuddin MS, Himeno T, Yamada Y, Morishita Y, Kondo M, Tsunekawa S, et al. Glucagon prevents cytotoxicity induced by methylglyoxal in a rat neuronal cell line model. Biomolecules. 2021;11(2):287.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. American Diabetes Association. Classification and diagnosis of diabetes: standards of medical care in diabetes-2020. Diabetes Care. 2020;43:S14-31.

    Article  Google Scholar 

  10. Wang L, Zhou B, Zhao Z, Yang L, Zhang M, Jiang Y, et al. Body-mass index and obesity in urban and rural China: findings from consecutive nationally representative surveys during 2004–18. Lancet. 2021;398(10294):53–63.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, et al. Using standardized serum creatinine values in the modification of diet in renal disease study equation for estimating glomerular filtration rate. Ann Intern Med. 2006;145(4):247–54.

    Article  CAS  PubMed  Google Scholar 

  12. Tesfaye S, Boulton AJ, Dyck PJ, Freeman R, Horowitz M, Kempler P, et al. Diabetic neuropathies: update on definitions, diagnostic criteria, estimation of severity, and treatments. Diabetes Care. 2010;33(10):2285–93.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Li F, Zhang Y, Li H, Lu J, Jiang L, Vigersky RA, et al. TIR generated by continuous glucose monitoring is associated with peripheral nerve function in type 2 diabetes. Diabetes Res Clin Pract. 2020;166:108289.

    Article  CAS  PubMed  Google Scholar 

  14. Xu F, Zhao LH, Wang XH, Wang CH, Yu C, Zhang XL, et al. Plasma 1,5-anhydro-D-glucitol is associated with peripheral nerve function and diabetic peripheral neuropathy in patients with type 2 diabetes and mild-to-moderate hyperglycemia. Diabetol Metab Syndr. 2022;14(1):24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sloan G, Selvarajah D, Tesfaye S. Pathogenesis, diagnosis and clinical management of diabetic sensorimotor peripheral neuropathy. Nat Rev Endocrinol. 2021;17(7):400–20.

    Article  PubMed  Google Scholar 

  16. van der Velde J, Koster A, Strotmeyer ES, Mess WH, Hilkman D, Reulen JPH, et al. Cardiometabolic risk factors as determinants of peripheral nerve function: the Maastricht Study. Diabetologia. 2020;63(8):1648–58.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Callaghan BC, Cheng HT, Stables CL, Smith AL, Feldman EL. Diabetic neuropathy: clinical manifestations and current treatments. Lancet Neurol. 2012;11(6):521–34.

    Article  PubMed  PubMed Central  Google Scholar 

  18. Wu F, Jing Y, Tang X, Li D, Gong L, Zhao H, et al. Anemia: an independent risk factor of diabetic peripheral neuropathy in type 2 diabetic patients. Acta Diabetol. 2017;54(10):925–31.

    Article  CAS  PubMed  Google Scholar 

  19. Bozadjieva Kramer N, Lubaczeuski C, Blandino-Rosano M, Barker G, Gittes GK, Caicedo A, et al. Glucagon resistance and decreased susceptibility to diabetes in a model of chronic hyperglucagonemia. Diabetes. 2021;70(2):477–91.

    Article  PubMed  Google Scholar 

  20. Shen Z, Chen M, Li Q, Ma J. Decreased glucagon in diabetic peripheral neuropathy patients with long duration type 2 diabetes. Postgrad Med J. 2024;100(1187):686–91.

    Article  PubMed  Google Scholar 

  21. Insuela DBR, Ferrero MR, Chaves ADS, Coutinho DS, Magalhães NDS, de Arantes ACS, et al. Pro-resolving role of glucagon in lipopolysaccharide-induced mice lung neutrophilia. J Endocrinol. 2023;259(1):e220196.

    Article  CAS  PubMed  Google Scholar 

  22. Hædersdal S, Andersen A, Knop FK, Vilsbøll T. Revisiting the role of glucagon in health, diabetes mellitus and other metabolic diseases. Nat Rev Endocrinol. 2023;19(6):321–35.

    Article  PubMed  Google Scholar 

  23. Færch K, Vistisen D, Pacini G, Torekov SS, Johansen NB, Witte DR, et al. Insulin resistance is accompanied by increased fasting glucagon and delayed glucagon suppression in individuals with normal and impaired glucose regulation. Diabetes. 2016;65(11):3473–81.

    Article  PubMed  Google Scholar 

  24. Osaka N, Kushima H, Mori Y, Saito T, Hiromura M, Terasaki M, et al. Anti-inflammatory and atheroprotective properties of glucagon. Diab Vasc Dis Res. 2020;17(5):1479164120965183.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sélley E, Kun S, Szijártó IA, Kertész M, Wittmann I, Molnár GA. Vasodilator effect of glucagon: receptorial crosstalk among glucagon, GLP-1, and receptor for glucagon and GLP-1. Horm Metab Res. 2016;48(7):476–83.

    Article  PubMed  Google Scholar 

  26. Motegi M, Himeno T, Nakai-Shimoda H, Inoue R, Ozeki N, Hayashi Y, et al. Deficiency of glucagon gene-derived peptides induces peripheral polyneuropathy in mice. Biochem Biophys Res Commun. 2020;532(1):47–53.

    Article  CAS  PubMed  Google Scholar 

  27. Marroqui L, Masini M, Merino B, Grieco FA, Millard I, Dubois C, et al. Pancreatic α cells are resistant to metabolic stress-induced apoptosis in type 2 diabetes. EBioMedicine. 2015;2(5):378–85.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Mooshage CM, Schimpfle L, Kender Z, Szendroedi J, Heiland S, Nawroth P, et al. Diametrical effects of glucose levels on microvascular permeability of peripheral nerves in patients with type 2 diabetes with and without diabetic neuropathy. Diabetes. 2023;72(2):290–8.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Funding

This study was financially supported by the Social Development Projects of Nantong (Grant Numbers MS12019019, HS2022004, and MS2023083), the Medical Research Project of the Jiangsu Health Commission (Grant Number Z2022058), and the National Natural Science Youth Fund of China (Grant Number 32101027).

Author information

Author notes

  1. Hao Hua and Rui Wang have contributed equally to this work.

Authors and Affiliations

  1. Department of Endocrinology, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No.666 Shengli Road, Nantong, 226001, China

    Hao Hua, Rui Wang, Yu-xian Xu, Feng Xu, Chun-hua Wang, Li-hua Zhao & Jian-bin Su

  2. Department of Nursing, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No.666 Shengli Road, Nantong, 226001, China

    Li-hua Wang

  3. Medical Research Center, Affiliated Hospital 2 of Nantong University, and First People’s Hospital of Nantong City, No.666 Shengli Road, Nantong, 226001, China

    Cheng-wei Duan

Authors
  1. Hao Hua
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Rui Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Yu-xian Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Feng Xu
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Chun-hua Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Li-hua Zhao
    View author publications

    You can also search for this author inPubMed Google Scholar

  7. Li-hua Wang
    View author publications

    You can also search for this author inPubMed Google Scholar

  8. Cheng-wei Duan
    View author publications

    You can also search for this author inPubMed Google Scholar

  9. Jian-bin Su
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

C.D. and J.S. were responsible for the study design, securing funding, and overseeing the entire research process. H.H. and R.W. contributed to the study design, patient recruitment, assessment of peripheral nerve function, and data analysis. L.W. and J.S. critically reviewed the manuscript. Y.X., F.X., C.W., L.Z., and L.W. were involved in the collection of the clinical data. L.W. also played a role in obtaining funding and interpreting the findings. H.H. drafted the initial version of the manuscript. All the authors reviewed and approved the final version of the manuscript.

Corresponding authors

Correspondence to Cheng-wei Duan or Jian-bin Su.

Ethics declarations

Ethics approval and consent to participate

This study received evaluation and approval from the Ethics Review Board of Affiliated Hospital 2 at Nantong University, under the reference number 2023KT228. All participants provided informed consent to take part in the study.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by-nc-nd/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Hua, H., Wang, R., Xu, Yx. et al. Glucagon: a potential protective factor against peripheral nerve compromise in patients with type 2 diabetes and obesity. Diabetol Metab Syndr 17, 35 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01601-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s13098-025-01601-2

Keywords

Diabetology & Metabolic Syndrome

ISSN: 1758-5996

Contact us