Letter to the Editor: Endocrine determinants of diabetic ketoacidosis outcomes in type 2 diabetes and insights into Gymnema sylvestre actions

Abstract

We read with great interest the recent articles by Chandrabalan et al on diabetic ketoacidosis (DKA) in type 2 diabetes mellitus (T2DM) and by Kodiyatar et al on adjuvant herbal therapies. These articles provide important insights into DKA in T2DM, both at a clinical and experimental level. However, further endocrine aspects need to be addressed. In one study a paradoxical relationship between pre-admission metformin use and reduced in-hospital mortality from DKA was noted; this may be related to preserved beta-cell function and a more favorable incretin-glucagon axis rather than a pharmacological effect per se. However, important endocrine effectors such as C-peptide, glucagon, and incretin hormones were not measured. Furthermore, currently available antidiabetic agents, such as glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors, have not been taken into account despite their possible effects on ketogenesis. An additional and underappreciated complexity is the concurrent occurrence of acute pancreatitis (AP) in DKA patients (DKA-AP), a complication that may affect at least 15% of DKA cases and that can neutralize key clinical and biochemical features of each condition, confounding diagnosis and worsening prognosis. At the same time, studies on Gymnema sylvestre have shown promising effects on glycemia and metabolism, while their endocrine effects have not been fully characterized. Recent data have shown possible effects of this herbal preparation on glucocorticoid receptors, suggesting a possible impact on the hypothalamus-pituitary-adrenal axis. We propose that future studies take into account detailed hormonal profiles and systematic screening for concurrent AP, which could help to further clarify the pathophysiology and mechanisms of currently available agents in T2DM-associated DKA.

Key Words: Diabetic ketoacidosis; Type 2 diabetes mellitus; Incretin axis; Glucagon-like peptide-1; Beta-cell function; Gymnema sylvestre

Core Tip: Endocrine parameters - including beta-cell reserve, incretin signaling, and glucagon dynamics - are critical but underexplored determinants of diabetic ketoacidosis (DKA) outcomes in type 2 diabetes mellitus. The concurrent occurrence of acute pancreatitis in DKA, which may affect at least 15% of cases and substantially worsens prognosis, adds diagnostic complexity by masking hallmark features of both conditions and amplifying metabolic and hormonal dysregulation. The metabolic effects of Gymnema sylvestre also require deeper hormonal characterization to clarify its mechanism of action.

TO THE EDITOR

We read with considerable interest two articles recently published in the World Journal of Experimental Medicine: The retrospective cohort study by Chandrabalan et al[1] examining risk factors for mortality and adverse outcomes in diabetic ketoacidosis (DKA) complicating type 2 diabetes mellitus (T2DM), and the experimental study by Kodiyatar et al[2] evaluating the antidiabetic effects of Gymnema sylvestre (GS) and metformin co-therapy in a streptozotocin-induced T2DM rat model. Both papers address important clinical and translational questions in diabetes care; however, we believe several endocrine and hormonal dimensions warrant further comment, as their omission may limit the interpretability and translational value of the findings.

THE PARADOX OF METFORMIN IN DKA MORTALITY: AN ENDOCRINE PERSPECTIVE

The study by Chandrabalan et al[1] presents a striking paradox that metformin usage before admission is independently associated with a 91% reduction in odds of in-hospital mortality, while its continuation after discharge is associated with a 6.6-fold risk of increasing mortality. The authors recognize that this is likely due to confounding bias and not a direct effect. However, it is worthwhile to explore the endocrine implications of this study. The main mechanism of action of metformin is through its activation of AMP-activated protein kinase. This activation reduces glucose production in the liver and enhances sensitivity to insulin[3]. Outpatients are administered metformin, considering that they are not insulinopenic and have sufficient beta-cell function to respond to an insulin sensitizing agent. In T2DM patients who present with DKA, the main causative pathophysiological mechanisms are relative (or absolute) insulin deficiency and hyperglucagonemia[4]. The apparent in-hospital protective effect of prior metformin use may therefore be a proxy for a preserved incretin-glucagon axis rather than a direct pharmacological benefit. More in detail, patients on metformin tend to have higher circulating glucagon-like peptide-1 (GLP-1) levels; metformin has been shown to increase GLP-1 secretion through bile acid–mediated mechanisms in the distal gut[5]. This enhanced incretin tone suppresses excess glucagonemia (which is a central driver of ketogenesis in DKA). Notably, the study does not report glucagon levels, C-peptide measurements, or incretin axis assessments at baseline or during admission. Incorporating these hormonal markers in future prospective studies would substantially clarify whether the protective association with metformin reflects residual beta-cell reserve, preserved GLP-1 signaling, or both. This distinction is clinically important: Patients with low C-peptide concentrations — indicating advanced beta-cell failure — are at substantially higher DKA risk and may require early transition to insulin-based regimens regardless of their prior oral antidiabetic therapy[6].

THE INCRETIN AXIS IN DKA RISK STRATIFICATION

Related to the above, the study’s analysis of antidiabetic medications focuses primarily on older agents (metformin, sulfonylureas) and sodium-glucose co-transporter 2 inhibitors (SGLT-2i). The authors note that SGLT-2i use was associated with prolonged hospital stay; this is consistent with the established euglycemic DKA risk of this drug class. However, no data are presented regarding GLP-1 receptor agonist (GLP-1RA) or dipeptidyl peptidase-4 (DPP-4) inhibitor use in the cohort, despite the authors’ own observation that patients on newer agents had apparent survival advantages. GLP-1RAs suppress glucagon secretion; however they may paradoxically reduce DKA risk in T2DM by attenuating the counter-regulatory hormonal milieu that drives ketogenesis[7]. In an analogous way, DPP-4 inhibitors, while generally safe, may modestly increase glucagonemia. Future studies examining DKA in T2DM should assess the full pharmacological burden of patients, including incretin-based therapies, as these agents exert direct effects on alpha-cell function that fundamentally alter ketogenic risk.

HORMONAL MECHANISMS OF GS - BEYOND GLUCOSE ABSORPTION INHIBITION

The experimental study by Kodiyatar et al[2] demonstrates that GS, alone and combined with metformin, significantly improves glycemic control, lipid profile, and renal function in a high-fat diet/streptozotocin T2DM rat model. While the authors acknowledge the role of gymnemic acids in reducing intestinal glucose absorption and stimulating insulin secretion, the broader endocrine pharmacology of GS merits more detailed discussion. Of particular interest is the insulinotropic effect of GS; this effect has been attributed to direct stimulation of pancreatic beta-cell regeneration and increased insulin secretion independent of glucose concentration[8]. However, the mechanism by which this occurs — whether through enhanced glucose-stimulated insulin secretion, upregulation of insulin gene transcription, or modulation of the incretin axis — remains incompletely characterized. In the study by Kodiyatar et al[2], fasting blood glucose and HbA1c were measured to assess glycemic control. There was no assessment though of fasting insulin, C-peptide, or of the homeostatic model assessment of insulin resistance. Without these indices, it is not possible to determine whether the observed glycemic improvement reflects enhanced insulin secretion, improved peripheral insulin sensitivity, or both — a distinction with mechanistic and translational implications. Furthermore, we have to bear in mind that the gymnemic acids share structural similarities with the steroidal saponins. Additionally, they have been shown to interact with glucocorticoid signaling pathways in adipose tissue[9]. As glucocorticoid excess is a well-established driver of both insulin resistance and dyslipidemia (parameters assessed by Kodiyatar et al[2]), future research should examine whether GS exerts any modulatory effects on the hypothalamic-pituitary-adrenal (HPA) axis activity or cortisol metabolism. This would enrich our understanding of its lipid-lowering and insulin-sensitizing properties observed in the current model.

CONCURRENT PANCREATITIS IN DKA: A CLINICALLY IMPORTANT COMPLICATION THAT MODIFIES THE ENDOCRINE PICTURE

Abdominal pain, nausea, vomiting, and elevated inflammatory markers are all present in DKA and AP. The presence of AP may minimize the severity of biochemical abnormalities associated with DKA, such as the severity of acidosis. A recent retrospective study and literature review by Chen et al[10] found DKA-AP may comprise at least 15% of DKA cases. DKA-AP, if not diagnosed, has a significantly increased mortality rate compared to DKA and AP. Increased total cholesterol levels (≥ 7.71 mmol/L), increased triglyceride levels (≥ 11.90 mmol/L), increased abdominal pain duration (≥ 3 days), are independent predictors of DKA-AP. The predictive model has an area under the receiver operating characteristic curve of 0.933. Hypertriglyceridemia, which may cause AP via increased free fatty acids, which affect the pancreas, may be one of the key pathophysiological links between DKA and AP. From an endocrine perspective, lipid disorders associated with DKA-AP may further disrupt hormone signaling pathways, which may exacerbate glucagon excess. This may have direct implications for the risk stratification approach proposed for patients with DKA in T2DM. We therefore encourage future studies examining DKA in T2DM to systematically screen for concomitant AP through lipase, amylase, and triglyceride measurements, and to assess the degree to which this comorbidity modifies the endocrine and hormonal profiles under discussion.

CONCLUSION

Both studies contribute to the diabetes literature. However, the endocrine dimensions of DKA pathophysiology in T2DM — particularly the roles of glucagon excess, beta-cell reserve, incretin tone, and counter-regulatory hormone dynamics — remain underexplored. The added complexity of concurrent AP, which may affect at least 15% of DKA patients and significantly worsens prognosis[10], points to the importance of comprehensive endocrine and biochemical profiling. Similarly, a more complete hormonal characterization of GS’s mechanism of action, including insulin secretory indices and potential HPA axis interactions, is warranted. We encourage the authors and future investigators to incorporate these endocrine parameters into study designs addressing these important questions.