Rapid Glycaemic Control Leading to Painful Neuropathy: A Case of Treatment-Induced Neuropathy of Diabetes in a Young Patient

Abstract

Introduction

Intensive glycaemic control is essential for managing Type 1 Diabetes Mellitus (T1DM), yet rapid metabolic optimization can trigger Treatment-Induced Neuropathy of Diabetes (TIND). This iatrogenic condition, characterized by acute neuropathic pain and autonomic dysfunction, is increasingly relevant with the use of advanced automated insulin delivery (AID) systems.

Case Presentation

A 19-year-old male with a 10-year history of poorly controlled T1DM (baseline HbA1c 13.7%) was transitioned to an automated hybrid closed-loop system (Medtronic MiniMed 780G). Following a rapid HbA1c reduction of 6.3% over six weeks, the patient developed severe, “electric shock-like” neuropathic pain in the lower limbs and upper back without associated autonomic nervous system involvement. Nerve conduction studies confirmed a length-dependent sensorimotor axonal polyneuropathy. The patient’s pain was refractory to duloxetine but showed significant improvement with gabapentin alongside clinical recovery observed over 4 weeks. To stabilize glucose levels, the AID system was discontinued in favor of a less intensive multiple daily injection (MDI) regimen.

Conclusion

Rapid glycemic correction in patients with high baseline HbA1c carries a significant risk of TIND. Clinicians should consider close monitoring and individualized adjustment of blood glucose descent in high-risk individuals, even when utilizing advanced AID systems, to prevent debilitating neurological complications.

Introduction

The management of Type 1 Diabetes Mellitus (T1DM) has been fundamentally shaped by the principle that intensive glycemic control significantly reduces the risk of long-term microvascular and macrovascular complications. Since the landmark findings of the Diabetes Control and Complications Trial (DCCT), achieving near-normal glycated hemoglobin (HbA1c) levels has remained the therapeutic gold standard.¹ In the modern era, the integration of advanced technologies, such as continuous glucose monitoring (CGM) and automated insulin delivery (AID) systems, has empowered clinicians and patients to achieve these targets with greater precision and speed than ever before.^2,3

A paradoxical and iatrogenic complication of rapid glycemic improvement is the development of an acute, painful sensory neuropathy, historically known as “insulin neuritis” and more recently redefined as Treatment-Induced Neuropathy of Diabetes (TIND). TIND is characterized by severe neuropathic pain and autonomic dysfunction that emerges shortly after a significant drop in HbA1c.⁴ While TIND classically presents in older adults with decades of poorly controlled diabetes, its occurrence in young adults and adolescents represents an increasingly recognized clinical dilemma. The clinical definition of TIND was formalized by Gibbons and Freeman (2015), who identified a threshold of a 2% or greater reduction in HbA1c over a three-month period as the primary risk factor for its development. Crucially, their analysis demonstrated that the severity of the neuropathy, as well as the risk of accompanying retinopathy or nephropathy progression, are strongly correlated with both the magnitude and velocity of the HbA1c decline.⁴ Although exact incidence remains unknown, TIND is likely underdiagnosed due to clinical overlap with typical diabetic neuropathy.

This phenomenon is not a new clinical observation, having been documented shortly after the widespread introduction of insulin therapy. Early descriptions by Caravati (1933) and later by Rundles (1945) highlighted cases of acute pain and paraesthesia following the initiation of insulin in patients with chronic hyperglycaemia.^5,6 Despite these early historical accounts, the condition remained poorly understood for decades, often being misdiagnosed as standard diabetic peripheral neuropathy. Modern re-evaluations emphasize that while traditional diabetic neuropathy is a result of chronic metabolic stress, the pathophysiology of rapid glycemic drops induce intense epineurial arteriovenous shunting, triggering acute endoneurial ischemia, localized tissue hypoxia, and ectopic firing during small nerve fiber regeneration.⁷ Notably, TIND predominantly affects small unmyelinated sensory and autonomic nerve fibers, which may not be fully reflected on routine nerve conduction studies that primarily evaluate large myelinated fibers.⁸

The advent of highly efficient technology, such as the Medtronic 780G automated hybrid closed-loop system, has introduced a new dimension to this clinical challenge. While these systems excel at reducing glucose variability and maximizing Time in Range (TIR), they currently lack built-in algorithmic parameters to constrain or stage the velocity of long-term HbA1c reduction in individuals with severe baseline hyperglycemia.³ Current literature establishes that patients with a high baseline HbA1c and a long duration of preceding poor control are at the highest physiological risk for TIND.⁴

In this report, we present the case of a 19-year-old male with long-standing T1DM who developed severe, treatment-resistant TIND following a precipitous HbA1c reduction of 6.3% in just six weeks after transitioning to an automated insulin delivery (AID) system (Medtronic MiniMed 780G). This case is presented in accordance with the CARE guidelines to illustrate the critical need for balanced glycaemic descent in the era of advanced diabetes technology.

Case Presentation

A 19-year-old male with a 10-year history of type 1 diabetes mellitus presented with acute onset severe neuropathic pain following recent intensification of glycemic control. Prior to treatment optimization, his glycemic control was poor, with a baseline HbA1c of 13.7%. He was initially managed with a basal-bolus insulin regimen consisting of insulin degludec (30 units once daily) and insulin aspart (15 units three times daily). Subsequently, he was transitioned to continuous subcutaneous insulin infusion using an insulin pump (Medtronic 780G system), resulting in a rapid improvement in glycemic control. His HbA1c decreased to 7.4% within 6 weeks (Table 1). Approximately 2–3 weeks after initiation of intensive insulin therapy, the patient developed severe tingling and electric shock-like pain. The pain was described as persistent and debilitating, leading to multiple emergency department visits. It was predominantly distributed in the lower limbs and extended to the upper back. There were no associated autonomic symptoms such as orthostatic dizziness, gastrointestinal disturbances, or abnormal sweating.

Table 1.

Chronological Summary of Patient Course and Glycemic Metrics

Timeframe	Clinical Status & Interventions	HbA1c (%)	Diagnostic Findings
Baseline (Week 0)	Transitioned from MDI (degludec/aspart) to Medtronic MiniMed 780G AID pump	13.7%	Severe chronic hyperglycemia; asymptomatic for acute neuropathy
Week 2–3	Onset of acute, severe, electric shock-like lower limb and back pain	Unmeasured	ED visits; normal spinal/brain MRI; normal CRP/ESR
Week 6	Diagnostic workup completed; initial pain therapy started	7.4% (Drop of 6.3%)	NCS shows sensorimotor polyneuropathy; B12 212 pmol/L (borderline); isolated high FT4
Week 6–7	Duloxetine ineffective; switched to Gabapentin 300 mg TID; Pump stopped	7.4%	Significant pain control with gabapentin; transitioned to MDI
Week 10 (Follow-up)	Outpatient neurology review; near-complete pain resolution	Stable	Gradual recovery documented over 4 weeks

The radiological assessment focused on investigating suspected transverse myelitis through contrast-enhanced MRI studies of the brain, cervical spine, and lumbar spine, all of which were concluded as unremarkable with no evidence of acute vascular insult, hemorrhage, mass lesion, or midline shift. Laboratory findings revealed an isolated elevation of Free T4 (FT4) levels (23.20 pmol/L and 22.60 pmol/L) with normal Thyroid Stimulating Hormone (TSH) levels (0.67 mIU/L and 0.84 mIU/L), a pattern consistent with non-thyroidal illness or transient analytical variation rather than primary thyrotoxicosis. Biochemical levels were predominantly normal, including Glucose at 4.7 mmol/L, Urea between 2.7 and 3.4 mmol/L, Creatinine between 43 and 49 µmol/L, and normal electrolytes such as Sodium at 139 mmol/L, Potassium at 4.1 mmol/L, Chloride at 100 mmol/L, and Calcium at 2.48 mmol/L. Liver and general metabolic markers were also normal, including ALT at 18 U/L, Alkaline Phosphatase at 114 U/L, Total Bilirubin at 7 µmol/L, Albumin at 38 g/L, and Total Protein at 76 g/L. Nutritional markers demonstrated a serum Vitamin B12 level of 212 pmol/L, which falls within the borderline/low-normal reference range. While borderline B12 levels can occasionally contribute to peripheral nerve symptoms, the hyperacute, explosive onset of severe lancinating pain closely timed with a 6.3% HbA1c reduction was overwhelmingly characteristic of acute TIND. Nevertheless, precautionary oral B12 supplementation was administered. As well, vitamin D3 was sufficient at 65 nmol/L.

Hematological and inflammatory investigations showed a normal C-Reactive Protein (CRP) of 1.6 mg/L and an ESR of 5 mm/hr. Complete blood count (CBC) results included a White Blood Cell count of 5.90 x 10³/uL, Hemoglobin at 14.3 g/L, and Platelets at 332 x 10³/uL. Specific hematological variations included a high monocyte percentage of 9.6% and a low Mean Platelet Volume (MPV) of 7.3 fL. Coagulation profiles were normal with a PT of 12.0 seconds (INR 1.02) and an APTT of 31.1 seconds (Ratio 1.02). Finally, cardiac marker testing showed hs-Troponin I levels within normal limits at 3.00 ng/L and less than 4.00 ng/L. Neurological evaluation, including nerve conduction studies, demonstrated evidence of length-dependent sensorimotor axonal polyneuropathy affecting both upper and lower limbs. The potential causes of acute neuropathy were considered and excluded based on clinical assessment and available investigations. The temporal relationship between rapid glycemic correction and symptom onset was highly suggestive of treatment-induced neuropathy of diabetes. The patient was initially treated with duloxetine 60 mg daily, with minimal improvement. Subsequently, gabapentin 300 mg three times daily was initiated, resulting in significant symptomatic relief. Tramadol was used as needed for breakthrough pain. The patient was followed up by a neurologist, and gradual clinical improvement was noted over 4 weeks. Given the suspected diagnosis, insulin pump therapy was discontinued, and glycemic control was re-established using a less intensive insulin regimen.

Discussion

Treatment-induced neuropathy of diabetes (TIND), also referred to as insulin neuritis, is a rare but increasingly recognized iatrogenic complication associated with rapid correction of chronic hyperglycemia.⁹ It is characterized by the acute onset of severe neuropathic pain and/or autonomic dysfunction occurring within weeks of substantial improvement in glycaemic control.⁴ In the present case, a 19-year-old patient with longstanding poorly controlled type 1 diabetes mellitus developed severe painful neuropathic symptoms shortly after initiation of intensive insulin therapy using a hybrid closed-loop insulin pump system. The marked temporal relationship between rapid glycaemic improvement and symptom onset strongly supports the diagnosis of TIND.

TIND was first systematically characterized by Gibbons and Freeman, who demonstrated that rapid reduction in HbA1c is strongly associated with the development of acute neuropathic symptoms, particularly when HbA1c decreases by more than 2 percentage points over a three-month period.¹⁰ In our patient, HbA1c decreased dramatically from 13.7% to 7.4% within only six weeks, representing a reduction of 6.3 percentage points and substantially exceeding the previously reported risk threshold. The magnitude and speed of glycaemic correction in this case likely contributed significantly to the development of neuropathic injury.

Unlike classical distal symmetric diabetic polyneuropathy, which generally develops gradually over years in the setting of chronic hyperglycemia, TIND presents acutely and is frequently severe and debilitating.^11–13 Our patient developed persistent tingling and electric shock-like pain approximately 2–3 weeks after initiation of intensive insulin therapy, resulting in multiple emergency department visits because of uncontrolled symptoms. The acute onset and rapid progression of symptoms in close proximity to glycaemic correction were highly suggestive of TIND rather than progression of chronic diabetic neuropathy. However, because the patient had long-standing poorly controlled diabetes (baseline HbA1c 13.7%), it is plausible that underlying, asymptomatic chronic diabetic sensorimotor polyneuropathy was already present, which accounts for the large-fiber changes identified on standard nerve conduction studies. The lack of specialized small-fiber diagnostic testing (such as skin punch biopsy for intraepidermal nerve fiber density) and formal autonomic reflex testing represents a diagnostic limitation in this report.

The exact pathophysiological mechanisms underlying TIND remain incompletely understood; however, several hypotheses have been proposed. Rapid correction of chronic hyperglycemia is believed to produce sudden metabolic and microvascular changes within peripheral nerves. Proposed mechanisms include epineurial arteriovenous shunting leading to endoneurial ischemia, neuronal apoptosis triggered by abrupt glucose deprivation, oxidative stress, and microvascular dysregulation resulting in nerve hypoxia.¹⁰ In addition, regeneration of injured small nerve fibers may contribute to severe neuropathic pain through abnormal ectopic neuronal firing.¹⁴ These mechanisms may explain the paradoxical occurrence of severe neuropathic symptoms despite apparent metabolic improvement.

Most published reports of TIND involve adults with long-standing poorly controlled diabetes and frequently include autonomic dysfunction such as orthostatic hypotension, gastrointestinal dysmotility, resting tachycardia, or abnormal sweating.^11,15 Interestingly, our patient did not demonstrate clinically significant autonomic manifestations despite severe neuropathic pain. This observation highlights the heterogeneity of TIND presentations and suggests that painful sensory neuropathy may occur in isolation without overt autonomic involvement. In youth and pediatric TIND cohorts, literature demonstrates a dominant triad of acute severe pain, profound weight loss (cachexia), and widespread autonomic dysregulation (such as gastroparesis or orthostatic intolerance).¹⁶ In contrast, our 19-year-old patient presented with isolated severe sensory pain without autonomic or cachectic features, broadening the clinical spectrum observed in young adults.

Another clinically important aspect of this case is the association with advanced diabetes technology. The increasing use of continuous subcutaneous insulin infusion systems and hybrid closed-loop insulin delivery devices has substantially improved glycaemic outcomes in patients with type 1 diabetes mellitus. However, these technologies may facilitate very rapid correction of chronic hyperglycemia, particularly in patients with markedly elevated baseline HbA1c levels. In the present case, initiation of the Medtronic 780G insulin pump system was followed by a profound and rapid reduction in HbA1c within a short period. Importantly, the association with the Medtronic MiniMed 780G system in this case highlights a technology-driven dilemma rather than a device defect. AID systems are not inherently neurotoxic; rather, their extraordinary efficacy in normalizing glucose levels can facilitate a precipitous metabolic descent in patients with extreme baseline hyperglycemia. As automated closed-loop technologies become the standard of care globally, clinicians must recognize that unadjusted algorithmic targets in patients with severe baseline hyperglycemia can inadvertently precipitate treatment-induced neuropathy in diabetes (TIND).

The diagnosis of TIND remains primarily clinical and requires careful exclusion of alternative aetiologies of acute neuropathy. In our patient, other potential causes, including thyroid dysfunction, were excluded through laboratory and clinical evaluation. The characteristic temporal association between rapid glycaemic correction and symptom onset, combined with electrophysiological evidence of axonal polyneuropathy, strongly supported the diagnosis. Recognition of this temporal relationship is particularly important because symptoms may otherwise be misinterpreted as progression of diabetic neuropathy, functional pain syndromes, or unrelated neurological disease, potentially resulting in unnecessary investigations and delayed treatment.

Management of TIND remains challenging because there is currently no universally established treatment strategy. Therapy is generally supportive and focuses on symptom control and stabilization of glycaemic fluctuations.¹¹ Neuropathic pain agents, including duloxetine, pregabalin, and gabapentin, are commonly used.¹⁷ In our patient, duloxetine produced minimal symptomatic benefit, whereas gabapentin administration resulted in significant improvement in pain severity. Tramadol was additionally required for breakthrough pain. This clinical response is consistent with previous reports demonstrating variable responsiveness to neuropathic pain therapies in TIND patients.^10,15 Given that multiple interventions occurred concurrently, including gabapentin initiation, insulin regimen adjustment, and the natural self-limiting course of TIND, it is difficult to isolate which single factor contributed most to pain resolution, and clinical recovery likely reflects a combination of these factors.

This case underscores the importance of cautious and individualized glycaemic optimization, particularly in patients with chronically poor baseline glycaemic control. Although achieving optimal glycaemic targets remains essential in preventing long-term diabetic complications, overly rapid correction of chronic hyperglycemia may itself precipitate acute neurological injury. Clinicians should therefore maintain a high index of suspicion for TIND in patients presenting with acute neuropathic symptoms shortly after initiation or intensification of insulin therapy. Careful monitoring and gradual glycaemic correction strategies may help minimize the risk of this potentially debilitating but potentially reversible iatrogenic complication.

Conclusion

This case highlights a critical clinical paradox: the emergence of Treatment-Induced Neuropathy of Diabetes (TIND) precipitated by the rapid glycemic optimization of advanced diabetes technology. While hybrid closed-loop systems like the Medtronic MiniMed 780G excel at maximizing Time in Range, their capacity to drive a precipitous drop in HbA1c (6.3% over six weeks) can trigger a severe metabolic adaptation in peripheral nerves, causing debilitating sensory neuropathic pain. Notably, this case demonstrates that TIND can present as an isolated, severe painful neuropathy without the widespread autonomic dysfunction or cachexia typical in younger cohorts.

As automated insulin delivery (AID) systems become standard care, clinicians must remain vigilant. For patients with high baseline HbA1c levels and a history of prolonged poor control, clinicians should emphasize close clinical monitoring, avoid excessive short-term glucose fluctuations, and individualize treatment intensity rather than pursuing immediate, aggressive glycemic normalization.

Data Sharing Statement

The data that support the findings of this study are available upon reasonable request from the corresponding author. The data are not publicly available due to privacy and ethical restrictions.

Ethical Approval and Consent

In our institution, ethical approval is not required for case reports.

Consent for Publication

Written informed consent was obtained from the patient for the publication of this case report and any accompanying data.

Author Contributions

All authors made a significant contribution to the work reported, whether that is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising or critically reviewing the article; gave final approval of the version to be published; have agreed on the journal to which the article has been submitted; and agreed to be accountable for all aspects of the work.

Disclosure

The authors declare that they have no known competing financial interests or personal relationships that could have influenced the work reported in this paper.