Type 2 diabetes remission in a non-obese patient: interplay between glucotoxicity reversal and catabolism-induced weight loss: a case report

¹Institut National de Nutrition et de Technologie Alimentaire, Tunis, Tunisia

^&Corresponding author
Insaf Jameleddine, Institut National de Nutrition et de Technologie Alimentaire, Tunis, Tunisia

Introduction    

Type 2 diabetes mellitus (T2D) ranks among the metabolic diseases with the most alarming epidemiological trajectory worldwide. According to the 10^th edition of the International Diabetes Federation Diabetes Atlas, approximately 537 million adults were living with diabetes in 2021, a figure projected to reach 783 million by 2045 [1]. Type 2 diabetes accounts for approximately 90% of diabetes cases and results from a combination of insulin resistance and progressive beta-cell dysfunction, involving multiple effector organs conceptually grouped under the term "ominous octet". Although traditionally considered chronic and irreversible, the T2D paradigm has been profoundly challenged by growing evidence of remission. In 2021, an international expert group defined remission as an HbA1c below 6.5%, measured at least three months after stopping all glucose-lowering pharmacotherapy [2].

The best-documented remission strategies involve bariatric surgery (remission rates of 30 to 63% depending on the procedure) and very-low-calorie diets (VLCD) as demonstrated in the DiRECT trial [3]. These strategies operate primarily through substantial weight loss and reduction of hepatic and pancreatic visceral fat, according to the "twin cycle" hypothesis proposed by Taylor et al. [4]. A complementary pathway involves glucotoxicity reversal through early intensive insulin therapy. A study was conducted by Ilkova et al. demonstrating that transient insulin therapy could induce prolonged drug-free glycemic control in patients with newly diagnosed T2D [5]. These findings were confirmed and quantified by Weng et al. (one-year remission rate of 51% with CSII) [6] and by the meta-analysis of Kramer et al. (66% at three months, 46% at twelve months) [7], with early intervention being the principal determinant of sustained remission [8]. However, when these two mechanisms coexist in the same patient, a major challenge arises: distinguishing the contribution of glucotoxicity reversal from that of weight loss, especially when involuntary catabolic weight loss reaches a metabolically significant magnitude. We report the case of a 40-year-old man, non-obese at admission (BMI 21.87 kg/m²), who experienced an involuntary weight loss of 9 kg (~13% of estimated initial body weight) concurrent with severely decompensated T2D, and who achieved complete and sustained remission following transient basal insulin therapy combined with metformin.

Patient and observation     

Patient information: a 40-year-old male carpenter was admitted to our department on September 26, 2022, for management of newly diagnosed diabetes. He was married for 11 years and father of two children, a non-smoker, sedentary, and reported alcohol cessation 13 years prior. His family history was notable for T2D in both parents and a brother, maternal obesity, as well as maternal dyslipidemia and dysthyroidism. He had no personal medical or surgical history and reported no drug allergies. The illness had begun four months earlier, marked by the progressive onset of cardinal symptoms of diabetes (polyuria, polydipsia, asthenia) and an involuntary weight loss of 9 kg occurring in this context of newly discovered diabetes. This weight loss reflected a catabolic state related to relative insulin deficiency and osmotic glucosuria, rather than voluntary caloric restriction. He had initially been placed on gliclazide 60 mg and metformin 850 mg twice daily for nine days before hospitalization. The initial outpatient workup had revealed severe hyperglycemia with an HbA1c of 13.7% and a fasting plasma glucose (FPG) of 2.65 g/L without ketotic decompensation.

Clinical findings: at admission, the patient weighed 61 kg for a height of 1.67 m, yielding a BMI of 21.87 kg/m². His weight prior to the catabolic episode was estimated at approximately 70 kg (BMI ∼25.1 kg/m²), corresponding to a weight loss of approximately 13% of initial body weight, a figure which, although involuntary, carries non-negligible metabolic significance. Blood pressure was 99/64 mmHg supine and 114/75 mmHg standing, without orthostatic hypotension. Electrocardiogram (ECG) showed regular sinus rhythm at 70 bpm with no abnormalities. Foot examination revealed cutaneous dryness and onychomycosis of the right great toe with keratosis pilaris of the left foot; the patient was referred to dermatology. Peripheral pulses were present and symmetrical.

Timeline: the patient's clinical course is summarized chronologically as follows. Four months before admission, the patient developed polyuria, polydipsia, and asthenia, together with an involuntary weight loss of 9 kg. Nine days before hospitalization, gliclazide 60 mg and metformin 850 mg twice daily were started, and the initial workup showed an HbA1c of 13.7% and a fasting plasma glucose of 2.65 g/L. On 26 September 2022, the patient was admitted (weight 61 kg, body mass index 21.87 kg/m²), and laboratory testing on 27 September 2022 confirmed severe hyperglycemia (HbA1c 12.2%, FPG 8 mmol/L). Transient basal insulin (insulin isophane 8 IU twice daily) combined with metformin was then initiated, and gliclazide was discontinued. At five months, on insulin isophane 6 IU twice daily and metformin, glycemic control had markedly improved (FPG 0.91 g/L, HbA1c 5.2%), and episodes of daytime hypoglycemia led to discontinuation of insulin, with metformin maintained. One month after stopping insulin (six months after diagnosis), HbA1c was 5.1%, and metformin was then progressively tapered and discontinued. At twelve months from diagnosis, six months after cessation of all pharmacotherapy, HbA1c was 5.5%, meeting the criteria for remission. Remission was sustained at 32 months, with an HbA1c of 5.3% and no glucose-lowering therapy.

Diagnostic assessment: anti-GAD serology performed on October 12, 2022, was negative, confirming the diagnosis of T2D in the context of family history and absence of autoimmune markers. Laboratory workup on September 27, 2022 revealed an HbA1c of 12.2% and FPG of 8 mmol/L. Complete blood count was normal (WBC 7,670/mm³, Hb 14.3 g/dL, platelets 316,000/mm³). Transaminases (AST 19 U/L, ALT 8 U/L), CRP (1 mg/L), and TSH (2.36 μIU/mL) were normal. The lipid panel showed total cholesterol of 3.72 mmol/L, HDL-cholesterol of 1.06 mmol/L, and triglycerides of 0.58 mmol/L. LDL-cholesterol was 0.92 g/L (2.38 mmol/L), within target for moderate cardiovascular risk (target below 1.15 g/L per the 2019 ESC/EAS guidelines). Serum calcium was 2.59 mmol/L. Serum creatinine was 69.4 μmol/L with an eGFR of 115.4 mL/min (CKD-EPI). Urinalysis was negative. A comprehensive complications screening was performed. No macrovascular complications were identified: no history of stroke or transient ischemic attack, no carotid bruits, no history of myocardial infarction or chest pain, no electrocardiographic abnormalities, no intermittent claudication, and posterior tibial pulses were present and symmetrical. Microvascular screening included a normal fundoscopic examination, microalbuminuria below 30 mg/L with creatinine clearance by CKD-EPI of 115.4 mL/min, excluding diabetic nephropathy. There were no signs of autonomic neuropathy (no orthostatic hypotension, no motor diarrhea, no constipation, no resting tachycardia), peripheral sensory examination was intact for tactile and deep sensation, and the Neuropathic Pain Questionnaire (DN4) score was 1/10, excluding hyperalgesic neuropathy.

Therapeutic intervention: given the severity of hyperglycemia, transient insulin therapy was initiated: insulin isophane (Insulatard®) 8 IU twice daily combined with metformin, after discontinuation of gliclazide. The patient was discharged with self-monitoring instructions and close outpatient follow-up.

Follow-up and outcomes: at five months, the patient was on Insulatard® 6 IU twice daily and metformin 850 mg daily. A remarkable glycemic improvement was documented (FPG 0.91 g/L, HbA1c 5.2%). Episodes of daytime hypoglycemia prompted complete discontinuation of insulin therapy, with metformin maintained at 850 mg twice daily. One month after insulin discontinuation (six months post-diagnosis), HbA1c was 5.1%. Metformin was progressively tapered and then discontinued. At twelve months from diagnosis, six months after complete cessation of all pharmacotherapy, HbA1c was 5.5%, meeting the definition of T2D remission according to the 2021 ADA/EASD/Diabetes UK consensus criteria [2]. Extended follow-up confirmed the durability of remission: at 32 months from initial diagnosis, HbA1c remained at 5.3% without any glucose-lowering therapy.

Patient perspective: the patient expressed relief at being able to discontinue all diabetes medications while maintaining normal blood glucose values. He recalled being worried at the time of diagnosis, particularly by the rapid and involuntary weight loss, but felt reassured by the early and structured management he received. He remains motivated to preserve his remission through a healthy lifestyle and regular follow-up.

Informed consent: written informed consent was obtained from the patient for the publication of this case report and any accompanying images. A copy is available for review by the editor upon request.

Discussion     

This case reports a complete and durable T2D remission in a non-obese patient following transient basal insulin therapy. While glucotoxicity reversal constitutes an appealing and biologically plausible explanation, it cannot be accepted as the sole mechanism without considering the potential impact of the 9 kg catabolic weight loss observed prior to treatment initiation. A rigorous analysis of this case therefore requires discussion of three non-mutually exclusive mechanistic scenarios.

Glucotoxicity reversal through insulin therapy

Glucotoxicity refers to the deleterious effects of chronic hyperglycemia on beta-cell function, operating through oxidative stress resulting from reactive oxygen species overproduction, endoplasmic reticulum stress, and beta-cell dedifferentiation. These mechanisms are at least partially reversible upon early restoration of normoglycemia [6,7]. In our patient, several arguments support this mechanism: presentation with severe hyperglycemia (HbA1c 13.7%) in the context of recent diagnosis, rapid glycemic normalization following insulin initiation, and sustained remission for 32 months after complete discontinuation of all pharmacotherapy. These observations are consistent with the data of Weng et al. [6] and Kramer et al. [7], who demonstrated that early intervention is the principal determinant of sustained remission. Moreover, non-obese T2D represents a phenotype in which beta-cell dysfunction predominates over insulin resistance [9], rendering these patients potentially more responsive to a strategy exclusively targeting beta-cell recovery. In this framework, the benefit of insulin therapy extends beyond its direct glucose-lowering effect: it provides functional rest to beta cells, interrupting the vicious cycle of glucotoxicity [5].

Contribution of catabolic weight loss

A major confounding factor, insufficiently considered in similar case reports, is the weight loss preceding treatment initiation. In our patient, the involuntary weight loss of 9 kg represents approximately 13% of the estimated initial body weight of ~70 kg. This magnitude is comparable to the 15 kg threshold identified in the DiRECT trial as a predictor of remission in obese patients [3], and proportionally even more significant in a lean individual. The twin cycle hypothesis of Taylor et al. [4] posits that T2D remission results from the reduction of hepatic steatosis (restoring hepatic insulin sensitivity and normalizing hepatic glucose production) and the reduction of intra-pancreatic fat (enabling recovery of insulin secretion). Importantly, this reduction of ectopic fat can occur regardless of the pathway through which it is achieved, whether voluntary or catabolic. Data suggest that reduction of hepatic and pancreatic fat can occur even with modest weight loss in non-obese individuals, owing to greater susceptibility of these ectopic compartments to caloric deficit [10]. Furthermore, the concept of "normal-weight type 2 diabetes" or "skinny fat" describes individuals whose BMI is normal but whose proportion of visceral and ectopic fat is disproportionately elevated relative to muscle mass [10]. With a prior BMI of ~25.1 kg/m² and reported sedentary lifestyle, this profile cannot be excluded in our patient. In this context, even a modest reduction of ectopic fat deposits may have played a determining role in remission, through mechanisms similar to those described in obese populations.

A combined and mutually reinforcing mechanism

The most plausible scenario, and the most scientifically rigorous, is that of synergy between the two preceding mechanisms. The catabolic weight loss prior to treatment initiation likely initiated a reduction of ectopic fat, triggering recovery of hepatic insulin sensitivity and partially relieving the pancreas. Insulin therapy, introduced in this favorable context, subsequently corrected hyperglycemia, lifting residual glucotoxicity and enabling beta-cell redifferentiation. These two processes therefore likely potentiated each other, with rapid glycemic normalization preventing glucotoxicity recurrence while ectopic adipose tissue reduction restored insulin sensitivity. This combined mechanism is consistent with data from Kramer et al. who showed that beta-cell recovery is more complete when the glucotoxic burden is rapidly and durably lifted, conditions met in this case by both insulin therapy and the improvement in insulin sensitivity resulting from weight loss [8]. It is also consistent with the work of Rothberg et al. highlighting that different remission pathways are not mutually exclusive and may share common mechanisms [9].

Comparison of T2D remission strategies

Table 1 summarizes the main published strategies for T2D remission and positions the present case within this spectrum. It highlights that remission pathways vary by target population and predominant mechanisms.

Implications for clinical practice

This case underscores several important points for clinical practice. First, aggressive management of severe hyperglycemia at the time of diagnosis through transient insulin therapy remains a justified and potentially curative strategy in non-obese patients, regardless of its exact mechanism [2]. Second, catabolic weight loss associated with uncontrolled diabetes should not be overlooked in the initial assessment: its magnitude can reach metabolically significant values capable of contributing to remission through mechanisms independent of insulin therapy. Third, the 2021 consensus definition does not specify the modality of remission [2], which legitimizes combined pathways but demands greater rigor in mechanistic attribution at the level of case reports. From a guideline perspective, current therapeutic algorithms focus primarily on weight-centered approaches [4], which may inadvertently neglect patients with normal or subnormal BMI. Yet these patients, often harboring a "skinny fat" phenotype with relative visceral adiposity, may benefit from an intervention simultaneously targeting glucotoxicity and ectopic fat reduction, however modest [10]. A personalized approach accounting for pre-illness BMI, the kinetics of weight loss, and diabetes duration thus appears more appropriate than a uniform algorithm.

Limitations

This report has several limitations inherent to case reports. As a single case, its findings cannot be generalized and do not establish causality. The most important limitation is the inability to dissociate the respective contributions of glucotoxicity reversal and catabolic weight loss in achieving remission. The 9 kg loss (~13% of initial weight), although involuntary, represents a metabolically significant magnitude that may have contributed to hepatic and pancreatic ectopic fat reduction, and thus to beta-cell recovery, independently of insulin therapy. The absence of hepatic and pancreatic imaging (MRI or ultrasound with steatosis quantification) before and after management precludes assessment of the contribution of ectopic fat content changes to the observed remission. Similarly, the absence of formal beta-cell function measurements (stimulated C-peptide, HOMA-B) limits our ability to characterize the degree of beta-cell recovery, although such measurements have not been shown to predict remission in intervention trials such as DiRECT. Furthermore, no data on weight evolution during follow-up are available, precluding assessment of whether the patient regained weight and to what extent this influenced remission maintenance. The contribution of spontaneous lifestyle modifications (dietary changes, physical activity) cannot be entirely excluded, although no structured intervention was prescribed. Finally, this case describes remission following transient basal insulin therapy (insulin isophane twice daily) rather than the more intensive regimens (CSII or basal-bolus MDI) used in landmark trials, and the follow-up duration, while satisfactory at 32 months, does not predict the risk of long-term relapse. Continued surveillance is therefore essential.

Conclusion     

We report a case of complete and durable T2D remission in a non-obese patient following transient basal insulin therapy combined with metformin, with sustained remission documented at 32 months. However, attributing this remission solely to glucotoxicity reversal would be scientifically reductive: the prior catabolic weight loss of approximately 13%, occurring in the context of severely decompensated diabetes, constitutes a major confounding factor whose contribution to visceral fat reduction and beta-cell recovery cannot be excluded. A combined mechanism, in which insulin therapy and weight loss mutually potentiate each other, represents the most plausible and most intellectually honest hypothesis. This case illustrates the complexity of mechanistic attribution in T2D remission reports and underscores the need for rigorous assessment of all contributing factors, including prior weight loss and relative visceral adiposity, even in patients with normal BMI. It also highlights the importance of early and aggressive management of severe hyperglycemia at the time of diagnosis. Prospective studies integrating ectopic fat imaging, beta-cell function measurements, and rigorous weight monitoring are needed to disentangle the respective contributions of different remission mechanisms, particularly in the non-obese population.

Competing interests     

The authors declare no competing interests.

Authors' contributions     

All authors participated in the clinical management of the patient and in the conception, drafting, and critical revision of the manuscript. All authors read and approved the final version of the manuscript and agree to be accountable for all aspects of the work.

Table     

Table 1: summary of published strategies for type 2 diabetes remission and positioning of the present case

References