Latent autoimmune diabetes in adults (LADA) is an adult-onset form of autoimmune diabetes combining features of both type 1 and type 2 diabetes. Defined by islet autoantibodies, most commonly glutamic acid decarboxylase (GAD) antibodies, it presents later in life and progresses more slowly toward insulin dependence, leading to frequent misclassification as type 2 diabetes mellitus (T2DM). LADA is not rare, accounting for 2-12% of adult-onset diabetes' however, it remains under-recognised; diagnostic delays result in prolonged hyperglycaemia, inappropriate treatment and accelerated β-cell decline. Adults with atypical glycaemic patterns, the rapid loss of glycaemic control, or coexisting autoimmune disease should be evaluated using islet autoantibodies and C-peptide testing (1). LADA exists on a spectrum from classic autoimmune diabetes to a T2DM-like phenotype, rendering diagnosis challenging, particularly in individuals retaining β-cell function at onset or presenting with obesity or insulin resistance (2). Early insulin initiation may preserve endogenous secretion (3), and guidelines support C-peptide-guided treatment decisions (4).

The present case report describes the case of a 39-year-old man with long-standing, severely uncontrolled diabetes of initially undetermined type who presented with chronic watery diarrhoea, significant unintentional weight loss, persistent hyperglycaemia and a pruritic vesicular rash, a constellation that prompted evaluation for neuroendocrine tumour, Crohn's disease and malabsorption syndromes before the underlying autoimmune diabetes was recognised.

A 39-year-old man with diabetes of unknown type, hypertension and chronic medication non-adherence presented at the Wellstar Spalding Medical Center (Griffin, GA, USA) with a 3-month history of diffuse watery diarrhoea, nausea, vomiting and severe cramping abdominal pain. Symptoms had worsened over the preceding year, accompanied by profound unintentional weight loss from 113.4 kg (250 lb) to 57.2 kg (126 lb) over a period of 12 months, accelerating over the final 6 months. Collateral history from his mother confirmed he had been well until ~1 year earlier. He reported a pruritic vesicular rash beginning on the buttocks that spread to the left leg before partially resolving and persistent angular lip fissures. He denied fevers, chest pain, dyspnoea and substance use.

Of note, 1 year earlier, he had been hospitalised with similar symptoms, treated as colitis with intravenous fluids and a 7-day course of intravenous antibiotics and corticosteroids. His HbA1c was then >15%, and he was discharged on insulin. His family history included a father with severe uncontrolled diabetes and a brother with thyroid disease. Home medications were insulin glargine at 20 units, sliding-scale insulin, pantoprazole, ondansetron, cetirizine and hyoscyamine. He has a documented allergy to penicillins.

Upon admission he was afebrile (37.0˚C), with a blood pressure of 108/74 mmHg, a heart rate of 80 beats/min, a respiratory rate of 15/min and an oxygen saturation of 100% in room air. His height was 1.778 m and his weight was 57.2 kg, with a body mass index of 18.1 kg/m², reduced from an estimated 35.9 kg/m² at his pre-illness weight and representing a loss of ~50% of total body weight. He appeared thin, cachectic and ill, but non-toxic, alert and oriented. The oral mucosa was dry with bilateral angular fissures and no intra-oral lesions. A cardiac examination revealed normal heart sounds without murmurs, 2+ pulses, and no oedema; the lungs were clear. The abdomen was soft with diffuse mild-to-moderate tenderness, no rebound or guarding and normal bowel sounds. A skin examination revealed erythematous plaques over the buttocks with scattered vesicles, crusted lesions and excoriations without cellulitis; the left leg showed no active rash. Acanthosis nigricans was absent. A neurological examination was intact, and he was tearful with a depressed affect, but cooperative.

A timeline summarising the key clinical events from initial symptom onset through hospitalisation and discharge is presented in Table I.

The present case report highlights the diagnostic challenge of LADA, which is frequently misclassified as T2DM. The patient described herein presented with adult-onset diabetes and a family history suggestive of T2DM and was managed accordingly until deteriorating glycaemic control prompted re-evaluation, revealing islet autoantibody positivity. Progressive β-cell failure following years of presumed T2DM is a well-described trajectory (4).

Under updated American Diabetes Association guidance, LADA is classified within the type 1 diabetes mellitus (T1DM) rubric, reflecting autoimmune β-cell destruction (5). Pathogenesis is primarily cell-mediated: Peripheral blood mononuclear cells suppress insulin secretion, and dysfunctional regulatory T-cells contribute to loss of immune tolerance (6). Patients may test positive for one or more islet autoantibodies, including GAD, IA-2A, insulin, ZnT8A, or tetraspanin 7 antibodies (7). Consensus criteria generally include adult-onset diabetes, typically after 30 years of age, islet autoantibody positivity, and an initial non-insulin-requiring course. Compared with T2DM, patients generally exhibit fewer metabolic syndrome features and more rapid C-peptide decline, although β-cell loss is typically slower than in classic T1DM (8). The patient described herein satisfied these criteria.

The antibody panel obtained, GAD-65, islet cell antibodies and ZnT8, reflects diagnostic yield and local availability. GAD antibodies are the most sensitive single marker of adult-onset autoimmune diabetes and may persist longer than several other islet autoantibodies. Islet cell antibodies, although less standardized, provide complementary evidence of islet-directed autoimmunity. ZnT8 antibodies may provide incremental diagnostic sensitivity and contribute to identification of multiple-autoantibody positivity, a phenotype associated with more rapid β-cell decline and earlier insulin requirement. IA-2A was not obtained; its inclusion could have further refined immunologic characterization as IA-2A positivity has been shown to be associated with a more rapidly progressive phenotype and a higher prevalence of coexisting celiac disease (9,10). Nonetheless, positivity for three distinct islet autoantibodies together with a C-peptide of 0.12 nmol/l strongly supports an autoimmune basis, as multiple-autoantibody positivity provides greater specificity than any single marker alone.

As gastrointestinal and cutaneous manifestations predominated rather than classical hyperglycaemic symptoms, several alternative diagnoses were entertained. Diagnostic confusion arose as diabetes had already been established and presumed to be type 2; consequently, the constellation of cachexia, diarrhoea and rash was initially interpreted as a separate coexisting process, rather than potentially related to profound insulin deficiency (11). An abrupt classic T1DM presentation was less consistent with the multi-year non-insulin-requiring course and presentation with HHS rather than ketoacidosis. The level of β-hydroxybutyrate was only 0.80 mmol/l and the anion gap was normal, suggesting sufficient residual insulin action to suppress substantial ketogenesis. As LADA lies along the autoimmune T1DM spectrum, the distinction largely reflects the tempo of β-cell loss and the timing of insulin dependence rather than fundamentally different pathology.

A neuroendocrine tumour was considered due to weight loss, secretory-type diarrhoea, mildly elevated carcinoembryonic antigen and a transient response to octreotide. However, glucagon, gastrin and chromogranin A levels were normal, imaging demonstrated no corresponding lesion, and the octreotide response could reflect its anti-secretory effects rather than tumour-directed activity. Hyperglycaemia was also better accounted for by insulin deficiency than by counter-regulatory hormone excess. Crohn's disease was considered due to positive anti-Saccharomyces antibodies, crampy abdominal pain, prior colitis, and biopsy-proven mild ileitis and was treated empirically. However, these antibodies have limited positive predictive value in isolation, the levels of inflammatory markers were low, and no skip lesions, ulceration, granulomata, or transmural inflammation were identified. Malabsorption syndromes, including celiac disease, were also considered due to weight loss, diarrhoea, low levels of faecal elastase and angular cheilitis; however, normal total IgA, negative gliadin antibodies, normal duodenal histology and the absence of steatorrhea argued against celiac disease.

A critical caveat applies when interpreting the clinical improvement. As empirical corticosteroid and mesalamine therapy was administered concurrently with insulin, improvement cannot be attributed to glycaemic correction alone. Several findings nevertheless favour a predominantly metabolic explanation: Faecal calprotectin and C-reactive protein levels were low, colonoscopic and histologic abnormalities were mild and non-specific without diagnostic features of Crohn's disease, and the degree of cachexia was consistent with profound insulin deficiency.

Gastrointestinal manifestations are not hallmark features of LADA, although autoimmune comorbidities, including thyroid disease, celiac disease and dermatitis herpetiformis, have been reported, reflecting shared autoimmune predisposition rather than a direct causal relationship (9,11). Reported associations are summarized in Table IV. Despite chronic diarrhoea and a vesicular rash, evaluation did not confirm celiac disease or another specific enteropathy in the patient in the present case report.

Progression to HHS is atypical; however, it has been reported and may occur when progressive β-cell destruction produces severe insulin deficiency without sufficient absolute insulin deficiency to generate marked ketogenesis (12).

The mechanism of chronic diarrhoea also merits consideration. Sustained hyperglycaemia may produce gastrointestinal dysfunction through altered autonomic regulation and intestinal motility. The low faecal elastase of 47 µg/g falls within a range conventionally interpreted as severe exocrine pancreatic insufficiency; however, several considerations argue against primary pancreatic disease in this case. Faecal elastase-1 measures concentration, rather than total output and can yield falsely low values in watery stool due to dilution. In one series, 11% of diarrheal samples with values <200 µg/g normalized following correction for water content, supporting repeat testing on a formed stool specimen before definitive interpretation (13,14). Imaging, including MRCP (images not available) demonstrated no ductal dilatation, calcification, pancreatic atrophy, or mass and steatorrhea was absent. Reduced exocrine pancreatic function has also been described in longstanding insulin-deficient diabetes (15), potentially reflecting the loss of insulin-mediated trophic effects on acinar tissue. Thus, the low elastase in the present case may reflect stool dilution and diabetes-associated exocrine hypofunction, rather than independent pancreatic pathology.

At a pathophysiologic level, the autoimmune nature of LADA is consistent with predominantly cell-mediated β-cell injury, including impaired immune tolerance and abnormalities in regulatory T-cell function (15). This progressive autoimmune destruction explains the transition from an initially non–insulin-requiring phenotype to profound endogenous insulin deficiency.

C-peptide declines more slowly in LADA than in classic T1DM, although generally more rapidly than in T2DM. Management can therefore be guided in part by residual β-cell function: C-peptide values <0.3 nmol/l support treatment as insulin-deficient T1DM, values of 0.3-0.7 nmol/l represent an intermediate range in which insulin should be considered alongside other therapies, and values >0.7 nmol/l may permit a modified T2DM-based strategy with continued monitoring (8,15,16). At 0.12 nmol/l, the patient described herein had profound endogenous insulin deficiency and was clearly insulin-requiring. Agents, including dipeptidyl peptidase-4 (DPP-4) inhibitors, glucagon-like peptide-1 (GLP-1) receptor agonists and thiazolidinediones have been investigated for potential β-cell-preserving effects, whereas sulfonylureas may accelerate the deterioration of β-cell function and sodium-glucose transport protein 2 (SGLT2) inhibitors require caution due to the risk of ketoacidosis (17).

Compared with T2DM, LADA has been associated with poorer glycaemic control and differences in long-term microvascular outcomes, while higher GAD antibody titres have been associated with cardiovascular events in some cohorts (18). These observations support maintaining a high index of suspicion for autoimmune diabetes in adults whose clinical course is atypical for T2DM and considering islet autoantibody assessment when classification remains uncertain (19-21).

The present case report has certain limitations which should be mentioned. The absence of longitudinal follow-up precludes the documentation of progressive β-cell failure and sustained symptom resolution. As immunosuppression was administered concurrently with insulin, their relative contributions cannot be separated. As the rash was not biopsied, dermatitis herpetiformis cannot be formally excluded, and IA-2A and stimulated C-peptide were not obtained.

In conclusion, the present case report emphasizes that profound insulin deficiency may present with systemic manifestations that mimic malignancy, inflammatory bowel disease, or malabsorptive disorders and may therefore be overlooked when diabetes has already been presumed to be type 2.