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Open access

Michelle Maher, Mohammed Faraz Rafey, Helena Griffin, Katie Cunningham and Francis M Finucane

Summary

A 45-year-old man with poorly controlled type 2 diabetes (T2DM) (HbA1c 87 mmol/mol) despite 100 units of insulin per day and severe obesity (BMI 40.2 kg/m2) was referred for bariatric intervention. He declined bariatric surgery or GLP1 agonist therapy. Initially, his glycaemic control improved with dietary modification and better adherence to insulin therapy, but he gained weight. We started a low-energy liquid diet, with 2.2 L of semi-skimmed milk (equivalent to 1012 kcal) per day for 8 weeks (along with micronutrient, salt and fibre supplementation) followed by 16 weeks of phased reintroduction of a normal diet. His insulin was stopped within a week of starting this programme, and over 6 months, he lost 20.6 kg and his HbA1c normalised. However, 1 year later, despite further weight loss, his HbA1c deteriorated dramatically, requiring introduction of linagliptin and canagliflozin, with good response. Five years after initial presentation, his BMI remains elevated but improved at 35.5 kg/m2 and his glycaemic control is excellent with a HbA1c of 50 mmol/mol and he is off insulin therapy. Whether semi-skimmed milk is a safe, effective substrate for carefully selected patients with severe obesity complicated by T2DM remains to be determined. Such patients would need frequent monitoring by an experienced multidisciplinary team.

Learning points:

  • Meal replacement programmes are an emerging therapeutic strategy to allow severely obese type 2 diabetes patients to achieve clinically impactful weight loss.

  • Using semi-skimmed milk as a meal replacement substrate might be less costly than commercially available programmes, but is likely to require intensive multidisciplinary bariatric clinical follow-up.

  • For severely obese adults with poor diabetes control who decline bariatric surgery or GLP1 agonist therapy, a milk-based meal replacement programme may be an option.

  • Milk-based meal replacement in patients with insulin requiring type 2 diabetes causes rapid and profound reductions in insulin requirements, so rigorous monitoring of glucose levels by patients and their clinicians is necessary.

  • In carefully selected and adequately monitored patients, the response to oral antidiabetic medications may help to differentiate between absolute and relative insulin deficiency.

Open access

Yael Lefkovits and Amanda Adler

Summary

Necrobiosis lipoidica diabeticorum (NLD) is a chronic granulomatous dermatitis generally involving the anterior aspect of the shin, that arises in 0.3–1.2% of patients with diabetes mellitus (1). The lesions are often yellow or brown with telangiectatic plaque, a central area of atrophy and raised violaceous borders (2). Similar to other conditions with a high risk of scarring including burns, stasis ulcers and lupus vulgaris, NLD provides a favourable environment for squamous cell carcinoma (SCC) formation (3). A number of cases of SCC from NLD have been recorded (3, 4, 5); however, our search of the literature failed to identify any cases of either metastatic or fatal SCC which developed within an area of NLD. This article describes a patient with established type 1 diabetes mellitus who died from SCC which developed from an area of NLD present for over 10 years. Currently, there are a paucity of recommendations in the medical literature for screening people with NLD for the early diagnosis of SCC. We believe that clinicians should regard non-healing ulcers in the setting of NLD with a high index of clinical suspicion for SCC, and an early biopsy of such lesions should be recommended.

Learning points:

  • Non-healing, recalcitrant ulcers arising from necrobiosis lipoidica diabeticorum, which fail to heal by conservative measures, should be regarded with a high index of clinical suspicion for malignancy.

  • If squamous cell carcinoma is suspected, a biopsy should be performed as soon as possible to prevent metastatic spread, amputation or even death.

  • Our literature search failed to reveal specific recommendations for screening and follow-up of non-healing recalcitrant ulcers in the setting of necrobiosis lipoidica diabeticorum.

  • Further research is required in this field.

Open access

Suguru Watanabe, Jun Kido, Mika Ogata, Kimitoshi Nakamura and Tomoyuki Mizukami

Summary

Hyperglycemic hyperosmolar state (HHS) and diabetic ketoacidosis (DKA) are the most severe acute complications of diabetes mellitus (DM). HHS is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis. A 14-year-old Japanese boy presented at the emergency room with lethargy, polyuria and polydipsia. He belonged to a baseball club team and habitually drank sugar-rich beverages daily. Three weeks earlier, he suffered from lassitude and developed polyuria and polydipsia 1 week later. He had been drinking more sugar-rich isotonic sports drinks (approximately 1000–1500 mL/day) than usual (approximately 500 mL/day). He presented with HHS (hyperglycemia (1010 mg/dL, HbA1c 12.3%) and mild hyperosmolality (313 mOsm/kg)) without acidosis (pH 7.360), severe ketosis (589 μmol/L) and ketonuria. He presented HHS in type 1 diabetes mellitus (T1DM) with elevated glutamate decarboxylase antibody and islet antigen 2 antibody. Consuming beverages with high sugar concentrations caused hyperglycemia and further exacerbates thirst, resulting in further beverage consumption. Although he recovered from HHS following intensive transfusion and insulin treatment, he was significantly sensitive to insulin therapy. Even the appropriate amount of insulin may result in dramatically decreasing blood sugar levels in patients with T1DM. We should therefore suspect T1DM in patients with HHS but not those with obesity. Moreover, age, clinical history and body type are helpful for identifying T1DM and HHS. Specifically, drinking an excess of beverages rich in sugars represents a risk of HHS in juvenile/adolescent T1DM patients.

Learning points:

  • Hyperglycemic hyperosmolar state (HHS) is characterized by severe hyperglycemia and hyperosmolality without significant ketosis and acidosis.

  • The discrimination between HHS of type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus (T2DM) in initial presentation is difficult.

  • Pediatrician should suspect T1DM in patients with HHS but not obesity.

  • Age, clinical history and body type are helpful for identifying T1DM and HHS.

  • Children with T1DM are very sensitive to insulin treatment, and even appropriate amount of insulin may result in dramatically decreasing blood sugar levels.

Open access

Aoife Garrahy, Matilde Bettina Mijares Zamuner and Maria M Byrne

Summary

Coexistence of autoimmune diabetes and maturity-onset diabetes of the young (MODY) is rare. We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and glucokinase (GCK) MODY. A 32-year-old woman was treated with insulin for gestational diabetes at age 32 years; post-partum, her fasting blood glucose was 6.0 mmol/L and 2-h glucose was 11.8 mmol/L following an oral glucose tolerance test, and she was maintained on diet alone. Five years later, a diagnosis of LADA was made when she presented with fasting blood glucose of 20.3 mmol/L and HbA1C 125 mmol/mol (13.6%). GCK-MODY was identified 14 years later when genetic testing was prompted by identification of a mutation in her cousin. Despite multiple daily insulin injections her glycaemic control remained above target and her clinical course has been complicated by multiple episodes of hypoglycaemia with unawareness. Although rare, coexistence of latent autoimmune diabetes of adulthood and monogenic diabetes should be considered if there is a strong clinical suspicion, for example, family history. Hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA. This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA.

Learning points:

  • We report the first case of coexisting latent autoimmune diabetes of adulthood (LADA) and GCK-MODY.

  • It has been suggested that mutations in GCK may lead to altered counter-regulation and recognition of hypoglycaemia at higher blood glucose levels than patients without such mutation. However, in our case, hypoglycaemic unawareness developed secondary to frequent episodes of hypoglycaemia using standard glycaemic targets for LADA.

  • This case highlights the importance of setting fasting glucose targets within the expected range for GCK-MODY in subjects with coexisting LADA to avoid hypoglycaemia.

Open access

A Veltroni, G Zambon, S Cingarlini and M V Davì

Summary

Insulin autoimmune syndrome (IAS), a rare cause of autoimmune hyperinsulinaemic hypoglycaemia, is relatively well known in Japan. The incidence in Caucasians is less than one-fifth of that reported in Japanese people, but it is becoming increasingly recognised worldwide in non-Asians as well. Drugs containing sulphydryl groups are known to be associated with the disease in genetically predisposed individuals. Moreover, several recent reports showed a direct association between the onset of IAS and the consumption of dietary supplements containing alpha-lipoic acid (LA). Insulinoma remains the most prevalent cause of hypersulinaemic hypoglycaemia in Caucasians. Consequently, primary investigation in these patients is generally focused on localisation of the pancreatic tumour, often with invasive procedures followed by surgery. We described a case of an Italian woman presenting to us with severe recurrent hypoglycaemia associated with high insulin and C-peptide levels and no evidence of pancreatic lesions at imaging diagnostic procedures. She had taken LA until 2 weeks before hospitalisation. After an evaluation of her drug history, an autoimmune form of hypoglycaemia was suspected and the titre of insulin autoantibodies was found to be markedly elevated. This allowed us to diagnose LA-related IAS, thus preventing any unnecessary surgery and avoiding invasive diagnostic interventions.

Learning points:

  • IAS is a rare cause of hyperinsulinaemic hypoglycaemia that typically affects Asian population, but it has been increasingly recognised in Caucasian patients.

  • It should be considered among the differential diagnosis of hyperinsulinaemic hypoglycaemia to avoid unnecessary diagnostic investigations and surgery.

  • It should be suspected in the presence of very high serum insulin levels (100–10  000  μU/mL) associated with high C-peptide levels.

  • There is a strong association with administration of drugs containing sulphydryl groups included LA, a dietary supplement commonly used in Western countries to treat peripheral neuropathy.

Open access

D Cappellani, C Sardella, M C Campopiano, A Falorni, P Marchetti and E Macchia

Summary

Insulin autoimmune syndrome (IAS), or Hirata disease, is a rare hypoglycaemic disorder caused by the presence of high titer of insulin autoantibodies (IAA) in patients without previous exposure to exogenous insulin. Even though its pathogenesis is not fully understood, striking evidences link IAS to previous exposure to sulphydryl-containing medications, like alpha-lipoic acid, a widely used nutritional supplement. Although challenging, a careful differential diagnosis from other causes of hyperinsulinaemic hypoglycaemia (such as insulinoma) is mandatory, since these conditions require different therapeutic approaches. In the present study, we report a 35-year-old woman originally from Sri Lanka who was referred to our University Hospital on suspicion of occult insulinoma. Her medical history was positive for endometriosis, treated with estroprogestins and alpha-lipoic acid. The latter supplement was begun 2 weeks before the first hypoglycaemic episode. Our tests confirmed the presence of hypoglycaemia associated with high insulin and C-peptide concentrations. When insulin concentrations were compared using different assays, the results were significantly different. Moreover, insulin values significantly decreased after precipitation with polyethylene glycol. An assay for IAA proved positive (530 U/mL). A genetic analysis revealed the presence of HLA-DRB1*04,15, an immunogenetic determinant associated with IAS. On the basis of clinical data we avoided a first-line approach with immunosuppressive treatments, and the patient was advised to modify her diet, with the introduction of frequent low-caloric meals. During follow-up evaluations, glucose levels (registered trough a flash glucose monitoring system) resulted progressively more stable. IAA titer progressively decreased, being undetectable by the fifteenth month, thus indicating the remission of the IAS.

Learning points:

  • Insulin autoimmune syndrome (IAS) is a rare cause of hyperinsulinaemic hypoglycaemia, whose prevalence is higher in East Asian populations due to the higher prevalence of specific immunogenetic determinants. Nevertheless, an increasing number of IAS cases is being reported worldwide, due to the wide diffusion of medications such as alpha-lipoic acid.

  • Differential diagnosis of IAS from other causes of hyperinsulinemic hypoglycaemia is challenging. Even though many tests can be suggestive of IAS, the gold standard remains the detection of IAAs, despite that dedicated commercial kits are not widely available.

  • The therapeutic approach to IAS is problematic. As a matter of fact IAS is often a self-remitting disease, but sometimes needs aggressive immunosuppression. The benefits and risks of any therapeutic choice should be carefully weighted and tailored on the single patient.

Open access

Ilaria Teobaldi, Vincenzo Stoico, Fabrizia Perrone, Massimiliano Bruti, Enzo Bonora and Alessandro Mantovani

Summary

Honey has been used as a wound dressing for hundreds of years by ancient civilizations, but only recently it has acquired scientific interest because of its relevant biological properties. In the last decade, indeed, several trials and observational studies have reported that, compared to conventional treatment (e.g. antiseptics, polyurethane film, paraffin gauze, soframycin-impregnated gauze), honey dressings seem to be better in healing time of different types of wounds, including diabetic foot ulcers. However, to date, information about a potential favorable biological effect of honey dressings on diabetic ulcers with exposed tendon are still scarce. Notably, foot or leg ulcers with exposed tendon are serious complications in patients with type 2 diabetes, as they are associated with an increased risk of adverse outcome. Therefore, the use of effective and safe treatments to bring these lesions to timely healing is very important in clinical practice. We herein report the case of a Caucasian adult patient with type 2 diabetes presenting a chronic right posterior lower limb ulcer (Texas University Classification (TUC) 2D) with tendon exposure that was successfully treated with honey dressings (glucose oxidase (GOX) positive with peroxide activity) in addition to systemic antibiotic therapy, surgical toilette and skin graft. In our case, the use of honey dressing for treating exposed tendon tissue probably allowed the timely wound healing. Although further studies are required, such treatment may constitute part of the comprehensive management of diabetic wounds, including those with tendon exposure, and should be considered by clinicians in clinical practice.

Learning points:

  • Honey has been used as a wound dressing for hundreds of years, but only recently it has acquired scientific interest for its biological properties.

  • Several studies have documented that, compared to conventional dressings, honey seems to be better in healing time of different types of wounds, including diabetic foot ulcers.

  • Our case report is the first to highlight the importance to use honey dressings also for the treatment of ulcers with tendon exposure in patients with type 2 diabetes, suggesting that this kind of dressing should be considered by clinicians in clinical practice.

Open access

Miriam Hinaa Ahmad and Ismat Shafiq

Summary

We report a case of a 21-year-old African American female with history of pre-diabetes, and a diagnosis of a rare leukemia, blastic-plasmacytoid dendritic neoplasm (BPDCN), who developed diabetic ketoacidosis (DKA) after the third dose of PEG-asparaginase infusion. She was successfully treated with insulin. Asparaginase is a vital part of treatment protocols for acute lymphoblastic leukemia (ALL) in combination with other chemotherapeutic drugs. Asparaginase therapy has been reported to cause hyperglycemia especially when used in conjunction with glucocorticoids for the treatment of ALL in the pediatric population. Multiple mechanisms for hyperglycemia have been hypothesized which include decreased insulin secretion, impaired insulin receptor function and excess glucagon formation. Hyperglycemia is usually self-limiting but can deteriorate to diabetic ketoacidosis. DKA is a rare adverse effect with asparaginase therapy with an incidence rate of about 0.8%.

Learning points:

  • DKA is a rare finding following asparaginase therapy.

  • Hyperglycemia is most commonly seen with asparaginase treatment when used along with glucocorticoid.

  • Frequent blood glucose monitoring and prompt initiation of insulin treatment with hyperglycemia can prevent severe complications.

  • Patients and physician education on this complication can reduce morbidity due to DKA.

Open access

Seong Keat Cheah, David Halsall, Peter Barker, John Grant, Abraham Mathews, Shyam Seshadri and Singhan Krishnan

Summary

A frail 79-year-old lady with dementia presented with a 2-year history of frequent falls. Recurrent hypoglycaemic episodes were diagnosed and treated with continuous glucose infusion in multiple hospital admissions. Hypoadrenalism and hypothyroidism were ruled out. Whilst hypoglycaemic (blood glucose 1.6 mmol/L), both plasma C-peptide and proinsulin concentrations, were inappropriately elevated at 4210 pmol/L (174–960) and >200 pmol/L (0–7) respectively with plasma insulin suppressed at 12 pmol/L (0–180). Whilst reported cases of proinsulinoma are typically pancreatic in origin, radiological investigations of the pancreas in this patient did not identify abnormalities. Unexpectedly contrast CT identified a heterogeneously enhancing mass (6.6 cm) at the lower pole of the left kidney consistent with renal cell carcinoma. Non-islet cell tumour-induced hypoglycaemia has been associated with renal malignancy; however, a serum IGF2:IGF1 ratio measured at <10 effectively excludes this diagnosis. Concomitantly on the CT, extensive peripherally enhancing heterogeneous mass lesions in the liver were identified, the largest measuring 12 cm. A palliative approach was taken due to multiple comorbidities. On post-mortem, the kidney lesion was confirmed as clear cell renal carcinoma, whilst the liver lesions were identified as proinsulin-secreting neuroendocrine tumours. In conclusion, the diagnosis of proinsulinoma can be missed if plasma proinsulin concentration is not measured at the time of hypoglycaemia. In this case, the plasma insulin:C-peptide ratio was too high to be accounted for by the faster relative clearance of insulin and was due to proinsulin cross-reactivity in the C-peptide assay. In addition, the concomitant malignancy proved to be a challenging red herring.

Learning points:

  • Even in non-diabetics, hypoglycaemia needs to be excluded in a setting of frequent falls. Insulin- or proinsulin-secreting tumours are potentially curable causes.

  • Whilst investigating spontaneous hypoglycaemia, if plasma insulin concentration is appropriate for the hypoglycaemia, it is prudent to check proinsulin concentrations during the hypoglycaemic episode.

  • Proinsulin cross-reacts variably with C-peptide and insulin assays; the effect is method dependent. In this case, the discrepancy between the insulin and C-peptide concentrations was too great to be accounted for by the faster relative clearance of insulin, raising the suspicion of assay interference. The C-peptide assay in question (Diasorin liaison) has been shown to be 100% cross reactive with proinsulin based on spiking studies with a proinsulin reference preparation.

  • Whilst reported cases of proinsulinoma and 99% of insulinomas are of pancreatic origin, conventional imaging studies (CT, MRI or ultrasound) fail to detect neuroendocrine tumours <1 cm in 50% of cases.

  • The concomitant renal mass identified radiologically proved to be a red herring.

  • In view of the rarity of proinsulinoma, no conclusive association with renal cell carcinoma can be established.

Open access

Sebastian Hörber, Sarah Hudak, Martin Kächele, Dietrich Overkamp, Andreas Fritsche, Hans-Ulrich Häring, Andreas Peter and Martin Heni

Summary

Diabetic ketoacidosis is a life-threatening complication of diabetes mellitus. It usually occurs in patients with type 1 diabetes where it is typically associated with only moderately increased blood glucose. Here, we report the case of a 52-year-old female patient who was admitted to the emergency unit with severely altered mental status but stable vital signs. Laboratory results on admission revealed very high blood glucose (1687 mg/dL/93.6 mmol/L) and severe acidosis (pH <7) with proof of ketone bodies in serum and urine. Past history revealed a paranoid schizophrenia diagnosed 10 years ago and for which the patient was treated with risperidone for many years. Acute treatment with intravenous fluids, intravenous insulin infusion and sodium bicarbonate improved the symptoms. Further laboratory investigations confirmed diagnosis of autoimmune type 1 diabetes. After normalization of blood glucose levels, the patient could soon be discharged with a subcutaneous insulin therapy.

Learning points:

  • Diabetic ketoacidosis as first manifestation of type 1 diabetes can occur with markedly elevated blood glucose concentrations in elder patients.

  • Atypical antipsychotics are associated with hyperglycemia and an increased risk of new-onset diabetes.

  • First report of risperidone-associated diabetic ketoacidosis in new-onset type 1 diabetes.

  • Patients treated with atypical antipsychotics require special care and regular laboratory examinations to detect hyperglycemia and diabetic ketoacidosis.

  • In cases when the diagnosis is in doubt, blood gas analysis as well as determination of C-peptide and islet autoantibodies can help to establish the definite diabetes type.