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Open access

Elaine E Sanderson, Mark Shah, Amanda J Hooper, Damon A Bell, and Catherine S Choong

Summary

We report a case of an 11-year-old girl presenting with a new diagnosis of diabetes associated with a heterozygous missense mutation in the insulin receptor (INSR) gene. This case highlights that INSR gene variants can be a cause for monogenic diabetes in children and adolescents and the need for genetic evaluation in atypical presentations of diabetes. We also describe the possible role of metformin in treating individuals with type A insulin resistance syndrome due to INSR gene variants.

Learning points

  • Insulin receptor (INSR) gene variants can be a cause of monogenic diabetes in children and adolescents.

  • Genetic evaluation should be considered in children and adolescents with type 2 diabetes (T2D), particularly where there is an atypical presentation and/or positive family history.

  • Metformin may have a role in the treatment of type A insulin resistance syndrome due to heterozygous mutation of the INSR gene.

Open access

Arunan Sriravindrarajah, Amelia Fernandes, Ted Wu, and Samantha Hocking

Summary

Maturity-onset diabetes of the young type 3 (MODY3) accounts for approximately 50% of cases of MODY. First-line treatment with sulfonylureas has been well established for individuals with MODY3. In contrast, the use of sodium-glucose co-transporter 2 (SGLT2) inhibitors in the treatment of individuals with MODY3 remains unclear. This case illustrates the in vivo effect of an SGLT2 inhibitor in a 30-year-old woman with MODY3 with poor glycaemic control despite the treatment with supramaximal doses of sulfonylurea and metformin. The addition of a SGLT2 inhibitor resulted in a rapid improvement in glycaemic control without any hypoglycaemic episodes. This case suggests that SGLT2 inhibitors may be an effective and potent treatment option in addition to sulfonylureas for individuals with MODY3.

Learning points

  • Maturity-onset diabetes of the young type 3 (MODY3) arises from mutations in the hepatocyte nuclear factor-1alpha gene, which controls the expression of sodium-glucose co-transporter 2 (SGLT2) in the kidneys.

  • Paradoxically, despite individuals with MODY3 having reduced expression of SGLT2, SGLT2 inhibitors induce higher glycosuria in individuals with MODY3 compared to individuals with type 2 diabetes mellitus.

  • SGLT2 inhibitors may be an effective treatment for achieving glycaemic control in individuals with MODY3.

Open access

Ana Dugic, Michael Kryk, Claudia Mellenthin, Christoph Braig, Lorenzo Catanese, Sandy Petermann, Jürgen Kothmann, and Steffen Mühldorfer

Summary

Drinking fruit juice is an increasingly popular health trend, as it is widely perceived as a source of vitamins and nutrients. However, high fructose load in fruit beverages can have harmful metabolic effects. When consumed in high amounts, fructose is linked with hypertriglyceridemia, fatty liver and insulin resistance. We present an unusual case of a patient with severe asymptomatic hypertriglyceridemia (triglycerides of 9182 mg/dL) and newly diagnosed type 2 diabetes mellitus, who reported a daily intake of 15 L of fruit juice over several weeks before presentation. The patient was referred to our emergency department with blood glucose of 527 mg/dL and glycated hemoglobin (HbA1c) of 17.3%. Interestingly, features of diabetic ketoacidosis or hyperosmolar hyperglycemic state were absent. The patient was overweight with an otherwise unremarkable physical exam. Lipase levels, liver function tests and inflammatory markers were closely monitored and remained unremarkable. The initial therapeutic approach included i.v. volume resuscitation, insulin and heparin. Additionally, plasmapheresis was performed to prevent potentially fatal complications of hypertriglyceridemia. The patient was counseled on balanced nutrition and detrimental effects of fruit beverages. He was discharged home 6 days after admission. At a 2-week follow-up visit, his triglyceride level was 419 mg/dL, total cholesterol was 221 mg/dL and HbA1c was 12.7%. The present case highlights the role of fructose overconsumption as a contributory factor for severe hypertriglyceridemia in a patient with newly diagnosed diabetes. We discuss metabolic effects of uncontrolled fructose ingestion, as well as the interplay of primary and secondary factors, in the pathogenesis of hypertriglyceridemia accompanied by diabetes.

Learning points

  • Excessive dietary fructose intake can exacerbate hypertriglyceridemia in patients with underlying type 2 diabetes mellitus (T2DM) and absence of diabetic ketoacidosis or hyperosmolar hyperglycemic state.

  • When consumed in large amounts, fructose is considered a highly lipogenic nutrient linked with postprandial hypertriglyceridemia and de novo hepatic lipogenesis (DNL).

  • Severe lipemia (triglyceride plasma level > 9000 mg/dL) could be asymptomatic and not necessarily complicated by acute pancreatitis, although lipase levels should be closely monitored.

  • Plasmapheresis is an effective adjunct treatment option for rapid lowering of high serum lipids, which is paramount to prevent acute complications of severe hypertriglyceridemia.

Open access

Milad Darrat, Brian Gilmartin, Carmel Kennedy, and Diarmuid Smith

Summary

Acute respiratory distress syndrome (ARDS) is a rare but life-threatening complication of diabetic ketoacidosis (DKA). We present the case of a young female, with no previous diagnosis of diabetes, presenting in DKA complicated by ARDS requiring extra corporeal membrane oxygenation (ECMO) ventilator support. This case report highlights the importance of early recognition of respiratory complications of severe DKA and their appropriate management.

Learning points

  • ARDS is a very rare but life-threatening complication in DKA.

  • The incidence of ARDS remains unknown but less frequent than cerebral oedema in DKA.

  • The mechanism of ARDS in DKA has multifactorial aetiology, including genetic predisposition.

  • Early recognition and consideration of rare pulmonary complication of DKA can increase survival rate and provide very satisfactory outcomes.

  • DKA patients who present with refractory ARDS can be successfully rescued by ECMO support.

Open access

Ulla Kampmann, Per Glud Ovesen, Niels Møller, and Jens Fuglsang

Summary

During pregnancy, maternal tissues become increasingly insensitive to insulin in order to liberate nutritional supply to the growing fetus, but occasionally insulin resistance in pregnancy becomes severe and the treatment challenging. We report a rare and clinically difficult case of extreme insulin resistance with daily insulin requirements of 1420 IU/day during pregnancy in an obese 36-year-old woman with type 2 diabetes (T2D) and polycystic ovary syndrome (PCOS). The woman was referred to the outpatient clinic at gestational week 12 + 2 with a hemoglobin A1c (HbA1c) at 59 mmol/mol. Insulin treatment was initiated immediately using Novomix 30, and the doses were progressively increased, peaking at 1420 units/day at week 34 + 4. At week 35 + 0, there was an abrupt fall in insulin requirements, but with no signs of placental insufficiency. At week 36 + 1 a, healthy baby with no hypoglycemia was delivered by cesarean section. Blood samples were taken late in pregnancy to search for causes of extreme insulin resistance and showed high levels of C-peptide, proinsulin, insulin-like growth factor (IGF-1), mannan-binding-lectin (MBL) and leptin. CRP was mildly elevated, but otherwise, levels of inflammatory markers were normal. Insulin antibodies were undetectable, and no mutations in the insulin receptor (INSR) gene were found. The explanation for the severe insulin resistance, in this case, can be ascribed to PCOS, obesity, profound weight gain, hyperleptinemia and inactivity. This is the first case of extreme insulin resistance during pregnancy, with insulin requirements close to 1500 IU/day with a successful outcome, illustrating the importance of a close interdisciplinary collaboration between patient, obstetricians and endocrinologists.

Learning points

  • This is the first case of extreme insulin resistance during pregnancy, with insulin requirements of up to 1420 IU/day with a successful outcome without significant fetal macrosomia and hypoglycemia.

  • Obesity, PCOS, T2D and high levels of leptin and IGF-1 are predictors of severe insulin resistance in pregnancy.

  • A close collaboration between patient, obstetricians and endocrinologists is crucial for tailoring the best possible treatment for pregnant women with diabetes, beneficial for both the mother and her child.

Open access

R K Dharmaputra, K L Wan, N Samad, M Herath, J Wong, S Sarlos, S R Holdsworth, and N Naderpoor

Summary

Insulin autoimmune syndrome (IAS) is a rare cause of non-islet cell hypoglycaemia. Treatment of this condition is complex and typically involves long-term use of glucocorticoids. Immunotherapy may provide an alternative in the management of this autoimmune condition through the suppression of antibodies production by B-lymphocyte depletion. We present a case of a 62-year-old male, with refractory hypoglycaemia initially presenting with hypoglycaemic seizure during an admission for acute psychosis. Biochemical testing revealed hypoglycaemia with an inappropriately elevated insulin and C-peptide level and no evidence of exogenous use of insulin or sulphonylurea. Polyethylene glycol precipitation demonstrated persistently elevated free insulin levels. This was accompanied by markedly elevated anti-insulin antibody (IA) titres. Imaging included CT with contrast, MRI, pancreatic endoscopic ultrasound and Ga 68-DOTATATE position emission tomography (DOTATATE PET) scan did not reveal islet cell aetiology for hyperinsulinaemia. Maintenance of euglycaemia was dependent on oral steroids and dextrose infusion. Complete resolution of hypoglycaemia and dependence on glucose and steroids was only achieved following treatment with plasma exchange and rituximab.

Learning points

  • Insulin autoimmune syndrome (IAS) should be considered in patients with recurrent hyperinsulinaemic hypoglycaemia in whom exogenous insulin administration and islet cell pathologies have been excluded.

  • Biochemical techniques play an essential role in establishing high insulin concentration, insulin antibody titres, and eliminating biochemical interference. High insulin antibody concentration can lead to inappropriately elevated serum insulin levels leading to hypoglycaemia.

  • Plasma exchange and B-lymphocyte depletion with rituximab and immunosuppression with high dose glucocorticoids are effective in reducing serum insulin levels and hypoglycaemia in insulin autoimmune syndrome (IAS).

  • Based on our observation, the reduction in serum insulin level may be a better indicator of treatment efficacy compared to anti-insulin antibody (IA) titre as it demonstrated greater correlation to the frequency of hypoglycaemia and to hypoglycaemia resolution.

Open access

Vinaya Srirangam Nadhamuni, Donato Iacovazzo, Jane Evanson, Anju Sahdev, Jacqueline Trouillas, Lorraine McAndrew, Tom R Kurzawinski, David Bryant, Khalid Hussain, Satya Bhattacharya, and Márta Korbonits

Summary

A male patient with a germline mutation in MEN1 presented at the age of 18 with classical features of gigantism. Previously, he had undergone resection of an insulin-secreting pancreatic neuroendocrine tumour (pNET) at the age of 10 years and had subtotal parathyroidectomy due to primary hyperparathyroidism at the age of 15 years. He was found to have significantly elevated serum IGF-1, GH, GHRH and calcitonin levels. Pituitary MRI showed an overall bulky gland with a 3 mm hypoechoic area. Abdominal MRI showed a 27 mm mass in the head of the pancreas and a 6 mm lesion in the tail. Lanreotide-Autogel 120 mg/month reduced GHRH by 45% and IGF-1 by 20%. Following pancreaticoduodenectomy, four NETs were identified with positive GHRH and calcitonin staining and Ki-67 index of 2% in the largest lesion. The pancreas tail lesion was not removed. Post-operatively, GHRH and calcitonin levels were undetectable, IGF-1 levels normalised and GH suppressed normally on glucose challenge. Post-operative fasting glucose and HbA1c levels have remained normal at the last check-up. While adolescent-onset cases of GHRH-secreting pNETs have been described, to the best of our knowledge, this is the first reported case of ectopic GHRH in a paediatric setting leading to gigantism in a patient with MEN1. Our case highlights the importance of distinguishing between pituitary and ectopic causes of gigantism, especially in the setting of MEN1, where paediatric somatotroph adenomas causing gigantism are extremely rare.

Learning points

  • It is important to diagnose gigantism and its underlying cause (pituitary vs ectopic) early in order to prevent further growth and avoid unnecessary pituitary surgery. The most common primary tumour sites in ectopic acromegaly include the lung (53%) and the pancreas (34%) (): 76% of patients with a pNET secreting GHRH showed a MEN1 mutation ().

  • Plasma GHRH testing is readily available in international laboratories and can be a useful diagnostic tool in distinguishing between pituitary acromegaly mediated by GH and ectopic acromegaly mediated by GHRH. Positive GHRH immunostaining in the NET tissue confirms the diagnosis.

  • Distinguishing between pituitary (somatotroph) hyperplasia secondary to ectopic GHRH and pituitary adenoma is difficult and requires specialist neuroradiology input and consideration, especially in the MEN1 setting. It is important to note that the vast majority of GHRH-secreting tumours (lung, pancreas, phaeochromocytoma) are expected to be visible on cross-sectional imaging (median diameter 55 mm) (). Therefore, we suggest that a chest X-ray and an abdominal ultrasound checking the adrenal glands and the pancreas should be included in the routine work-up of newly diagnosed acromegaly patients.

Open access

Wann Jia Loh, Lily Mae Dacay, Clara Si Hua Tan, Su Fen Ang, Fabian Yap, Su Chi Lim, and Joan Khoo

Summary

Activating mutation of glucokinase gene (GCK) causes resetting of insulin inhibition at a lower glucose threshold causing hyperinsulinaemic hypoglycaemia (GCK-HH). This is the first reported case who tolerated years of regular fasting during Ramadhan, presenting only with seizure and syncope now. We describe a case with GCK gene variant p.T65I diagnosed in a 51-year-old woman with hypoglycaemia unawareness even at glucose level of 1.6 mmol/L. Insulin and C-peptide levels during hypoglycaemia were suggestive of hyperinsulinism, but at a day after intravenous glucagon, hypoglycaemia occurred with low insulin and C-peptide levels, pointing against insulinoma as the underlying aetiology. Imaging studies of the pancreas and calcium arterial stimulation venous sampling were unremarkable. A review of old medical records revealed asymptomatic hypoglycaemia years ago. Genetic testing confirmed activating mutation of GCK. Hypoglycaemia was successfully controlled with a somatostatin analogue. This case highlights the importance of consideration of genetic causes of hypoglycaemia in adulthood, especially when imaging is uninformative.

Learning points

  • Consider genetic causes of endogenous hyperinsulinism hypoglycaemia in adulthood, especially when imaging is uninformative.

  • Late presentation of activating mutation of GCK can occur because of hypoglycaemia unawareness.

  • Long-acting somatostatin analogue may be useful for the treatment of activating mutation of GCK causing hypoglycaemia.

  • Depending on the glucose level when the blood was taken, and the threshold of glucose-stimulated insulin release (GSIR), the serum insulin and C-peptide levels may be raised (hyperinsulinaemic) or low (hypoinsulinaemic) in patients with activating mutation of GCK.

  • Glucagon may be useful to hasten the process of unmasking the low insulin level during hypoglycaemia below the GSIR level of which insulin released is suppressed.

Open access

Sarah Ying Tse Tan, Swee Ping Teh, Manish Kaushik, Tze Tein Yong, Shivani Durai, Claudia Jong-Chie Tien, and Daphne Su-Lyn Gardner

Summary

Gestational hypertriglyceridemia-induced pancreatitis is associated with significant maternal and fetal morbidity and mortality. We report a case of gestational hypertriglyceridemia-induced pancreatitis in a primigravida at 31-weeks gestation, complicated by impending preterm labor and metabolic acidosis requiring hemodialysis. This was successfully managed with therapeutic plasma exchange (TPE), followed by i.v. insulin, low-fat diet, and omega-3. Triglyceride levels stabilized after TPE and the patient underwent an uncomplicated term delivery. In pregnancy, elevated estrogen and insulin resistance exacerbate hypertriglyceridemia. Management is challenging as risks and benefits of treatment options need to be weighed against fetal wellbeing. We discuss management options including a review of previous case reports detailing TPE use, dietary optimization, and delivery timing. This case emphasizes the importance of multidisciplinary care to optimize maternal and fetal outcomes.

Learning points

  • Gestational hypertriglyceridemia-induced pancreatitis has high morbidity.

  • A multidisciplinary team approach is a key as maternal and fetal needs must be addressed.

  • Rapid lowering of triglycerides is crucial and can be achieved successfully and safely with plasma exchange.

  • A low-fat diet while ensuring adequate nutrition in pregnancy is important.

  • Timing of delivery requires consideration of fetal maturity and risk of recurrent pancreatitis.

Open access

Kieran Palmer, Scott Weerasuriya, Benjamin Whitelaw, and Rajaventhan Srirajaskanthan

Summary

We report a rare case of posterior reversible encephalopathy syndrome (PRES), precipitated by ectopic Cushing’s syndrome, in a patient with a metastatic pancreatic neuroendocrine tumour. A 55-year-old female presented as a hypertensive emergency with seizures and severe biochemical disturbance, including alkalosis, hypokalaemia and hyperglycaemia. MRI showed vasogenic oedema in the parieto-occipital region, consistent with a diagnosis of PRES. She had a significantly raised serum cortisol (>6000 nmol/L) which did not suppress with dexamethasone. Plasma adrenocorticotropic hormone (ACTH) concentrations were neither suppressed nor raised but were consistently within the normal reference range. The unexpected finding of a normal ACTH may be explained by either tumour secretion of unmeasured ACTH-related peptides, immunoassay antibody interference or episodic ACTH secretion. PRES is usually reversible with prompt and appropriate treatment. Hypercortisolism associated PRES is rare and may be associated with a worse outcome.

Learning points

  • PRES secondary to ectopic Cushing’s syndrome is very rare.

  • PRES in this context may indicate a worse prognosis.

  • In ectopic Cushing’s syndrome, if the serum ACTH level is normal, consider testing for ACTH-related peptides or interfering antibodies.

  • Further research is required to establish the best treatment approach and to improve patients’ outcomes.