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Summary
Familial renal glucosuria (FRG) is a rare renal tubular disorder characterized by increased urinary glucose excretion despite normoglycemia. It is most commonly caused by pathogenic variants in the solute carrier family V member 2 (SLC5A2) gene. This gene encodes the sodium–glucose cotransporter 2, crucial for glucose reabsorption. We report the case of a 44-year-old male referred to the endocrinology outpatient clinic for unexplained glucosuria despite well-controlled diabetes mellitus with metformin and gliclazide therapy. His main complaints were nocturia and an unintentional 5 kg weight loss in 1 year. A 24-h urinary collection revealed overt glucosuria (23.3 g/1.73 m2/24 h), generalized aminoaciduria, and increased uric acid excretion (fractional excretion: 6.4%). Whole-exome sequencing revealed a novel heterozygous c.469-1G>A likely pathogenic variant in the SLC5A2 gene. Specific analysis of the maturity-onset diabetes of the young type (MODY) gene panel showed no pathogenic variants in the hepatocyte nuclear factor-1A (HNF-1A; MODY3) nor in other MODY-associated genes. We assume that the association of glucosuria, aminoaciduria, and increased uric acid excretion can be explained by the combination of diabetes and the likely pathogenic SLC5A2 variant in this patient. In conclusion, we describe a well-controlled diabetic patient with FRG, associated with a novel heterozygous c.469-1G>A likely pathogenic variant in the SLC5A2 gene.
Learning points
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The diagnosis of a renal tubular disorder should be considered in patients with unexplained glucosuria and diabetes mellitus, especially if the latter is well controlled.
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FRG usually presents with glucosuria but may be associated with generalized aminoaciduria and hyperuricosuria.
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Genetic analysis should be considered in patients with young-onset diabetes and glucosuria, particularly with a positive family history.
Clinical Medical School, University of Oxford, Oxford, UK
Green Templeton College, University of Oxford, Oxford, UK
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Green Templeton College, University of Oxford, Oxford, UK
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NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
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NIHR Biomedical Research Centre, Oxford University Hospitals Foundation Trust, Oxford, UK
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Summary
The use of a low-carbohydrate diet (LCD) reduces insulin requirements in insulinopenic states such as type 1 diabetes mellitus (T1DM). However, the use of potentially ketogenic diets in this clinical setting is contentious and the mechanisms underlying their impact on glycaemic control are poorly understood. We report a case of a patient with a late-onset classic presentation of T1DM who adopted a very low-carbohydrate diet and completely avoided insulin therapy for 18 months, followed by tight glycaemic control on minimal insulin doses. The observations suggest that adherence to an LCD in T1DM, implemented soon after diagnosis, can facilitate an improved and less variable glycaemic profile in conjunction with temporary remission in some individuals. Importantly, these changes occurred in a manner that did not lead to a significant increase in blood ketone (beta-hydroxybutyrate) concentrations. This case highlights the need for further research in the form of randomised controlled trials to assess the long-term safety and sustainability of carbohydrate-reduced diets in T1DM.
Learning points
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This case highlights the potential of low-carbohydrate diets (LCDs) in type 1 diabetes mellitus (T1DM) to mediate improved diabetes control and possible remission soon after diagnosis.
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Could carbohydrate-reduced diets implemented early in the course of T1DM delay the decline in endogenous insulin production?
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Adherence to an LCD in T1DM can facilitate an improved and less variable glycaemic profile.
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This case suggests that LCDs in T1DM may not be associated with a concerning supraphysiological ketonaemia.
University of Glasgow, Glasgow, UK
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Search for other papers by Gregory C Jones in
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Summary
A 20-year-old South Asian male presented with polyuria, polydipsia, HbA1c 81 mmol/mol, BMI 28.8 and family history of both type 1 and type 2 diabetes mellitus. As autoantibody testing was negative and c-peptide level demonstrated significant endogenous insulin secretion, type 1 diabetes was excluded. Given his age and family history, the differential diagnosis included maturity-onset diabetes of the young (MODY), a rare form of diabetes caused by a single-gene variant. A high probability of MODY was calculated and he was subsequently referred for genetic testing. Although a useful tool, the pre-test probability calculator for MODY is only validated in White Europeans. A heterogenous variant of unknown clinical significance of the NEUROD1 gene was detected, leading to gliclazide use with poor response. The patient responded well to metformin. Type 2 diabetes was considered the most likely diagnosis. This case highlights the diagnostic challenges in young patients of Asian ethnicity and the importance of interpreting genetic results of unknown significance within the clinical context. Ethnicity-specific BMI thresholds should be used when classifying patients as overweight or obese.
Learning points
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Variants of unknown significance detected by genetic sequencing should be interpreted within the context of the patient’s other clinical parameters.
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It is important to use ethnicity-specific BMI thresholds for obesity.
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Diagnosis of type 2 diabetes mellitus at younger ages is becoming increasingly common.
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The pre-test probability calculator for MODY is only validated in White Europeans; although a useful guide, results should be interpreted with caution in patients of other ethnicities.
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Ghent University, Ghent, Belgium
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Summary
Mitotane is used for treatment of advanced adrenocortical carcinoma. It is administered when the carcinoma is unresectable, metastasized, or at high-risk of recurrence after resection. In addition, mitotane is considered to have direct adrenolytic effects. Because of its narrow therapeutic–toxic range, therapeutic drug monitoring (TDM) is warranted. In 2020, a left-sided adrenal gland tumor was found (5.8 cm) in a 38-year-old man. Considering the size of this lesion and inability to exclude an adrenocortical carcinoma on imaging, a laparoscopic adrenalectomy was performed. Histopathologic examination determined presence of an adrenocortical carcinoma (pT2N0M0 ENSAT stadium II; ki67 10–15%). There was no evidence for residual or metastatic disease but given the high risk of recurrence, adjuvant therapy with mitotane was initiated. During TDM, a sudden and spuriously high level of mitotane was observed but without signs or symptoms of toxicity. After exploration, it was found that this high concentration was completely due to uncontrolled hypertriglyceridemia. After correction thereof, mitotane levels were again in the therapeutic range. This observation underscores the importance of TDM sampling in a fasting state with concurrent control of prevalent or incident dyslipidemia.
Learning points
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TDM of mitotane is advocated to achieve therapeutic levels while avoiding toxicity. For correct TDM, sampling should be done at least 12 h after last intake of mitotane.
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Although sampling in fasting conditions in not explicitly mentioned in the guidelines, fasting state should be considered as elevated serum triglyceride levels might cause spuriously high mitotane levels.
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In patients undergoing treatment with mitotane and presenting with too high or unexplained fluctuating mitotane levels without signs or symptoms of toxicity, hypertriglyceridemia as a possible cause should be investigated.
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If dyslipidemia occurs in patients under mitotane treatment, other causes than mitotane (e.g. alcohol abuse and diabetes) should be considered and appropriate treatment should be initiated.
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Search for other papers by Chandima Idampitiya in
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Summary
Type 1 diabetes mellitus (T1DM) is an autoimmune disorder caused by the destruction of the pancreatic beta cells, which produce insulin. Individuals with T1DM usually require at least 3-5 years to develop microvascular complications in comparison to people with type 2 diabetes (T2DM), who may develop complications even before the diagnosis of diabetes. We discuss a patient who presented with proliferative diabetic retinopathy subsequently diagnosed with T1DM and diabetic neuropathy following investigations. Diabetic retinopathy or other microvascular complications as the presenting feature of T1DM is rarely known or reported in the literature. A 33-year-old healthcare worker had been seen by the opticians due to 1-week history of blurred vision. The ophthalmology assessment had confirmed proliferative retinopathy in the right eye and severe non-proliferative retinopathy in the left eye with bilateral clinically significant macular oedema. His BMI was 24.9 kg/m2. The nervous system examination revealed bilateral stocking type peripheral neuropathy. The random venous glucose was 24.9 mmol/L. Plasma ketones were 0.7 mmol/L and HbA1c was 137 mmol/mol. On further evaluation, the anti-glutamic acid decarboxylase (GAD) antibody was positive, confirming the diagnosis of T1DM. He was started on aflibercept injections in both eyes, followed by panretinal photocoagulation. Subsequent nerve conduction studies confirmed the presence of symmetrical polyneuropathy. The pathogenesis of the development of microvascular complications in T1DM is multifactorial. Usually, the development of complications is seen at least a few years following the diagnosis. The occurrence of microvascular complications at presentation is rare. This makes the management challenging and extremely important in preventing the progression of the disease.
Learning points
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The pathogenesis of the development of microvascular complications in type 1 diabetes mellitus is multifactorial.
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The development of complications is seen at least a few years following the diagnosis.
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Occurrence of microvascular complications at presentation is rare.
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This makes the management challenging and extremely important to prevent the progression of the disease.
Hospital Militar Central, Bogotá, Colombia
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Summary
Pancreatic dysgenesis (PD) is a rare congenital disease, with less than 100 cases reported in the literature. In most cases, patients are asymptomatic and the diagnosis is made incidentally. In this report, we present the case of two brothers with a history of intrauterine growth retardation, low birth weight, hyperglycemia, and poor weight gain. The diagnosis of PD and neonatal diabetes mellitus was made by an interdisciplinary team composed of an endocrinologist, a gastroenterologist, and a geneticist. Once the diagnosis was made, treatment with an insulin pump, pancreatic enzyme replacement therapy, and supplementation with fat-soluble vitamins was decided. The use of the insulin infusion pump facilitated the outpatient treatment of both patients.
Learning points
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Pancreatic dysgenesis is a relatively rare congenital anomaly; most of the time, patients are asymptomatic and are diagnosed incidentally.
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The diagnosis of pancreatic dysgenesis and neonatal diabetes mellitus should be made with an interdisciplinary team.
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Due to its flexibility, the use of an insulin infusion pump facilitated the management of these two patients.
Search for other papers by Rikako Nakajima in
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Summary
Unawareness of postprandial hypoglycemia for 5 years was identified in a 66-year-old man at a local clinic. The patient was referred to our hospital because of this first awareness of hypoglycemia (i.e. lightheadedness and impaired consciousness) developing after lunch. In a 75 g oral glucose tolerance test, the plasma glucose concentration was decreased to 32 mg/dL (1.8 mmol/L) at 150 min with relatively high concentrations of insulin (8.1 μU/mL), proinsulin (70.3 pmol/L), and C-peptide (4.63 ng/mL). In a prolonged fasting test, the plasma glucose concentration was decreased to 43 mg/dL (2.4 mmol/L) at 66 h with an insulin concentration of 1.4 μU/mL and a C-peptide concentration of 0.49 ng/mL. Computed tomography showed an 18 mm hyperenhancing tumor in the uncinate process of the pancreas. A selective arterial calcium stimulation test showed an elevated serum insulin concentration in the superior mesenteric artery. The patient was then diagnosed with insulinoma and received pancreaticoduodenectomy. Continuous glucose monitoring (CGM) using the Dexcom G6 system showed unawareness of hypoglycemia mainly during the daytime before surgery. When the sensor glucose value was reduced to 55 mg/dL (3.1 mmol/L), the Dexcom G6 system emitted an urgent low glucose alarm to the patient four times for 10 days. Two months after surgery, an overall increase in daily blood glucose concentrations and resolution of hypoglycemia were shown by CGM. We report a case of insulinoma with unawareness of postprandial hypoglycemia in the patient. The Dexcom G6 system was helpful for assessing preoperative hypoglycemia and for evaluating outcomes of treatment by surgery.
Learning points
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Insulinoma occasionally leads to postprandial hypoglycemia.
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The CGM system is useful for revealing the presence of unnoticed hypoglycemia and for evaluating treatment outcomes after surgical resection.
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The Dexcom G6 system has an urgent low glucose alarm, making it particularly suitable for patients who are unaware of hypoglycemia.
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Summary
The etiology of foot drop is diverse from various diseases to mechanic injuries and includes neuropathy of the peroneal nerve. Peroneal neuropathy might also be one of the forms of diabetic neuropathy, very rarely reported as the first sign of diabetes. We describe three cases of children with newly diagnosed type 1 diabetes (TID) who developed unilateral peroneal nerve palsies and tibial nerve palsies, presenting clinically as a foot drop. In two of our cases, the symptoms of foot drop occurred shortly after starting treatment for severe diabetes ketoacidosis. In the third patient, food drop was a reason for the initial medical consultation, but eventually, TID was diagnosed. The presented cases highlight that neuropathy can be observed not only as a chronic complication of T1D, but it can also appear at the time of disease manifestation. The incorrect position of the lower limb during a keto coma may contribute to the development of neuropathy.
Learning points
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Neuropathy can be observed not only as a chronic complication of type 1 diabetes (T1D), but it can also appear at the time of disease manifestation.
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The incorrect position of the lower limb causing external pressure during a keto coma may contribute to the development of neuropathy.
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It is important to examine the glycemia in patients with acute peroneal neuropathy, as this kind of peripheral neuropathy can be associated with newly diagnosed T1D. Normalization of glycemia might lead to rapid neuronal recovery.
Clinic for Pediatrics and Adolescent Medicine/Metabolism Laboratory, Universitätsklinikum Münster, Münster, Germany
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Summary
Traditional guidelines for type 1 diabetics do not restrict carbohydrates to improve clinical outcomes for patients. This paper highlights the favorable blood glucose control outcomes when a type 1 diabetic focuses on caloric intake from protein and healthy fats instead of the traditional carbohydrate-focused meals. We followed a male type 1 diabetic in his 20s adopting a ketogenic diet through a process of slowly lowering total daily carbohydrate intake. Diabetes-related biomarkers were measured throughout the process. Diabetes-related biomarkers saw massive improvements and ended up in the official non-diabetic range. Total daily insulin requirements dropped by 70%. The patient also experienced great improvements in his quality of life. This study demonstrates the possibility of improving diabetes-related biomarkers through dietary changes, which have positive effects on health outcomes in patients living with this disease.
Learning points
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The adaptation of a ketogenic diet improved diabetes-related biomarkers in this patient.
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Diabetes-related biomarkers, such as HbA1c, are the main risk factors for developing complications in diabetics.
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The ketogenic diet is a feasible approach to minimizing the risk of developing complications in diabetics.
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Total daily insulin requirements dropped by 67% adapting a ketogenic diet.
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The patient experienced enormous changes in the quality of life after adapting to the new diet.
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The safe and physiological state of ketosis might be associated with additional benefits for the patient
School of Cardiovascular Medicine & Sciences, King's College London, London, UK
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School of Cardiovascular Medicine & Sciences, King's College London, London, UK
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Summary
A Caucasian man in his 60s with recent diagnosis of metastatic renal cell carcinoma presented to the emergency department with a 5-day history of severe polyuria, polydipsia and fatigue and 1-day history of confusion, abdominal pain, nausea and vomiting. Investigations revealed an overlap of diabetic ketoacidosis (DKA) and hyperosmolar hyperglycaemic state (HHS). He had received the first dose of immunotherapy with nivolumab and ipilimumab 3 weeks prior to this attendance. New-onset type 1 diabetes (T1DM) was confirmed based on the clinical features at presentation, seropositivity for glutamic acid decarboxylase antibodies and significant insulin deficiency. He is currently on a multiple daily injections of insulin and uses intermittent-scanned glucose monitoring. Given the irreversible impact on beta-cell function and clinical response with insulin resulting in improved diabetes control, immunotherapy was resumed for his metastatic cancer with good radiological response. Although rare, new-onset T1DM can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes.
Learning points
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Although rare, new onset of T1DM after immunotherapy can present with DKA and HSS overlap after a single dose of nivolumab/ipilimumab in individuals without pre-existing history of diabetes and normal glycaemic parameters.
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Due to the irreversible destruction of beta-cells, treatment with steroids is not indicated in contrast to other settings such as immunotherapy-induced hypophysitis.
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Presence of low c-peptide levels post-acute presentation is indicative of an irreversible impact on beta-cell function and supports resuming immunotherapy given the significant benefits on cancer prognosis.
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Clinicians must maintain a high index of suspicion in regards to diagnosis and management of new-onset type 1 diabetes and advice patients on reporting symptoms suggestive of diabetes and/or diabetes-related hyperglycaemic emergencies.
