Summary

Maturity-onset diabetes of the young (MODY) is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with dominant inheritance of beta-cell dysfunction. There are few reports of the coinheritance of glucokinase (GCK) and hepatocyte nuclear factor 1 alpha gene (HNF1A) variants underlying MODY in patients. Herein, we describe a case involving combinations of monoallelic GCK and HNF1A variants associated with MODY. A 10-year-old Japanese girl with a three-generation family history of diabetes without obesity showed high levels of urinary glucose during a school screening test. Her glucose metabolism profile revealed 124 mg/dL of fasting glucose, 6.9% glycated hemoglobin (HbA1c), and 2.78 ng/mL of C-peptide immunoreactivity levels. In a 75-g oral glucose tolerance test, her base glucose, peak glucose, insulin resistance, and homeostasis model assessment of beta cell function levels were 124 mg/dL, 210 mg/dL (120 min), 1.71, and 33%, respectively. Based on the clinical phenotype of GCK-MODY, alimentary and exercise therapy without oral hypoglycemic agents were used to maintain her fasting glucose and HbA1c levels. We explored the coinheritance of MODY with GCK and HNF1A variants in this and past cases and found that careful clinical follow-up is required to firmly establish phenotypic features. Moreover, the accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype–phenotype correlations.

Learning points

• MODY is a group of monogenic forms of diabetes mellitus characterized by early-onset diabetes with the dominant inheritance of beta-cell dysfunction.

• MODY2 and MODY3 caused by heterozygous loss-of-function variants in the glucokinase (GCK) and hepatocyte nuclear factor 1 alpha (HNF1A) genes, respectively, are the most common forms of the disease.

• Few cases of MODY have previously been reported as being associated with the coinheritance of GCK and HNF1A variants.

• Careful clinical follow-up is required to firmly establish phenotypic features in the coinheritance of MODY with GCK and HNF1A variants.

• The accumulation of data on genetically confirmed MODY associated with the coinheritance of GCK and HNF1A variants will be useful for understanding genotype–phenotype correlations.

Summary

An 89-year-old woman presented with a 6-year history of occasional episodes of impaired consciousness that were relieved by ingestion of a snack. Three months before presenting to our hospital, she had been hospitalized in a local hospital with subdural hematoma caused by a head contusion, where previously unrecognized hypoglycemia was discovered. Fasting plasma glucose concentration was 37 mg/dL, with a relatively high serum level of insulin (34.9 µU/mL). Computed tomography showed a 14 mm hyperenhancing tumor in the tail of the pancreas and she was referred to our hospital for further investigation. A prolonged fasting test revealed the plasma glucose concentration reduced to 43 mg/dL (2.4 mmol/L) at 8 h after the last meal. Serum insulin, proinsulin, and C-peptide concentrations were 21.1 µU/mL, 16.9 pmol/L, and 2.72 ng/mL, respectively. Subsequent intravenous administration of 1 mg of glucagon increased the plasma glucose concentration to 76 mg/dL (4.2 mmol/L). Moreover, the insulin-to-C-peptide molar ratio was 0.14. These data indicated the presence of insulinoma. Interestingly, serum anti-insulin antibodies were elevated (21.1 U/mL), although she had no history of taking exogenous insulin injection, alpha lipoic acid, or sulfhydryl group-containing agents. Human leukocyte antigen (HLA) typing revealed HLA-DRB1*0407 and HLA-DRB1*1405 alleles. Treatment with diazoxide prevented hypoglycemia, but was discontinued due to weight gain and leg edema. Elevated serum anti-insulin antibodies persisted almost 1 year after the diagnosis of insulinoma. We present a rare case of insulinoma concomitant with serum anti-insulin antibodies.

Learning points

• Insulinoma presenting with concomitant anti-insulin antibodies appears rare.

• Insulin/C-peptide molar ratio and serum insulin concentration are useful for differentiating insulinoma and autoimmune syndrome.

• Flash glucose monitoring systems appear suitable for evaluating treatment outcomes.

Summary

An 82-year-old woman with a 60-year history of a lung tumor presented with hypoglycemia. Non-islet cell tumor hypoglycemia (NICTH) was suspected; however, her hypoglycemia stabilized with supplemental food. She was discharged, based on her wishes, and planned to undergo surgery later. After discharge, the hypoglycemia worsened rapidly and required immediate resection. Postoperatively, the hypoglycemia resolved. Western immunoblot analysis confirmed the presence of big insulin-like growth factor 2, confirming NICTH. This patient experienced the rapid progression of symptoms after an unprecedentedly long-term asymptomatic state. Therefore, when NICTH is suspected, early intervention is recommended regardless of the presence of asymptomatic state.

Learning points

• In patients with NICTH, the onset of hypoglycemia is usually within a year of tumor detection, and few reports regarding long-term asymptomatic NICTH have been documented.

• NICTH can cause rapidly progressive symptoms after a long-term asymptomatic state, as in this case, and an asymptomatic state does not preclude the necessity for intervention, especially when patients are at risk for malnutrition.

• Tumor resection is the only curative treatment for patients with NICTH, but there is no consensus regarding the timing of surgery. However, considering the possibility of rapid symptom progression, patients should be examined and treated in a timely manner.

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

• 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.

• FRG usually presents with glucosuria but may be associated with generalized aminoaciduria and hyperuricosuria.

• Genetic analysis should be considered in patients with young-onset diabetes and glucosuria, particularly with a positive family history.

Summary

Congenital hyperinsulinism is the leading cause of persistent hypoglycaemia in infants and children; however, it is uncommon to be diagnosed in adulthood. We describe the cases of two sisters who presented with hyperinsulinaemic hypoglycaemia aged 47 and 57 years old, who were subsequently diagnosed with compound heterozygous likely pathogenic variants in the ABCC8 gene, a known cause of monogenic congenital hyperinsulinism. We discuss the typical presenting features, investigation findings, and treatment strategies for patients with this condition.

Learning Points

• Congenital hyperinsulinism is a rare cause of hyperinsulinaemic hypoglycaemia diagnosed in adulthood.

• Clinical presentation is similar to an insulinoma, and imaging modalities may assist in differentiation.

• There are minimal medical therapies currently available for patients non-responsive to diazoxide (such as those with ABCC8 and KCNJ11 variants).

• Continuous glucose monitoring can be helpful in giving patients autonomy in managing their disease, as well as relieving anxiety and fear associated with hypoglycaemia.

Summary

Hemichorea–hemiballismus (HCHB) syndrome is a syndrome characterized by choreic movements which are irregular, nonrepetitive, and random movements, and ballismus which are spontaneous and violent movements. HCHB syndrome with a metabolic cause is a rare presentation that can be precipitated by uncontrolled diabetes. Presented here is a case of HCHB syndrome with right-sided neuroimaging findings and contralateral chorea due to uncontrolled type 2 diabetes mellitus. This patient was found to be obtunded with a blood glucose of greater than 500 mg/dL by EMS. After the administration of insulin, she was able to answer clarifying questions of noncompliance with her antihyperglycemic medications. She had a computed tomography without contrast of the head which showed hyperdense lesions in the right caudate nucleus and putamen consistent with HCHB syndrome. She was started on treatment for nonketotic hyperglycemia with insulin. As her mentation improved, she was able to cooperate with physical examination, which revealed irregular and violent movements in the left upper and lower extremities. Her hemichorea and hemiballismus improved with strict glycemic control, and she was able to be discharged to a skilled nursing facility for further rehabilitation. She would later have repeated hospitalizations for poor glycemic control, and repeat neuroimaging would reveal the resolution of hyperdensities after 4 months. HCHB syndrome due to uncontrolled diabetes has been termed diabetic striatopathy and is characterized by poor glycemic control, unilateral striatal hyperdensity on CT imaging, and contralateral choreic movements. Diabetic striatopathy remains a poorly understood disease, and the exact pathophysiologic mechanism has not been definitively elucidated.

Learning points

• Diabetic striatopathy is a relatively new term for metabolic etiology of hemichorea–hemiballismus syndrome and was coined in 2009.

• The triad for diabetic striatopathy is poor glycemic control, unilateral striatal hyperdensity on CT imaging, and contralateral choreic movements.

• Multiple etiologies have been suggested for the cause of diabetic striatopathy including petechial hemorrhage, mineral deposition, myelin destruction, and infarction with reactive astrocytosis; however, the exact mechanism has yet to be determined.

• Antidopaminergic medications may be used to control the choreic movements of diabetic striatopathy; however, the mainstay of treatment is glycemic control, often with insulin therapy.

Summary

Although most published cases of lead poisoning come from occupational exposures, some traditional remedies may also contain toxic amounts of lead. Here, we report the case of a 58-year-old female who presented with abdominal pain, generalized tiredness, and decreased food intake, with anemia and elevated levels of lead. The patient was found to be taking herbal capsules for diabetes prior to the presentation. This case highlights the need for increased awareness that some herbal remedies may contain potentially harmful levels of heavy metals, and people who use them are at risk of developing associated toxicities.

Learning points

• Individuals who support traditional medicine often incorrectly believe that herbal remedies for diabetes are free from side effects, leading them to favor these treatments over contemporary medications.

• Herbal medications are freely available online, even without a prescription.

• The accessibility of herbal medicines without prescriptions, coupled with the false belief in their lack of side effects, misleads educated individuals toward quackery treatments. Misinformation spread via social media exacerbates this issue.

• Heavy metals are present in toxic levels in the drugs, causing complications.

• Lead is the most common heavy metal found in such herbal medicines.

• Lead poisoning leads to anemia and other systemic complications which could have been fatal if not found in time.

Summary

A previously healthy 17-year-old female presented to the emergency department with complaints of vomiting, shortness of breath, and tachycardia. She was found to have an elevated blood glucose and was admitted for presumed new onset type 1 diabetes mellitus (T1DM). During the admission, she was noted to have frequent episodes of hypoglycemia despite conservative insulin dosing and high urine output with glucosuria, which seemed out of proportion to her glucose levels and fluid status. She also had persistent hyponatremia despite normalization of blood glucose. Further work-up was initiated to investigate alternative or additional diagnoses to explain these atypical findings. Adrenocorticotropic hormone (ACTH) level was elevated, consistent with the diagnosis of Addison’s disease, which led to the subsequent diagnosis of autoimmune polyglandular syndrome type II (APS-2). This is one of the first reports in the literature of concurrent diagnosis of T1DM and Addison’s disease at initial presentation and demonstrates the importance of not anchoring to one diagnosis.

Learning points

• This case shows the importance of considering multiple diagnoses and investigating atypical signs and symptoms.

• This case highlights the importance of a thorough history including review of systems.

• Hyponatremia and recurrent hypoglycemia in a person with type 1 diabetes should raise suspicion for adrenal insufficiency.

• This case makes us consider the screening for Addison’s disease in a person with new onset type 1 diabetes in addition to autoimmune thyroid disease and celiac disease.

• People with an autoimmune disease should be monitored for other autoimmune diseases in the future.

Summary

Kabuki syndrome is a genetic disorder characterised by distinctive facial features, developmental delays, and multisystem congenital anomalies. Endocrine complications such as premature thelarche and short stature are common, whereas disorders of glycaemic control are less frequent. We describe a 23-year-old white female referred to the diabetes clinic for hyperglycaemia during haemodialysis. She was subsequently diagnosed with Kabuki syndrome based on characteristic clinical features, confirmed by detecting a heterozygous pathogenic variant in KMT2D. She was known to have had multiple congenital anomalies at birth, including complex congenital heart disease and a single dysplastic ectopic kidney, and received a cadaveric transplanted kidney at the age of 13. She had hyperglycaemia consistent with post-transplant diabetes mellitus (DM) and was started on insulin. Examination at the time revealed truncal obesity. She developed acute graft rejection and graft failure 14 months post-transplant and she was started on haemodialysis. Her blood glucose levels normalised post-graft explant, but she was hyperglycaemic again during haemodialysis at the age of 23. Given her clinical phenotype, negative diabetes antibodies and normal pancreas on ultrasound, she was assumed to have type 2 DM and achieved good glycaemic control with gliclazide.

Learning points

• Involve clinical genetics early in the investigative pathway of sick neonates born with multiple congenital anomalies to establish a diagnosis to direct medical care.

• Consider the possibility of Kabuki syndrome (KS) in the differential diagnoses in any neonate with normal karyotyping or microarray analysis and with multiple congenital anomalies (especially cardiac, renal, or skeletal), dysmorphic facial features, transient neonatal hypoglycaemia and failure to thrive.

• Consider the possibility of diabetes as an endocrine complication in KS patients who are obese or who have autoimmune disorders.

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

• 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.

• Could carbohydrate-reduced diets implemented early in the course of T1DM delay the decline in endogenous insulin production?

• Adherence to an LCD in T1DM can facilitate an improved and less variable glycaemic profile.

• This case suggests that LCDs in T1DM may not be associated with a concerning supraphysiological ketonaemia.