Severe recurrent hypoglycaemia in a patient with aggressive melanoma

. We present a case of hypoglycemia in a young patient without diabetes mellitus who presented initially with enlarging neck mass and weight loss, and was found to have aggressive melanoma with metastasis to multiple organs and diffuse lymphadenopathy. He had presented to the emergency room two times with neuroglycopenic symptoms that required admission and intravenous dextrose continuously. Evaluation of hypoglycemia included C-peptide, insulin levels, insulin-like growth factor (IGF) -I and -II, and ß- hydroxybutyrate. Insulin levels were suppressed appropriately during hypoglycemia, however, IGF-II:IGF-I ratio was high, suggesting non-islet tumour induced hypoglycemia. The presence of IGF-II produced by large tumors results in a low hepatic glucose output and increased uptake by skeletal muscle, resulting in hypoglycemia especially in a patient with extremely low appetite such as our patient. Treating the culprit malignancy leads to resolution of hypoglycemia, but corticosteroids have been used to suppress IGF-II levels and alleviate symptoms.

Hypoglycemia due to insulin autoimmune syndrome (Hirata’s disease): a rare cause of hypoglycaemia

Although the most common cause of recurrent hypoglycaemia is diabetes mellitus as patient is on antidiabetic medications which can be prevented by modification of antidiabetic doses, nutrition therapy and lifestyle modifications. Some endogenous hyperinsulinemic conditions like insulinoma, functional beta cell disorders and insulin autoimmune syndromes, hormonal deficiencies can cause serious and sometimes life threatening hypoglycaemia. So further laboratory evaluation like plasma/serum glucose levels, c-peptide levels, insulin levels, insulin antibodies and imaging studies are needed to evaluate unexplained hypoglycaemia. Here we report a case of insulin autoimmune syndrome in a 67 year old Indian male who had presented to us with multiple episodes of spontaneous hypoglycaemia. On further workup, the patient was found to have endogenous hyperinsulinemic hypoglycemia. As the patient’s abdominal imaging revealed no apparent cause of EHH, on further evaluation he came positive for insulin antibodies. Patient was diagnosed as IAS and he was given frequent small meals and complex carbohydrate diet and he had improved symptomatically. The incidence of IAS is most common in Japan and very few cases have been reported from India, so it should be kept in differential diagnosis of recurrent hypoglycaemia.

Recurrent hypoglycaemia and dilated cardiomyopathy: delayed presentation of Sheehan’s syndrome

Sheehan’s syndrome (SS) is ischaemic necrosis of the pituitary gland due to massive postpartum haemorrhage. The clinical manifestations may vary from subtle to life-threatening and may present immediately after delivery or many years later. We present a case history of a 58-year-old non-diabetic woman who had undetected SS and presented with two unusual manifestations, including recurrent hypoglycaemia and dilated cardiomyopathy 34 years after delivery. The dilated cardiomyopathy reversed partially after treatment.

Can Anti-Hypertensives Cause Hypoglycaemia? - A Rare Presentation of Recurrent Hypoglycaemia Secondary to an ACE-Inhibitor

Introduction: Angiotensin-converting enzyme (ACE) inhibitors are commonly prescribed Anti-hypertensives which are first line treatments in patients with Diabetes. We report a rare but significant side-effect of ACE inhibitor treatment, relevant to Diabetic and non-diabetic patients alike. Case Details: We report the case of a 79 year male, with a background of Hypertension (HTN), established on Ramipril and Bendroflumethiazide, who was admitted following an episode of unresponsiveness secondary to Hypoglycaemia, which was initially presumed secondary to Alcohol, the intake of which was minimal. He did not have a history of Diabetes Mellitus. 7 weeks later, he had a similar presentation and as found to be profoundly Hypoglycaemic. On arrival, his observations were unremarkable except for CBG 1.9 and GCS of 14/15, which responded well to IM glucagon, and IV Dextrose. Relevant investigations revealed significantly impaired renal functions and normal CT imaging. There was no history of alcohol intake or intoxication. Management: Following acute management and stabilisation, he was admitted under the Endocrine and Diabetes team, who suspended his regular medications, including his ACE-I. As an inpatient, he underwent extensive biochemical investigations which were unremarkable followed by a prolonged 72 hours fasting test and an Oral Glucose Tolerance Test, wherein no significant drop in Blood Glucose was noted in both. Subsequently, there were no further episodes of hypoglycaemia and he remained asymptomatic whilst off his ACE-I and he was safely discharged. He was followed up in our Endocrine clinic and was found to have no episodes of Hypoglycaemia since discharge and remained asymptomatic. Discussion: We report the rare presentation of recurrent hypoglycaemia in a non- diabetic secondary to ACE-I. Hypoglycaemia may be defined by the Whipple’s triad, a classical triad of hypoglycaemic symptoms, low Blood Glucose levels and relief of symptoms following ingestion of glucose. The mechanism by which ACE-I treatment leads to hypoglycaemia remains unclear. It has been postulated that ACE-I related alterations in the Kininogen-Kinin system, are associated with hypoglycaemia. This mechanism may lead to an increase in Insulin sensitivity, mediated by increased muscle tissue uptake and diminished hepatic glucose production. Another proposed mechanism is the suppressive effect that ACE-inhibitors exhibit on the peripheral sympathomimetic overactivity, thus causing Hypoglycaemia. Exacerbating factors comprise of concurrent renal impairment, as in this case. The first case of ACE-I induced Hypoglycaemia was reported in 1985, with the usage of Captopril. To the best of our knowledge, this is one of the rare peculiar cases wherein an ACE-I has been implicated as the underlying aetiology causing Hypoglycaemia in a Non-Diabetic.

Recurrent hypoglycaemia and a slowly rising hemidiaphragm: A case report.

A 92-year-old man presented to the hospital with recurrent hypoglycemia with a chronically raised right hemidiaphragm. A CT thorax-abdomen-pelvis showed a large abdominal mass. A ‘big’ IGF-2 secreting non-islet cell tumour was suspected and confirmed. The patient was treated with low dose prednisolone.

Consequences of recurrent hypoglycaemia on brain function in diabetes

The discovery of insulin and its subsequent mass manufacture transformed the lives of people with type 1 and 2 diabetes. Insulin, however, was a drug with a ‘dark side’. It brought with it the risk of iatrogenic hypoglycaemia. In this short review, the cellular consequences of recurrent hypoglycaemia, with a particular focus on the brain, are discussed. Using the ventromedial hypothalamus as an exemplar, this review highlights how recurrent hypoglycaemia has an impact on the specialised cells in the brain that are critical to the regulation of glucose homeostasis and the counterregulatory response to hypoglycaemia. In these cells, recurrent hypoglycaemia initiates a series of adaptations that ensure that they are more resilient to subsequent hypoglycaemia, but this leads to impaired hypoglycaemia awareness and a paradoxical increased risk of severe hypoglycaemia. This review also highlights how hypoglycaemia, as an oxidative stressor, may also exacerbate chronic hyperglycaemia-induced increases in oxidative stress and inflammation, leading to damage to vulnerable brain regions (and other end organs) and accelerating cognitive decline. Pre-clinical research indicates that glucose recovery following hypoglycaemia is considered a period where reactive oxygen species generation and oxidative stress are pronounced and can exacerbate the longer-term consequence of chronic hypoglycaemia. It is proposed that prior glycaemic control, hypoglycaemia and the degree of rebound hyperglycaemia interact synergistically to accelerate oxidative stress and inflammation, which may explain why increased glycaemic variability is now increasingly considered a risk factor for the complications of diabetes. Graphical abstract

Cold-induced dishabituation in rodents exposed to recurrent hypoglycaemia

Aims/hypothesis Recurrent hypoglycaemia in people with diabetes leads to progressive suppression of counterregulatory hormonal responses to subsequent hypoglycaemia. Recently it has been proposed that the mechanism underpinning this is a form of adaptive memory referred to as habituation. To test this hypothesis, we use two different durations of cold exposure to examine whether rodents exposed to recurrent hypoglycaemia exhibit two characteristic features of habituation, namely stimulus generalisation and dishabituation. Methods In the first study (stimulus generalisation study), hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamps were performed in non-diabetic rodents exposed to prior moderate-duration cold (4°C for 3 h) or control conditions. In the second study (dishabituation study), rodents exposed to prior recurrent hypoglycaemia or saline (154 mmol/l NaCl) injections over 4 weeks underwent a longer-duration cold (4°C for 4.5 h) exposure followed 24 h later by a hyperinsulinaemic–hypoglycaemic (2.8 mmol/l) glucose clamp. Output measures were counterregulatory hormone responses during experimental hypoglycaemia. Results Moderate-duration cold exposure blunted the adrenaline (epinephrine) response (15,266 ± 1920 vs 7981 ± 1258 pmol/l, Control vs Cold; p < 0.05) to next day hypoglycaemia in healthy non-diabetic rodents. In contrast, the suppressed adrenaline response (Control 5912 ± 1417 vs recurrent hypoglycaemia 1836 ± 736 pmol/l; p < 0.05) that is associated with recurrent hypoglycaemia was restored following longer-duration cold exposure (recurrent hypoglycaemia + Cold 4756 ± 826 pmol/l; not significant vs Control). Conclusions/interpretation Non-diabetic rodents exhibit two cardinal features of habituation, namely stimulus generalisation and dishabituation. These findings provide further support for the hypothesis that suppressed counterregulatory responses following exposure to recurrent hypoglycaemia in diabetes result from habituation. Graphical abstract