Recurrent Episodes Of Hypoglycemia Research Articles

Genetic analysis of fructose-1,6-bisphosphatase (FBPase) deficiency in nine consanguineous Pakistani families.

Fructose-1,6-bisphosphatase (FBPase) deficiency is a rare inherited metabolic disorder characterized by recurrent episodes of hypoglycemia, ketosis and lactic acidosis. FBPase is encoded by FBP1 gene and catalyzes the hydrolysis of fructose-1,6-bisphosphate to fructose-6-phosphate in the last step of gluconeogenesis. We report here FBP1 mutations in nine consanguineous Pakistani families affected with FBPase deficiency. Nine families having one or two individuals affected with FBPase deficiency were enrolled over a period of 3 years. All FBP1 exonic regions including splicing sites were PCR-amplified and sequenced bidirectionally. Familial cosegregation of mutations with disease was confirmed by direct sequencing and PCR-RFLP analysis. Three different FBP1 mutations were identified. Each of two previously reported mutations (c.472C>T (p.Arg158Trp) and c.841G>A (p.Glu281Lys)) was carried by four different families. The ninth family carried a novel 4-bp deletion (c.609_612delAAAA), which is predicted to result in frameshift (p.Lys204Argfs*72) and loss of FBPase function. The novel variant was not detected in any of 120 chromosomes from normal ethnically matched individuals. FBPase deficiency is often fatal in the infancy and early childhood. Early diagnosis and prompt treatment is therefore crucial to preventing early mortality. We recommend the use of c.472C>T and c.841G>A mutations as first choice genetic markers for molecular diagnosis of FBPase deficiency in Pakistan.

Management of hypoglycemia

Hypoglycemia is a condition characterized by an abnormally low level of blood glucose and has significant clinical consequences if left untreated. It is a potential adverse event in the treatment of diabetes mellitus. Causes of hypoglycemia are varied, but in diabetic patients, it is most often iatrogenic. Medication changes or overdoses, infection, dietary changes, and changes in activity levels are some of the important reasons for a person to develop hypoglycemia. Prompt diagnosis and treatment of hypoglycemia is an essential component of the management of diabetes. Evaluation of the cause is important, especially if there are recurrent episodes of hypoglycemia.

Spontaneous Hypoglycemia After Islet Transplantation: The Case For Using Non-Hepatic Sites.

This Perspective provides a brief history of intrahepatic alloislet and autoislet transplantation in humans and an update of the recent success rates. It also examines the important role that hypoglycemia plays in clinical outcomes. On the one hand, recurrent serious hypoglycemic episodes related to insulin therapy are a major criterion for alloislet transplantation. On the other hand, spontaneous clinical hypoglycemia, perhaps related to the accompanying Roux-en-Y procedure for total pancreatectomy, is a complication of autoislet transplantation. Complex alterations in glucagon secretion compromise counter-regulation of hypoglycemia in both situations. The glucagon response to hypoglycemia is intrinsically defective in type 1 diabetes before transplant because of the absence of physiological regulation of α-cell secretion by neighboring β-cells. Glucagon secretion from intrahepatic islets during systemic hypoglycemia is also defective, although β-cells in the graft are normally regulated by glucose and arginine. My personal perspective is that the latter is caused by intrahepatic glycogenolysis stimulated by systemic hypoglycemia with consequent increases in intrahepatic glucose flux, which incorrectly signals intrahepatic α-cells to be quiescent. This defect is liver-specific, which strongly suggests modifying the current approach to islet transplantation by placing a portion of allo- and autoislets in nonhepatic sites in addition to hepatic sites to ensure physiological glucagon secretion as a strategy to ameliorate post-transplant hypoglycemia.

Chronic exposure to KATP channel openers results in attenuated glucose sensing in hypothalamic GT1-7 neurons

Individuals with Type 1 diabetes (T1D) are often exposed to recurrent episodes of hypoglycaemia. This reduces hormonal and behavioural responses that normally counteract low glucose in order to maintain glucose homeostasis, with altered responsiveness of glucose sensing hypothalamic neurons implicated. Although the molecular mechanisms are unknown, pharmacological studies implicate hypothalamic ATP-sensitive potassium channel (KATP) activity, with KATP openers (KCOs) amplifying, through cell hyperpolarization, the response to hypoglycaemia. Although initial findings, using acute hypothalamic KCO delivery, in rats were promising, chronic exposure to the KCO NN414 worsened the responses to subsequent hypoglycaemic challenge. To investigate this further we used GT1-7 cells to explore how NN414 affected glucose-sensing behaviour, the metabolic response of cells to hypoglycaemia and KATP activity. GT1-7 cells exposed to 3 or 24 h NN414 exhibited an attenuated hyperpolarization to subsequent hypoglycaemic challenge or NN414, which correlated with diminished KATP activity. The reduced sensitivity to hypoglycaemia was apparent 24 h after NN414 removal, even though intrinsic KATP activity recovered. The NN414-modified glucose responsiveness was not associated with adaptations in glucose uptake, metabolism or oxidation. KATP inactivation by NN414 was prevented by the concurrent presence of tolbutamide, which maintains KATP closure. Single channel recordings indicate that NN414 alters KATP intrinsic gating inducing a stable closed or inactivated state. These data indicate that exposure of hypothalamic glucose sensing cells to chronic NN414 drives a sustained conformational change to KATP, probably by binding to SUR1, that results in loss of channel sensitivity to intrinsic metabolic factors such as MgADP and small molecule agonists.

Editorial: Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain.

Editorial: Molecular Mechanism of Neuronal Dysfunction in the Diabetic Brain.

Recurrent Hypoglycaemia: an Uncommon Presentation in Sheehan Syndrome

Sheehan’s syndrome is a rare but potentially serious postpartum complication. Though most common and early symptoms are lactation failure and amenorrhea, some cases might be relatively asymptomatic which are diagnosed in later years when features of hypothyroidism and adrenal insufficiency predominate. Recurrent hypoglycaemia, due to adrenal insufficiency, though described is a rare complication of Sheehan syndrome. Here we report a case of Sheehan syndrome which presented with recurrent episodes of hypoglycaemia,

The Price of a 15-Year Delay in Diagnosis of Sheehan's Syndrome

We describe a case of a 48-year-old woman who presented with a 15-year history of recurrent episodes of hypoglycemia and hyponatremia leading to altered behavior and generalized seizures. She underwent full clinical assessment, endocrine tests, and a pituitary magnetic resonance scan that showed pananterior hypopituitarism secondary to postpartum pituitary necrosis (Sheehan's syndrome). She was commenced on appropriate hormone replacement therapy, which led to significant improvement in lethargy, anorexia, muscle weakness, and episodes of hypoglycemia. In addition to the alleviation of her physical symptoms, she experienced a significant improvement in her psychological well-being and reduction in hospital visits. This case illustrates the impact of delay in diagnosis of an easily treatable medical condition and its socioeconomic implications, especially for the population of a developing country like India.

A Late-onset of Sheehan’s Syndrome Presenting with Life-threatening Hypoglycemia

We described a case of 40 year-old lady who presented with a 16 year history of generalized fatigue and recurrent episodes of hypoglycemia. She had a complete clinical evaluation, endocrine studies, and a pituitary magnetic resonance scans that revealed pan-hypopituitarism secondary to Sheehan’s syndrome. She was given hormone replacement therapy, which led to a significant improvement in lethargy, anorexia, muscle weakness, and episodes of hypoglycemia. This case shows the impact of delay in the diagnosis of an easily treatable medical condition and its consequences, especially for the population of a developing country like Ethiopia

Surgical Treatment for Hypoglycemia: A Case Report

A 55 year old female presented large left upper quadrant mass and episodes of recurrent hypoglycemia. Preoperative laboratory testing revealed normal insulin, IGF-I and IGF-II levels. Big-IGF-II levels were unable to be measured because the laboratory test was unavailable. A CT scan of her abdomen and pelvis revealed a large 19 × 15 × 12 cm left upper quadrant mass appearing to involve the pancreas, spleen, and left kidney. The mass was surgically extirpated and was consistent with a hemangiopericytoma. Subsequently, her hypoglycemic attacks along with abdominal symptoms resolved. We hypothesize that this patient’s hypoglycemic attacks were a consequence of tumor secretion of a pro-hormone form of IGF-II called ‘Big IGF-II’.

Seeking a low value of HbA1c may be dangerous under recurrent episodes of hypoglycaemia: A short report

Seeking a low value of HbA1c may be dangerous under recurrent episodes of hypoglycaemia: A short report

Maternally inherited diabetes and A3243G mitocondrial mutation in a Brazilian kindred: diagnosis after clinical suspicion in an internal medicine unit

Results We report a case of a 44-year's old woman admitted to the Internal Medicine ward with a two weeks history of signs and symptoms of community-acquired pneumonia and heart failure. She was known to have DM since the third decade of life, hearing loss since the adolescence in addition to hypertension and was in use of metformin, losartan, simvastatin and NPH insulin, with recurrent episodes of hypoglycemia. Physical examination showed a 23Kg/m BMI. Muscular weakness and ptosis were absent. Ophthalmological examination was unremarkable. She had a low C peptide (0.34ng/mL) and a glycated hemoglobin of 6.7%. Audiogram revealed severe bilateral neurossensorial loss mainly in high frequencies. Echocardiogram showed an enlarged atrium (42mm), a low ejection fraction (43%) with lateral and inferolateral hypertrophy. Familial history was noteworthy: his son died at 21 because of high undiagnosed hyperglycemia. Three of four brothers also had DM and one additionally had deafness and history of stroke and seizures, raising the suspicion of MELAS syndrome. Blood sample were collected from the kindred for molecular testing and using specific primers to the relevant region of mtDNA bp 3558-3539 and bp 3130-3149 PCR amplification was carried out. The A3243G mutation was identified in blood leukocytes with 70% heteroplasmy in the proband and with variable percentage in the family.

Nesidioblastosis: A Rare Case of Post Prandial Hypoglycemia in a Patient With Gastric Bypass Surgery

A 46-year-old man with recurrent episodes of hypoglycemia for two-years admitted with recent worsening of symptoms that ranged from dizziness, diaphoresis and disorientation to seizures and loss of consciousness. His symptoms were mostly postprandial with low random home sugars (50-80 mg/dL) despite consuming sugary drinks and candies. History remarkable for Roux-en-Y gastric bypass (RYGB) surgery 5 years ago for obesity, anxiety disorder and daily alcohol use (40 g/day). Denied diabetes, use of diabetic medications or weight loss supplements. Unremarkable physical exam with normal mental status. Labs [Table 1] demonstrated elevated proinsulin and C-peptide levels with negative urine toxicology screen and sulfonylurea assay. CT scan of the head and abdomen were unremarkable. Gastroenterology (GI) was consulted for an evaluation with endoscopic ultrasound (EUS) to rule out insulinoma. Although insulinoma was the working diagnosis in-addition to other differential diagnoses as listed [Table 2], a negative monitored 72-hour fasting test [Fig. 1] without any symptomatic hypoglycemic episodes essentially ruled out insulinoma. Recurrent post-prandial hypoglycemia with neuroglycopenic symptoms in the setting of RYGB and endogenous hyperinsulinism with negative 72-hour fasting test suggested nesidioblastosis as the likely diagnosis. Our patient was managed with Diazoxide (3-8mg/kg/day divided into 3 doses) and, complex carbohydrates were added to his diet. His hypoglycemic symptoms improved at subsequent follow-ups. Nesidioblastosis is rare in adults and, seen in patients who had undergone gastric bypass surgery with etiology linked to persistent hyper-secretion of glucagon-likepeptide-1 causing beta cells hypertrophy. Post-prandial neuroglycopenia is a classic manifestation but can be challenging to diagnose due to its rarity and the difficulty to localize on imaging. Selective arterial calcium stimulation and venous sampling can confirm the diagnosis, invasively [1-3]. Often patients are referred to GI for evaluation with EUS, but with RYGB, EUS is technically not feasible to evaluate pancreas due to the altered anatomy. However, a certain diagnosis can be made based on the history, labs [Table 1] and a negative 72-hour fasting test without the need for invasive tests. With increasing prevalence of obesity and gastric bypass surgeries, we as gastroenterologists shall expect to see more of this rare, but interesting metabolic complication of gastric bypass surgery.Figure 1Reference: [1] Service, G.J., et al. N Engl J Med, 2005. 353(3): p. 249-54. [2]. Kellogg, T.A., et al. Surg Obes Relat Dis, 2008. 4(4): p. 492-9. [3] Ritz, P. and H. Hanaire. Diabetes Metab, 2011. 37(4): p. 274-81.Figure 2Figure 3

Dead in bed syndrome: Mystery and fear

AbstractDead in bed (DIB) syndrome is a poorly understood cause of sudden and mysterious death in young people with type 1 diabetes on insulin therapy. Severe nocturnal hypoglycemia with unawareness is the most plausible mechanism which precipitates fatal arrhythmia in the vulnerable individual. Avoiding recurrent hypoglycemic episodes; screening for proarrhythmic condition in high-risk people with positive family history; and using real-time continuous glucose monitoring device in those with nighttime hypoglycemia and hypoglycemia unawareness can help to reduce the incidence of this deadly condition.

Occult insulinoma in a Meckel's diverticulum: a case report

Insulinoma is a deceptive endocrine tumour of the pancreas due to its bizarre and nonspecific symptom complex. It is also difficult to localize preoperatively, especially when present in an ectopic location. A 65 year old woman presented with recurrent episodes of hypoglycaemia. She was erroneously under treatment for psychotic disorder. A suspicion of insulinoma led us to investigate her further. Investigations revealed fasting hypoglycaemia, endogenous hyperinsulinism, and a pancreatic parenchymal lesion. On exploration, an incidental Meckel’s diverticulum with a nodule was also found. Histopathology showed an insulinoma of the Meckel’s diverticulum and a benign non-functioning adenoma in the pancreatic nodule. Surgery eventually resulted in restoration of euglycaemia and complete disappearance of patient's symptoms.

Eating Disorders in children and adolescents with Type 1 and Type 2 Diabetes: prevalence, risk factors, warning signs.

Diabetes is associated with increased risk for eating disorders, various dependent on type of diabetes. Binge eating disorder is more common in patient with type 2 diabetes (T2DM). Whereas, intentional omission of insulin doses for the purpose of weight loss occurs mainly in patient with type 1 diabetes (T1DM), however, in some patients with type 2 diabetes omission of oral hypoglycemic drugs can be present. Risk factors for the development of eating disorders in patients with diabetes include: age, female gender, greater body weight, body image dissatisfaction, history of dieting and history of depression. Poor glycemic control, recurrent episodes of ketoacidosis or recurrent episodes of hypoglycemia, secondary to intentional insulin overdose, missed clinical appointments, dietary manipulation and low self-esteem should raise concern. The consequence of eating disorders or disordered eating patterns in patients with diabetes is poor glycemic control and hence higher possibility of complications such as nephropathy, retinopathy and premature death.

Recurrent hypoglycemia in a patient of neurofibromatosis type 1 and type 1 diabetes mellitus: Munchausen′s syndrome mimicking Insulinoma

A 35-year-old widow having neurofibromatosis type 1 (NF 1) and type 1 diabetes mellitus (DM) was admitted for abdominal pain, vomiting and recent onset low blood sugars. During hospitalization, the patient developed recurrent episodes of hypoglycemia despite stopping insulin. A possibility of insulinoma was made due to the presence of abdominal pain, vomiting, hypoglycemia, and association of insulinoma with NF 1. However, surprisingly c-peptide was very low and plasma insulin levels were high. A detailed psychiatric evaluation of the patient revealed Munchausen's syndrome as a cause of recurrent hypoglycemia. Unrecognized psychiatric illnesses in type 1 DM may lead to overzealous investigation. In conclusion, the clinical presentations of persons with factitious disorder are varied and impact every area of medicine, factitious causes should always be considered in unclarified recurrent hypoglycemia, especially in cases presented with dramatic but inconsistent medical history, and an unusual personal behavior.

The highest (3600 IU) reported overdose of insulin glargine ever and management.

Sir, Insulin glargine (LANTUS® SOLOSTAR®; Sanofi Aventis, Deutschland) – relatively a new medication in the treatment of diabetes mellitus – is a long-acting insulin for meeting the basal insulin requirement with an ongoing effect up to 24 h.[1,2] In literature, there are small number of cases regarding with overdose use of insulin glargine. One of these cases with regard to insulin glargine overdose was by Lu and Inboriboon, who had reported a case of suicide attempt with 2700 units of insulin glargine resulting 96 h of hypoglycemia.[3] Herein, we report another case of insulin glargine overdose resulting 120 h of hypoglycemia in a diabetic patient who had attempted suicide with 3600 units of insulin glargine. To our knowledge, this is the highest reported insulin glargine dose ever. In this present case, a 45-year-old-male patient with type-2 diabetes mellitus and major depression was admitted to emergency department with the loss of consciousness after self-administered 3600 units of insulin glargine. Patient's laboratory findings on admission were as follows: Blood glucose level - 20 mg/dl, potassium - 2,8 mmol/L, serum level of sulfonylurea - 0,0 mg/μL, C-peptide - 0.0956 (0.51–2.7 ng/mL normally), and serum insulin value - 216 mU/L (2.6–25 normally). Patient treated with continuous intravenous dextrose infusion and 1 mg of glucagon hydrochloride. On follow-up, the patient needed 120 h of intravenous glucose infusion for the recurrent hypoglycemic episodes. At the end of the 5th day, no hypoglycemia attack was observed. The patient discharged without any permanent complications on the 6th day of hospitalization. Then, he referred to a psychiatry clinic. Hypoglycemia is the most frequent side effect of insulin glargine. The timing of hypoglycemia and its duration differs according to the insulin formulations. Insulin glargine is known to have no peak effect. The plasma concentration versus time profile of insulin glargine is relatively more stable with no peak in 24 h compared to conventional human insulin.[4,5] This allows once-daily administration as basal therapy. However, overdose use of insulin glargine may rarely present with prolonged hypoglycemia attacks.[3] As a result, we aimed to emphasize in this letter that emergency and intensive care physicians should be aware of overdose use of insulin glargine present with prolonged hypoglycemia attacks. In these cases, intensive care physicians should immediately initiate continuous dextrose infusions, and the patients should be monitored closely with frequent blood glucose samples to prevent the risk of prolonged hypoglycemia episodes. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Congenital Hyperinsulinism and Cochlear Hypoplasia in a Rare Case of Pallister-Hall Syndrome

Pallister-Hall syndrome (PHS) is characterized by a spectrum of anomalies, which include polydactyly, hypothalamic hamartoma, laryngotracheal cleft, bifid epiglottis, imperforate anus, and renal abnormalities. Hypoplastic cochlea is a rare reported association of PHS. A baby girl was born at 31 weeks gestation with birth weight of 1.2 kg. The endotracheal intubation was extremely difficult due to narrow trachea. She was noted to be dysmorphic and have recurrent hypoglycemic episodes requiring high concentration of glucose infusion. The investigations revealed an inappropriately high plasma insulin and C-peptide level during hypoglycemia with low free fatty acids and β-hydroxy butyrate suggestive of congenital hyperinsulinism (CHI). MRI of the brain revealed the presence of a large hypothalamic hamartoma. The cochlea was noted to be truncated bilaterally with reduced number of turns. The cytogenetic analysis revealed GLI3 mutation consistent with diagnosis of PHS. This is the first reported case of CHI in association with PHS. Our patient also had hypoplastic cochlea, which is a unique but rarely reported feature of PHS. Int J Clin Pediatr. 2015;4(2-3):154-157 doi: http://dx.doi.org/10.14740/ijcp196w

Type 1 diabetes mellitus-common cases.

Tight glycemic control in type 1 diabetes mellitus patients is associated with the risk of hypoglycemia. Diabetic patients are forced to change their lifestyle to adjust to the disease condition and survive it. The best way to manage diabetes would be to develop a therapy, which could adjust to the patient's conditions. Here, I present few cases wherein switching to a long-acting basal insulin analog helped combat recurrent hypoglycemic episodes experienced by the patients.

Long-term results of the surgical management of insulinoma patients with MEN1: a Groupe d'étude des Tumeurs Endocrines (GTE) retrospective study.

Management of insulinomas in the context of MEN1 remains poorly studied. The aim of this study was to evaluate long-term results of various surgical approaches in a large cohort of insulinoma-MEN1 patients. Consecutive insulinoma-MEN1 patients operated on for a nonmetastatic insulinoma between 1957 and 2010 were retrospectively selected from the MEN1 database of the French Endocrine Tumor Group. The type of surgery was categorized as distal pancreatectomy (DP), total pancreatectomy/cephalic duodenopancreatectomy (TP/CDP), or enucleation (E). Primary endpoint was time until recurrence of hypoglycemia after initial surgery. Secondary endpoints were post-operative complications. The study included 73 patients (median age=28 years). Surgical procedures were DP (n=46), TP/CDP (n=9), or E (n=18). After a median post-operative follow-up of 9.0 years (inter-quartile range (IQR): 2.5-16.5 years), 60/73 patients (82.2%) remained hypoglycemia free. E and TP/CDP were associated with a higher risk of recurrent hypoglycemia episodes (unadjusted hazard ratio: 6.18 ((95% CI: 1.54-24.8); P=0.010) for E vs DP and 9.51 ((95% CI: 1.85-48.8); P=0.007) for TP/CDP vs DP. After adjustment for International Union against Cancer pTNM classification, enucleation remained significantly associated with a higher probability of recurrence. Long-term complications had occurred in 20 (43.5%) patients with DP, five (55.6%) with TP/CDP, but in none of the patients who have undergone E (P=0.002). In the French Endocrine database, DP is associated with a lower risk for recurrent hypoglycemia episodes. Due to lower morbidity, E alone might be considered as an alternative.