Recurrent Episodes Of Hypoglycemia Research Articles

Increased risk of stroke in patients with chronic kidney disease after recurrent hypoglycemia.

In this study, we aimed to investigate the effect of hypoglycemia on cardiovascular outcomes in a sample of patients with chronic kidney disease (CKD). Information about study participants was extracted from the National Health Insurance Research Database of Taiwan for the years 1998 through 2008. We conducted this retrospective cohort study of patients with CKD, with and without hypoglycemia, to evaluate the risk of overall mortality and cardiovascular complications including stroke, coronary heart disease, and congestive heart failure in both groups. This study included 46,135 patients with CKD, of whom 2,117 (4.59%) were hospitalized and had hypoglycemia. Results of multivariate Cox proportional hazard regression analyses indicated that stroke (hazard ratio [HR] = 1.62, 95% confidence interval [CI] = 1.29-2.03), coronary heart disease (HR = 1.25, 95% CI = 1.00-1.57), congestive heart failure (HR = 1.49, 95% CI = 1.13-1.98), and death (HR = 2.53, 95% CI = 1.99-3.21) were associated with hypoglycemia in patients with CKD. Recurrent episodes of hypoglycemia were associated with a higher risk of death (HR = 33.0, 95% CI = 22.3-48.8 for >2 episodes, p for trend <0.0001), and a similar trend was observed for other multiple cardiovascular events. We observed an increased risk of stroke and overall mortality in patients with hypoglycemia compared to those without hypoglycemia, regardless of whether the patient had diabetes. CKD was associated with a higher risk of stroke and mortality in patients with hypoglycemia. Recurrent hypoglycemia considerably increased the risk of stroke and overall mortality in patients with CKD regardless of whether they had diabetes. These results suggest that hypoglycemia has a crucial role in stroke and death in patients with CKD.

Paraneoplastic hypoglycemia in a patient with a malignant solitary fibrous tumor.

SummaryHypoglycemia is a common medical emergency. It is the most frequent complication induced by anti-diabetic treatment. However, it can be observed in other conditions unrelated to diabetes such as insulinoma, autoimmune disorders, and neoplasia. Herein, we report the case of a rare cause of severe and recurrent hypoglycemia in a 77-year-old woman with a malignant solitary fibrous tumor (MSFT). A 77-year-old woman was admitted to the emergency department for loss of consciousness induced by severe hypoglycemia. Her standard laboratory findings were unremarkable. HbA1c, albumin, renal, liver, thyroid, and adrenal function tests were normal. Cerebral CT scan was also normal. At the time of confirmed hypoglycemia, the serum level of insulin and C-peptide was low. On the basis of the past medical history and the absence of other comment etiologies, a paraneoplastic cause was suspected. Thus, the diagnosis of a non-islet cell tumor-induced hypoglycemia (NICTH) was established by the presence of incompletely processed precursors of IGF2 (big IGF2) in plasma electrophoresis. However, the IGF1 level was low. Therapy with corticosteroids improved hypoglycemia and clinical symptoms. NICTH is a rare cause of hypoglycemia. It should be considered in patients with mesenchymal or malignant epithelial tumors suffering from recurrent episodes of hypoglycemia. The diagnosis will be established in the case of low serum insulin concentrations and elevated levels of big IGF2. Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels.Learning points NICTH is a very rare condition that should be considered in patients known to have mesenchymal or malignant epithelial tumors and suffering from recurrent episodes of hypoglycemia.The diagnosis of an NICTH is established on the basis of the hypoinsulinemic hypoglycemia, the MSFT history, and the presence of paraneoplastic secretion of IGF1 or an immature form of IGF2.Treatment with corticosteroids, GH, or both can improve hypoglycemic symptoms and restore plasma glucose to normal levels in NICTH.

Recurrent episodes of hypoglycemia caused by insulinoma in a patient with type 2 diabetes mellitus

Recurrent episodes of hypoglycemia caused by insulinoma in a patient with type 2 diabetes mellitus

Neuroprotective effect of estrogen on hypoglycemic injury in hypothalamic mouse cells (767.6)

Glucose is the main metabolic fuel of the brain. Recurrent episodes of hypoglycemia can lead to seizures, coma, and even death. The hypothalamus; a region involved in feeding and energy balance is most vulnerable to this injury. In the present study we report neuroprotection of estrogen on hypoglycemic injury in a hypothalamic cell line. The cell viability, toxicity and proliferation were determined using MTT, lactate dehydrogenase (LDH) assay, and cell count. There was a significant increase in the cell count and increase in mitochondrial function in the presence of estrogen (p&lt;0.0001) when exposed to hypoglycemia within 24 hours. The attenuation of the death pathways was only seen within the first 24 hours and gradually decreased with time. Percent cytotoxicity also increased in the absence of glucose and decreased in the presence of estrogen within 24 hours. Two pathways seemed viable in mediating estrogen action, the phospho‐AKT pathway, and a pathway involving caveolin‐1 (CAV‐1). In order to determine estrogen mode of action, PRAS 40 was analyzed via ELISA assay, which showed no change when exposed to hypoglycemic shock. This suggested that the phospho‐AKT pathway was not involved in estrogen mode of action. Our current efforts are focused on determining whether estrogen neuroprotection is mediated through CAV‐1 and re‐testing the phospho‐AKT pathway via western blot analysis.

Increased capacity for glycogen turnover in the rat ventromedial hypothalamus (VMH) following hypoglycemia (LB449)

Recurrent hypoglycemia impairs the ability of the VMH to initiate a counterregulatory response and contributes to hypoglycemia‐associated autonomic failure (HAAF). We hypothesize that mobilization of VMH glycogen during and following hypoglycemia interferes with local glucose sensing and that genes associated with increased glycogen turnover will be upregulated after single and recurrent episodes of hypoglycemia. VMH were dissected from rats (N=23) 6 h after a single episode of insulin‐induced hypoglycemia (IIH) (acute), 24 h after the third of 3 recurrent episodes of IIH (recurrent), and saline‐treated euglycemia (control). RNA was extracted for RNA sequencing and real time‐PCR (RT‐PCR) analysis for glucose metabolism genes. One‐way ANOVA identified genes with statistically significant expression changes between treatments, principal component (PC) analysis of significantly different genes separated data points by treatment group, and genes significantly correlated with the PCs were identified. Glycogen synthase, phosphorylase kinase, glycogen phosphorylase, and UDP‐glucose pyrophosphorylase were significantly increased after acute hypoglycemia compared to control in the RT‐PCR analysis. Glycogen phosphorylase was upregulated in the acute treatment groups from both RNAseq and RT‐PCR compared to control and showed sustained elevation in the recurrent treatment from RT‐PCR analysis. These data provide evidence supporting the hypothesis that glycogen metabolism contributes to impaired glucose counterregulation and identify genes that are associated with novel hypotheses for future exploration. Supported by DK082609Grant Funding Source: DK082609

Proinsulinoma causing severe hypoglycemia in a patient with type 1 diabetes mellitus

Case presentation: A 49 year male a 35 year history of Type 1 Diabetes Mellitus (T1DM) was evaluated for recurrent episodes of hypoglycemia. After being weaned off of all exogenous insulin, the patient continued to have frequent and severe episodes of hypoglycemia often associated with seizures. Results: During an observed hypoglycemic reaction in our office he was found to have a serum glucose level of 64 mg/dl, a serum insulin level of 64 μIU/ml (reference range is &lt;17 μIU/ml) and a C-peptide level of 0.6 ng/ml (reference range is 0.8 ng/ml – 3.1 ng/ml). Serum and urine sulfonylurea levels were negative. During a formal diagnostic 72 hour fast, he developed severe hypoglycemia within four hours of beginning the fast and seized. No diagnostic laboratory studies were obtained during the hypoglycemic event! He underwent surgical exploration, where a 0.8 cm well-differentiated, islet cell tumor was resected. Following resection of the tumor, the spontaneous hypoglycemia resolved, and maintenance exogenous insulin was reinstituted. Histoimmunochemical staining was positive for chromogranin, synaptophysin, amylin, and proinsulin but negative for insulin. Immunostaining of the tumor was also positive for Toll-like receptors-3 (TLR3) and Wnt5a. Conclusion: This is the first case report of a patient with a long history of T1DM who developed a recurrent hypoglycemia due to a proinsulin-secreting islet cell tumor which resolved following its resection.

Dipeptidyl Peptidase-4 Inhibitors Have Protective Effect on Cognitive Impairment in Aged Diabetic Patients With Mild Cognitive Impairment

Older adults with type 2 diabetes have an increased risk for mild and severe cognitive impairment probably as consequence of chronic hyperglycemia or fasting plasma glucose levels. Variability in glucose level and recurrent hypoglycemic episodes are also associated with cognitive impairment. Dipeptidyl peptidase-4 inhibitor (DPP-4I) therapy affects glycemic variability. The purpose of this study was to evaluate the effect of DPP-4I therapy on changes in cognitive function in older patients with type 2 diabetes complicated by mild cognitive impairment. This retrospective longitudinal study used data from a database of 240 older patients with type 2 diabetes, "drug naive," affected by mild cognitive impairment, subsequently treated for 2 years with antidiabetic drugs (DPP-4I group: DPP-4I + metformin, n = 120; SU group: sulfonylurea + metformin, n = 120) and reassessed in our ambulatory by comprehensive clinical, cognitive, instrumental examinations, and continuous subcutaneous glucose monitoring. At baseline, larger mean amplitude of glycemic excursion values correlated with poorer Mini-Mental State Examination and composite cognitive function scores. We found that higher body mass index, higher 2-hour postprandial glucose, and greater mean amplitude of glycemic excursion values measured at baseline were significant independent predictors of cognitive worsening. In addition, reduction in mean amplitude of glycemic excursions and the use of DPP-4I therapy predicted improvement in cognitive functions. In older patients with type 2 diabetes affected by mild cognitive impairment, DPP-4I administration improves glucose control and protects against worsening in cognitive functioning.

In need of glucose – case report of a rare cause of symptomatic hypoglycaemia

Among the hypoglycemia-induced diseases we find insulinoma, insulinomatosis and also the non-insulinoma pancreatogenic hypoglycemia-syndrome (NIPHS). NIPHS is frequently caused by nesidioblastosis, which is characterized by functionally hyperactive beta cells within normal pancreatic islets. While the persistent hyperinsulinemic hypoglycemia is frequent in children, adult-onset nesidioblastosis is rare. Here we present a case of a 67-year-old female patient, who suffered from recurrent hypoglycemic episodes accompanied by cold sweats, muscle cramps, loss of consciousness, improvement of symptoms with dietary intake and weight gain. A prolonged oral glucose tolerance test with subsequent fasting revealed low- and below-normal blood glucose levels, but no disease defining hypoglycemia. Endoscopic ultrasound showed no pancreatic lesion. Ga-DOTATOC-PET/CT found 2 somatostatin receptor-positive areas in the pancreatic body and tail. By arterial calcium stimulation and venous sampling these regions showed an inappropriate insulin secretion. The clinical course until surgery was complicated by severe symptoms occurring several times a day. A therapeutic approach with acarbose and the intake of slowly absorbable carbohydrate was insufficient. Oral therapy with diazoxide was highly effective controlling the symptoms but had to be discontinued due to hypertrichosis, hypotension and edema. Thus pasireotide, a non-selective somatostatin analogue, was applied off-label achieving effective control of symptoms and blood glucose levels until surgical exploration. Finally, distal pancreatectomy was performed and pathological examination revealed adult nesidioblastosis. Postoperatively, the patient was asymptomatic without any medication or dietary interventions and lost 9 kg. The present case illustrates a rare case of adult nesidioblastosis as well as a possible targeted and pathophysiologically specific therapeutic approach with the nonselective somatostatin analogue pasireotide.

Recurrent hypoglycaemia in type 1 diabetes mellitus resulting from intensive academic activity: an illustrative case report

Abstract We report a common diabetes management problem illustrated by an adolescent female university student with recurrent episodes of hypoglycaemia on Tuesdays when she has intensive academic activity lasting most of the day. Steps taken to reduce the risk of hypoglycaemia were patient education and empowerment, frequent self monitoring of blood glucose, reduction in insulin dose on Tuesdays and emphasizing availability of ongoing professional guidance and support anytime she may need it. One of the challenges encountered in the management of this patient was her family’s inability to afford the cost of basal-bolus regimen or continuous subcutaneous insulin infusion via insulin pump; the two insulin regimens that best fit into university lifestyle. Conclusion: Adolescents with diabetes mellitus attending tertiary educational institutions may be at increased risk of hypoglycaemia, particularly on days when they have intensive academic activities.

Diazoxide treatment for persistent hypoglycemia in a small for gestational age preterm infant with adequate low insulin levels

Abstract Small for gestational age (SGA) newborn infants can have prolonged hypoglycemia due to diminished glycogen stores, diminished alternative energy substrates, or hyperinsulinism. Recurrent episodes of hypoglycemia are strongly correlated with persistent neuro-developmental and physical growth deficits. Treatment includes glucose supplements or medications affecting insulin secretion, gluconeogenesis, or glycogenolysis. Diazoxide suppresses insulin secretion by acting as an ATP-sensitive potassium channel agonist to prevent membrane depolarization, calcium influx, and insulin secretion. Therefore, it is used in persistent hypoglycemia of neonates associated with hyperinsulinism. We report a case of a female SGA preterm infant who had persistent hypoglycemia (&gt;2 weeks of age) with low adequate serum insulin levels and no other clear biochemical evidence of hyperinsulinism or other abnormalities. As a result of an inability to control her glucose levels without high intravenous levels of glucose and continuous glucagon infusion, she was treated successfully with diazoxide, which was discontinued when the infant reached 5 kg. No side effects were noted. In rare cases of persistent hypoglycemia, and a need for high glucose infusion rate but with adequate low insulin levels even without biochemical evidence supportive of hyperinsulinism, diazoxide treatment can be offered with close monitoring of glucose levels and possible side effects. The exact mechanism is not clear and deserves further evaluation.

Connecting Cardiovascular Disease and Dementia: Further Evidence

Cognitive impairment is highly prevalent in the elderly, and it accounts for a large part of the burden of disability and of the use of healthcare resources. The major types of dementia are Alzheimer disease and vascular dementia.[1][1] For many years, atherosclerosis was not considered to play a

Investigation and management of acute hypoglycemia

Since prolonged severe hypoglycemia could lead to permanent neurological sequelae, it must be treated immediately. But at the same time, the cause of hypoglycemia should be determined to prevent future recurrence of hypoglycemia preferably at bedside while the patient is still in an emergency room. Most of the cases, this could be done by asking proper questions and taking physical findings in parallel with the treatment, without waiting for the detailed results of critical samples. In taking history of the patients, one should not forget to ask the following questions; (1) preexisting medical problems (especially diabetes mellitus, CNS tumors, adrenal insufficiency, hepatic failure, arrhythmia, citrin deficiency or chronic infections), (2) medication history (especially insulin, oral hypoglycemic agents, beta-blocker, disopyramide, or extended use of antibiotics containing pivalic acid), (3) timing of hypoglycemia following the last meal (VERY important). In taking physical findings, presence or absence of hepatomegaly and circulatory collapse is the most important. Hypoglycemia within 2-3 hours after meal almost invariably suggests the presence of hyperinsulinemia. Hypoglycemia caused by a defect in glycogenolysis typically occurs 5-8 hours following the last meal and is usually accompanied by hepatomegaly. Recurrent episodes of hypoglycemia after an overnight fast likely suggest a problem in gluconeogenesis. Circulatory collapse at hypoglycemia suggests the presence of adrenal insufficiency. IV steroid in addition to IV glucose should be considered to prevent neurological sequelae. Critical samples should be taken at the time of hypoglycemia to make a causal diagnosis. Although the turnaround time of endocrine tests or tandem mass-spectrometry is usually long, results available on site often give a clue to the diagnosis. Relatively low ketone bodies by urine dipsticks suggest the presence of hyperinsulinemia or rare disorders of fatty-acid oxidation defects. Hyponatremia accompanied by hyperkalemia suggests primary (not secondary) adrenal insufficiency. Response to initial therapy also gives an important clue to the diagnosis. The need to continue IV glucose over normal resting hepatic glucose production to maintain normoglycemia (4-6 mg/kg.min in neonates) strongly suggests the presence of hyperinsulinemia. Never infuse too much glucose to the patients which could obscure the diagnosis. Finally, I will spend some time to show current state-of-the art in the diagnosis and management of congenital hyperinsulinism and discuss how the patients should be managed in the Asia-Pacific region.

Case Scenario: Hypotonia in Infancy

NFANTS with hypotonia of unknown etiology pose a unique challenge as many of the potential diagnoses have major, often conflicting, anesthetic management implications. The differential diagnosis of hypotonia is long and includes possibilities such as Duchenne muscular dystrophy, central core disease, and multiminicore disease. Intravenous anesthetic techniques are recommended because hyperkalemia or malignant hyperthermia is associated with the use of volatile anesthetics. However, the differential diagnosis of infants with hypotonia also includes mitochondrial disorders. In children with mitochondrial disorders, an intravenous anesthetic technique that includes propofol could lead to metabolic decompensation because propofol alters mitochondrial electron transfer. This dilemma is often encountered when hypotonic infants require anesthesia for diagnostic tests such as magnetic resonance imaging and muscle biopsies for definitive diagnosis.

Pancreas Transplant Alone

The goal of this review is to highlight the significant improvements, over the past four decades, in outcomes after a pancreas transplant alone (PTA) in patients with brittle diabetes and recurrent episodes of hypoglycemia and/or hypoglycemic unawareness. A successful PTA—in contrast to intensive insulin regimens and insulin pumps—restores normoglycemia without the risk of hypoglycemia and prevents, halts, or reverses the development or progression of secondary diabetes complications. In this International Pancreas Transplant Registry (IPTR) analysis, we reviewed the records of 1,929 PTA recipients from December 1966 to December 2011. We computed graft survival rates according to the Kaplan-Meier method and used uni- and multivariate analyses. In the most recent era (January 2007–December 2011), patient survival rates were >95% at 1 year posttransplant and >90% at 5 years. Graft survival rates with tacrolimus-based maintenance therapy were 86% at 1 year and 69% at 3 years and with sirolimus, 94 and 84%. Graft survival rates have significantly improved owing to marked decreases in technical and immunologic graft failure rates (P < 0.05). As a result, the need for a subsequent kidney transplant has significantly decreased, over time, to only 6% at 5 years. With patient survival rates of almost 100% and graft survival rates of up to 94% at 1 year, a PTA is now a highly successful long-term option. It should be considered in nonuremic patients with brittle diabetes in order to achieve normoglycemia, to avoid hypoglycemia, and to prevent the development or progression of secondary diabetes complications.

Double jeopardy: hypoglycaemia and advanced hepatocellular carcinoma

Nonislet cell tumour-induced hypoglycaemia is an uncommon, but serious complication of malignancy. The aetiopathogenesis is largely as a result of tumoral overproduction of incompletely processed insulin-like growth factor-II. We describe the case of a 30-year-old black male patient who presented with recurrent hypoglycaemic episodes in the absence of diabetes or any medications known to cause hypoglycaemia. Extensive investigations revealed that the hypoglycaemia was the result of an advanced hepatocellular carcinoma.

Die chirurgische Technik der Pankreastransplantation

The transplantation of a cadaveric donor pancreas represents a therapeutic option for the type 1 diabetic. A precondition is the proof of negative serum C-peptide after glucagon stimulation (< 0.02 ng/ml) as it is found in the typical patient with type 1 or a pancreoprive diabetes. The pancreas can be transplanted alone (PTA) or after a kidney (PAK), either following a preceding living related or cadaveric kidney transplantation. The majority of pancreata worldwide are transplanted simultaneously with a kidney (SPK) in stage 4 and 5 (eGFR < 29 ml/min) of chronic kidney disease. The beneficial effect of physiological glucose regulation on mortality, kidney failure and diabetic complications (cardiovascular, neuropathy, retinopathy) is well established. Patient survival rate at 1 year after transplantation is above 90 %, pancreas graft survival overall after 1 year is about 80 %. Type 1 diabetic patients with recurrent hypoglycemic episodes or major complications due to dysregulated glucose metabolism qualify for pancreas transplantation alone in case of a stable kidney function. Patients with chronic kidney disease stage 4 and 5 are candidates for SPK. Pancreatic transplantation into the right iliac fossa. Although technically demanding, pancreas transplantation is safely performable with a low periprocedural morbidity and mortality. Potential perioperative complications include inflammation, rejection or graft thrombosis. After a successful transplantation, long-term physiological glucose regulation can be achieved which results in a prolonged life expectancy and quality of life in type 1 diabetic patients.

Recurrent hypoglycemia: boosting the brain’s metabolic flexibility

For people with diabetes, recurrent episodes of hypoglycemia limit the brain's ability to sense dangerously low blood sugar levels. In this issue of the JCI, the mechanisms behind this clinical problem of hypoglycemia unawareness are addressed by Herzog et al. The authors provide compelling evidence that recurrent hypoglycemia enhances transport of lactate into the brain and, although not itself a major alternative fuel source, lactate may preserve neuronal function during hypoglycemia by maintaining neuronal glucose metabolism. These findings redefine our understanding of the brain's metabolic adaptations that result from recurrent hypoglycemia.

Hypoglycemia associated with fluoxetine treatment in a patient with type 1 diabetes

We report on a patient with type 1 diabetes mellitus who presented with recurrent episodes of hypoglycemia and a marked reduction in her daily insulin requirements after introduction of fluoxetine. This 25-year-old Caucasian woman had been followed up at the outpatient clinic for type 1 diabetes mellitus and pre-pregnancy care. She used a continuous subcutaneous insulin infusion with lispro and her daily insulin dose was 0.5 IU/kg per day. She had no chronic diabetic complications or hypoglycemia unawareness. Fluoxetine at a daily dose of 20 mg had been started because of depressive symptoms and within one week, she presented recurrent hypoglycemic episodes that prompted a progressive reduction in the insulin dose down to 0.3 IU/kg per day. The reduced insulin requirements continued during the period of fluoxetine treatment while glycated hemoglobin remained stable. She had no concurrent additional cause to explain the reduced insulin requirements. After fluoxetine was stopped, insulin requirements progressively increased and returned to the patient´s usual dose.

Insulin Antibody Properties and Its Change Induced by Insulin Detemir in Type 2 Diabetic Patients with Recurrent Hypoglycemic Episodes: A Report of Two Cases

Insulin Antibody Properties and Its Change Induced by Insulin Detemir in Type 2 Diabetic Patients with Recurrent Hypoglycemic Episodes: A Report of Two Cases

Recurrent episodes of hypoglycemia induced by moxifloxacin

An elderly diabetic male with pneumonia presented with multiorgan failure. He developed hypoglycemic episodes with moxifloxacin that responded only to withdrawal of moxifloxacin.