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Journal of Diabetes Investigation Mar 2024This report describes a patient who developed recurrent hypoglycemia episodes after 23 days of antiplatelet therapy with clopidogrel for left subclavian artery stent... (Review)
Review
This report describes a patient who developed recurrent hypoglycemia episodes after 23 days of antiplatelet therapy with clopidogrel for left subclavian artery stent implantation. The patient suffered from palpitation, profuse sweating and weakness on the 23rd day of clopidogrel treatment. The minimum plasma glucose was 2.2 mmol/L, and the hypoglycemia was associated with significantly elevated levels of insulin. A diagnosis of insulin autoimmune syndrome (IAS) was made with the presence of insulin autoantibody and a comprehensive differential diagnosis of other conditions related with hypoglycemia. Clopidogrel was stopped, and the patient was treated with acarbose and had frequent low-carbohydrate meals; his hypoglycemia did not occur within 10 days. To date, seven cases of IAS induced by clopidogrel have been reported. Most reported cases were male aged in their 70s, and the hypoglycemic attack appeared 1-4 weeks after exposure to clopidogrel, characterized by severe hyperinsulinemia hypoglycemia with high titers of insulin autoantibodies. Most IAS cases can resolve spontaneously when they stop using the trigger medicine. Severe cases had been treated with drugs that reduce pancreatic insulin secretion (such as somatostatin and diazoxide), immunosuppressants (glucocorticoids, azathioprine and rituximab) and even immunoadsorption to remove the insulin autoantibody from the body. Considering the hypoglycemic attack might increase the risk of cardiovascular events among patients taking clopidogrel, we recommend that doctors should be aware of IAS as a rare severe adverse effect of clopidogrel, and be vigilant for the symptoms related with hypoglycemia in clopidogrel users.
Topics: Humans; Male; Female; Clopidogrel; Hypoglycemia; Hypoglycemic Agents; Insulin; Hyperinsulinism; Autoimmune Diseases; Autoantibodies
PubMed: 38063248
DOI: 10.1111/jdi.14110 -
AACE Clinical Case Reports 2023To illustrate an unusual case of type 2 diabetes mellitus (T2DM) developing many years after the diagnosis of hyperinsulinism hyperammonemia (HI/HA) syndrome.
BACKGROUND/OBJECTIVE
To illustrate an unusual case of type 2 diabetes mellitus (T2DM) developing many years after the diagnosis of hyperinsulinism hyperammonemia (HI/HA) syndrome.
CASE REPORT
This article reports about a 36-year-old female with a history of congenital hyperinsulinism due to HI/HA syndrome, which was diagnosed in infancy. The patient presented with hypoglycemia and seizures as an infant and was treated with diazoxide and a low-protein diet for many years with reduction in her hypoglycemic events. She subsequently developed T2DM >30 years later. Genetic analysis was positive for a glutamate dehydrogenase 1 gene () alteration. She was treated with metformin and a glucagon-like peptide 1 agonist, with significant improvement in her blood glucose control and weight loss.
DISCUSSION
HI/HA syndrome is a rare genetic syndrome that manifests in childhood with signs and symptoms of hypoglycemia and neurologic symptoms. This is the first case reported in the literature of a patient with HI/HA syndrome due to a alteration who developed T2DM much later in life. Patients with this disorder usually have recurrent hypoglycemia and require long-term medical therapy or very occasionally may have a resolution. She had class 3 obesity and evidence of insulin resistance, which likely contributed to her risk of diabetes.
CONCLUSION
This is a rare case of T2DM presenting in a patient with HI/HA syndrome. This should be considered a possible outcome in patients with this disorder, especially in the presence of obesity.
PubMed: 37520762
DOI: 10.1016/j.aace.2023.04.011 -
Free Radical Biology & Medicine May 2024Mitochondrial ATP-sensitive K (mitoK) channels are involved in neuronal and cardiac protection from ischemia and oxidative stress. Penile erection is a neurovascular...
OBJECTIVE
Mitochondrial ATP-sensitive K (mitoK) channels are involved in neuronal and cardiac protection from ischemia and oxidative stress. Penile erection is a neurovascular event mediated by relaxation of the erectile tissue via nitric oxide (NO) released from nerves and endothelium. In the present study, we investigated whether mitoK channels play a role in the control of penile vascular tone and mitochondrial dynamics, and the involvement of NO.
METHODS
The effect of the selective mitoK activator BMS191095 was examined on vascular tone, on mitochondrial bioenergetics by real-time measurements with Agilent Seahorse and on ROS production by MitoSOX fluorescence in freshly isolated microarteries.
RESULTS
BMS191095 and diazoxide relaxed penile arteries, BMS191095 being one order of magnitude more potent. BMS191095-induced relaxations were reduced by mechanical endothelium removal and by inhibitors of the nitric oxide synthase (NOS) and PI3K enzymes. The NO-dependent component of the relaxation to BMS191095 was impaired in penile arteries from insulin resistant obese rats. The blockers of mitoK channel 5-HD, sarcolemma K (sarcK) channel glibenclamide, and large conductance Ca-activated K (BK) channel iberiotoxin, inhibited relaxations to BMS191095 and to the NO donor SNAP. BMS191095 reduced the mitochondrial bioenergetic profile of penile arteries and attenuated mitochondrial ROS production. Blockade of endogenous NO impaired and exogenous NO mimicked, respectively, the inhibitory effects of BMS191095 on basal respiration and oxygen consumed for ATP synthesis. Exogenous NO exhibited dual inhibitory/stimulatory effects on mitochondrial respiration.
CONCLUSIONS
These results demonstrate that selective activation of mitoK channels causes penile vasodilation, attenuates ROS production and inhibits mitochondrial respiration in part by releasing endothelial NO. These mechanisms couple blood flow and metabolism in penile arterial wall and suggest that activation of vascular mitoK channels may protect erectile tissue against ischemic injury.
Topics: Male; Rats; Animals; Vasodilation; Nitric Oxide; Reactive Oxygen Species; Adenosine Triphosphate; Respiration; Potassium Channels
PubMed: 38522485
DOI: 10.1016/j.freeradbiomed.2024.03.007 -
Cureus Apr 2024Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence...
Insulin autoimmune syndrome (IAS) or Hirata disease is a rare condition presenting as recurrent hypoglycemia, and associated with elevated insulin levels in the presence of insulin autoantibodies (IAAs) in patients who were never exposed to exogenous insulin and with no evidence of pancreatic abnormalities. IAS is much more frequent in East Asians, especially the Japanese population, compared to the lower incidence in Caucasians. However, it can be associated with other autoimmune diseases or drug use like methimazole and alpha-lipoic acid (ALA). We report a case of a 47-year-old Caucasian male presenting with a 12-month history of worsening episodes of fasting and post-prandial hypoglycemia associated with symptoms of dizziness, tremors, palpitations, and unconsciousness associated with hypoglycemia. Symptoms resolved with the administration of carbohydrate-containing foods, establishing Whipple's triad. At an outside facility, he had initial labs that showed elevated insulin levels (141 µU/ml) with normal glucose, C-peptide, and proinsulin levels, but there was no availability of an IAA lab assay. Given his symptoms, severity, and frequency of hypoglycemia, he was admitted to the hospital for a 72-hour fast, which showed the lowest glucose level of 64 mg/dl with inappropriately high insulin of 22.2 µU/ml, low C-peptide of 0.57 ng/ml, and undetectable proinsulin of <1.6 pmol/L, but with IAA being >50 U/ml (0.0-0.4 U/ml). He was treated with intensive dietary counseling with a low-carbohydrate diet and prednisone 20 mg twice daily initially. Additionally, he could not tolerate octreotide, diazoxide, and acarbose due to side effects. He is currently on prednisone 10 mg daily and nifedipine with no further hypoglycemic episodes, but still has a high IAA of >50 U/ml and serum insulin levels of 70-112 µU/ml. Our case highlights the importance of recognizing hypoglycemia and checking for IAA levels as first-line diagnostic tests, in the absence of which there could be a delay in diagnosis and leading to unnecessary lab and imaging testing. Our case is unique since it happened in a Caucasian without any prior exposure to a triggering factor and has not undergone self-remission yet, which happens in most of IAS cases.
PubMed: 38623323
DOI: 10.7759/cureus.58270 -
JCEM Case Reports Sep 2023We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as...
We describe initial manifestations, approach to diagnosis, and treatment of a patient with congenital disorder of glycosylation type 1b (CDG 1b), previously managed as acetylcarnitine deficiency. A 9-year-old girl initially diagnosed with and treated for acetylcarnitine deficiency at an outside hospital presented with recurrent hypoglycemia, failure to thrive, poor weight gain, and short stature. She had discontinued levocarnitine therapy because of lack of response, and testing with us demonstrated a normal carnitine and acyl carnitine panel and hyperinsulinemic hypoglycemia during a diagnostic fast. Oral diazoxide and hydrochlorothiazide were initiated with resolution of hypoglycemia. She had iron deficiency anemia, but an upper gastrointestinal evaluation was normal. Genetic testing confirmed a diagnosis of CDG 1b caused by deficiency of mannose phosphate isomerase. Oral mannose was started with gradual reduction in and eventual discontinuation of the diazoxide dose. Hypoglycemia in the pediatric age group needs a systematic approach. It is important to raise awareness of CDG 1b, which can present as persistent hyperinsulinemic hypoglycemia. Mannose supplementation can ameliorate clinical symptoms and biochemical abnormalities.
PubMed: 37908211
DOI: 10.1210/jcemcr/luad109 -
SAGE Open Medical Case Reports 2024Neonatal Graves disease is the most common cause of hyperthyroidism during the newborn period. Maternal Graves disease increases the risk of intrauterine growth...
Neonatal Graves disease is the most common cause of hyperthyroidism during the newborn period. Maternal Graves disease increases the risk of intrauterine growth restriction, small for gestational age, and neonatal Graves disease. Intrauterine growth restriction and small for gestational age are associated with hypoglycemia and transient neonatal hyperinsulinism. Neonatal Graves disease with severe persistent hypoglycemia has not been well described. We present the case of a female patient born at 34 weeks and 3 days with a birth weight of 1.6 kg (fifth percentile) to a mother with recent treatment for Graves disease. Prenatal ultrasounds were significant for intrauterine growth restriction and small for gestational age. The mother did not begin hyperthyroidism medical therapy until 23 weeks and 2 days of gestation. After the infant was born, the infant not only had symptoms of hyperthyroidism such as tachycardia and abnormal thyroid values but also had persistent hypoglycemia, which could be due to maternal propranolol usage, prematurity, IUGR, increased metabolism due to neonatal Graves, and transient stress-induced hyperinsulinism. The infant was started on methimazole for hyperthyroidism and propranolol for tachycardia. She was also started on diazoxide for persistent hypoglycemia. By 6 months of age, the hyperthyroidism and hypoglycemia had resolved. This is an interesting case of neonatal Graves disease with severe persistent hypoglycemia which we suspect is due to transient neonatal hyperinsulinism induced by multiple stress responses.
PubMed: 38463451
DOI: 10.1177/2050313X241237433 -
JCEM Case Reports Jul 2023Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription...
Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in early infancy. Mutations in the gene for heterozygous hepatocyte nuclear transcription factor 4-alpha () account for approximately 5% of cases and are inherited in an autosomal dominant fashion or arise as de novo mutations. This case describes a unique presentation of parental gonadal, or germline, mosaicism as the suspected inheritance pattern for siblings with congenital hyperinsulinism caused by mutations. Two siblings presented with hypoglycemia in the first hours of life and were subsequently confirmed to have hyperinsulinism. In each patient, glycemic control was achieved at relatively low doses of diazoxide. Both siblings tested positive for the same mutation, whereas the parents tested negative for mutations. Gonadal, or germline, mosaicism became the presumed leading diagnosis, given 2 unaffected parents with 2 children with congenital hyperinsulinism. The older sibling demonstrated additional clinical features of liver disease and renal Fanconi syndrome, both of which are associated with mutations. Genetic testing plays an important role in the diagnosis and management of congenital hyperinsulinism. mutations may arise by a range of mechanisms, including gonadal, or germline, mosaicism. mutations have phenotypic variance that may affect multiple organ systems at any age.
PubMed: 37908999
DOI: 10.1210/jcemcr/luad089 -
Nutrition & Diabetes Jun 2024We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release...
BACKGROUND
We previously reported that, among all the naturally occurring amino acids, L-valine is the most powerful luminal stimulator of glucagon-like peptide 1 (GLP-1) release from the upper part of the rat small intestine. This makes L-valine an interesting target for nutritional-based modulation of GLP-1 secretion. However, the molecular mechanism of L-valine-induced secretion remains unknown.
METHODS
We aimed to investigate the effect of orally given L-valine in mice and to identify the molecular details of L-valine stimulated GLP-1 release using the isolated perfused rat small intestine and GLUTag cells. In addition, the effect of L-valine on hormone secretion from the distal intestine was investigated using a perfused rat colon.
RESULTS
Orally given L-valine (1 g/kg) increased plasma levels of active GLP-1 comparably to orally given glucose (2 g/kg) in male mice, supporting that L-valine is a powerful stimulator of GLP-1 release in vivo (P > 0.05). Luminal L-valine (50 mM) strongly stimulated GLP-1 release from the perfused rat small intestine (P < 0.0001), and inhibition of voltage-gated Ca-channels with nifedipine (10 μM) inhibited the GLP-1 response (P < 0.01). Depletion of luminal Na did not affect L-valine-induced GLP-1 secretion (P > 0.05), suggesting that co-transport of L-valine and Na is not important for the depolarization necessary to activate the voltage-gated Ca-channels. Administration of the K-channel opener diazoxide (250 μM) completely blocked the L-valine induced GLP-1 response (P < 0.05), suggesting that L-valine induced depolarization arises from metabolism and opening of K-channels. Similar to the perfused rat small intestine, L-valine tended to stimulate peptide tyrosine-tyrosine (PYY) and GLP-1 release from the perfused rat colon.
CONCLUSIONS
L-valine is a powerful stimulator of GLP-1 release in rodents. We propose that intracellular metabolism of L-valine leading to closure of K-channels and opening of voltage-gated Ca-channels are involved in L-valine induced GLP-1 secretion.
Topics: Animals; Glucagon-Like Peptide 1; Male; Valine; Rats; Mice; Intestine, Small; KATP Channels; Calcium Channels; Colon; Mice, Inbred C57BL; Rats, Wistar
PubMed: 38862477
DOI: 10.1038/s41387-024-00303-4 -
Biomedicines Dec 2023Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of...
Modulation of mitochondrial K channels represents a pharmacological strategy to promote cardioprotective effects. Isothiocyanates emerge as molecules capable of releasing hydrogen sulfide (HS), an endogenous pleiotropic gasotransmitter responsible for anti-ischemic cardioprotective effects also through the involvement of mitoK channels. Erucin (ERU) is a natural isothiocyanate resulting from the enzymatic hydrolysis of glucosinolates (GSLs) present in Mill. seeds, an edible plant of the family. In this experimental work, the specific involvement of mitoK channels in the cardioprotective effect induced by ERU was evaluated in detail. An in vivo preclinical model of acute myocardial infarction was reproduced in rats to evaluate the cardioprotective effect of ERU. Diazoxide was used as a reference compound for the modulation of potassium fluxes and 5-hydroxydecanoic acid (5HD) as a selective blocker of K channels. Specific investigations on isolated cardiac mitochondria were carried out to evaluate the involvement of mitoK channels. The results obtained showed ERU cardioprotective effects against ischemia/reperfusion (I/R) damage through the involvement of mitoK channels and the consequent depolarizing effect, which in turn reduced calcium entry and preserved mitochondrial integrity.
PubMed: 38137502
DOI: 10.3390/biomedicines11123281 -
Journal of Neurodevelopmental Disorders Apr 2024Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region,...
BACKGROUND
Prader-Willi syndrome (PWS) is a rare neurobehavioral-metabolic disease caused by the lack of paternally expressed genes in the chromosome 15q11-q13 region, characterized by hypotonia, neurocognitive problems, behavioral difficulties, endocrinopathies, and hyperphagia resulting in severe obesity if energy intake is not controlled. Diazoxide choline extended-release (DCCR) tablets have previously been evaluated for their effects on hyperphagia and other behavioral complications of people with PWS in a Phase 3 placebo-controlled study of participants with PWS, age 4 and older with hyperphagia (C601) and in an open label extension study, C602.
METHODS
To better understand the longer-term impact of DCCR, a cohort from PATH for PWS, a natural history study that enrolled participants with PWS age 5 and older, who met the C601 age, weight and baseline hyperphagia inclusion criteria and had 2 hyperphagia assessments ≥ 6 months apart, were compared to the C601/C602 cohort. Hyperphagia was measured using the Hyperphagia Questionnaire for Clinical Trials (HQ-CT, range 0-36). The primary analysis used observed values with no explicit imputation of missing data. A sensitivity analysis was conducted in which all missing HQ-CT assessments in the C601/C602 cohort were assigned the highest possible value (36), representing the worst-case scenario. Other behavioral changes were assessed using the Prader-Willi Syndrome Profile questionnaire (PWSP).
RESULTS
Relative to the PATH for PWS natural history study cohort, the DCCR-treated C601/C602 cohort showed significant improvements in HQ-CT score at 26 weeks (LSmean [SE] -8.3 [0.75] vs. -2.5 [0.43], p < 0.001) and 52 weeks (LSmean [SE] -9.2 [0.77] vs. -3.4 [0.47], p < 0.001). The comparison between the cohorts remained significant in the worst-case imputation sensitivity analysis. There were also significant improvements in all domains of the PWSP at 26 weeks (all p < 0.001) and 52 weeks (all p ≤ 0.003) for C601/C602 participants compared to the PATH for PWS participants.
CONCLUSION
Long-term administration of DCCR to people with PWS resulted in changes in hyperphagia and other behavioral complications of PWS that are distinct from the natural history of the syndrome as exemplified by the cohort from PATH for PWS. The combined effects of administration of DCCR should reduce the burden of the syndrome on the patient, caregivers and their families, and thereby may benefit people with PWS and their families.
TRIAL REGISTRATION
Clinical study C601 was originally registered on ClinicalTrials.gov on February 22, 2018 (NCT03440814). Clinical study C602 was originally registered on ClinicalTrials.gov on October 22, 2018 (NCT03714373). PATH for PWS was originally registered on ClinicalTrials.gov on October 24, 2018 (NCT03718416).
Topics: Humans; Prader-Willi Syndrome; Female; Male; Hyperphagia; Child; Adult; Adolescent; Diazoxide; Young Adult; Delayed-Action Preparations; Child, Preschool; Cohort Studies
PubMed: 38671361
DOI: 10.1186/s11689-024-09536-x