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Diabetes Mar 2022Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by... (Review)
Review
Secretion of insulin from pancreatic β-cells is complex, but physiological glucose-dependent secretion is dominated by electrical activity, in turn controlled by ATP-sensitive potassium (KATP) channel activity. Accordingly, loss-of-function mutations of the KATP channel Kir6.2 (KCNJ11) or SUR1 (ABCC8) subunit increase electrical excitability and secretion, resulting in congenital hyperinsulinism (CHI), whereas gain-of-function mutations cause underexcitability and undersecretion, resulting in neonatal diabetes mellitus (NDM). Thus, diazoxide, which activates KATP channels, and sulfonylureas, which inhibit KATP channels, have dramatically improved therapies for CHI and NDM, respectively. However, key findings do not fit within this simple paradigm: mice with complete absence of β-cell KATP activity are not hyperinsulinemic; instead, they are paradoxically glucose intolerant and prone to diabetes, as are older human CHI patients. Critically, despite these advances, there has been little insight into any role of KATP channel activity changes in the development of type 2 diabetes (T2D). Intriguingly, the CHI progression from hypersecretion to undersecretion actually mirrors the classical response to insulin resistance in the progression of T2D. In seeking to explain the progression of CHI, multiple lines of evidence lead us to propose that underlying mechanisms are also similar and that development of T2D may involve loss of KATP activity.
Topics: Animals; Blood Glucose; Calcium; Congenital Hyperinsulinism; Diabetes Mellitus, Type 2; Humans; Insulin Resistance; Insulin Secretion; KATP Channels; Mice; Mice, Knockout; Mutation; Potassium Channels, Inwardly Rectifying; Sulfonylurea Receptors
PubMed: 35196393
DOI: 10.2337/db21-0755 -
Acta Chirurgica Belgica Apr 2022Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated,...
Surgery is the ideal treatment of insulinoma. However, systemic therapy may be required to prevent severe preoperative hypoglycaemia, when surgery is contraindicated, delayed or refused and in case of unresectable metastatic disease. Diazoxide is commonly used but is not always effective and can cause serious side effects. Somatostatin analogues (octreotide and lanreotide) may be an alternative option. We report the case of a 27-year-old patient with insulinoma in whom diazoxide was compared with lanreotide before operation. A diagnosis of insulinoma was made on the basis of a fasting test and a 2 cm tumour confirmed in the body of the pancreas, with a high uptake of 111-In-pentreotide. Diazoxide was initiated and increased to a maximal tolerated dose of 450 mg/day. Because of dyspnoea and persisting hypoglycaemia, diazoxide was shifted to lanreotide 120 mg. All symptoms resolved without hypoglycaemia. According to the EORTC quality score of life, the score without treatment, under diazoxide, under lanreotide and after surgery were respectively 84.7, 73.3, 90.9 and 99.1. Thus, providing a positive Octreoscan, somatostatin analogues may be a safe, effective and well-tolerated option in patients with insulinoma refractory and/or intolerant to diazoxide or with a high risk of fluid retention.
Topics: Adult; Diazoxide; Humans; Insulinoma; Octreotide; Pancreatic Neoplasms; Somatostatin
PubMed: 32375590
DOI: 10.1080/00015458.2020.1765676 -
The Journal of Biological Chemistry Jan 2020MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of...
MicroRNA 199 (miR-199) negatively impacts pancreatic β-cell function and its expression is highly increased in islets from diabetic mice as well as in plasma of diabetic patients. Here we investigated how miR-199 expression is regulated in β-cells by assessing expression of miR-199 precursors (primiR-199a1, primiR-199a2, and primiR-199b) and mature miR-199 (miR-199-3p and miR-199-5p) and promoter transcriptional activity assays in mouse islets and mouse insulinoma cells (MIN6) under different stimuli. We found that mouse islets equally express miR-199-3p and miR-199-5p. However, the primiRNA expression levels differed; although primiR-199a1 expression was about 30% greater than that of primiR-199a2, primiR-199b is barely detected in islets. We observed a 2-fold increase in primiR-199a1 and primiR-199a2 mRNA levels in mouse islets cultured in 10 mm glucose compared with 5.5 mm glucose. Similar responses to glucose were observed in MIN6 cells. Exposure to 30 mm KCl to induce membrane depolarization and calcium influx increased expression of primiR-199a2 but not of primiR-199a1 in MIN6 cells, indicating that calcium influx was involved. Transcriptional activity studies in MIN6 cells also revealed that primiR-199a2 promoter activity was enhanced by glucose and reduced by 2-deoxy-D-glucose-induced starvation. KCl and the potassium channel blocker tolbutamide also stimulated primiR-199a2 promoter activity. Calcium channel blockade by nifedipine reduced primiR-199a2 promoter activity in MIN6 cells, and diazoxide-mediated calcium influx inhibition blunted glucose up-regulation of miR-199-3p in islets. In conclusion, we uncover that glucose acutely up-regulates miR-199 family expression in β-cells. Glucose metabolism and calcium influx are involved in primiR-199a2 expression but not primiR-199a1 expression.
Topics: Animals; Calcium; Cell Line; Cell Membrane; Female; Glucose; Insulin-Secreting Cells; Male; Mice; MicroRNAs; Up-Regulation
PubMed: 31882540
DOI: 10.1074/jbc.RA119.010356 -
JFMS Open Reports 2022A 5.5 month-old intact male Maine Coon cat was presented to a referral hospital for a history of muscle fasciculations, lethargy and seizures associated with refractory...
CASE SUMMARY
A 5.5 month-old intact male Maine Coon cat was presented to a referral hospital for a history of muscle fasciculations, lethargy and seizures associated with refractory hypoglycemia. Diagnostic testing for hypothyroidism, hyposomatotropism or hypoadrenocorticism, inborn errors of metabolism (ie, storage diseases and urea cycle disorders), infection or iatrogenic hypoglycemia were negative. An inappropriately high serum insulin level was noted in the face of marked hypoglycemia. The insulin:glucose ratio was 0.44 (<0.3) and the amended insulin:glucose ratio was 1268 (<30). Thoracic radiography and abdominal ultrasonography did not identify a cause for this elevated insulin level. Stabilization with a low, but adequate, blood glucose occurred with corticosteroid therapy, with further significant improvement with the addition of diazoxide. Peripheral neuropathy developed several months later, and concerns for quality of life led to humane euthanasia approximately 1 year after the initial diagnosis. Insulin levels remained high at the time of euthanasia. Necropsy found no gross lesions, though microscopic degeneration of the sciatic nerve and subjectively mildly increased size and number of pancreatic islets was noted. These findings were consistent with a diagnosis of congenital hyperinsulinism.
RELEVANCE AND NOVEL INFORMATION
This is the first reported case of congenital hyperinsulinism in a cat and may parallel the diffuse form of hypoglycemic hyperinsulinism reported in humans and a single dog. It should be considered a differential diagnosis in kittens presenting for refractory hypoglycemia.
PubMed: 36458207
DOI: 10.1177/20551169221136473 -
Frontiers in Endocrinology 2023Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent... (Review)
Review
Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infancy/childhood and is a serious condition associated with severe recurrent attacks of hypoglycemia due to dysregulated insulin secretion. Timely diagnosis and effective treatment are crucial to prevent severe hypoglycemia that may lead to life-long neurological complications. In pancreatic β-cells, adenosine triphosphate (ATP)-sensitive K (K) channels are a central regulator of insulin secretion vital for glucose homeostasis. Genetic defects that lead to loss of expression or function of K channels are the most common cause of HI (K-HI). Much progress has been made in our understanding of the molecular genetics and pathophysiology of K-HI in the past decades; however, treatment remains challenging, in particular for patients with diffuse disease who do not respond to the K channel activator diazoxide. In this review, we discuss current approaches and limitations on the diagnosis and treatment of K-HI, and offer perspectives on alternative therapeutic strategies.
Topics: Humans; Child; Sulfonylurea Receptors; Adenosine Triphosphate; Congenital Hyperinsulinism; Mutation; Insulin Secretion
PubMed: 37056678
DOI: 10.3389/fendo.2023.1161117 -
Endocrine Apr 2021This study aimed to analyze the clinical and genetic characteristics of Chinese children with congenital hyperinsulinemia (CHI) that is spontaneously relieved.
OBJECTIVE
This study aimed to analyze the clinical and genetic characteristics of Chinese children with congenital hyperinsulinemia (CHI) that is spontaneously relieved.
METHODS
The patient group comprised 200 children with CHI that were treated at the Beijing Children's Hospital from January 2006 to December 2018. The patients were divided into two groups according to their prognosis: the spontaneous remission group (n = 92) and the nonspontaneous remission group (n = 108). The clinical characteristics, pathogenic genes, diagnosis and treatment process, and follow-up data of both groups were analyzed retrospectively.
RESULTS
Of the 200 children with CHI, 92 achieved spontaneous remission. The age of spontaneous remission was between one month and nine years, and 47 of the children were relieved before the age of one year. The median age of onset was 85 days (range: 1-2825 days) in the spontaneous remission group and 2 days (range: 1-210 days) in the nonspontaneous remission group (P < 0.05). The mean birth weight was 3.44 ± 0.76 kg for the spontaneous remission group and 3.95 ± 0.75 kg for the nonspontaneous remission group (P < 0.05). Of the 92 children in the spontaneous remission group, 65 were treated with diazoxide with effective rate of 81.5% (53/65). In 12 cases in which diazoxide treatment failed, octreotide was used with an effective rate of 83.3% (10/12). Of the 108 children in the nonspontaneous remission group, 88 were treated with diazoxide with an effective rate of 43.2 % (38/88), and 29 children were treated with octreotide with an effective rate of 48.28% (14/29). Of the 30 children in the spontaneous remission group that underwent mutation analysis of CHI-related pathogenic genes, 10 children (10/30, 33.3%) carried mutations. Of the 48 children in the nonspontaneous remission group that underwent mutation analysis of CHI-related pathogenic genes, 37 children (37/48, 77.1%) were found to carry mutations. All of the differences in the indices mentioned above were statistically significant.
CONCLUSIONS
The rate of spontaneous remission of CHI was significantly higher in children with late age of CHI onset, light birth weight, effective diazoxide treatment, and no common pathogenic gene mutations. Spontaneous remission was also possible for a small number of children that carried mutations in the ABCC and KCNJ11 genes and in whom diazoxide treatment failed.
Topics: Child; China; Congenital Hyperinsulinism; DNA Mutational Analysis; Diazoxide; Humans; Infant; Mutation; Retrospective Studies
PubMed: 33502730
DOI: 10.1007/s12020-020-02585-x -
Clinical Medicine Insights. Case Reports 2023Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We...
Diazoxide is one of the FDA-approved pharmacologic treatments for hyperinsulinemic hypoglycemia, however, its adverse effects in infants are not well described. We reported a 37-week-old boy with the diagnosis of hypoglycemia. We started a dextrose infusion, but we used oral diazoxide, due to hypoglycemia episodes despite the increase in dextrose intake. The newborn had a normoglycemic condition after gradually increasing the diazoxide dose to 15 mg/kg/day. He was fully breastfed and discharged at 14 days of age with ongoing diazoxide. In weekly serial clinical follow-ups, the parents noticed an increase in the growth of forehead and facial hair that was diagnosed as diazoxide-induced hypertrichosis. Diazoxide was gradually tapered, and hypertrichosis continued until 1 month after dioxide discontinuation. Diazoxide use in NICU settings has increased over time. Diazoxide has many side effects, one of which is hypertrichosis. Many diazoxide side effects have been reported in adults or children and few studies have reported the prevalence of these adverse effects of diazoxide in neonates and infants.
PubMed: 36726424
DOI: 10.1177/11795476231151330 -
Journal of Bioenergetics and... Feb 2023Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral...
AIM/INTRODUCTION
Diabetes Mellitus is a chronic degenerative disease, and its main biochemical characteristic is hyperglycemia due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. Hyperglycemia causes dyslipidemia and stimulates oxidative damage, leading to the main symptoms, such as fatigue and culminates in diabetic complications. Previous studies have shown that ATP-sensitive potassium channels counteract muscle fatigue and metabolic stress in healthy mouse models. To determine the effect of diazoxide on muscle strength development during diabetes, we tested the effect of diazoxide in streptozotocin-diabetic rats in muscle function, lipid profile and oxidative stress biomarkers.
MATERIALS AND METHODS
Wistar rats were divided into 4 groups of six animals each: (1) Control group, (2) diabetes group, (3) Control group + diazoxide, and (4) Diabetic + diazoxide (DB + DZX). 4 weeks after rats were sacrificed, soleus and extensor digitorum longus muscles (EDL) were extracted to prepare homogenates and serum was obtained for biochemical measurements. Oxidative damage was evaluated by the thiobarbituric acid method and the fluorescent for reactive oxygen species (ROS) probe 2,4-HDCFDA, respectively.
RESULTS
Diabetic rats with diazoxide administration showed an increase in the development of muscle strength in both muscles; in turn, the onset of fatigue was longer compared to the group of diabetic rats without treatment. Regarding the lipid profile, diazoxide decreased total cholesterol levels in the group of diabetic rats treated with diazoxide (x̅46.2 mg/dL) compared to the untreated diabetic group (x̅=104.4 mg/dL); secondly, diazoxide decreased triglyceride concentrations (x̅=105.3 mg/dL) compared to the untreated diabetic rats (x̅=412.2 mg/dL) as well as the levels of very low-density lipoproteins (x̅=20.4 mg/dL vs. x̅=82.44 mg/dL). Regarding the various markers of oxidative stress, the diabetic group treated with diazoxide was able to reduce the concentrations of TBARS and total reactive oxygen species as well as preserve the concentrations of reduced glutathione.
CONCLUSION
Diazoxide administration in diabetic rats increases muscle strength development in EDL and soleus muscle, decreases fatigue, reduces cholesterol and triglyceride concentrations and improves oxidative stress parameters such as TBARS, ROS, and glutathione status.
Topics: Mice; Rats; Animals; Diazoxide; Streptozocin; Rats, Wistar; Reactive Oxygen Species; Diabetes Mellitus, Experimental; Thiobarbituric Acid Reactive Substances; Oxidative Stress; Hyperglycemia; Muscle, Skeletal; Lipids; Triglycerides; Cholesterol
PubMed: 36723797
DOI: 10.1007/s10863-023-09958-7 -
Frontiers in Endocrinology 2022Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and... (Review)
Review
Congenital hyperinsulinemia (CHI), is a clinically heterogeneous disorder that presents as a major cause of persistent and recurrent hypoglycemia during infancy and childhood. There are 16 subtypes of CHI-related genes. Phosphomannomutase 2 hyperinsulinemia (PMM2-HI) is an extremely rare subtype which is first reported in 2017, with only 18 families reported so far. This review provides a structured description of the genetic pathogenesis, and current diagnostic and therapeutic advances of PMM2-HI to increase clinicians' awareness of PMM2-HI.
Topics: Humans; Child; Hyperinsulinism; Hypoglycemia; Phosphotransferases (Phosphomutases)
PubMed: 36726472
DOI: 10.3389/fendo.2022.1102307 -
Cureus Nov 2023Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms,...
Insulinomas are a rare cause of recurrent hypoglycemia in non-diabetic patients. Diagnosis requires hypoglycemia (plasma glucose <50 mg/dL), neuroglycopenic symptoms, and prompt relief of symptoms following the administration of glucose, known as Whipple's triad. The gold standard diagnostic tests are measuring insulin, C-peptide, and glucose during a 72-hour fast. In the preoperative period and in patients with unresectable or metastatic tumors, medical management with diazoxide and octreotide can be considered for recurrent hypoglycemia. We present a case of insulinoma in a 37-year-old woman who initially presented after a seizure-related motor vehicle accident. Upon admission, her initial glucose level was 32 mg/dL, indicating a likely hypoglycemic seizure. During her hospitalization, she had recurrent episodes of fasting and postprandial hypoglycemia, ranging from 32-70 mg/dL. She exhibited the characteristics of Whipple's triad when values dropped below 50 mg/dL. These episodes necessitated continuous infusions of 10% dextrose. Tests for insulin autoantibodies, sulfonylurea screens, and thyroid function yielded unremarkable results. A 72-hour fasting test was initiated to investigate potential endogenous causes of excessive insulin production. Laboratory results from a venous glucose level of 46 mg/dL indicated a notable rise in C peptide and insulin levels, alongside beta hydroxybutyrate suppression, all of which fulfilled the diagnostic criteria for insulinoma. An abdominal magnetic resonance imaging (MRI) unveiled a 1.3 cm mass in the pancreatic tail. This case emphasizes the importance of employing a focused approach when evaluating non-diabetic individuals displaying hypoglycemia with positive Whipple's triad. This targeted method not only enables early detection of this rare condition but also assists in eliminating other common causes of recurrent hypoglycemia in non-diabetic individuals. Moreover, in addition to this diagnosis being rare, it is important to note that patients with insulinomas typically do not exhibit a glucose level low enough to induce seizures during their initial presentation.
PubMed: 38074057
DOI: 10.7759/cureus.48514