Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

Beltrand, Jacques; Elie, Caroline; Busiah, Kanetee; Fournier, Emmanuel; Boddaert, Nathalie; Bahi‐Buisson, Nadia; Vera, Miriam; Bui-Quoc, Emmanuel; Ingster-Moati, I.; Berdugo, Marianne; Simon, Albane; Gozalo, Claire; Djerada, Zoubir; Flechtner, Isabelle; Tréluyer, Jean‐Marc; Scharfmann, Raphaël; Cavé, Hélène; Vaivre‐Douret, Laurence; Polak, Michel

doi:10.2337/dc15-0837

Cited by 81 publications

(107 citation statements)

References 28 publications

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“…While, glipizide may prevent kainic acid-induced hippocampal neuronal cell death [26] , sulphonylurea therapy in neonatal diabetic individuals show improvements in neuropsychomotor impairment. Glyburide has been shown to improve high fat diet-induced anxiety and cognitive impairment [27] and reduce the expression of myosin-IIB in the frontal cortex and hippocampus of diabetic rats [28] . In our study glibenclamide treatment partially reversed cognitive impairment in diabetic rat thus confirming the cognitive impairment in these animals to be mediated by T2D [29] .…”

Section: Resultsmentioning

confidence: 99%

Characterization of Cognitive Impairment in Type 2 Diabetic Rats

Mehta¹,

Banerjee²

2017

pharmaceutical-sciences

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Among all the secondary complications of type 2 diabetes, cognitive impairment associated with diabetes is less well studied and characterized. We made an attempt to investigate the molecular mechanisms involved in cognitive decline in high fat diet-streptozotocin model of type 2 diabetes. High-fat diet and a single low dose streptozotocin (25 mg/kg) were used to induce diabetes in Sprague-Dawley rats. Developments of cognitive deficit in these animals were measured using change in transfer latency in elevated plus maze test and stepdown latency in passive avoidance test. This was followed by biochemical estimation of acetylcholinesterase and reduced glutathione levels followed by histological evaluation of cortical and hippocampal slices. The high fat diet-streptozotocin animals developed type 2 diabetes, characterized by an increase in fasting blood glucose levels >250 mg/kg, marked increase (P<0.001) in triglyceride (207±7.2) and total cholesterol level (125.3±2.7) with a decrease (P<0.001) in high-density lipoproteins (14.27±1.1) when compared to control animals. After 4 weeks of development of type 2 diabetes high fat diet-streptozotocin animals showed signs of cognitive deficit with a significant decline in step-down latency (P<0.001) and a significant increase in transfer latency (P<0.001) compared to controls. The high fat diet-streptozotocin animals also showed significant decrease (P<0.001) in cortico-hippocampal glutathione levels and increase in (P<0.001) acetylcholinesterase activity as compared to control animals suggesting type 2 diabetes-associated oxidative stress and decrease in hippocampal Ach activity. Immunohistochemical studies in these animals showed pronounced astrogliosis and microglial activation in the cortical and hippocampal slices suggesting neuroinflammatory changes. We also found significant loss (P<0.001) of hippocampal neurons at CA1 and CA3 region in the diabetic rats as compared with healthy controls. Antidiabetic compound glibenclamide (10 mg/kg for 3 weeks) partly reversed the above neurobehavioral, biochemical and histological changes in the diabetic rat brain. Hence we show that high fat diet-streptozotocin type 2 diabetic rats may develop signs of cognitive impairment. This cognitive decline was found to be associated with an increase in acetylcholinesterase activity and loss of hippocampal neurons. Oxidative stress and neuroinflammatory changes in the brain of these animals may be responsible for hippocampal neuronal loss, which could be partly reversed upon glibenclamide treatment.

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Section: Resultsmentioning

confidence: 99%

Characterization of Cognitive Impairment in Type 2 Diabetic Rats

Mehta¹,

Banerjee²

2017

pharmaceutical-sciences

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“…In these patients, switching from insulin to sulfonylurea leads to the improvement of metabolic control [19]. Interestingly, that sulfonylurea in neonatal diabetes secondary to mutations in potassium-channel subunits produces measurable improvements in neuropsychomotor impairments, which are greater in younger patients [19, 24]. Furthermore, it was speculated that rather than a drug that targets both SUR1 and SUR2 isoforms, such as glibenclamide, a SUR1-specific drug, such as gliclazide, might influence neurological symptoms more effectively as only SUR1 isoforms are present in neuronal K ATP channels [18].…”

Section: Discussionmentioning

confidence: 99%

ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective

et al. 2016

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Maturity-onset diabetes of the young (MODY) is a heterogeneous group of diseases associated with gene mutations leading to dysfunction of pancreatic β-cells. Thirteen identified MODY variants differ from each other by the clinical course and treatment requirement. Currently, MODY subtypes 1–5 are best-studied, descriptions of the other forms are sporadic. This article reports a MODY12 clinical case, caused by a mutation in the gene of the ATP-binding cassette transporter sub-family C member 8 (ABCC8), encoding sulfonylurea receptor 1. Diabetes manifested in a 27-year-old non-obese man with epilepsy in anamnesis. No evidence of ketosis was present, pancreatic antibodies were undetectable, and C-peptide remained within the reference range. During the initial investigation, non-proliferative diabetic retinopathy and elevated albumin excretion rate was revealed. After 4 months, diabetes was complicated by pre-proliferative retinopathy and diabetic macular edema. Recurrent hypoglycemia and an increase in body weight was observed on moderate and even small insulin doses. Taking into account the clinical features and the presence of diabetes in four generations on the maternal side, screening for all MODY subtypes was performed. A mutation in the ABCC8 gene was found in proband and in his mother. After the insulin discontinuation, gliclazide modified release combined with sodium/glucose cotransporter 2 (SGLT2) inhibitors was started. This treatment eliminated hypoglycemia and improved glycemic variability parameters. A decrease in the amplitude of glucose excursions was documented by continuous glucose monitoring. After 3 months of treatment, glycemic control was still optimal, and no hypoglycemic episodes were observed. The case report demonstrates the clinical features of ABCC8-associated MODY and the therapeutic potential of a combination of sulfonylurea with SGLT2 inhibitor in this disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s13300-016-0192-9) contains supplementary material, which is available to authorized users.

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“…Patients with mutations in these two genes respond to high-dose SUs and show excellent glucose control without any increase in hypoglycaemia and glucose variability [46]. Improvements in neurological function are also seen in these patients after treatment with SU [47, 48]. In such patients, treatment with insulin reduces the glucose level but does not elicit an optimal response – and, more specifically, the neurological functions do not show any improvement [49].…”

Section: Monogenic Diabetes: the Field Where Precision Diabetes Has Amentioning

confidence: 99%

Precision Diabetes Is Slowly Becoming a Reality

Mohan

Radha

2019

Med Princ Pract

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The concept of precision medicine is becoming increasingly popular. The use of big data, genomics and other “omics” like metabolomics, proteomics and transcriptomics could make the dream of personalised medicine become a reality in the near future. As far as polygenic forms of diabetes like type 2 and type 1 diabetes are concerned, interesting leads are emerging, but precision diabetes is still in its infancy. However, with regard to monogenic forms of diabetes like maturity-onset diabetes of the young and neonatal diabetes mellitus, rapid strides have been made and precision diabetes has already become part of the clinical tools used at advanced diabetes centres. In patients with some monogenic form of diabetes, if the appropriate gene defects are identified, insulin injections can be stopped and be replaced by oral sulphonylurea drugs. In the coming years, rapid advances can be expected in the field of precision diabetes, thereby making the control of diabetes more effective and hopefully leading to prevention of its complications and improvement of the quality of life of people afflicted with diabetes.

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Sulfonylurea Therapy Benefits Neurological and Psychomotor Functions in Patients With Neonatal Diabetes Owing to Potassium Channel Mutations

Cited by 81 publications

References 28 publications

Characterization of Cognitive Impairment in Type 2 Diabetic Rats

Characterization of Cognitive Impairment in Type 2 Diabetic Rats

ABCC8-Related Maturity-Onset Diabetes of the Young (MODY12): Clinical Features and Treatment Perspective

Precision Diabetes Is Slowly Becoming a Reality

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