Sulphonylurea Receptor Research Articles

Expression and influence of KATP in umbilical artery smooth muscle cells of patients with hypertensive disorders of pregnancy

The objective of this study is to investigate the expression and influence of adenosine triphosphate-sensitive potassium channel (KATP) in human umbilical arterial smooth muscle cells (HUASMCs) of patients with hypertensive disorders of pregnancy (HDP). Western blotting was used to detect the protein expression levels of KATP inwardly rectifying potassium channel (Kir)6.1 and sulphonylurea receptor (SUR)2B subunits in HUASMCs from patients with normal parturients (NP), gestational hypertension (GH), chronic hypertension (CH), preeclampsia (PE) and chronic hypertension with superimposed preeclampsia (CHSP), respectively. There was no significant difference in the protein expression of Kir6.1 subunit in NP group, GH group, CH group, PE group and CHSP group (P > 0.05). The protein expression of SUR2B subunit was gradually decreased in NP group, GH group, CH group, PE group and CHSP group, with statistically significant difference among the groups (P < 0.05). The altered expression level of KATP SUR2B subunit may be involved in the pathogenesis of HDP. The severity of HDP may be related to the degree of decrease of SUR2B subunit.

Focal Congenital Hyperinsulinism (CHI) Due To Paternally Inherited Variant in ABCC8 Gene: Importance of Genetic Testing &amp; PET Imaging in Stratification &amp; Management of Diazoxide Unresponsive CHI

Congenital Hyperinsulinism (CHI) may be transient or permanent and inherited either in autosomal recessive or dominant forms. Variants in ABCC8 and KCNJ11 genes coding for Sulphonyl Urea Receptor (SUR1) and potassium channel subunit (Kir6.2) respectively, account for 82% cases of diazoxide-unresponsive patients and 45% of all cases of CHI. The histology of CHI is classified into focal and diffuse. Approximately half of all cases can be classified as diffuse, 40 % as focal, and 10% of cases are considered atypical. We report a 1 month old male with recurrent hypoglycemia detected with focal congenital hyperinsulinism secondary to a paternally inherited heterozygous ABCC8 gene mutation. Focal disease results due to inheritance of a monoallelic recessive paternal ABCC8 or KCNJ11 variant together with somatic Loss of Heterozygosity (LOH) of the maternal allele at 11p15 within a pancreatic progenitor cell. Infants &amp; children with focal disease may be cured by resection of their hyperplastic lesion and the risk for postoperative diabetes is significantly lower as compared to that following pancreatectomy for diffuse CHI. The report describes molecular mechanisms underlying CHI &amp; emphasises the need of genetic testing and diagnostic functional imaging modalities in diazoxide unresponsive CHI to guide management and improve clinical outcomes.

Hypoxia Promotes Atrial Tachyarrhythmias via Opening of ATP-Sensitive Potassium Channels.

Hypoxia-ischemia predisposes to atrial arrhythmia. Atrial ATP-sensitive potassium channel (KATP) modulation during hypoxia has not been explored. We investigated the effects of hypoxia on atrial electrophysiology in mice with global deletion of KATP pore-forming subunits. Whole heart KATP RNA expression was probed. Whole-cell KATP current and action potentials were recorded in isolated wild-type (WT), Kir6.1 global knockout (6.1-gKO), and Kir6.2 global knockout murine atrial myocytes. Langendorff-perfused hearts were assessed for atrial effective refractory period (ERP), conduction velocity, wavefront path length (WFPL), and arrhymogenicity under normoxia/hypoxia using a microelectrode array and programmed electrical stimulation. Heart histology was assessed. Expression patterns were essentially identical for all KATP subunit RNA across human heart, whereas in mouse, Kir6.1 and SUR2 (sulphonylurea receptor) were higher in ventricle than atrium, and Kir6.2 and SUR1 were higher in atrium. Compared with WT, Kir6.2 global knockout atrial myocytes had reduced tolbutamide-sensitive current and action potentials were more depolarized with slower upstroke and reduced peak amplitude. Action potential duration was prolonged in 6.1-gKO atrial myocytes, absent of changes in other ion channel gene expression or atrial myocyte hypertrophy. In Langendorff-perfused hearts, baseline atrial ERP was prolonged and conduction velocity reduced in both KATP knockout mice compared with WT, without histological fibrosis. Compared with baseline, hypoxia led to conduction velocity slowing, stable ERP, and WFPL shortening in WT and 6.1-gKO hearts, whereas WFPL was stable in Kir6.2 global knockout hearts due to ERP prolongation with conduction velocity slowing. Tolbutamide reversed hypoxia-induced WFPL shortening in WT and 6.1-gKO hearts through ERP prolongation. Atrial tachyarrhythmias inducible with programmed electrical stimulation during hypoxia in WT and 6.1-gKO mice correlated with WFPL shortening. Spontaneous arrhythmia was not seen. KATP block/absence leads to cellular and tissue level atrial electrophysiological modification. Kir6.2 global knockout prevents hypoxia-induced atrial WFPL shortening and atrial arrhythmogenicity to programmed electrical stimulation. This mechanism could be explored translationally to treat ischemically driven atrial arrhythmia.

Rapid Characterization of the Functional and Pharmacological Consequences of Cantú Syndrome KATP Channel Mutations in Intact Cells.

Gain-of-function of KATP channels, resulting from mutations in either KCNJ8 (encoding inward rectifier sub-family 6 [Kir6.1]) or ABCC9 (encoding sulphonylurea receptor [SUR2]), cause Cantú syndrome (CS), a channelopathy characterized by excess hair growth, coarse facial appearance, cardiomegaly, and lymphedema. Here, we established a pipeline for rapid analysis of CS mutation consequences in Landing pad HEK 293 cell lines stably expressing wild type (WT) and mutant human Kir6.1 and SUR2B. Thallium-influx and cell membrane potential, reported by fluorescent Tl-sensitive Fluozin-2 and voltage-sensitive bis-(1,3-dibutylbarbituric acid)trimethine oxonol (DiBAC4(3)) dyes, respectively, were used to assess channel activity. In the Tl-influx assay, CS-associated Kir6.1 mutations increased sensitivity to the ATP-sensitive potassium (KATP) channel activator, pinacidil, but there was strikingly little effect of pinacidil for any SUR2B mutations, reflecting unexpected differences in the molecular mechanisms of Kir6.1 versus SUR2B mutations. Compared with the Tl-influx assay, the DiBAC4(3) assay presents more significant signal changes in response to subtle KATP channel activity changes, and all CS mutants (both Kir6.1 and SUR2B), but not WT channels, caused marked hyperpolarization, demonstrating that all mutants were activated under ambient conditions in intact cells. Most SUR2 CS mutations were markedly inhibited by <100 nM glibenclamide, but sensitivity to inhibition by glibenclamide, repaglinide, and PNU37883A was markedly reduced for Kir6.1 CS mutations. Understanding functional consequences of mutations can help with disease diagnosis and treatment. The analysis pipeline we have developed has the potential to rapidly identify mutational consequences, aiding future CS diagnosis, drug discovery, and individualization of treatment. SIGNIFICANCE STATEMENT: We have developed new fluorescence-based assays of channel activities and drug sensitivities of Cantú syndrome (CS) mutations in human Kir6.1/SUR2B-dependent KATP channels, showing that Kir6.1 mutations increase sensitivity to potassium channel openers, while SUR2B mutations markedly reduce K channel opener (KCO) sensitivity. However, both Kir6.1 and SUR2B CS mutations are both more hyperpolarized than WT cells under basal conditions, confirming pathophysiologically relevant gain-of-function, validating DiBAC4(3) fluorescence to characterize hyperpolarization induced by KATP channel activity under basal, non KCO-activated conditions.

Inwardly rectifying potassium channels (K&lt;sub&gt;IR&lt;/sub&gt;) in GtoPdb v.2023.1

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

Targeting Host Sulphonyl Urea Receptor 2 Can Reduce Severity of Helicobacter pylori Associated Gastritis.

While most Helicobacter pylori-infected individuals remain asymptomatic throughout their lifetime, in a significant proportion, the resulting severe chronic gastritis drives the development of gastric cancer. In this study, we examine a new therapeutic target, a host potassium channel regulatory subunit, SUR2 (encoded by ABCC9), with potential to protect against H pylori-associated diseases. SUR2 gene (ABCC9) expression in human gastric biopsies was analyzed by quantitative polymerase chain reactions. Helicobacter-infected mice were administered the SUR2-channel agonists, pinacidil and nicorandil, then gastric tissues analyzed by histology, immunohistochemistry and quantitative polymerase chain reaction, and splenic tissues by enzyme-linked immunosorbent assays. Invitro studies were performed on human and mouse macrophages, human gastric epithelial cells and mouse splenocytes. ABCC9 expression in human and mouse stomachs is downregulated with H pylori infection. Treatment of Helicobacter-infected mice with SUR2 channel modulators, pinacidil or nicorandil, significantly reduced gastritis severity. In gastric epithelial cells, nicorandil-induced opening of the SUR2 channel increased intracellular K+ and prevented H pylori-mediated Ca2+ influx and downstream pro-inflammatory signaling. SUR2 is a novel host factor that regulates Helicobacter pathogenesis. Pharmacological targeting of SUR2 provides a potential approach for reducing the severity of H pylori-associated gastritis, without eradicating infection.

Inwardly rectifying potassium channels (K&lt;sub&gt;IR&lt;/sub&gt;) in GtoPdb v.2021.3

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

Therapeutic Efficacy of Ficus Glomerata Leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Albino Rats

Present study was aimed to evaluate the anti-diabetic efficacy of Ficus glomerata in Alloxan monohydrate induced albino rats. Oral administration of fresh Ficus glomerataleaves (2 - 4 g/day) for 60 days shows significant blood glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level became normal when fed with Ficus glomerata leaves. It is amply revealed that fresh Ficus glomerata indica leaves possessed anti-diabetic properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Ficus glomerata leaves to be almost similar effect like insulin treatment in alloxan monohydrate administered animal model. From the present investigation it appeared that Ficus glomerata leaves might have some ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans located in the pancreas. Once they bind to the Sulphonyl urea receptors, the K+ -ATP channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated.

Aerobic Exercise Increases Expression Of SUR1 And SUR2A Subunits Of K ATP -channels In Murine Diabetic Ventricular Cardiomyocytes.

Diabetes mellitus (DM) is one of the most prevalent and rapidly increasing non-communicable chronic diseases around the world. It has been related to left ventricular disfunction, as well to its electric remodeling. Cellular and molecular underlying mechanisms remains unveiled, at least in part. Phenotypic consequences includes QT Interval prolongation, ventricular arrhytmia, and cardiac sudden death. KATP-channels are considered as couplers of metabolism to membrane electric behavior in ventricular cells. At early DM stages, reduction in KATP-channels expression has been claimed as one of the main cardiac dysfunction underlying mechanisms. Physical exercise (PE) is postulated as a preventive and therapeutic intervention for diabetic cardiomyopathy. PURPOSE: to explore aerobic PE effects on expression of KATP-channel sulphonylurea receptors (SURs) in diabetic cardiomyocites. METHODS: 3 weeks male Wistar rats were randomly asigned to four groups, control with (EC) and without exercise (NEC); diabetes with (ED) and without exercise (NED) groups (n = 5, each). IP streptozotocin at 100 mg/Kg dosis was used to induce DM. DM was considered when glycaemia was ≥250 mg/dl in tail blood. EC and ED performed exercise in a treadmill 5 min at a 15 m/min pace, followed by 20 min at 20 m/min, along 13 consecutive days. NEC and NED spent similar periods of time in a nonfuctioning treadmill. At the end of the program animals were eutanized and tissue samples were obtained from the ventricular apex. Subsecuently, Real Time Polymerase Chain Reaction (rtPCR) was used to SURs expression quantitation. RESULTS: significant differences were found for weight and glycaemia between NEC and EC when compared to NED as well as to ED (p = 0.05). Relative expression (mRNA SURx/β-actin genes) was higher in ED: for SUR1, ED vs. NED were 10.54 ± 3.53 vs 1.32 ± 0.38 (p = 0.007), as well when compared to NEC (1.29 ± 0.47, p = 0.01). Similarly, SUR2A expression was higher in ED than in NED; 10.68 ± 2.54/1.22 ± 0.45 (p = 0.002), and than in NEC (1.18 ± 0.33, p = 0.06). No differences were found in the expression of SUR2B. CONCLUSIONS: Aerobic PE increases SUR1 and SUR2A isoforms of the KATP-channels sulfonylurea receptors. This phenomenon could be related to cardioprotective effects of aerobic physical exercise in Diabetes Mellitus.

Initial treatment of diabetes in Italy. A nationwide population-based study from of the ARNO Diabetes Observatory

Background and aimsTo investigate diabetes treatment initiation and continuation in the next sixth months in newly diagnosed Italian subjects. Methods and resultsWe analyzed administrative claims of 11,300,750 Italian residents. Subjects with incident diabetes were identified by glucose lowering drug prescriptions, disease-specific co-payment exemptions and hospital discharge codes occurring in 2018 but not in 2017. Incident cases were 65,932 of whom 91.4% received the prescription of a glucose lowering drug. Among the latter, those receiving a prescription of a noninsulin medication but no insulin were 84.8%, those receiving a prescription of insulin only were 9.4%, and those receiving prescriptions of both insulin and noninsulin drugs were 5.8%. Metformin was the most frequently drug initially prescribed in noninsulin treated subjects (~85%) and sulphonylurea receptor (SUR) agonists collectively ranked as second (~13%). Lispro (35%) and glargine (34%) were the most frequently prescribed molecules in subjects who were insulin treated. Differences in prescriptions were found in age categories, with increased use of SUR agonists across decades. In the first six months, as many as 50% of noninsulin treated patients continued with the initial drug, ~15% added a second agent, ~5% switched to another medication, and ~30% discontinued any glucose lowering treatment. ConclusionsThese data document that current guidelines are often neglected because prescriptions of SUR agonists as first agent are still quite common and insulin is prescribed more than expected. They point out the urgent need to improve the dissemination and implementations of guidelines in diabetes care.

Pancreatic Islets Exhibit Dysregulated Adaptation of Insulin Secretion after Chronic Epinephrine Exposure.

Chronic adrenergic stimulation is the dominant factor in impairment of the β-cell function. Sustained adrenergic exposure generates dysregulated insulin secretion in fetal sheep. Similar results have been shown in Min6 under the elevated epinephrine condition, but impairments after adrenergic removal are still unknown and a high rate of proliferation in Min6 has been ignored. Therefore, we incubated primary rats’ islets with half maximal inhibitory concentrations of epinephrine for three days, then determined their insulin secretion responsiveness and related signals two days after removal of adrenaline via radioimmunoassay and qPCR. Insulin secretion was not different between the exposure group (1.07 ± 0.04 ng/islet/h) and control (1.23 ± 0.17 ng/islet/h), but total islet insulin content after treatment (5.46 ± 0.87 ng/islet/h) was higher than control (3.17 ± 0.22 ng/islet/h, p < 0.05), and the fractional insulin release was 36% (p < 0.05) lower after the treatment. Meanwhile, the mRNA expression of Gαs, Gαz and Gβ1-2 decreased by 42.8% 19.4% and 24.8%, respectively (p < 0.05). Uncoupling protein 2 (Ucp2), sulphonylurea receptor 1 (Sur1) and superoxide dismutase 2 (Sod2) were significantly reduced (38.5%, 23.8% and 53.8%, p < 0.05). Chronic adrenergic exposure could impair insulin responsiveness in primary pancreatic islets. Decreased G proteins and Sur1 expression affect the regulation of insulin secretion. In conclusion, the sustained under-expression of Ucp2 and Sod2 may further change the function of β-cell, which helps to understand the long-term adrenergic adaptation of pancreatic β-cell.

Therapeutic Efficacy of Ficus Glomerata leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Albino Rats

Present study was aimed to evaluate the anti-diabetic efficacy of Ficus glomerata in Alloxan monohydrate induced in the albino rats. Oral administration of fresh Ficus glomerata leaves (2-4 g/day) for 60 days shows significant blood which is glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level becamenormal when fed with Ficus glomerata leaves. It is amply revealed that fresh Ficus glomerata indica leaves possessed anti-diabetic properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Ficus glomerata leaves to be almost similar effect like insulin treat ment in alloxan monohydrate administered animal model. From the present investigation it appeared that Ficus glomerata leaves might have some ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans loca ted in the pancreas. Once they bind to the Sulphonyl urea receptors, the channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated.

The surprising complexity of KATP channel biology and of genetic diseases.

The ATP-sensitive K+ channel (KATP) is formed by the association of four inwardly rectifying K+ channel (Kir6.x) pore subunits with four sulphonylurea receptor (SUR) regulatory subunits. Kir6.x or SUR mutations result in KATP channelopathies, which reflect the physiological roles of these channels, including but not limited to insulin secretion, cardiac protection, and blood flow regulation. In this issue of the JCI, McClenaghan et al. explored one of the channelopathies, namely Cantu syndrome (CS), which is a result of one kind of KATP channel mutation. Using a knockin mouse model, the authors demonstrated that gain-of-function KATP mutations in vascular smooth muscle resulted in cardiac remodeling. Moreover, they were able to reverse the cardiovascular phenotypes by administering the KATP channel blocker glibenclamide. These results exemplify how genetic mutations can have an impact on developmental trajectories, and provide a therapeutic approach to mitigate cardiac hypertrophy in cases of CS.

Nucleotide inhibition of the pancreatic ATP-sensitive K+ channel explored with patch-clamp fluorometry.

Pancreatic ATP-sensitive K+ channels (KATP) comprise four inward rectifier subunits (Kir6.2), each associated with a sulphonylurea receptor (SUR1). ATP/ADP binding to Kir6.2 shuts KATP. Mg-nucleotide binding to SUR1 stimulates KATP. In the absence of Mg2+, SUR1 increases the apparent affinity for nucleotide inhibition at Kir6.2 by an unknown mechanism. We simultaneously measured channel currents and nucleotide binding to Kir6.2. Fits to combined data sets suggest that KATP closes with only one nucleotide molecule bound. A Kir6.2 mutation (C166S) that increases channel activity did not affect nucleotide binding, but greatly perturbed the ability of bound nucleotide to inhibit KATP. Mutations at position K205 in SUR1 affected both nucleotide affinity and the ability of bound nucleotide to inhibit KATP. This suggests a dual role for SUR1 in KATP inhibition, both in directly contributing to nucleotide binding and in stabilising the nucleotide-bound closed state.

Therapeutic Potential of Aegle marmelos (Linn.) Leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Experimental Rats

Present study was aimed to evaluate the anti-diabetic activity of Aegle marmelos in Alloxan monohydrate induced albino rats. Oral administration of fresh Aegle marmelos leaves (2 - 4 g/day) for 28 days shows significant blood glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level became normal when fed with Aegle marmelos leaves. It is amply revealed that Aegle marmelos leaves possessed anti-diabetic and beta cells restoration properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Aegle marmelos leaves to be almost similar effect like insulin treatment in alloxan monohydrate administered experimental animal model. From the present study it appeared that Aegle marmelos might have some key ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans located in the pancreas. Once they bind to the Sulphonyl urea receptors, the K+ -ATP channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated. During the course of study, Aegle marmelos leaves fed experimental animals were normal blood glucose levels compared to insulin treated animals.

Inwardly rectifying potassium channels (version 2019.4) in the IUPHAR/BPS Guide to Pharmacology Database

The 2TM domain family of K channels are also known as the inward-rectifier K channel family. This family includes the strong inward-rectifier K channels (Kir2.x) that are constitutively active, the G-protein-activated inward-rectifier K channels (Kir3.x) and the ATP-sensitive K channels (Kir6.x, which combine with sulphonylurea receptors (SUR1-3)). The pore-forming α subunits form tetramers, and heteromeric channels may be formed within subfamilies (e.g. Kir3.2 with Kir3.3).

In Silico Analysis of New Potent Anti-hyperglycemic Molecule for Diabetes Type 2 Management

Diabetes mellitus Type 2 happens to be one of the most challenging health concerns in recent times and has spiked an alarming rise taking it into epidemic category. For management of this epidemic, sulphonylureas have been cornerstone in its treatment. The inefficiency and impairment of insulin to function has been compensated by treatment with anti-hyperglycemic agents (glibenclamide). However, this has been linked with cases of hypoglycemia. In order to rectify this, the present study focuses on development of better drug analogue. Sulphonylurea receptor (SUR1) was modeled with reliable efficiency and confirmed for structural validation. The docking results were strongly supported by molecular dynamics data and molecular mechanics-generalized born surface area (MM-GBSA) calculations. Successful docking of predicted sulphonylurea receptor with designed analogue (C24H26ClN3O4S) was illustrated with stronger binding energy (− 8.3 kcal/mol) having seven hydrophobic contacts and two hydrogen bonds (Ile103and Leu116) with the receptor protein. In case of SUR1-glibenclamide complex, a binding energy of − 7.1 kcal/mol was contributed from four hydrophobic contacts and three hydrogen bonds. The predicted molecule when scrutinized for pharmacophore and QSAR properties, like polar surface area, molar refractivity, oral bioavailability, solubility, transport across the gut, resistance to blood brain barrier and intestinal absorption, showed values mostly falling in prescribed range. It also highlighted that the inhibitor is non-toxic and non-carcinogenic property. Therefore, C24H26ClN3O4S can be used as a better and potent drug for treatment of diabetes Type 2 in comparison to glibenclamide.

Diabetes mellitus associated with the mutation of the ABCC8 gene (MODY 12): features of clinical course and therapy

Maturity-Onset Diabetes of the Young (MODY) is a heterogeneous group of diseases associated with genes mutations leading to dysfunction of pancreatic β-cells. Among the 14 identified MODY variants, MODY 1–5 are the most studied. The article reports a MODY 12 clinical case, with mutation in ABCC8, encoding the sulphonylurea receptor. Diabetes mellitus manifested in a 27-year-old man with hyperglycaemia up to 24 mmol/L, without ketosis. Non-proliferative diabetic retinopathy, microalbuminuria, dyslipidaemia and carotid atherosclerosis were revealed upon initial examination. The levels of pancreatic islet cell antibodies and glutamate decarboxylase antibodies were negative, while the level of C-peptide was within the normal range. Insulin therapy in the basal-bolus regimen was provided with a gradual dose reduction due to frequent hypoglycaemia. The preproliferative retinopathy with macular oedema was revealed after 4 months of therapy, and panretinal photocoagulation of both eyes was performed. A molecular genetics study revealed a mutation in the gene ABCC8, the same mutation was found in patient’s mother and uncle. Insulin therapy was cancelled, and the treatment of gliclazide MR 60 mg/day was initiated, which resulted in extreme glycaemic excursions. Thereby, sodium–glucose cotranporter-2 (SGLT2) inhibitor dapagliflozin 10 mg/day was added. A reduction in glucose variability parameters were observed on combination therapy. After 6 months till 1.5 years of treatment, glycaemic control was optimal, no hypoglycaemic episodes were observed. This case study demonstrates clinical features of MODY 12, and the potential of combination of sulfonylurea and SGLT2 inhibitor in the treatment of this disease.

Diabetes mellitus associated with the mutation of the ABCC8 gene (MODY 12): features of clinical course and therapy

Maturity-Onset Diabetes of the Young (MODY) is a heterogeneous group of diseases associated with genes mutations leading to dysfunction of pancreatic -cells. Among the 14 identified MODY variants, MODY 15 are the most studied. The article reports a MODY 12 clinical case, with mutation in ABCC8, encoding the sulphonylurea receptor. Diabetes mellitus manifested in a 27-year-old man with hyperglycaemia up to 24 mmol/L, without ketosis. Non-proliferative diabetic retinopathy, microalbuminuria, dyslipidaemia and carotid atherosclerosis were revealed upon initial examination. The levels of pancreatic islet cell antibodies and glutamate decarboxylase antibodies were negative, while the level of C-peptide was within the normal range. Insulin therapy in the basal-bolus regimen was provided with a gradual dose reduction due to frequent hypoglycaemia. The preproliferative retinopathy with macular oedema was revealed after 4 months of therapy, and panretinal photocoagulation of both eyes was performed. A molecular genetics study revealed a mutation in the gene ABCC8, the same mutation was found in patients mother and uncle. Insulin therapy was cancelled, and the treatment of gliclazide MR 60 mg/day was initiated, which resulted in extreme glycaemic excursions. Thereby, sodiumglucose cotranporter-2 (SGLT2) inhibitor dapagliflozin 10 mg/day was added. A reduction in glucose variability parameters were observed on combination therapy. After 6 months till 1.5 years of treatment, glycaemic control was optimal, no hypoglycaemic episodes were observed. This case study demonstrates clinical features of MODY 12, and the potential of combination of sulfonylurea and SGLT2 inhibitor in the treatment of this disease.

Mitochondrial Potassium Channels as Determinants of Cell Fate

Mitochondria play a central role in various pathophysiological processes ranging from ageing to cardiac disease, inflammation, neurodegeneration, cell death and cancer. The mitochondrial outer and inner membranes both harbor a plethora of ion channels with different selectivity and function. Many of these channels, by modulating mitochondrial energy metabolism, membrane potential and reactive oxygen production, are emerging as important participants in life-and-death decisions of the cell. Several potassium channels, for example mitoKv1.3, mitoIKCa and mitoTASK-3, are highly expressed in cancer cell mitochondria. We are developing new pharmacological tools to control the function of various potassium channels present in the inner mitochondrial membrane with the aim of inducing apoptosis of cancer cells, while leaving healthy cells unaffected. According to our results, combination of specific, novel mitochondria-targeted channel inhibitors may become a promising strategy against poor-prognosis cancers such as pancreatic ductal adenocarcinoma and triple negative breast cancer and to kill cancer stem cells. On the other hand, activation of some mitochondrial potassium channels such as mitoKCa and mitoKATP can protect cells against ischemic damage. The role of mitoKATP versus plasmamembrane-located KATP channel in this protection as well as its molecular identity however are still debated. Reconstitution of a mitochondria-specific cation channel together with a mitochondria-located Sulphonylurea Receptor gives rise to a channel activity whose biophysical and pharmacological profiles strongly resemble the characteristics of mitoKATP. Activation of this channel modulates mitochondrial physiology and cell fate. Altogether, mitochondrial potassium channels are important pharmacological targets both in the context of cancer and ischemia.