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• W1973201327 abstract "The discovery that their neonatal diabetes is caused by gain-of-function mutations in the KATP channel has enabled many patients to switch from insulin to oral sulphonylurea drugs. Here, I review molecular, physiological, and clinical features of this change in therapy. The discovery that their neonatal diabetes is caused by gain-of-function mutations in the KATP channel has enabled many patients to switch from insulin to oral sulphonylurea drugs. Here, I review molecular, physiological, and clinical features of this change in therapy. Neonatal diabetes (ND) is a relatively rare genetic disorder that affects about 1 in 200,000 live births (Hattersley and Ashcroft, 2005Hattersley A.T. Ashcroft F.M. Diabetes. 2005; 54: 2503-2513Crossref PubMed Scopus (347) Google Scholar). It is characterized by diabetes that presents within the first 6 months of life, which may either be permanent or follow a remitting-relapsing time course. While there are multiple causes of ND, activating mutations in the ATP-sensitive potassium (KATP) channel subunits Kir6.2 (KCNJ11) and SUR1 (ABCC8) are the most common, accounting for around 50% of cases. Rarely, patients with these mutations may have diabetes diagnosed outside the neonatal period. About a third of ND patients with Kir6.2 mutations also have neurological symptoms (Hattersley and Ashcroft, 2005Hattersley A.T. Ashcroft F.M. Diabetes. 2005; 54: 2503-2513Crossref PubMed Scopus (347) Google Scholar). A minority have DEND syndrome, which is characterized by muscle weakness, severe mental and motor developmental delay, epilepsy, and neonatal diabetes. Most, however, have an intermediate condition (iDEND syndrome), which manifests as ND accompanied by delayed speech and walking and often muscle weakness. The KATP channel is a plasma membrane K-selective pore that links cellular metabolism and electrical excitability in numerous cell types (Nichols, 2006Nichols C.G. Nature. 2006; 440: 470-476Crossref PubMed Scopus (604) Google Scholar). At low levels of metabolism, channel activity keeps the membrane potential at a negative (hyperpolarized) level, damping down electrical activity. Conversely, closure of KATP channels by metabolically generated ATP precipitates membrane depolarization, stimulating action potential firing and its attendant cellular consequences. In this way, the KATP channel transduces alterations in metabolism into changes in cellular processes such as hormone secretion, muscle contraction, and neurotransmitter release. Pancreatic β cells, for example, match insulin release to fluctuations in blood glucose via metabolically induced changes in KATP channel activity, secretion being stimulated by KATP channel closure. Sulphonylurea drugs, which bind directly to the KATP channel and cause it to shut, also stimulate insulin secretion (Gribble and Reimann, 2003Gribble F.M. Reimann F. Diabetologia. 2003; 46: 875-891Crossref PubMed Scopus (245) Google Scholar). KATP channels comprise four pore-forming Kir6.2 subunits and four regulatory sulphonylurea receptor subunits: either SUR1 (endocrine cells, many neurones), SUR2A (heart and skeletal muscle), or SUR2B (smooth muscle, some neurones) (Nichols, 2006Nichols C.G. Nature. 2006; 440: 470-476Crossref PubMed Scopus (604) Google Scholar). The exquisite sensitivity of the KATP channel to small changes in metabolism derives from its dual regulation by adenine nucleotides. It is closed by nonhydrolytic binding of ATP to Kir6.2 and opened by interaction of Mg-nucleotides with SUR. Channel activity is thus determined by the balance between these inhibitory and stimulatory effects. All mutations that cause ND increase the whole-cell KATP current in heterologous expression studies (Ashcroft, 2007Ashcroft F.M. Am. J. Physiol. Endocrinol. Metab. 2007; 293: E880-E889Crossref PubMed Scopus (93) Google Scholar). This reduces glucose-dependent depolarization of the β cell and prevents activation of electrical activity and insulin secretion. In general, the larger the KATP current, the more severe the disease phenotype. Although a few ND mutations increase the whole-cell KATP current by enhancing the density of KATP channels in the plasmalemma (Mankouri et al., 2006Mankouri J. Taneja T.K. Smith A.J. Ponnambalam S. Sivaprasadarao A. EMBO J. 2006; 25: 4142-4151Crossref PubMed Scopus (38) Google Scholar), most act by decreasing the ability of MgATP to inhibit the channel (Gloyn et al., 2004Gloyn A.L. Pearson E.R. Antcliff J.F. Proks P. Bruining G.J. Slingerland A.S. Howard N. Srinivasan S. Silva J.M. Molnes J. et al.N. Engl. J. Med. 2004; 350: 1838-1849Crossref PubMed Scopus (903) Google Scholar; reviewed by Ashcroft, 2007Ashcroft F.M. Am. J. Physiol. Endocrinol. Metab. 2007; 293: E880-E889Crossref PubMed Scopus (93) Google Scholar). To date, >40 mutations in Kir6.2, at 26 distinct residues, have been linked to ND, the most prevalent being R201H (which just produces diabetes) and V59M (which causes iDEND). One cluster of mutations lines the putative ATP-binding pocket and is suggested to act by preventing ATP binding. Many mutations, however, lie distant to the ATP-binding site in regions of the channel known to be involved in opening and closing (gating) of the pore. These mutations decrease ATP inhibition allosterically, by stabilizing the open conformation of the channel in both the absence and presence of ATP. A few Kir6.2 mutations also appear to enhance the stimulatory effect of Mg-nucleotides at SUR1. Importantly, it is the magnitude of the change in KATP current and not the underlying molecular mechanism that dictates the clinical phenotype. SUR1 mutations linked to ND may also act directly, by enhancing MgATP activation, or indirectly, by altering channel gating and reducing ATP inhibition at Kir6.2 (reviewed by Ashcroft, 2007Ashcroft F.M. Am. J. Physiol. Endocrinol. Metab. 2007; 293: E880-E889Crossref PubMed Scopus (93) Google Scholar). Interestingly, ND-SUR1 mutations generally decrease ATP sensitivity less than ND-Kir6.2 mutations. They also cause less severe disease, with only one patient with DEND syndrome being reported to date (Proks et al., 2006Proks P. Arnold A.L. Bruining J. Girard C. Flanagan S.E. Larkin B. Colclough K. Hattersley A.T. Ashcroft F.M. Ellard S.E. Hum. Mol. Genet. 2006; 15: 1793-1800Crossref PubMed Scopus (175) Google Scholar). Precisely how ND mutations cause the neurological features associated with some ND mutations remains a matter of speculation. However, KATP channels are expressed in skeletal muscle and throughout the brain. A gain-of-function mutation in a K-channel is expected to reduce cellular electrical activity: thus, the simplest explanation for the epilepsy found in DEND syndrome is that it results from reduced activity of inhibitory interneurones and a consequent loss of inhibitory tone. It is significant that, at least in the hippocampus, inhibitory neurones are reported to have a greater density of KATP channels than excitatory neurones (Zawar et al., 1999Zawar C. Plant T.D. Schirra C. Konnerth A. Neumcke B. J. Physiol. 1999; 514: 327-341Crossref PubMed Scopus (168) Google Scholar). The muscle weakness commonly seen in iDEND patients might reflect the enhanced activity of either neuronal or muscle KATP channels. However, the evidence favors a neuronal origin, because muscle weakness has been observed in at least one patient with an SUR1 mutation (Proks et al., 2006Proks P. Arnold A.L. Bruining J. Girard C. Flanagan S.E. Larkin B. Colclough K. Hattersley A.T. Ashcroft F.M. Ellard S.E. Hum. Mol. Genet. 2006; 15: 1793-1800Crossref PubMed Scopus (175) Google Scholar), despite the lack of SUR1 expression in muscle. Furthermore, the muscle weakness and ataxic gait of a patient with a Kir6.2 mutation was improved by treatment with gliclazide, which interacts only with SUR1 (Koster et al., 2008Koster J.C. Cadario F. Peruzzi C. Colombo C. Nichols C.G. Barbetti F. J. Clin. Endocrinol. Metab. 2008; 93: 1054-1061Crossref PubMed Scopus (78) Google Scholar). A key question is why neurological symptoms are found only for mutations that produce very large KATP currents in functional studies. One possibility is that this reflects differences in cell metabolism and/or the complement of ion channels that regulate the membrane potential in different tissues. Another conundrum is that despite the fact that Kir6.2 is expressed in the heart, no cardiac abnormalities have been reported in patients. This is also true of mice carrying gain-of-function mutations targeted to cardiac myocytes (Koster et al., 2001Koster J.C. Knopp A. Flagg T.P. Markova K.P. Sha Q. Enkvetchakul D. Betsuyaku T. Yamada K.A. Nichols C.G. Circ. Res. 2001; 89: 1022-1029Crossref PubMed Scopus (59) Google Scholar). Why this is the case remains unresolved but may be related to the fact that cardiac KATP channels contain SUR2A rather than SUR1 subunits. Mouse models have traditionally illuminated understanding of human disease, and ND is no exception. Several mouse models have been generated that express KATP channels with reduced ATP sensitivity only in pancreatic β cells (Koster et al., 2000Koster J.C. Marshall B.A. Ensor N. Corbett J.A. Nichols C.G. Cell. 2000; 100: 645-654Abstract Full Text Full Text PDF PubMed Scopus (236) Google Scholar, Remedi et al., 2009Remedi M.S. Kurata H.T. Scott A. Wunderlich F.T. Rother E. Kleinridders A. Tong A. Brüning J.C. Koster J.C. Nichols C.G. Cell Metab. 2009; 9: 140-151Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar, Girard et al., 2009Girard C.A. Wunderlich F.T. Shimomura K. Collins S. Kaizik S. Proks P. Abdulkader F. Clark A. Ball V. Zubcevic L. et al.J. Clin. Invest. 2009; 119: 80-90PubMed Google Scholar). These mice show elevated blood glucose levels shortly after birth (or induction of the mutant gene) and develop severe diabetes within a few weeks. Insulin secretion is markedly reduced, not only because of a failure of glucose-dependent KATP closure, but also due to a progressive decrease in β cell mass and insulin content and a loss of normal islet architecture. Normalization of blood glucose levels with either glibenclamide or insulin (by islet transplantation) therapy prevents the changes in insulin content and β cell mass, suggesting that they are a secondary consequence of untreated hyperglycemia. Crucially, although glibenclamide was able to prevent diabetes if given prior to induction of the mutant Kir6.2 gene, it was unable to reverse established hyperglycemia (Remedi et al., 2009Remedi M.S. Kurata H.T. Scott A. Wunderlich F.T. Rother E. Kleinridders A. Tong A. Brüning J.C. Koster J.C. Nichols C.G. Cell Metab. 2009; 9: 140-151Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). Thus, it appears that if hyperglycemia is prolonged, it may be difficult to restore β cell mass, a finding that has implications for other types of diabetes as well as ND. These studies indicate that in mice, the reduced insulin secretion found in uncompensated ND is not only a consequence of overactive KATP channels, but also due to a reduction in insulin content and β cell mass. To what extent this occurs in humans is unknown because patients will have been on insulin (or sulphonylurea) therapy since diagnosis. The discovery of a KATP channel mutation is of considerable clinical importance. In the past, patients with ND were treated with insulin injections because their clinical characteristics suggested an unusually early-onset form of type 1 diabetes. However, the discovery that many patients had gain-of-function mutations in KATP channel genes led to an immediate change in treatment: the use of sulphonylurea drugs to block the open channels (Pearson et al., 2006Pearson E.R. Flechtner I. Njølstad P.R. Malecki M.T. Flanagan S.E. Larkin B. Ashcroft F.M. Klimes I. Codner E. Iotova V. et al.Neonatal Diabetes International Collaborative GroupN. Engl. J. Med. 2006; 355: 467-477Crossref PubMed Scopus (727) Google Scholar). Most ND patients are now managed on sulphonylureas, which have become the therapy of choice. This has not only transformed their quality of life, it has also had marked clinical benefits. Fluctuations in blood glucose, a common problem in neonatal patients, are substantially reduced (Zung et al., 2004Zung A. Glaser B. Nimri R. Zadik Z. J. Clin. Endocrinol. Metab. 2004; 89: 5504-5507Crossref PubMed Scopus (156) Google Scholar), and hypoglycemic episodes are far less common. Plasma glucose levels are also lower, as indicated by a significant reduction in HbA1C levels (Pearson et al., 2006Pearson E.R. Flechtner I. Njølstad P.R. Malecki M.T. Flanagan S.E. Larkin B. Ashcroft F.M. Klimes I. Codner E. Iotova V. et al.Neonatal Diabetes International Collaborative GroupN. Engl. J. Med. 2006; 355: 467-477Crossref PubMed Scopus (727) Google Scholar), which decreases the risk of diabetic complications. Interestingly, oral glucose is far more effective than intravenous glucose at triggering insulin secretion in ND patients treated with sulphonylureas (Pearson et al., 2006Pearson E.R. Flechtner I. Njølstad P.R. Malecki M.T. Flanagan S.E. Larkin B. Ashcroft F.M. Klimes I. Codner E. Iotova V. et al.Neonatal Diabetes International Collaborative GroupN. Engl. J. Med. 2006; 355: 467-477Crossref PubMed Scopus (727) Google Scholar). One hypothesis is that this difference is due to hormones (incretins), such as GLP-1 and GIP, that are secreted in response to the presence of food in the gut lumen or neurotransmitters, such as acetylcholine, released in response to the sight and smell of food. These agents produce a marked amplification of insulin secretion primarily by acting on downstream targets such as exocytosis. Because one pathway by which these agents act requires a KATP-dependent increase in [Ca2+]i, it is suggested that stimulatory hormones and neurotransmitters are ineffective in untreated ND, but that closure of KATP channels by sulphonylureas, which leads to elevation of [Ca2+]i, renders them operational. The amplifying effects of glucose itself on insulin secretion will also be enabled only after sulphonylureas have closed mutant KATP channels. The various amplifying pathways are of considerable clinical significance, since they ensure that insulin secretion in ND patients treated with drugs is regulated by meals. Although sulphonylureas are highly effective in treating most patients, not all respond. However, there is an excellent correlation between the patient response and the extent to which the sulphonylurea tolbutamide blocks the whole-cell current through the equivalent heterozygous recombinant KATP channel (Pearson et al., 2006Pearson E.R. Flechtner I. Njølstad P.R. Malecki M.T. Flanagan S.E. Larkin B. Ashcroft F.M. Klimes I. Codner E. Iotova V. et al.Neonatal Diabetes International Collaborative GroupN. Engl. J. Med. 2006; 355: 467-477Crossref PubMed Scopus (727) Google Scholar; see also review, Ashcroft, 2007Ashcroft F.M. Am. J. Physiol. Endocrinol. Metab. 2007; 293: E880-E889Crossref PubMed Scopus (93) Google Scholar). When the block is <65%, all patients fail to respond to sulphonylureas, whereas when the block is >75%, at least some patients respond. Thus, mutation-specific sulphonylurea failure is caused by a reduction in drug sensitivity. Most patients who have successfully transferred to sulphonylureas were children at the time of transfer. Why fewer adults are able to switch remains unclear, but studies of mouse models of ND suggest a possible explanation. Mice with severe untreated diabetes for more than 2 months have few functioning β cells (Remedi et al., 2009Remedi M.S. Kurata H.T. Scott A. Wunderlich F.T. Rother E. Kleinridders A. Tong A. Brüning J.C. Koster J.C. Nichols C.G. Cell Metab. 2009; 9: 140-151Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). No β cell loss occurs, however, if mice are given insulin therapy (Remedi et al., 2009Remedi M.S. Kurata H.T. Scott A. Wunderlich F.T. Rother E. Kleinridders A. Tong A. Brüning J.C. Koster J.C. Nichols C.G. Cell Metab. 2009; 9: 140-151Abstract Full Text Full Text PDF PubMed Scopus (74) Google Scholar). This may explain why most patients respond to sulphonylureas: insulin treatment will have largely prevented severe hyperglycemia (and maintained insulin content and β cell mass). Perhaps those patients with sulphonylurea-sensitive mutations who failed to respond to drug therapy had poor long-term blood glucose control, leading to a decline in β cell mass and function. It is an acknowledged fact that insulin therapy does not regulate glucose homeostasis perfectly, and thus older patients, who have taken insulin for longer, would be less likely to be able to transfer to sulphonylureas. In type 2 diabetes, sulphonylurea efficacy often declines with time, and most patients eventually progress to insulin. It is too early to say whether this will be the case for ND, as widespread sulphonylurea therapy has only been implemented in this patient group within the last 4 years. However, a few patients have been successfully treated for many years with these drugs without secondary failure. The neurological complications associated with DEND and iDEND are believed to arise from hyperactivity of KATP channels in nerve and muscle. An important question, therefore, is whether sulphonylureas can ameliorate the neurological problems. There is increasing evidence that this is the case. Several patients with iDEND have reported improved motor tone, coordination, and gait after switching to sulphonylurea therapy (Slingerland et al., 2006Slingerland A.S. Nuboer R. Hadders-Algra M. Hattersley A.T. Bruining G.J. Diabetologia. 2006; 49: 2559-2563Crossref PubMed Scopus (103) Google Scholar, Mlynarski et al., 2007Mlynarski W. Tarasov A.I. Gach A. Girard C.A. Pietrzak I. Zubcevic L. Kusmierek J. Klupa T. Malecki M.T. Ashcroft F.M. Nat. Clin. Pract. Neurol. 2007; 3: 640-645Crossref PubMed Scopus (86) Google Scholar, Shimomura et al., 2007Shimomura K. Hörster F. de Wet H. Flanagan S.E. Ellard S. Hattersley A.T. Wolf N.I. Ashcroft F. Ebinger F. Neurology. 2007; 69: 1342-1349Crossref PubMed Scopus (89) Google Scholar, Koster et al., 2008Koster J.C. Cadario F. Peruzzi C. Colombo C. Nichols C.G. Barbetti F. J. Clin. Endocrinol. Metab. 2008; 93: 1054-1061Crossref PubMed Scopus (78) Google Scholar). Enhanced cognitive function (Mlynarski et al., 2007Mlynarski W. Tarasov A.I. Gach A. Girard C.A. Pietrzak I. Zubcevic L. Kusmierek J. Klupa T. Malecki M.T. Ashcroft F.M. Nat. Clin. Pract. Neurol. 2007; 3: 640-645Crossref PubMed Scopus (86) Google Scholar, Slingerland et al., 2008Slingerland A.S. Hurkx W. Noordam K. Flanagan S.E. Jukema J.W. Meiners L.C. Bruining G.J. Hattersley A.T. Hadders-Algra M. Diabet. Med. 2008; 25: 277-281Crossref PubMed Scopus (88) Google Scholar) and abolition of epileptic seizures (Shimomura et al., 2007Shimomura K. Hörster F. de Wet H. Flanagan S.E. Ellard S. Hattersley A.T. Wolf N.I. Ashcroft F. Ebinger F. Neurology. 2007; 69: 1342-1349Crossref PubMed Scopus (89) Google Scholar) have also been described. These results suggest that sulphonylureas cross the blood-brain barrier in sufficient amounts to close neuronal KATP channels. Consistent with this idea, a clear increase in blood flow in some brain regions was seen following glibenclamide treatment in SPECT scans (Mlynarski et al., 2007Mlynarski W. Tarasov A.I. Gach A. Girard C.A. Pietrzak I. Zubcevic L. Kusmierek J. Klupa T. Malecki M.T. Ashcroft F.M. Nat. Clin. Pract. Neurol. 2007; 3: 640-645Crossref PubMed Scopus (86) Google Scholar). This suggests the drug closes neuronal KATP channels, stimulating neuronal activity and thereby blood flow. Although these limited examples suggest that sulphonylureas can indeed improve mental and motor function, development did not return fully to normal. This may be because of an inability to raise sulphonylureas in the brain to a concentration high enough to close all KATP channels or because of irreversible neuronal damage caused by KATP channel overactivity. More studies are required, in particular to determine whether early implementation of drug therapy or higher doses produces a greater amelioration of neurological problems. A consistent finding is that the sulphonylurea dose required to maintain normoglycemia declines with time after transfer. Why this happens is unclear, but a particular concern is whether improvements in neurological function can be maintained when the drug dose is lowered. The discovery that mutations in Kir6.2 and SUR1 can cause ND has led to an increased understanding of the relationship between KATP channel structure and function and transformed therapy for patients with these mutations. Nevertheless, many questions remain to be answered, of which the most pressing include why some mutations result in a remitting-relapsing form of diabetes and why other mutations cause neurological problems in addition to diabetes. Comparison of the human and mice data suggests that the mouse can provide a reasonable model for human ND. Analysis of mouse models of the relevant human mutations may thus facilitate understanding of the questions that remain." @default.
• W1973201327 created "2016-06-24" @default.
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• W1973201327 date "2010-03-01" @default.
• W1973201327 modified "2023-09-23" @default.
• W1973201327 title "New Uses for Old Drugs: Neonatal Diabetes and Sulphonylureas" @default.
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