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Original Article -ATP-Sensitive K؉ Channel Signaling in Glucokinase Deficient Diabetes Maria S

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Original Article -ATP-Sensitive K؉ Channel Signaling in Glucokinase Deficient Diabetes Maria S Original Article -ATP-Sensitive K؉ Channel Signaling in Glucokinase Deficient Diabetes Maria S. Remedi, Joseph C. Koster, Brian L. Patton, and Colin G. Nichols As the rate-limiting controller of glucose metabolism, glu- gous inactivating GK mutations cause permanent neonatal cokinase represents the primary ␤-cell “glucose sensor.” diabetes in humans (12,13), which is characterized by Inactivation of both glucokinase (GK) alleles results in perinatal hyperglycemia and low birth weight (14). The permanent neonatal diabetes; inactivation of a single allele disease usually requires insulin treatment through the causes maturity-onset diabetes of the young type 2 (MODY- .؊/؊ patient’s lifetime, starting within the first month of life 2). Similarly, mice lacking both alleles (GK ) exhibit Targeted disruption of the neuroendocrine knockout of severe neonatal diabetes and die within a week, whereas ؉/؊ GK (nGK) gene in mice also causes diabetes (15). These heterozygous GK mice exhibit markedly impaired glu- ␤ cose tolerance and diabetes, resembling MODY-2. Glucose mice lack glucokinase in pancreatic -cells and neurons metabolism increases the cytosolic [ATP]-to-[ADP] ratio, but maintain normal liver glucokinase activity. Heterozy- ؉ which closes ATP-sensitive K channels (KATP channels), gous null mice show early-onset mild diabetes caused by -leading to membrane depolarization, Ca2؉ entry, and insu- an impaired insulin-secretory response to glucose, resem lin exocytosis. Glucokinase insufficiency causes defective bling MODY-2. Importantly, homozygous nGK-deficient KATP channel regulation, which may underlie the impaired mice show severe perinatal diabetes, as in permanent secretion. To test this prediction, we crossed mice lacking .(؉/؊ neonatal diabetes, and die within a few days of birth (15 neuroendocrine glucokinase (nGK ) with mice lacking ϩ -؊/؊ ATP-sensitive K channels (KATP channels) couple glu KATP channels (Kir6.2 ). Kir6.2 knockout rescues peri- -natal lethality of nGK؊/؊, although nGK؊/؊Kir6.2؊/؊ ani- cose metabolism to cellular electrical activity and there mals are postnatally diabetic and still die prematurely. fore play a critical role in excitation-secretion coupling in -nGK؉/؊ animals are diabetic on the Kir6.2؉/؉ background the pancreatic ␤-cell. Glucose metabolism raises the cyto but only mildly glucose intolerant on the Kir6.2؊/؊ back- solic [ATP]-to-[ADP] ratio, which causes closure of the ؉ ؊ ground. In the presence of glutamine, isolated nGK / K channel and depolarization of the ␤-cell membrane. Kir6.2؊/؊ islets show improved insulin secretion compared ATP ؉/؊ ؉/؉ Membrane depolarization, in turn, leads to opening of with nGK Kir6.2 . The significant abrogation of 2ϩ -؊/؊ ؉/؊ voltage-dependent Ca channels and a rise in intracellu nGK and nGK phenotypes in the absence of KATP 2ϩ demonstrate that a major factor in glucokinase deficiency lar [Ca ], which triggers insulin vesicle exocytosis (16) (Fig. 1). Glucose metabolism has additional downstream is indeed altered KATP signaling. The results have implica- tions for understanding and therapy of glucokinase-related actions, including generation of GTP, which may activate diabetes. Diabetes 54:2925–2931, 2005 “KATP-independent” pathways of insulin secretion. Na- ively, both electrical triggering of secretion through KATP channels and nonelectrical effects of glucose metabolism through ATP generation could be affected by glucokinase lucose metabolism in pancreatic ␤-cells is nec- deficiency. The relative importance of each component is essary to stimulate insulin secretion (1). Glu- not clear, and it might be presumed that the consequences cokinase, which phosphorylates glucose in the of failure to generate ATP should be much more devastat- Gfirst, rate-limiting reaction, is a key component ing than simply blocking electrical signaling. in the secretory pathway (2,3), and mutations of the GK It has previously been shown that glucose fails to close Ϫ/Ϫ ␤ gene are diabetogenic in humans (4). Heterozygous inac- KATP channels in nGK -cells (17). Sulfonylureas act by tivating mutations cause maturity-onset diabetes of the closing the KATP channel independently of glucose metab- young type 2 (MODY-2), an autosomal, dominantly inher- olism, resulting in membrane depolarization and conse- ited form of diabetes characterized by an early age of quent stimulation of insulin secretion (18). Consistent with onset and pancreatic ␤-cell dysfunction (5–11). Homozy- the idea that the primary downstream consequence of nGK deficiency is simply failure to close KATP channels, the sulfonylurea tolbutamide was effective at both inhibiting From the Department of Cell Biology and Physiology, Washington University Ϫ/Ϫ School of Medicine, St. Louis, Missouri. KATP channels and stimulating insulin secretion in nGK Address correspondence and reprint requests to Colin G. Nichols, the ␤-cells (17). These results imply that the defect in insulin Department of Cell Biology and Physiology, Washington University School of secretion in glucokinase deficiency results essentially Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. E-mail: cnichols@cellbio. wustl.edu. from the defective regulation of KATP channels, rather than Received for publication 3 May 2005 and accepted in revised form 7 July from nonelectrical consequences of altered metabolism. 2005. Further indirect support for this hypothesis comes from: DMEM, Dulbecco’s modified Eagle medium; GSIS, glucose-stimulated insu- ϩ 1) the demonstration that mice with ATP-insensitive ␤-cell lin secretion; KATP channel, ATP-sensitive K channel; MODY-2, maturity- onset diabetes of the young type 2. KATP channels also die from neonatal diabetes (19) and 2) © 2005 by the American Diabetes Association. the recent dramatic demonstration that gain-of-function The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance KATP mutations also cause permanent neonatal diabetes in with 18 U.S.C. Section 1734 solely to indicate this fact. humans (20–24). A critical prediction is that the conse- DIABETES, VOL. 54, OCTOBER 2005 2925 KATP AND GLUCOKINASE-DEFICIENCY DIABETES Isolation of pancreatic islets and ␤-cells. Experiments using animals were performed in accordance with the relevant laws and institutional guidelines and were approved by the Washington University animal studies committee. Anesthetized mice were killed by cervical dislocation. Pancreata were re- moved and injected with Hank’s balanced salt solution containing type XI collagenase (0.5 mg/ml), pH 7.4. (Sigma, St. Louis, MO). Pancreata were digested for 7 min at 37°C then hand-shaken and washed three times in cold Hank’s solution (29). Islets were isolated by hand under a dissecting micro- scope and pooled. Islets were maintained overnight in CMRL-1640 (5.6 mmol/l glucose) supplemented with FCS (10%), penicillin (100 units/ml), and strep- tomycin (100 mg/ml). Blood glucose and insulin levels. Blood glucose was assayed using a glucose dehydrogenase–based enzymatic assay and quantitated using a Glu- cometer Elite XL meter (Bayer, Elkhart, IN). Blood insulin levels were assayed on 15 ␮l of mouse serum using an enzyme-linked immunosorbent assay kit with a rat insulin standard according to manufacturer’s procedure (Crystal Chem, Downers Grove, IL). Intraperitoneal glucose tolerance tests were performed on 5-week-old mice after a 16-h fast. Animals were injected intraperitoneally with glucose (1 g/kg). Blood was isolated from the tail vein at the times indicated and assayed for glucose as described above. Intraperi- toneal insulin tolerance tests were performed on 4-month-old mice after a 6-h fast. Animals were injected intraperitoneally with insulin (0.5 unit/kg). Blood FIG. 1. Glucokinase knockout can disrupt both electrical and nonelec- was isolated from the tail vein at the times indicated and assayed for glucose trical signaling. Glucose metabolism generates ATP, which stimulates as described above. insulin secretion through KATP-dependent (1) and KATP-independent Insulin release experiments. After overnight incubation, pancreatic islets ؊/؊ (2) pathways. In Kir6.2 islets, the KATP-dependent pathway (1) will (10 per well in 12-well plates) were preincubated in glucose-free Dulbecco’s be permanently “on,” and glucose-dependent regulation will then modified Eagle medium (DMEM) supplemented with 3 mmol/l of glucose for ,occur via K -independent (2) pathways. In nGK؊/؊Kir6.2؉/؉ islets ATP 2 h. The release assay was initiated by supplementing the DMEM glucose-free glucose metabolism is lost, and both pathways (1 and 2) will be “off.” ϩ ؊/؊ ؊/؊ media with D -glucose (1, 7, 16.7, or 23 mmol/l) as indicated. For amino acid In nGK Kir6.2 islets, the KATP-independent pathway (2) will be stimulation of insulin release, Krebs-Ringer buffer supplemented with D- “off,” but the KATP-dependent pathway (1) should remain permanently on.” PKC, protein kinase C; VDCC, voltage-dependent Ca2؉ channel. glucose and glutamine (10 mmol/l) was used in place of DMEM. Islets were“ incubated for 60 min at 37°C, and medium was removed and assayed for insulin content using a rat insulin radioimmunoassay (Linco, St. Charles, MO). quences of nGK deficiency should be abrogated in animals Each experiment was repeated in triplicate. that lack KATP channels. Mice lacking Kir6.2-dependent Statistics. Data are presented as means Ϯ SE. Differences among the four KATP channel activity in all tissues have been generated by genotypes were tested
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