Expression of an activating mutation in the gene encoding the KATP channel subunit Kir6.2 in mouse pancreatic β cells recapitulates neonatal diabetes

Girard, Christophe A.; Wunderlich, Frank; Shimomura, Kenju; Collins, Stephan C.; Kaizik, Stephan; Proks, Peter; Abdulkader, Fernando; Clark, Anne; Ball, Vicky; Zubcevic, Lejla; Bentley, Liz; Clark, Rebecca; Church, Chris; Hugill, Alison; Galvanovskis, Juris; Cox, Roger D.; Rorsman, Patrik; Brüning, Jens C.; Ashcroft, Frances M.

doi:10.1172/jci35772

Cited by 95 publications

(153 citation statements)

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“…In two mouse model studies of K ATP -related hyperglycaemia, the proportion of β cells was significantly decreased and the proportion of α cells was either normal [14] or decreased [15]. After transplantation of normal islets to prevent diabetes, the insulin content of the endogenous islets was normal.…”

Section: Discussionmentioning

confidence: 99%

Human Pancreas Endocrine Cell Populations and Activating ABCC8 Mutations

Busiah¹,

Verkarre²,

Cavé³

et al. 2014

Horm Res Paediatr

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Background/Aims: Activating mutations in the ABCC8 gene encoding the K_ATP channel subunit SUR1 cause β-cell dysfunction with non-autoimmune diabetes mellitus in neonates or infants. We investigated whether activating ABCC8 mutations affect endocrine pancreas development. Methods: We studied a male infant with compound heterozygous ABCC8 mutations (p.Arg826Trp/p.Ile93Thr) causing neonatal diabetes mellitus. He died of ketoacidosis. Postmortem pancreas specimens were evaluated by fluorescent microscopy after immunostaining for insulin, glucagon, somatostatin, and PCNA, and Hoechst 33342 nuclear staining. We compared the findings to those in 5 age-matched controls. Results: The number of islets was decreased and the number of single or small clusters of insulin cells increased in the patient compared to the age-matched controls. The islets in the patient had an insulin-cell core surrounded by intermingled glucagon and somatostatin cells. The insulin/Hoechst surface ratio was decreased and the glucagon/Hoechst surface ratio increased in the patient (4.3 and 8.8%, respectively) versus the controls (8.2 and 3.1%, respectively). Somatostatin surface staining was similar in the patient and controls (4 vs. 4.7%). PCNA staining was increased 3- to 3.5-fold, indicating increased insulin-cell proliferation compared to controls. Conclusion: Activating ABCC8 mutations impaired the balance between β and α cells in the patient, suggesting an effect on β-cell mass development.

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Section: Discussionmentioning

confidence: 99%

Human Pancreas Endocrine Cell Populations and Activating ABCC8 Mutations

Busiah¹,

Verkarre²,

Cavé³

et al. 2014

Horm Res Paediatr

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“…In Sur1 K/K mice, which lack the regulatory subunit of the channel, only a very small amount of insulin in response to glucose is triggered, as assessed by perfusion of pancreas (Shiota et al 2002) and batch incubation of isolated pancreatic islets (Doliba et al 2004). Recently, in pancreatic b-cell-specific Kir6.2 mutant mice, only a small amount of insulin in response to glucose was induced (Girard et al 2009, Remedi et al 2009). Intra-gastric glucose injection via gavage resulted in no or a very small insulin secretion in both Kir6.2 K/K and Sur1 K/K mice (Shiota et al 2002, Miki et al 2005.…”

Section: Introductionmentioning

confidence: 99%

Cephalic phase insulin secretion is KATP channel independent

Seino

Miki

Fujimoto

et al. 2013

Journal of Endocrinology

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Glucose-induced insulin secretion from pancreatic b-cells critically depends on the activity of ATP-sensitive K C channels (K ATP channel). We previously generated mice lacking Kir6.2, the pore subunit of the b-cell K ATP channel (Kir6.2 K/K ), that show almost no insulin secretion in response to glucose in vitro. In this study, we compared insulin secretion by voluntary feeding (self-motivated, oral nutrient ingestion) and by forced feeding (intra-gastric nutrient injection via gavage) in wild-type (Kir6.2 C/C ) and Kir6.2 K/K mice. Under ad libitum feeding or during voluntary feeding of standard chow, blood glucose levels and plasma insulin levels were similar in Kir6.2 C/C and Kir6.2 K/K mice. By voluntary feeding of carbohydrate alone, insulin secretion was induced significantly in Kir6.2 K/K mice but was markedly attenuated compared with that in Kir6.2 C/C mice. On forced feeding of standard chow or carbohydrate alone, the insulin secretory response was markedly impaired or completely absent in Kir6.2 K/K mice. Pretreatment with a muscarine receptor antagonist, atropine methyl nitrate, which does not cross the blood-brain barrier, almost completely blocked insulin secretion induced by voluntary feeding of standard chow or carbohydrate in Kir6.2 K/K mice. Substantial glucose-induced insulin secretion was induced in the pancreas perfusion study of Kir6.2 K/K mice only in the presence of carbamylcholine. These results suggest that a K ATP channel-independent mechanism mediated by the vagal nerve plays a critical role in insulin secretion in response to nutrients in vivo.

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“…Recently, a novel mouse model (β-V59M), which expresses one of the most common Kir6.2 mutations found in PNDM patients, was created (Girard et al 2008). In human patients, the V59M mutation is the most common cause of i-DEND syndrome (Hattersley and Ashcroft 2005).…”

Section: Mouse Models Of Pndmmentioning

confidence: 99%