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1 M Brissova , MJ Fowler , WE Nicholson , et al. (2005) Assessment of human pancreatic islet architecture and composition by laser scanning confocal microscopy. J Histochem Cytochem 53, 1087–1097.
2 O Cabrera , DM Berman , NS Kenyon , et al. (2006) The unique cytoarchitecture of human pancreatic islets has implications for islet cell function. Proc Natl Acad Sci U S A 103, 2334–2339.
3 A Nadal , I Quesada & B Soria (1999) Homologous and heterologous asynchronicity between identified α-, β- and δ-cells within intact islets of Langerhans in the mouse. J Physiol 517, 85–93.
6 RH Unger & L Orci (2010) Paracrinology of islets and the paracrinopathy of diabetes. Proc Natl Acad Sci U S A 107, 16009–16012.
GJ Taborsky Jr & TO Mundinger (2012) Minireview: the role of the autonomic nervous system in mediating the glucagon response to hypoglycemia. Endocrinology
I Quesada , E Tuduri , C Ripoll , et al. (2008) Physiology of the pancreatic α-cell and glucagon secretion: role in glucose homeostasis and diabetes. J Endocrinol
10 RH Unger , E Aguilar-Parada , WA Muller , et al. (1970) Studies of pancreatic α cell function in normal and diabetic subjects. J Clin Invest 49, 837–848.
E Bertin , P Arner , J Bolinder , et al. (2001) Action of glucagon and glucagon-like peptide-1-(7-36) amide on lipolysis in human subcutaneous adipose tissue and skeletal muscle in vivo
. J Clin Endocrinol Metab
13 C Longuet , EM Sinclair , A Maida , et al. (2008) The glucagon receptor is required for the adaptive metabolic response to fasting. Cell Metab 8, 359–371.
17 A Ohneda , E Aguilar-Parada , AM Eisentraut , et al. (1969) Control of pancreatic glucagon secretion by glucose. Diabetes 18, 1–10.
18 A Salehi & E Vieira (2006) Gylfe E Paradoxical stimulation of glucagon secretion by high glucose concentrations. Diabetes 55, 2318–2323.
19 E Vieira & A Salehi (2007) Gylfe E Glucose inhibits glucagon secretion by a direct effect on mouse pancreatic α cells. Diabetologia 50, 370–379.
S Gopel , Q Zhang , L Eliasson , et al. (2004) Capacitance measurements of exocytosis in mouse pancreatic α-, β- and δ-cells within intact islets of Langerhans. J Physiol
21 SO Gopel , T Kanno , S Barg , et al. (2000) Regulation of glucagon release in mouse α-cells by KATP channels and inactivation of TTX-sensitive Na+ channels. J Physiol 528, 509–520.
22 E Tuduri , L Marroqui , S Soriano , et al. (2009) Inhibitory effects of leptin on pancreatic α-cell function. Diabetes 58, 1616–1624.
23 GJ Taborsky Jr, B Ahren & PJ Havel (1998) Autonomic mediation of glucagon secretion during hypoglycemia: implications for impaired α-cell responses in type 1 diabetes. Diabetes 47, 995–1005.
24 B Thorens (2011) Brain glucose sensing and neural regulation of insulin and glucagon secretion. Diabetes Obes Metab 13, Suppl. 1, 82–88.
P Rorsman , SA Salehi , F Abdulkader , et al. (2008) K(ATP)-channels and glucose-regulated glucagon secretion. Trends Endocrinol Metab
PE MacDonald , YZ De Marinis , R Ramracheya , et al. (2007) A KATP channel-dependent pathway within α cells regulates glucagon release from both rodent and human islets of Langerhans. PLoS Biol
27 E Gylfe (2013) Glucose control of glucagon secretion: there is more to it than KATP channels. Diabetes 62, 1391–1393.
28 YJ Liu , E Vieira & E Gylfe (2004) A store-operated mechanism determines the activity of the electrically excitable glucagon-secreting pancreatic α-cell. Cell Calcium 35, 357–365.
30 SJ Le Marchand & DW Piston (2010) Glucose suppression of glucagon secretion: metabolic and calcium responses from α-cells in intact mouse pancreatic islets. J Biol Chem 285, 14389–14398.
32 P Detimary , S Dejonghe , Z Ling , et al. (1998) The changes in adenine nucleotides measured in glucose-stimulated rodent islets occur in β cells but not in α cells and are also observed in human islets. J Biol Chem 273, 33905–33908.
34 H Heimberg , A De Vos , D Pipeleers , et al. (1995) Differences in glucose transporter gene expression between rat pancreatic α- and β-cells are correlated to differences in glucose transport but not in glucose utilization. J Biol Chem 270, 8971–8975.
35 F Schuit , A De Vos , S Farfari , et al. (1997) Metabolic fate of glucose in purified islet cells. Glucose-regulated anaplerosis in β cells. J Biol Chem 272, 18572–18579.
36 S Sekine , Y Ito , M Hashimoto , et al. (1994) Characterization of monoclonal antibodies to chitinase A1 and enhancement of chitinase A1 activity by monoclonal antibodies. Biochem Biophys Res Commun 204, 7–16.
37 C Zhao , MC Wilson , F Schuit , et al. (2001) Expression and distribution of lactate/monocarboxylate transporter isoforms in pancreatic islets and the exocrine pancreas. Diabetes 50, 361–366.
39 R Cheng-Xue , A Gomez-Ruiz , N Antoine , et al. (2013) Tolbutamide controls glucagon release from mouse islets differently than glucose: involvement of K(ATP) channels from both α-cells and δ-cells. Diabetes 62, 1612–1622.
40 G da Silva Xavier , H Farhan , H Kim , et al. (2011) Per-arnt-sim (PAS) domain-containing protein kinase is downregulated in human islets in type 2 diabetes and regulates glucagon secretion. Diabetologia 54, 819–827.
41 I Leclerc , G Sun , C Morris , et al. (2011) AMP-activated protein kinase regulates glucagon secretion from mouse pancreatic α cells. Diabetologia 54, 125–134.
E Vieira , L Marroquí , AC Figueroa , et al. (2013) Involvement of the clock gene Rev-erb α in the regulation of glucagon secretion in pancreatic α-cells. PLOS ONE
E Dumonteil , C Magnan , B Ritz-Laser , et al. (2000) Glucose regulates proinsulin and prosomatostatin but not proglucagon messenger ribonucleic acid levels in rat pancreatic islets. Endocrinology
50 V Leclercq-Meyer , J Marchand , MC Woussen-Colle , et al. (1985) Multiple effects of leucine on glucagon, insulin, and somatostatin secretion from the perfused rat pancreas. Endocrinology 116, 1168–1174.
52 SC Collins , J Luan , AJ Thompson , et al. (2007) Adiponectin receptor genes: mutation screening in syndromes of insulin resistance and association studies for type 2 diabetes and metabolic traits in UK populations. Diabetologia 50, 555–562.
J Hong , R Abudula , J Chen , et al. (2005) The short-term effect of fatty acids on glucagon secretion is influenced by their chain length, spatial configuration, and degree of unsaturation: studies in vitro
54 CS Olofsson , A Salehi , SO Gopel , et al. (2004) Palmitate stimulation of glucagon secretion in mouse pancreatic α-cells results from activation of l-type calcium channels and elevation of cytoplasmic calcium. Diabetes 53, 2836–2843.
56 E Flodgren , B Olde , S Meidute-Abaraviciene , et al. (2007) GPR40 is expressed in glucagon producing cells and affects glucagon secretion. Biochem Biophys Res Commun 354, 240–245.
58 K Fujiwara , F Maekawa , K Dezaki , et al. (2007) Oleic acid glucose-independently stimulates glucagon secretion by increasing cytoplasmic Ca2+ via endoplasmic reticulum Ca2+ release and Ca2+ influx in the rat islet α-cells. Endocrinology 148, 2496–2504.
60 S Piro , ET Maniscalchi , A Monello , et al. (2010) Palmitate affects insulin receptor phosphorylation and intracellular insulin signal in a pancreatic α-cell line. Endocrinology 151, 4197–4206.
61 S Gremlich , C Bonny , G Waeber , et al. (1997) Fatty acids decrease IDX-1 expression in rat pancreatic islets and reduce GLUT2, glucokinase, insulin, and somatostatin levels. J Biol Chem 272, 30261–30269.
62 PM Bourlon , A Faure-Dussert , B Billaudel , et al. (1996) Relationship between calbindin-D28K levels in the A and B cells of the rat endocrine pancreas and the secretion of insulin and glucagon: influence of vitamin D3 deficiency and 1,25-dihydroxyvitamin D3. J Endocrinol 148, 223–232.
66 H Klandorf & BL Clarke (1987) Brown J Altered glucagon release in biotin deficiency. Gen Comp Endocrinol 65, 133–140.
LC Wilkes , CJ Bailey , B Thompson , et al. (1990) Effect of gastrin-releasing peptide on the secretion of mouse islet hormones in vitro
. J Endocrinol
69 P Miralles , E Peiro , P Degano , et al. (1990) Inhibition of insulin and somatostatin secretion and stimulation of glucagon release by homologous galanin in perfused rat pancreas. Diabetes 39, 996–1001.
O Cabrera , MC Jacques-Silva , S Speier , et al. (2008) Glutamate is a positive autocrine signal for glucagon release. Cell Metab
72 R Rodriguez-Diaz , R Dando , MC Jacques-Silva , et al. (2011) α Cells secrete acetylcholine as a non-neuronal paracrine signal priming β cell function in humans. Nat Med 17, 888–892.
E Tuduri , E Filiputti , EM Carneiro , et al. (2008) Inhibition of Ca2+ signaling and glucagon secretion in mouse pancreatic α-cells by extracellular ATP and purinergic receptors. Am J Physiol Endocrinol Metab
76 X Ma , Y Zhang , J Gromada , et al. (2005) Glucagon stimulates exocytosis in mouse and rat pancreatic α-cells by binding to glucagon receptors. Mol Endocrinol 19, 198–212.
WG Ding , E Renstrom , P Rorsman , et al. (1997) Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat α-cells by a protein kinase A-mediated mechanism. Diabetes
79 J de Heer , C Rasmussen , DH Coy , et al. (2008) Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas. Diabetologia 51, 2263–2270.
EC Opara , WM Burch , IL Taylor , et al. (1991) Pancreatic hormone response to neuropeptide Y (NPY) perifusion in vitro
. Regul Pept
81 Y Gosmain , C Cheyssac , et al. (2011) Glucagon gene expression in the endocrine pancreas: the role of the transcription factor Pax6 in α-cell differentiation, glucagon biosynthesis and secretion. Diabetes Obes Metab 13, Suppl. 1, 31–38.
82 T Jin (2008) Mechanisms underlying proglucagon gene expression. J Endocrinol 198, 17–28.
84 A Dey , GM Lipkind , Y Rouille , et al. (2005) Significance of prohormone convertase 2, PC2, mediated initial cleavage at the proglucagon interdomain site, Lys70-Arg71, to generate glucagon. Endocrinology 146, 713–727.
86 C Patzelt , HS Tager , RJ Carroll , et al. (1979) Identification and processing of proglucagon in pancreatic islets. Nature 282, 260–266.
88 E Dumonteil , B Ritz-Laser , C Magnan , et al. (1999) Chronic exposure to high glucose concentrations increases proglucagon messenger ribonucleic acid levels and glucagon release from InR1G9 cells. Endocrinology 140, 4644–4650.
R McGirr , CE Ejbick , DE Carter , et al. (2005) Glucose dependence of the regulated secretory pathway in αTC1-6 cells. Endocrinology
92 S Schinner , A Barthel , C Dellas , et al. (2005) Protein kinase B activity is sufficient to mimic the effect of insulin on glucagon gene transcription. J Biol Chem 280, 7369–7376.
E Yamato , Y Noma , Y Tahara , et al. (1990) Suppression of synthesis and release of glucagon by glucagon-like peptide-1 (7-36 amide) without affect on mRNA level in isolated rat islets. Biochem Biophys Res Commun
95 KE Mayo , LJ Miller , D Bataille , et al. (2003) International Union of Pharmacology. XXXV. The glucagon receptor family. Pharmacol Rev 55, 167–194.
96 LS Weinstein , S Yu , DR Warner , et al. (2001) Endocrine manifestations of stimulatory G protein α-subunit mutations and the role of genomic imprinting. Endocr Rev 22, 675–705.
97 SR Kimball , BA Siegfried & LS Jefferson (2004) Glucagon represses signaling through the mammalian target of rapamycin in rat liver by activating AMP-activated protein kinase. J Biol Chem 279, 54103–54109.
98 J Chen , EJ Ishac , P Dent , et al. (1998) Effects of ethanol on mitogen-activated protein kinase and stress-activated protein kinase cascades in normal and regenerating liver. Biochem J 334, 669–676.
100 MH Kedees , M Grigoryan , Y Guz , et al. (2009) Differential expression of glucagon and glucagon-like peptide 1 receptors in mouse pancreatic α and β cells in two models of α cell hyperplasia. Mol Cell Endocrinol 311, 69–76.
101 TJ Kieffer , RS Heller , CG Unson , et al. (1996) Distribution of glucagon receptors on hormone-specific endocrine cells of rat pancreatic islets. Endocrinology 137, 5119–5125.
102 RW Gelling , XQ Du , DS Dichmann , et al. (2003) Lower blood glucose, hyperglucagonemia, and pancreatic α cell hyperplasia in glucagon receptor knockout mice. Proc Natl Acad Sci U S A 100, 1438–1443.
103 SL Conarello , G Jiang , J Mu , et al. (2007) Glucagon receptor knockout mice are resistant to diet-induced obesity and streptozotocin-mediated β cell loss and hyperglycaemia. Diabetologia 50, 142–150.
104 Y Lee , MY Wang , XQ Du , et al. (2011) Glucagon receptor knockout prevents insulin-deficient type 1 diabetes in mice. Diabetes 60, 391–397.
105 H Sorensen , MS Winzell , CL Brand , et al. (2006) Glucagon receptor knockout mice display increased insulin sensitivity and impaired β-cell function. Diabetes 55, 3463–3469.
106 PM Vuguin , MH Kedees , L Cui , et al. (2006) Ablation of the glucagon receptor gene increases fetal lethality and produces alterations in islet development and maturation. Endocrinology 147, 3995–4006.
108 ED Berglund , DG Lustig , RA Baheza , et al. (2011) Hepatic glucagon action is essential for exercise-induced reversal of mouse fatty liver. Diabetes 60, 2720–2729.
112 S Herzig , F Long , US Jhala , et al. (2001) CREB regulates hepatic gluconeogenesis through the coactivator PGC-1. Nature 413, 179–183.
113 GC Band & CT Jones (1980) Functional activation by glucagon of glucose 6-phosphatase and gluconeogenesis in the perfused liver of the fetal guinea pig. FEBS Lett 119, 190–194.
114 M De Oya , WF Prigge & F Grande (1971) Suppression by hepatectomy of glucagon-induced hypertriglyceridemia in geese. Proc Soc Exp Biol Med 136, 107–110.
115 JC Penhos , CH Wu , J Daunas , et al. (1966) Effect of glucagon on the metabolism of lipids and on urea formation by the perfused rat liver. Diabetes 15, 740–748.
116 F Aubry , YL Marcel & J Davignon (1974) Effects of glucagon on plasma lipids in different types of primary hyperlipoproteinemia. Metabolism 23, 225–238.
A Charbonneau , K Couturier , MS Gauthier , et al. (2005) Evidence of hepatic glucagon resistance associated with hepatic steatosis: reversal effect of training. Int J Sports Med
119 A Charbonneau , A Melancon , C Lavoie , et al. (2005) Alterations in hepatic glucagon receptor density and in Gsα and Giα2 protein content with diet-induced hepatic steatosis: effects of acute exercise. Am J Physiol Endocrinol Metab 289, E8–E14.
122 NM Hoosein & RS Gurd (1984) Identification of glucagon receptors in rat brain. Proc Natl Acad Sci U S A 81, 4368–4372.
123 CS Cockram , W Kum , SK Ho , et al. (1995) Binding and action of glucagon in cultured mouse astrocytes. Glia 13, 141–146.
125 S Amir (1986) Central glucagon-induced hyperglycemia is mediated by combined activation of the adrenal medulla and sympathetic nerve endings. Physiol Behav 37, 563–566.
126 N Geary & GP Smith (1983) Selective hepatic vagotomy blocks pancreatic glucagon's satiety effect. Physiol Behav 31, 391–394.
N Geary & GP Smith (1982) Pancreatic glucagon and postprandial satiety in the rat. Physiol Behav
128 JR Martin & D Novin (1977) Decreased feeding in rats following hepatic-portal infusion of glucagon. Physiol Behav 19, 461–466.
131 W Langhans , U Zeiger , E Scharrer , et al. (1982) Stimulation of feeding in rats by intraperitoneal injection of antibodies to glucagon. Science 218, 894–896.
132 PB Jensen , N Blume , JD Mikkelsen , et al. (1998) Transplantable rat glucagonomas cause acute onset of severe anorexia and adipsia despite highly elevated NPY mRNA levels in the hypothalamic arcuate nucleus. J Clin Invest 101, 503–510.
133 AM Arafat , FH Perschel , B Otto , et al. (2006) Glucagon suppression of ghrelin secretion is exerted at hypothalamus-pituitary level. J Clin Endocrinol Metab 91, 3528–3533.
134 PI Mighiu , JT Yue , BM Filippi , et al. (2013) Hypothalamic glucagon signaling inhibits hepatic glucose production. Nat Med 19, 766–772.
135 IW Davidson , JM Salter & CH Best (1957) Calorigenic action of glucagon. Nature 180, 1124.
136 KS Nair (1987) Hyperglucagonemia increases resting metabolic rate in man during insulin deficiency. J Clin Endocrinol Metab 64, 896–901.
137 J Calles-Escandon (1994) Insulin dissociates hepatic glucose cycling and glucagon-induced thermogenesis in man. Metabolism 43, 1000–1005.
138 TM Tan , BC Field , KA McCullough , et al. (2013) Coadministration of glucagon-like peptide-1 during glucagon infusion in humans results in increased energy expenditure and amelioration of hyperglycemia. Diabetes 62, 1131–1138.
141 T Yahata & A Kuroshima (1982) Influence of endocrine and chemical factors on glucagon induced thermogenesis in brown adipocytes. Jpn J Physiol 32, 303–307.
KM Habegger , K Stemmer , C Cheng , et al. (2013) Fibroblast growth factor 21 mediates specific glucagon actions. Diabetes
Z Liu , W Kim , Z Chen , et al. (2011) Insulin and glucagon regulate pancreatic α-cell proliferation. PLoS ONE
150 PF Mery , V Brechler , C Pavoine , et al. (1990) Glucagon stimulates the cardiac Ca2+ current by activation of adenylyl cyclase and inhibition of phosphodiesterase. Nature 345, 158–161.
154 A Perea , F Clemente , J Martinell , et al. (1995) Physiological effect of glucagon in human isolated adipocytes. Horm Metab Res 27, 372–375.
159 A Gutzeit , CA Binkert , DM Koh , et al. (2012) Evaluation of the anti-peristaltic effect of glucagon and hyoscine on the small bowel: comparison of intravenous and intramuscular drug administration. Eur Radiol 22, 1186–1194.
160 E Mochiki , H Suzuki , S Takenoshita , et al. (1998) Mechanism of inhibitory effect of glucagon on gastrointestinal motility and cause of side effects of glucagon. J Gastroenterol 33, 835–841.
165 A Gastaldelli , S Baldi , M Pettiti , et al. (2000) Influence of obesity and type 2 diabetes on gluconeogenesis and glucose output in humans: a quantitative study. Diabetes 49, 1367–1373.
166 A Siafarikas , RJ Johnston , MK Bulsara , et al. (2012) Early loss of the glucagon response to hypoglycemia in adolescents with type 1 diabetes. Diabetes Care 35, 1757–1762.
167 S Dinneen , A Alzaid , D Turk , et al. (1995) Failure of glucagon suppression contributes to postprandial hyperglycaemia in IDDM. Diabetologia 38, 337–343.
168 P Shah , A Vella , A Basu , et al. (2000) Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus. J Clin Endocrinol Metab 85, 4053–4059.
171 H Zhou , T Zhang , JS Harmon , et al. (2007) Zinc, not insulin, regulates the rat α-cell response to hypoglycemia in vivo. Diabetes 56, 1107–1112.
H Zhou , T Zhang , E Oseid , et al. (2007) Reversal of defective glucagon responses to hypoglycemia in insulin-dependent autoimmune diabetic BB rats. Endocrinology
173 S Deng , M Vatamaniuk , X Huang , et al. (2004) Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects. Diabetes 53, 624–632.
174 JC Henquin & J Rahier (2011) Pancreatic α cell mass in European subjects with type 2 diabetes. Diabetologia 54, 1720–1725.
175 KH Yoon , SH Ko , JH Cho , et al. (2003) Selective β-cell loss and α-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab 88, 2300–2308.
177 P Tessari , S Inchiostro , R Barazzoni , et al. (1996) Hyperglucagonemia stimulates phenylalanine oxidation in humans. Diabetes 45, 463–470.
178 E Roth , F Muhlbacher , J Karner , et al. (1987) Free amino acid levels in muscle and liver of a patient with glucagonoma syndrome. Metabolism 36, 7–13.
179 MR Charlton & KS Nair (1998) Role of hyperglucagonemia in catabolism associated with type 1 diabetes: effects on leucine metabolism and the resting metabolic rate. Diabetes 47, 1748–1756.
180 G Boden , I Rezvani & OE Owen (1984) Effects of glucagon on plasma amino acids. J Clin Invest 73, 785–793.
182 C Guettet , N Rostaqui , D Mathe , et al. (1991) Effect of chronic glucagon administration on lipoprotein composition in normally fed, fasted and cholesterol-fed rats. Lipids 26, 451–458.
184 M Beylot , S Picard , C Chambrier , et al. (1991) Effect of physiological concentrations of insulin and glucagon on the relationship between nonesterified fatty acids availability and ketone body production in humans. Metabolism 40, 1138–1146.
186 Y Okuda , K Kawai & K Yamashita (1987) Age-related change in ketone body metabolism: diminished glucagon effect on ketogenesis in adult rats. Endocrinology 120, 2152–2157.
190 Y Lee , ED Berglund , MY Wang , et al. (2012) Metabolic manifestations of insulin deficiency do not occur without glucagon action. Proc Natl Acad Sci U S A 109, 14972–14976.
192 JC Parker , RK McPherson , KM Andrews , et al. (2000) Effects of skyrin, a receptor-selective glucagon antagonist, in rat and human hepatocytes. Diabetes 49, 2079–2086.
193 KF Petersen & JT Sullivan (2001) Effects of a novel glucagon receptor antagonist (Bay 27-9955) on glucagon-stimulated glucose production in humans. Diabetologia 44, 2018–2024.
194 KW Sloop , JX Cao , AM Siesky , et al. (2004) Hepatic and glucagon-like peptide-1-mediated reversal of diabetes by glucagon receptor antisense oligonucleotide inhibitors. J Clin Invest 113, 1571–1581.
195 MS Winzell , CL Brand , N Wierup , et al. (2007) Glucagon receptor antagonism improves islet function in mice with insulin resistance induced by a high-fat diet. Diabetologia 50, 1453–1462.
197 JW Day , N Ottaway , JT Patterson , et al. (2009) A new glucagon and GLP-1 co-agonist eliminates obesity in rodents. Nat Chem Biol 5, 749–757.
198 A Pocai , PE Carrington , JR Adams , et al. (2009) Glucagon-like peptide 1/glucagon receptor dual agonism reverses obesity in mice. Diabetes 58, 2258–2266.
200 MA Nauck , MM Heimesaat , K Behle , et al. (2002) Effects of glucagon-like peptide 1 on counterregulatory hormone responses, cognitive functions, and insulin secretion during hyperinsulinemic, stepped hypoglycemic clamp experiments in healthy volunteers. J Clin Endocrinol Metab 87, 1239–1246.
B Balas , MR Baig , C Watson , et al. (2007) The dipeptidyl peptidase IV inhibitor vildagliptin suppresses endogenous glucose production and enhances islet function after single-dose administration in type 2 diabetic patients. J Clin Endocrinol Metab
204 HE Lebovitz (2010) Adjunct therapy for type 1 diabetes mellitus. Nat Rev Endocrinol 6, 326–334.