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Horm Metab Res 2004; 36(11/12): 830-836
DOI: 10.1055/s-2004-82617
Review
© Georg Thieme Verlag KG Stuttgart · New York

Extrapancreatic Effects of GIP and GLP-1

A.  Vella1 , R.  A.  Rizza1
  • 1 Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Mayo Clinic & Foundation, Rochester MN, USA
Further Information

Publication History

Received 31 July 2004

Accepted after revision 11 August 2004

Publication Date:
18 January 2005 (online)

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Abstract

Incretin-based therapy promises to be a useful adjunct in the treatment of diabetes. Glucagon-like peptide-1 (GLP1) and, to a lesser extent, glucose-dependent insulinotropic polypeptide (GIP) are potent stimulators of insulin secretion, and consequently have significant effects on the regulation of the glucose metabolism. What has been less clear, however, is whether these hormones exert direct effects on glucose metabolism independent of their effect on pancreatic insulin and glucagon release. Glucose effectiveness and insulin action (the ability of glucose and insulin respectively to stimulate glucose uptake and suppress glucose release) have been reported by some investigators, but not others, to improve during incretin infusion. The purpose of this review is briefly to examine some of the numerous conflicting reports in the literature as to the presence or otherwise of extrapancreatic incretin effects. In addition, we will briefly discuss the gastrointestinal effects of incretins. These effects may be of considerable importance in the treatment of postprandial hyperglycemia although they are not, strictly speaking, the result of a direct incretin effect on glucose metabolism.

Key words

Incretins - Glucose effectiveness - Insulin action

References

  • 1 McCance D R. et al . Comparison of tests for glycated haemoglobin and fasting and two hour plasma glucose concentrations as diagnostic methods for diabetes.  Bmj. 1994;  308 (6940) 1323-1328
    PubMedGoogle Scholar
  • 2 Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus.  Diabetes Care. 1997;  20 (7) 1183-1197
    PubMedGoogle Scholar
  • 3 UK Prospective Diabetes Study (UKPDS) Group . Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34).  Lancet. 1998;  35 (9131) 854-865
    PubMedGoogle Scholar
  • 4 UK Prospective Diabetes Study (UKPDS) Group. . Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33).  Lancet. 1998;  352 (9131) 837-853
    CrossrefPubMedGoogle Scholar
  • 5 Heine R J. et al . What does postprandial hyperglycaemia mean?.  Diabet Med. 2004;  21 (3) 208-213
    CrossrefPubMedGoogle Scholar
  • 6 Shah P. et al . Impact of lack of suppression of glucagon on glucose tolerance in humans.  Am J Physiol. 1999;  277 (2 Pt 1) E283-E290
    PubMedGoogle Scholar
  • 7 Shah P. et al . Lack of suppression of glucagon contributes to postprandial hyperglycemia in subjects with type 2 diabetes mellitus.  J Clin Endocrinol Metab. 2000;  85 (11) 4053-4059
    CrossrefPubMedGoogle Scholar
  • 8 Vella A. et al . Effects of pramlintide, an amylin analogue, on gastric emptying in type 1 and 2 diabetes mellitus.  Neurogastroenterol Motil. 2002;  14 (2) 123-131
    CrossrefPubMedGoogle Scholar
  • 9 Dinneen S F. Mechanism of postprandial hyperglycaemia in diabetes mellitus.  Eur J Gastroenterol Hepatol. 1995;  7 (8) 724-729
    PubMedGoogle Scholar
  • 10 Basu A. et al . Impaired basal glucose effectiveness in NIDDM: contribution of defects in glucose disappearance and production, measured using an optimized minimal model independent protocol.  Diabetes. 1997;  46 (3) 421-432
    PubMedGoogle Scholar
  • 11 Basu A. et al . Effects of a change in the pattern of insulin delivery on carbohydrate tolerance in diabetic and nondiabetic humans in the presence of differing degrees of insulin resistance.  J Clin Invest. 1996;  97 (10) 2351-2361
    PubMedGoogle Scholar
  • 12 Vella A, Camilleri M, Rizza R A. The gastrointestinal tract and glucose tolerance.  Curr Opin Clin Nutr Metab Care. 2004;  7 (4) 479-484
    PubMedGoogle Scholar
  • 13 Frank J W. et al . Mechanism of accelerated gastric emptying of liquids and hyperglycemia in patients with type II diabetes mellitus.  Gastroenterology. 1995;  109 (3) 755-765
    PubMedGoogle Scholar
  • 14 Meier J J, Nauck M A. The potential role of glucagon-like peptide 1 in diabetes.  Curr Opin Investig Drugs. 2004;  5 (4) 402-410
    PubMedGoogle Scholar
  • 15 Drucker D J. Minireview: the glucagon-like peptides.  Endocrinology. 2001;  142 (2) 521-527
    CrossrefPubMedGoogle Scholar
  • 16 Drucker D J. Development of glucagon-like peptide-1-based pharmaceuticals as therapeutic agents for the treatment of diabetes.  Curr Pharm Des. 2001;  7 (14) 1399-1412
    CrossrefPubMedGoogle Scholar
  • 17 Vahl T, D’Alessio D. Enteroinsular signaling: perspectives on the role of the gastrointestinal hormones glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide in normal and abnormal glucose metabolism.  Curr Opin Clin Nutr Metab Care. 2003;  6 (4) 461-468
    CrossrefPubMedGoogle Scholar
  • 18 Kieffer T J. Gastro-intestinal hormones GIP and GLP-1.  Ann Endocrinol (Paris). 2004;  65 (1) 13-21
    PubMedGoogle Scholar
  • 19 Kieffer T J, Habener J F. The glucagon-like peptides.  Endocr Rev. 1999;  20 (6) 876-913
    CrossrefPubMedGoogle Scholar
  • 20 Pederson R A. et al . Enhanced glucose-dependent insulinotropic polypeptide secretion and insulinotropic action in glucagon-like peptide 1 receptor -/- mice.  Diabetes. 1998;  47 (7) 1046-1052
    PubMedGoogle Scholar
  • 21 Rocca A S, Brubaker P L. Role of the vagus nerve in mediating proximal nutrient-induced glucagon-like peptide-1 secretion.  Endocrinology. 1999;  140 (4) 1687-1694
    CrossrefPubMedGoogle Scholar
  • 22 Hansen L, Holst J J. The effects of duodenal peptides on glucagon-like peptide-1 secretion from the ileum. A duodeno-ileal loop?.  Regul Pept. 2002;  110 (1) 39-45
    CrossrefPubMedGoogle Scholar
  • 23 Balks H J. et al . Rapid oscillations in plasma glucagon-like peptide-1 (GLP-1) in humans: cholinergic control of GLP-1 secretion via muscarinic receptors.  J Clin Endocrinol Metab. 1997;  82 (3) 786-790
    CrossrefPubMedGoogle Scholar
  • 24 Ahren B. et al . Improved glucose tolerance and insulin secretion by inhibition of dipeptidyl peptidase IV in mice.  Eur J Pharmacol. 2000;  404 (1 - 2) 239-245
    CrossrefPubMedGoogle Scholar
  • 25 Ahren B, Holst J J. The cephalic insulin response to meal ingestion in humans is dependent on both cholinergic and noncholinergic mechanisms and is important for postprandial glycemia.  Diabetes. 2001;  50 (5) 1030-1038
    PubMedGoogle Scholar
  • 26 D’Alessio D A. et al . Elimination of the action of glucagon-like peptide 1 causes an impairment of glucose tolerance after nutrient ingestion by healthy baboons.  J Clin Invest. 1996;  97 (1) 133-138
    PubMedGoogle Scholar
  • 27 Edwards C M. et al . Glucagon-like peptide 1 has a physiological role in the control of postprandial glucose in humans: studies with the antagonist exendin 9-39.  Diabetes. 1999;  48 (1) 86-93
    CrossrefPubMedGoogle Scholar
  • 28 Hui H. et al . Glucagon-like peptide-1 inhibits apoptosis of insulin-secreting cells via a cyclic 5’-adenosine monophosphate-dependent protein kinase A- and a phosphatidylinositol 3-kinase-dependent pathway.  Endocrinology. 2003;  144 (4) 1444-1455
    CrossrefPubMedGoogle Scholar
  • 29 Delgado E. et al . Glucagon-like peptide-1 binding to rat skeletal muscle.  Peptides. 1995;  16 (2) 225-229
    CrossrefPubMedGoogle Scholar
  • 30 Villanueva-Penacarrillo M L. et al . Potent glycogenic effect of GLP-1(7-36)amide in rat skeletal muscle.  Diabetologia. 1994;  37 (11) 1163-1166
    PubMedGoogle Scholar
  • 31 Villanueva-Penacarrillo M L. et al . Glucagon-like peptide-1 binding to rat hepatic membranes.  J Endocrinol. 1995;  146 (1) 183-189
    PubMedGoogle Scholar
  • 32 Valverde I. et al . Presence and characterization of glucagon-like peptide-1(7 - 36) amide receptors in solubilized membranes of rat adipose tissue.  Endocrinology. 1993;  132 (1) 75-79
    CrossrefPubMedGoogle Scholar
  • 33 Egan J M. et al . Glucagon-like peptide-1(7-36) amide (GLP-1) enhances insulin-stimulated glucose metabolism in 3T3-L1 adipocytes: one of several potential extrapancreatic sites of GLP-1 action.  Endocrinology. 1994;  135 (5) 2070-2075
    CrossrefPubMedGoogle Scholar
  • 34 Miki H. et al . Glucagon-like peptide-1(7-36)amide enhances insulin-stimulated glucose uptake and decreases intracellular cAMP content in isolated rat adipocytes.  Biochim Biophys Acta. 1996;  1312 (2) 132-136
    PubMedGoogle Scholar
  • 35 Merida E. et al . Presence of glucagon and glucagon-like peptide-1-(7-36)amide receptors in solubilized membranes of human adipose tissue.  J Clin Endocrinol Metab. 1993;  77 (6) 1654-1647
    CrossrefPubMedGoogle Scholar
  • 36 Ghiglione M. et al . Glucagon-like peptide-1 does not have a role in hepatic carbohydrate metabolism.  Diabetologia. 1985;  28 (12) 920-921
    CrossrefPubMedGoogle Scholar
  • 37 Furnsinn C, Ebner K, Waldhausl W. Failure of GLP-1(7-36)amide to affect glycogenesis in rat skeletal muscle.  Diabetologia. 1995;  38 (7) 864-657
    CrossrefPubMedGoogle Scholar
  • 38 Nakagawa Y. et al . Glucagon-like peptide-1(7-36) amide and glycogen synthesis in the liver.  Diabetologia. 1996;  39 (10) 1241-1242
    PubMedGoogle Scholar
  • 39 Yang H. et al . GLP-1 action in L6 myotubes is via a receptor different from the pancreatic GLP-1 receptor.  Am J Physiol. 1998;  275 (3 Pt 1) C675-C683
    PubMedGoogle Scholar
  • 40 Luque M A. et al . Glucagon-like peptide-1 (GLP-1) and glucose metabolism in human myocytes.  J Endocrinol. 2002;  173 (3) 465-473
    CrossrefPubMedGoogle Scholar
  • 41 Acitores A. et al . Cell signalling of glucagon-like peptide-1 action in rat skeletal muscle.  J Endocrinol. 2004;  180 (3) 389-398
    CrossrefPubMedGoogle Scholar
  • 42 Benito E, Blazquez E, Bosch M A. Glucagon-like peptide-1-(7-36)amide increases pulmonary surfactant secretion through a cyclic adenosine 3’,5’-monophosphate-dependent protein kinase mechanism in rat type II pneumocytes.  Endocrinology. 1998;  139 (5) 2363-2368
    CrossrefPubMedGoogle Scholar
  • 43 Vara E. et al . Glucagon-like peptide-1(7-36) amide stimulates surfactant secretion in human type II pneumocytes.  Am J Respir Crit Care Med. 2001;  163 (4) 840-846
    PubMedGoogle Scholar
  • 44 Shughrue P J, Lane M V, Merchenthaler I. Glucagon-like peptide-1 receptor (GLP1-R) mRNA in the rat hypothalamus.  Endocrinology. 1996;  137 (11) 5159-5162
    CrossrefPubMedGoogle Scholar
  • 45 Turton M D. et al . A role for glucagon-like peptide-1 in the central regulation of feeding.  Nature. 1996;  379 (6560) 69-72
    CrossrefPubMedGoogle Scholar
  • 46 Wei Y, Mojsov S. Tissue-specific expression of the human receptor for glucagon-like peptide-I: brain, heart and pancreatic forms have the same deduced amino acid sequences.  FEBS Lett. 1995;  358 (3) 219-224
    CrossrefPubMedGoogle Scholar
  • 47 Goke R. et al . Distribution of GLP-1 binding sites in the rat brain: evidence that exendin-4 is a ligand of brain GLP-1 binding sites.  Eur J Neurosci. 1995;  7 (11) 2294-2300
    PubMedGoogle Scholar
  • 48 Tang-Christensen M. et al . Central administration of GLP-1-(7-36) amide inhibits food and water intake in rats.  Am J Physiol. 1996;  271 (4 Pt 2) R848-R856
    PubMedGoogle Scholar
  • 49 van Dijk G. et al . Central infusions of leptin and GLP-1-(7-36) amide differentially stimulate c-FLI in the rat brain.  Am J Physiol. 1996;  271 (4 Pt 2) R1096-R1100
    PubMedGoogle Scholar
  • 50 van Dijk G. et al . Glucagon-like peptide-1 and satiety.  Nature. 1997;  385 (6613) 214
    PubMedGoogle Scholar
  • 51 Thiele T E. et al . Central infusion of GLP-1, but not leptin, produces conditioned taste aversions in rats.  Am J Physiol. 1997;  272 (2 Pt 2) R726-R730
    PubMedGoogle Scholar
  • 52 Larsen P J. et al . Distribution of glucagon-like peptide-1 and other preproglucagon-derived peptides in the rat hypothalamus and brainstem.  Neuroscience. 1997;  77 (1) 257-270
    CrossrefPubMedGoogle Scholar
  • 53 Larsen P J, Tang-Christensen M, Jessop D S. Central administration of glucagon-like peptide-1 activates hypothalamic neuroendocrine neurons in the rat.  Endocrinology. 1997;  138 (10) 4445-4455
    CrossrefPubMedGoogle Scholar
  • 54 Donahey J C. et al . Intraventricular GLP-1 reduces short- but not long-term food intake or body weight in lean and obese rats.  Brain Res. 1998;  779 (1 - 2) 75-83
    CrossrefPubMedGoogle Scholar
  • 55 Tang-Christensen M, Vrang N, Larsen P J. Glucagon-like peptide 1(7-36) amide’s central inhibition of feeding and peripheral inhibition of drinking are abolished by neonatal monosodium glutamate treatment.  Diabetes. 1998;  47 (4) 530-537
    PubMedGoogle Scholar
  • 56 de Herder W W. et al . Food-dependent Cushing’s syndrome resulting from abundant expression of gastric inhibitory polypeptide receptors in adrenal adenoma cells.  J Clin Endocrinol Metab. 1996;  81 (9) 3168-3172
    CrossrefPubMedGoogle Scholar
  • 57 Croughs R J. et al . GIP-dependent adrenal Cushing’s syndrome with incomplete suppression of ACTH.  Clin Endocrinol (Oxf). 2000;  52 (2) 235-240
    CrossrefPubMedGoogle Scholar
  • 58 Starich G H, Bar R S, Mazzaferri E L. GIP increases insulin receptor affinity and cellular sensitivity in adipocytes.  Am J Physiol. 1985;  249 (6 Pt 1) E603-E607
    PubMedGoogle Scholar
  • 59 Beck B, Max J P. Gastric inhibitory polypeptide enhancement of the insulin effect on fatty acid incorporation into adipose tissue in the rat.  Regul Pept. 1983;  7 (1) 3-8
    CrossrefPubMedGoogle Scholar
  • 60 Oben J. et al . Effect of the entero-pancreatic hormones, gastric inhibitory polypeptide and glucagon-like polypeptide-1(7-36) amide, on fatty acid synthesis in explants of rat adipose tissue.  J Endocrinol. 1991;  130 (2) 267-272
    PubMedGoogle Scholar
  • 61 Dupre J. et al . Inhibition of actions of glucagon in adipocytes by gastric inhibitory polypeptide.  Metabolism. 1976;  25 (11) 1197-1199
    PubMedGoogle Scholar
  • 62 Yip R G. et al . Functional GIP receptors are present on adipocytes.  Endocrinology. 1998;  139 (9) 4004-4007
    CrossrefPubMedGoogle Scholar
  • 63 Lugari R. et al . Evidence for early impairment of glucagon-like peptide 1-induced insulin secretion in human type 2 (non insulin-dependent) diabetes.  Horm Metab Res. 2002;  34 (3) 150-154
    Article in Thieme ConnectPubMedGoogle Scholar
  • 64 Vilsboll T. et al . Reduced postprandial concentrations of intact biologically active glucagon-like peptide 1 in type 2 diabetic patients.  Diabetes. 2001;  50 (3) 609-613
    PubMedGoogle Scholar
  • 65 Basu A, Rizza RA. Glucose effectiveness: measurement in diabetic and nondiabetic humans.  Exp Clin Endocrinol Diabetes. 2001;  109 (2) S157-S165
    Article in Thieme ConnectPubMedGoogle Scholar
  • 66 Vella A. et al . Glucose-induced suppression of endogenous glucose production: dynamic response to differing glucose profiles.  Am J Physiol Endocrinol Metab. 2003;  285 (1) E25-E30
    PubMedGoogle Scholar
  • 67 Gutniak M. et al . Antidiabetogenic effect of glucagon-like peptide-1 (7 - 36)amide in normal subjects and patients with diabetes mellitus.  N Engl J Med. 1992;  326 (20) 1316-1322
    CrossrefPubMedGoogle Scholar
  • 68 D’Alessio D A. et al . Glucagon-like peptide 1 enhances glucose tolerance both by stimulation of insulin release and by increasing insulin-independent glucose disposal.  J Clin Invest. 1994;  93 (5) 2263-2266
    PubMedGoogle Scholar
  • 69 Vahl T P. et al . Effects of GLP-1-(7-36)NH2, GLP-1-(7-37), and GLP-1- (9-36)NH2 on intravenous glucose tolerance and glucose-induced insulin secretion in healthy humans.  J Clin Endocrinol Metab. 2003;  88 (4) 1772-1779
    CrossrefPubMedGoogle Scholar
  • 70 Vicini P, Caumo A, Cobelli C. Glucose effectiveness and insulin sensitivity from the minimal models: consequences of undermodeling assessed by Monte Carlo simulation.  IEEE Trans Biomed Eng. 1999;  46 (2) 130-137
    CrossrefPubMedGoogle Scholar
  • 71 Cobelli C. et al . Overestimation of minimal model glucose effectiveness in presence of insulin response is due to undermodeling.  Am J Physiol. 1998;  275 (6 Pt 1) E1031-E1036
    PubMedGoogle Scholar
  • 72 Caumo A. et al . Undermodeling affects minimal model indexes: insights from a two-compartment model.  Am J Physiol. 1999;  276 (6 Pt 1) E1171-E1193
    PubMedGoogle Scholar
  • 73 Cobelli C, Caumo A, Omenetto M. Minimal model SG overestimation and SI underestimation: improved accuracy by a Bayesian two-compartment model.  Am J Physiol. 1999;  277 (3 Pt 1) E481-E488
    PubMedGoogle Scholar
  • 74 Van Dijk G. et al . Effects of glucagon-like peptide-I on glucose turnover in rats.  Am J Physiol. 1996;  270 (6 Pt 1) E1015-E1021
    PubMedGoogle Scholar
  • 75 Vella A. et al . Effect of glucagon-like peptide 1(7-36) amide on glucose effectiveness and insulin action in people with type 2 diabetes.  Diabetes. 2000;  49 (4) 611-617
    CrossrefPubMedGoogle Scholar
  • 76 Meneilly G S. et al . Glucagon-like peptide-1 (7-37) augments insulin-mediated glucose uptake in elderly patients with diabetes.  J Gerontol A Biol Sci Med Sci. 2001;  56 (11) M681-M685
    PubMedGoogle Scholar
  • 77 Prigeon R L. et al . Suppression of glucose production by GLP-1 independent of islet hormones: a novel extrapancreatic effect.  Am J Physiol Endocrinol Metab. 2003;  285 (4) E701-E707
    PubMedGoogle Scholar
  • 78 Nishizawa M. et al . Effect of intraportal glucagon-like peptide-1 on glucose metabolism in conscious dogs.  Am J Physiol Endocrinol Metab. 2003;  284 (5) E1027-E1036
    PubMedGoogle Scholar
  • 79 Sandhu H. et al . Glucagon-like peptide 1 increases insulin sensitivity in depancreatized dogs.  Diabetes. 1999;  48 (5) 1045-1053
    PubMedGoogle Scholar
  • 80 Vella A. et al . Effect of glucagon-like peptide-1(7-36)-amide on initial splanchnic glucose uptake and insulin action in humans with type 1 diabetes.  Diabetes. 2001;  50 (3) 565-572
    PubMedGoogle Scholar
  • 81 Rolin B. et al . The major glucagon-like peptide-1 metabolite, GLP-1-(9-36)-amide, does not affect glucose or insulin levels in mice.  Eur J Pharmacol. 2004;  494 (2 - 3) 283-288
    CrossrefPubMedGoogle Scholar
  • 82 Vella A. et al . Lack of effect of exendin-4 and glucagon-like peptide-1-(7,36)-amide on insulin action in non-diabetic humans.  Diabetologia. 2002;  45 (10) 1410-1415
    PubMedGoogle Scholar
  • 83 Ryan A S. et al . Insulinotropic hormone glucagon-like peptide-1-(7-37) appears not to augment insulin-mediated glucose uptake in young men during euglycemia.  J Clin Endocrinol Metab. 1998;  83 (7) 2399-2404
    CrossrefPubMedGoogle Scholar
  • 84 Orskov L. et al . GLP-1 does not not acutely affect insulin sensitivity in healthy man.  Diabetologia. 1996;  39 (10) 1227-1232
    PubMedGoogle Scholar
  • 85 Freyse E J. et al . Glucagon-like peptide-1 has no insulin-like effects in insulin-dependent diabetic dogs maintained normoglycemic and normoinsulinemic.  Metabolism. 1999;  48 (1) 134-137
    CrossrefPubMedGoogle Scholar
  • 86 Meneilly G S. et al . Effect of glucagon-like peptide 1 (7-36 amide) on insulin-mediated glucose uptake in patients with type 1 diabetes.  Diabetes Care. 2003;  26 (3) 837-842
    PubMedGoogle Scholar
  • 87 Ahren B, Larsson H, Holst J J. Effects of glucagon-like peptide-1 on islet function and insulin sensitivity in noninsulin-dependent diabetes mellitus.  J Clin Endocrinol Metab. 1997;  82 (2) 473-478
    CrossrefPubMedGoogle Scholar
  • 88 Todd J F. et al . Glucagon-like peptide-1 (GLP-1): a trial of treatment in non-insulin-dependent diabetes mellitus.  Eur J Clin Invest. 1997;  27 (6) 533-536
    CrossrefPubMedGoogle Scholar
  • 89 Meier J J. et al . Normalization of glucose concentrations and deceleration of gastric emptying after solid meals during intravenous glucagon-like peptide 1 in patients with type 2 diabetes.  J Clin Endocrinol Metab. 2003;  88 (6) 2719-2725
    CrossrefPubMedGoogle Scholar
  • 90 Delgado-Aros S. et al . Effect of GLP-1 on gastric volume, emptying, maximum volume ingested, and postprandial symptoms in humans.  Am J Physiol Gastrointest Liver Physiol. 2002;  282 (3) G424-G431
    PubMedGoogle Scholar
  • 91 Greydanus M P. et al . Neurohormonal factors in functional dyspepsia: insights on pathophysiological mechanisms.  Gastroenterology. 1991;  100 (5 Pt 1) 1311-1318
    PubMedGoogle Scholar
  • 92 Delgado-Aros S. et al . Effects of glucagon-like peptide-1 and feeding on gastric volumes in diabetes mellitus with cardio-vagal dysfunction.  Neurogastroenterol Motil. 2003;  15 (4) 435-443
    CrossrefPubMedGoogle Scholar

A. Vella, M.D., M.R.C.P. (UK)

Division of Endocrinology, Diabetes & Metabolism, Department of Internal Medicine, Mayo Clinic & Foundation

200 First ST SW · Rochester MN 55905 · USA

Phone: +1 (507) 284-3754 ·

Fax: +1 (507) 284-;5745

Email: vella.adrian@mayo.edu

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