On 2014 Dec 05, Gaetano Santulli commented:

Jiang and colleagues report that beta2-adrenergic receptor (B2AR) knockout (KO) mice exhibit a diabetic retinopathy phenotype. We recently demonstrated that B2AR KO mice display a progressive impairment in insulin release that leads to glucose intolerance (1). Our report, which seems to be mechanistically important in the pathophysiology of diabetic rethinopathy (if an animal is glucose intolerant a diabetic retinophaty phenotype appears to be more than obvious) is completely ignored by the Authors. A functional role for B2AR in the regulation of insulin secretion and thereby in the pathogenesis of diabetes had been suggested by the evidence of a decreased number of B2AR in type I diabetes patients (2, 3). Findings from other groups support such a mechanism (4-7). In addition, human polymorphisms in the B2AR gene have been associated with obesity and other metabolic disorders (8, 9). Moreover, the Authors state that B2AR KO mice exhibit attributes of retinal changes common in diabetes, despite normal glucose levels. However, they do not provide any experiment to show glucose (or insulin) levels, nor in basal conditions, nor after a challenge, nor during a clamp assay. Similarly, the Authors also state that in their previous studies they have shown that B1AR KO mice exhibit retinal changes similar to diabetic animals in spite of normal glucose levels, quoting a paper in which there is no experiment showing the claimed normal glucose levels, as well.

We believe that the Readers will appreciate a clarification on these studies by the Authors and the Editors.

Gaetano Santulli MD, PhD 1,2, and Guido Iaccarino MD, PhD 3,4

From the Departments of 1Translational Medical Sciences and 2Advanced Biomedical Sciences, Federico II University, Naples Italy; 3Department of Medicine and Surgery, University of Salerno, Salerno, Italy; 4Multimedica Research Hospital, Milan, Italy.

Essential References 1. Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P, et al. Age-related impairment in insulin release: the essential role of beta(2)-adrenergic receptor. Diabetes. 2012;61(3):692-701. doi: 10.2337/db11-1027. PubMed PMID: 22315324; PubMed Central PMCID: PMC3282797; http://www.ncbi.nlm.nih.gov/pubmed/22315324

1. Schwab KO, Bartels H, Martin C, Leichtenschlag EM. Decreased beta 2-adrenoceptor density and decreased isoproterenol induced c-AMP increase in juvenile type I diabetes mellitus: an additional cause of severe hypoglycaemia in childhood diabetes? European journal of pediatrics. 1993;152(10):797-801. http://www.ncbi.nlm.nih.gov/pubmed/8223779. PubMed PMID: 8223779; http://www.ncbi.nlm.nih.gov/pubmed/8223779.
2. Noji T, Tashiro M, Yagi H, Nagashima K, Suzuki S, Kuroume T. Adaptive regulation of beta-adrenergic receptors in children with insulin dependent diabetes mellitus. Hormone and metabolic research. 1986;18(9):604-6. Epub 1986/09/01. doi: 10.1055/s-2007-1012385. PubMed PMID: 3023224; http://www.ncbi.nlm.nih.gov/pubmed/3023224.
3. Panagiotidis G, Stenstrom A, Lundquist I. Influence of beta 2-adrenoceptor stimulation and glucose on islet monoamine oxidase activity and insulin secretory response in the mouse. Pancreas. 1993;8(3):368-74. Epub 1993/05/01. http://www.ncbi.nlm.nih.gov/pubmed/8387193. PubMed PMID: 8387193; http://www.ncbi.nlm.nih.gov/pubmed/8387193.
4. Loubatieres A, Mariani MM, Sorel G, Savi L. The action of beta-adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of beta receptor. Diabetologia. 1971;7(3):127-32. http://www.ncbi.nlm.nih.gov/pubmed/4397807. PubMed PMID: 4397807; http://www.ncbi.nlm.nih.gov/pubmed/4397807.
5. Ahren B, Jarhult J, Lundquist I. Insulin secretion induced by glucose and by stimulation of beta 2 -adrenoceptors in the rat. Different sensitivity to somatostatin. Acta physiologica Scandinavica. 1981;112(4):421-6. http://www.ncbi.nlm.nih.gov/pubmed/6119001. PubMed PMID: 6119001; http://www.ncbi.nlm.nih.gov/pubmed/6119001.
6. Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F, Muzzin P. The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes. 2005;54(12):3490-5. Epub 2005/11/25. doi: 54/12/3490 [pii]. PubMed PMID: 16306366; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16306366.
7. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. The Journal of clinical investigation. 1997;100(12):3005-13. Epub 1998/01/31. doi: 10.1172/JCI119854. PubMed PMID: 9399946; PubMed Central PMCID: PMC508512; http://www.ncbi.nlm.nih.gov/pubmed/9399946.
8. Thomsen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG. beta2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes: comparison with FTO, MC4R, and TMEM18 polymorphisms in more than 64,000 individuals. The Journal of clinical endocrinology and metabolism. 2012;97(6):E1074-9. doi: 10.1210/jc.2011-3282. PubMed PMID: 22466342; http://www.ncbi.nlm.nih.gov/pubmed/22466342

On 2014 Dec 05, Gaetano Santulli commented:

Jiang and colleagues report that beta2-adrenergic receptor (B2AR) knockout (KO) mice exhibit a diabetic retinopathy phenotype. We recently demonstrated that B2AR KO mice display a progressive impairment in insulin release that leads to glucose intolerance (1). Our report, which seems to be mechanistically important in the pathophysiology of diabetic rethinopathy (if an animal is glucose intolerant a diabetic retinophaty phenotype appears to be more than obvious) is completely ignored by the Authors. A functional role for B2AR in the regulation of insulin secretion and thereby in the pathogenesis of diabetes had been suggested by the evidence of a decreased number of B2AR in type I diabetes patients (2, 3). Findings from other groups support such a mechanism (4-7). In addition, human polymorphisms in the B2AR gene have been associated with obesity and other metabolic disorders (8, 9). Moreover, the Authors state that B2AR KO mice exhibit attributes of retinal changes common in diabetes, despite normal glucose levels. However, they do not provide any experiment to show glucose (or insulin) levels, nor in basal conditions, nor after a challenge, nor during a clamp assay. Similarly, the Authors also state that in their previous studies they have shown that B1AR KO mice exhibit retinal changes similar to diabetic animals in spite of normal glucose levels, quoting a paper in which there is no experiment showing the claimed normal glucose levels, as well.

We believe that the Readers will appreciate a clarification on these studies by the Authors and the Editors.

Gaetano Santulli MD, PhD 1,2, and Guido Iaccarino MD, PhD 3,4

From the Departments of 1Translational Medical Sciences and 2Advanced Biomedical Sciences, Federico II University, Naples Italy; 3Department of Medicine and Surgery, University of Salerno, Salerno, Italy; 4Multimedica Research Hospital, Milan, Italy.

Essential References 1. Santulli G, Lombardi A, Sorriento D, Anastasio A, Del Giudice C, Formisano P, et al. Age-related impairment in insulin release: the essential role of beta(2)-adrenergic receptor. Diabetes. 2012;61(3):692-701. doi: 10.2337/db11-1027. PubMed PMID: 22315324; PubMed Central PMCID: PMC3282797; http://www.ncbi.nlm.nih.gov/pubmed/22315324

1. Schwab KO, Bartels H, Martin C, Leichtenschlag EM. Decreased beta 2-adrenoceptor density and decreased isoproterenol induced c-AMP increase in juvenile type I diabetes mellitus: an additional cause of severe hypoglycaemia in childhood diabetes? European journal of pediatrics. 1993;152(10):797-801. http://www.ncbi.nlm.nih.gov/pubmed/8223779. PubMed PMID: 8223779; http://www.ncbi.nlm.nih.gov/pubmed/8223779.
2. Noji T, Tashiro M, Yagi H, Nagashima K, Suzuki S, Kuroume T. Adaptive regulation of beta-adrenergic receptors in children with insulin dependent diabetes mellitus. Hormone and metabolic research. 1986;18(9):604-6. Epub 1986/09/01. doi: 10.1055/s-2007-1012385. PubMed PMID: 3023224; http://www.ncbi.nlm.nih.gov/pubmed/3023224.
3. Panagiotidis G, Stenstrom A, Lundquist I. Influence of beta 2-adrenoceptor stimulation and glucose on islet monoamine oxidase activity and insulin secretory response in the mouse. Pancreas. 1993;8(3):368-74. Epub 1993/05/01. http://www.ncbi.nlm.nih.gov/pubmed/8387193. PubMed PMID: 8387193; http://www.ncbi.nlm.nih.gov/pubmed/8387193.
4. Loubatieres A, Mariani MM, Sorel G, Savi L. The action of beta-adrenergic blocking and stimulating agents on insulin secretion. Characterization of the type of beta receptor. Diabetologia. 1971;7(3):127-32. http://www.ncbi.nlm.nih.gov/pubmed/4397807. PubMed PMID: 4397807; http://www.ncbi.nlm.nih.gov/pubmed/4397807.
5. Ahren B, Jarhult J, Lundquist I. Insulin secretion induced by glucose and by stimulation of beta 2 -adrenoceptors in the rat. Different sensitivity to somatostatin. Acta physiologica Scandinavica. 1981;112(4):421-6. http://www.ncbi.nlm.nih.gov/pubmed/6119001. PubMed PMID: 6119001; http://www.ncbi.nlm.nih.gov/pubmed/6119001.
6. Asensio C, Jimenez M, Kuhne F, Rohner-Jeanrenaud F, Muzzin P. The lack of beta-adrenoceptors results in enhanced insulin sensitivity in mice exhibiting increased adiposity and glucose intolerance. Diabetes. 2005;54(12):3490-5. Epub 2005/11/25. doi: 54/12/3490 [pii]. PubMed PMID: 16306366; http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16306366.
7. Large V, Hellstrom L, Reynisdottir S, Lonnqvist F, Eriksson P, Lannfelt L, et al. Human beta-2 adrenoceptor gene polymorphisms are highly frequent in obesity and associate with altered adipocyte beta-2 adrenoceptor function. The Journal of clinical investigation. 1997;100(12):3005-13. Epub 1998/01/31. doi: 10.1172/JCI119854. PubMed PMID: 9399946; PubMed Central PMCID: PMC508512; http://www.ncbi.nlm.nih.gov/pubmed/9399946.
8. Thomsen M, Dahl M, Tybjaerg-Hansen A, Nordestgaard BG. beta2-adrenergic receptor Thr164Ile polymorphism, obesity, and diabetes: comparison with FTO, MC4R, and TMEM18 polymorphisms in more than 64,000 individuals. The Journal of clinical endocrinology and metabolism. 2012;97(6):E1074-9. doi: 10.1210/jc.2011-3282. PubMed PMID: 22466342; http://www.ncbi.nlm.nih.gov/pubmed/22466342