The Human Genome Project has enabled researchers to discover that the same genes initiating the formation of new islets in fetal development also emerge when the pancreas is injured as a means of protection.More than 70 publications have now demonstrated the role of the regenerating (REG gene) and Reg (protein) family and the efficacy of shorter bioactive Reg peptides to transform progenitor cells within the pancreas into new in islets.Human Phase 2B trials have successfully been conducted in both type 1 and type 2 diabetes patients resulting in significant lowering of hemoglobin A1C among type 2 patients and significant rises in stimulated C-peptide, a marker of endogenous insulin production, even among type 1 patients with type 1 for 20 years.Reg peptides provide a completely unique and innovative approach, not requiring transplantation, and having the potential for insulin independence among type 1 and 2 patients.
In 1920, Moses Barron made the paradoxical observation that pancreatic stones causeislet neogenesis.Barron’s observation led Frederick Banting to design his initial studies of ligating the pancreatic ducts in dogs and collecting the remaining pancreatic secretions, which resulted in the discovery of insulin[2,3]. Prior to the widespread availability of insulin, surgeons performed ligations of the tail of the pancreas on diabetic children in the hopes of regenerating islets with demonstration of transient symptomatic improvement[4,5].
Thus, for almost a century, the regenerative capacity of the Islets of Langerhans had been well described, but not until the advent of the Human Genome Project is there now supporting data that islet neogenesis can be augmented within patients with diabetes without the use of transplantation and can potentially change the course of the disease known as diabetes.
Even though we have more than 30 new therapies available for use among type 2 patients and more than 20 insulin preparations available for the treatment of both type 1 and 2 diabetes, none address the underlying cause of diabetes: too few beta cells, which has significant repercussions for the entire islet. It is critical to understand that there is significantly more complexity of the islets in man, than in mice, which helps explain why so many therapies have been able to reverse diabetes, particularly in type 1 mouse models, and yet these successes cannot be translated into man.
When there is beta cell loss, there is initial alpha cell expansion and many otherphysiological changes that follow, ultimately leading to loss of the complete islet[6-9]. Autopsy studies conducted among both type 1 and 2 diabetes patients demonstrate that not only are there reductions in beta cell numbers, but there are also significant reductions in both the islet numbers and islet mass [6,7].Thus, not only is there loss of the secretion of insulin and amylin from the beta cell, but also loss of entire islets including alpha cells secreting glucagon, delta cells secreting somatostatin, gamma cells secreting pancreatic polypeptide and epsilon cells secreting ghrelin [6-9].
Each of these hormones play an important and intricate role in glucose homeostasis and gives us greater insight into why even with all of the current therapies available today, including technologies like glucose sensors and insulin pumps, glucose cannot be restored to normal levels [10-16]. Sensor data from non-diabetic humans demonstrate that 80% of all measured glucose levels lie within 60-100 mg/dL, with mean peak glucose levels after meals of <120 mg/dL .
A presentation at the 2016 American Diabetes Association Scientific sessions pointed out that despite all of the new diabetes therapeutics, among 70,657 patients with diabetes, the proportion of patients able to maintain their A1C below 7% has not increased to beyond 40% since 2008 . Linear regression curves from the Diabetes Control and Complications Trial (DCCT) and the United Kingdom Prospective Diabetes Study (UKPDS) show that A1C levels above 5.5% are associated with more complications [19,20]. This data is supported by A1C levels from the EPIC-Norfolk trial among non-diabetic individuals, which found that A1C levels above 5.5% are associated with significantly increased risks for vascular-related morbidity and mortality .
The data in healthy subjects underscores why it is so critical to have healthy functional islets for glucose and A1C levels to remain within the normal range.Even the “Bionic Pancreas,” which delivers both insulin and glucagon to patients with a computer algorithm that does not require manual adjustments by the patient, does not restore glucose levels into the normal range .
Too often, in the field of diabetes, we label patients as being, “noncompliant,” when in the field of diabetes; it is clearly the pancreas that is “noncompliant.”By the time diabetes is diagnosed, the beta cell tipping point has been exhausted.We can better understand why diabetes is an escalating and devastating global epidemic because none of the current therapies until now, have addressed the underlying etiology of diabetes.
The International Diabetes Federation estimates that there are 415 million adults living with diabetes worldwide and this number could rise to 642 million by 2040.Although most patients with the disease have type 2 diabetes, type 1 comprises 7-12% of all diabetes cases worldwide (29-50 million people) and the incidence of type 1 diabetes is increasing at a rate of 3% per year.We can better understand why diabetes is an escalating and devastating global epidemic because none of the current therapies until now, have addressed the underlying etiology of diabetes.
The Diabetes Future
Scientific teams from around the world have more recently shown, just as physicians recognized nearly a century ago, that acute pancreatic injury results in the formation of new islets from progenitor cells found in the pancreatic ductal population [23-39].With the advent of the Human Genome Project, the Regenerating Gene (REG) and regenerating gene protein (Reg) family has emerged among more than a dozen mammalian species, including man, as a key initiating factor in the process of islet neogenesis [40-66].In humans, the Reg genes are typically expressed only during fetal development when islets are formed for the first time, but are upregulated as a protective mechanism, when there is acute pancreatic injury to initiate the formation of new islets; additionally, the Reg gene has also been shown to be upregulated during pregnancy and pancreatitis [67-74].
The Reg gene proteins are a family of C-type lectin proteins that are expressed by the pancreas. A Reg knockout mouse model has also demonstrated the important role of Reg genes in glucose homeostasis with diminished [(3)H]thymidine incorporation in isolated islets from Reg knockout mice, and hyperplastic islets were induced by the injection of goldthioglucose with the average islet size in Reg knockout mice being significantly smaller than that of control Reg(+/+) mice.
The ability to translate this exciting genomic science into therapeutics has been shown by the discovery and efficacy of the shorter bioactive peptide regions of the Reg gene proteins [76-120].These shorter Reg gene peptides (Islet Neogenesis Associated Protein/INGAP, Human proIslet Peptide/HIP, Peptides Healing Islets of Langerhans/PHIL) have been shown as potential therapeutic agents in type 1 and 2 diabetes.
Shorter Reg peptides have been shown in both type 1 and 2 diabetes mouse models to reverse diabetes and in vitrostudies to transform human ductal tissue into islets, and most importantly, studies have been conducted in man through human phase 2B trials [76,77,118-120]. Among type 2 patients, Reg two peptides have been used in human clinical Trials, INGAP and HIP demonstrated a potential to improve diabetes[118-120].Among type 1 diabetes patients who have had the disease for 20 years, there was a significant rise in stimulated C-peptide (27%; p=0.0057), when INGAP was used subcutaneously at a dosage 600 mg, within 8 weeks of treatment [118-120].
Whenever discussing Reg and its role in diabetes treatment, it is important to distinguish between beta cell regeneration from existing beta cells and the genomic processes of islet neogenesis from ductal progenitors. The terms “beta cells” and “islets” are often, in error, used synonymously, even in the basic science literature. In man, beta cells must live within the islet, where their borders can be contiguous with the alpha, delta, epsilon and gamma cells, and islets most optimally function within the pancreas, where the islet mass gets a disproportionate amount of the blood supply to the pancreas.For example, despite islets only comprising 2% of the islet mass, islets receive 20% of the blood flow to the pancreas.
Islet neogenesis involves generation of whole new islets containing all five cell types, not just the beta cell secreting insulin and amylin, but also the other four cell types each secreting hormones which are intricately involved in glucose homeostasis.
Studies have shown that human pancreatic ductal progenitor cell can be transformed into new islets in the presence of the shorter Reg peptides [76,77].Reg gene proteins have been shown to upregulate transcription factors including PDX-1, NGN3, NeurodD1, Pax4, MafA, Nkx2.2, Nkx6.1, B4n4, MafB, Pax6,Nkx6.1 and Sox9, which are also stimulated by the shorter Reg peptides found within the binding region above andacting through the Reg receptor [68,76,78].In a study evaluating the presence of Reg peptide in newly forming islets directly budding from pancreatic exocrine ducts, staining for Reg peptide was found to be highly expressed in newest islet clusters just budding from exocrine ducts, again supporting the important role of Reg in transforming ductal progenitors to islets .
This data highlights the potential for patients with longstanding type 1 diabetes to develop new endogenous insulin production, andis consistent with the work of Jovanovic and colleagues who have demonstrated that within 10 weeks of pregnancy among consecutive patients with type 1 diabetes for an average of 20 years, that there is a rise of C-peptide into the normal range .This can be hypothesized in part, due to the expression of Reg and other growth factors contributing to islet neogenesis as well as the suppression of the mother’s immune system to protect the fetus from autoimmune attack since the fetus has 50% differing DNA from the mother.
pregnancy.There was a rise in C-peptide concentration from a non-detectable concentration pre-pregnancy to a mean concentration of 0.58 ng/ml (0.2 nmol/l) at 10 weeks of gestation.
Reg peptides represent a new therapeutic class of in the diabetes armamentarium, known as islet neogenesis agents.Reg peptide therapy holds true promise and the key to a future without diabetes as we know it today.
To date, the bioactive region of the Reg gene proteins have been identified in man and 17 other mammals.When a bioactive Reg peptide was labeled and injected into a mammal, it was exclusively found to bind in pancreatic ductal tissue, where progenitor cells reside and not found in any other organ .
The figure below demonstrates the region on the Reg gene proteins, which have been identified as the binding region to the Reg gene receptor that have been successfully used as novel therapies in both type 1 and 2 diabetes.
With Reg peptide therapies, the potential now exists to address the underlying cause of diabetes; too few beta cells and subsequent loss of islets, which neither insulin nor any current diabetes therapies on the market addresses.
The key to success in using these new Reg therapies is to generate new islets at a greater rate than destruction of beta cells within islets.The challenge among both type 1 and 2 diabetes is to maintain new islets containing new pools of beta cells and protect them from destruction; whether that be autoimmune attack in the case of type 1 diabetes or the multiple factors in type 2 leading to a tipping point in which the beta cells cannot generate enough insulin to maintain glucose levels in a normal range.
There are studies in both type 1 and type 2 diabetes demonstrating how to protect new insulin producing cells from destruction. Among type 1 diabetes, there is data to support biologic response modifiers that have a high safety and efficacy profile for protection of new endogenous insulin production. Early intervention with Reg therapy in those at risk for diabetes, may potentially prevent diabetes.In those already diagnosed with type 2 diabetes, there are many therapeutic options and lifestyle modifications to prevent beta cell apoptosis once new beta cell populations are restored with Reg therapies.
Among type 1 diabetes, which is an autoimmune disease, thirty years of trials utilizing various immune suppressing agents and therapies that act as biologic response modifiers have all shown great promise of generating immune tolerance to the autoimmune attack on beta cells, in mice but not in man.In contrast to type 1 mouse models, in man, even in an immune muted milieu, new beta cells are not generated at a rate to result in sustained insulin independence.This calls for the potential usage a biologic response modifier in combination with Reg peptide therapy among type 1 patients.
One possible biologic response modifier is oral interferon alpha which has been dosed at 1/1000 of the dosage used to treat hepatitis C and was shown to be safely given in a randomized trial with among new onset type 1 patients treated for 12 months with the ability for the treatment arm to maintain more beta cell mass than placebo.The future for using this, or another biologic response modifier, will be a new combination therapy approach, one which combines an agent to change the autoimmune response with a Reg agent to generate new islets.
There is now tremendous excitement in the field of type 1 diabetes to both generate new islets and protect new insulin-producing cells from autoimmune destruction.The use of Reg peptide therapy among type 2 diabetes is an entirely new approachand may also be used to prevent type 2 diabetes among those who have pre-diabetes.As shown in theToday Study among children and adolescence with type 2 diabetes, the majority of those diagnosed with diabetes, despite treatment with oral therapy and lifestyle modification go on to require insulin .
Due to lack of beta cells within a functional islet, even with all of the new therapies and insulins available, diabetes not only remains the leading cause of blindness, amputations and kidney failure requiring dialysis or transplants, but also the rates of life-threatening hypoglycemia requiring hospital admission now exceed those for hyperglycemia among older adults in the United States.
There is a desperate need for new therapies that address the underlying cause of diabetes.The advent of the Human Genome Project has provided a unique window for researchers in the field of regenerative medicine to develop therapies that can utilize progenitor cells in each organ that are present in times of acute injury to regenerate new healthy cells.Reg peptide therapy may not only be another treatment for diabetes, but also provide a completely unique and innovative approach, which addresses the underlying cause of the disease. Reg peptide therapy has the potential to be another break through therapy as insulin was a century ago.With research expanding beyond immunotherapy to include islet regeneration therapy, the dismantling of both type 1 and 2 diabetes is upon us.
I gratefully acknowledge Patrice Cocco and Susan Pierce for their courage and passion to change this disease and all of my patients with diabetes who are truly an inspirational force.
Dr. Levetan is a shareholder in Perle Bioscience and CureDM Holdings.
- Barron M (1920) The relation of the islets of Langerhans to diabetes with special reference to cases of pancreatic lithiasis. Surg Gynec Obstet19: 437-448.
- Banting FG, Best CH (1922) Pancreatic extracts. JLab Clin Med7:464-472.
- Banting FG, Best CH, Collip JB, Campbell WR, Fletcher AA (1922)Pancreatic extracts in thetreatment of diabetes mellitus. Preliminary report. Can Med Assoc 12: 141-146.
- De Takats G, Cuthbert FP (1933)Surgical attempts at increasing sugar tolerance. Arch Surg 750-764.
- DeTakats G (1930) Ligation of the tail of the pancreas in juvenile diabetes. Endocrinology 14: 255-264.
- Doniach I, Morgan AG (1973) Islets of Langerhans in juvenile diabetes mellitus. Clin Endocrinol (Oxf). 2:233-248.
- Deng S, Vatamaniuk M, Huang X, Doliba N, Lian MM, et al, (2004)Structural and functional abnormalities in the islets isolated from type 2 diabetic subjects.Diabetes 53:624-632 .
- Kilimnik G, Zhao B,Periwal JJ, Vipul Periwal, Piotr Witkowski, et al, (2011) Altered islet composition and disproportionate loss of large islets in patients with type 2 diabetes. PLoS One6:e27445.
- Yoon KH, Ko SH, Cho JH, Lee JM, Ahn YB, et al. (2003) Selective beta-cell loss and alpha-cell expansion in patients with type 2 diabetes mellitus in Korea. J Clin Endocrinol Metab88:2300-2308.
- Togliatto G, Trombetta A, Dentelli P, Baragli A, Rosso A, et al. (2010) Unacylated ghrelin rescues endothelial progenitor cell function in individuals with type 2 diabetes. Diabetes59:1016-1025.
- Granata R, Settanni F, Biancone L, Trovato L, Nano R, et al. (2007) Acylated and unacylated ghrelin promote proliferation and inhibit apoptosis of pancreatic beta-cells and human islets: involvement of 3′,5′-cyclic adenosine monophosphate/protein kinase A, extracellular signal-regulated kinase 1/2, and phosphatidyl inositol 3-Kinase/Akt signaling. Endocrinology 148:512-529.
- Brunicardi FC, Chaiken RL, Ryan AS, Seymour NE, Hoffmann JA, et al. (1996) Pancreatic polypeptide administration improves abnormal glucose metabolism in patients with chronic pancreatitis. J Clin Endocrinol Metab81:3566-3572.
- Rabiee A, Galiatsatos P, Salas-Carrillo R, Thompson MJ, Andersen DK, et al. (2011) Pancreatic polypeptide administration enhances insulin sensitivity and reduces the insulin requirement of patients on insulin pump therapy. J Diabetes Sci Technol 5:1521-1528.
- Levetan C, Want LL, Weyer C, Strobel SA, Crean J, et al. (2003) Impact of pramlintide on glucose fluctuations and postprandial glucose, glucagon, and triglyceride excursions among patients with type 1 diabetes intensively treated with insulin pumps. Diabetes Care 26:1-8.
- Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, et al. (2010) Effectiveness of sensor-augmented insulin-pump therapy in type 1 diabetes. N Engl J Med363:311-320.
- Bergenstal RM, Tamborlane WV, Ahmann A, Buse JB, Dailey G, et al.(2011) Sensor-augmented pump therapy for A1C reduction (STAR 3) study: results from the 6-month continuation phase. Diabetes Care 34:2403-2405.
- Christiansen JS (2006)What is normal glucose? – Continuous glucose monitoring data from healthy subjects. EASD, Copenhagen, 13-Sep-06. The 42nd Annual Meeting of the EASD, September 14-15, 2006, Copenhagen, Denmark.
- Higgins V (2016) Hemoglobin A1C below 7% remains elusive, despite new drugs.
- DCCT Research Group (1996) The absence of a glycemic threshold for the development of long-term complications: the perspective of the Diabetes Control and Complications Trial. Diabetes45:1289-1298.
- Stratton IM, Adler AI, Neil HA, Matthews DR, Manley SE,et al. (2000) Association of glycaemia with macrovascular and microvascular complications of type 2 diabetes (UKPDS 35): prospective observational study. BMJ 321:405-412.
- Khaw KT, Wareham N, Luben R, Bingham S, Oakes S, et al, (2001) Glycated haemoglobin, diabetes, and mortality in men in Norfolk cohort of European prospective investigation of cancer and nutrition (EPIC-Norfolk). BMJ 322: 15-18.
- Russell SJ, El-Khatib FH, Sinha M, Magyar K, McKeon K, et al. (2014) Outpatient Glycemic Control with a Bionic Pancreas in Type 1 Diabetes Outpatient Glycemic Control with a Bionic Pancreas in Type 1 Diabetes. N Engl J Med 371: 313-325.
- Rosenberg L, Brown RA, Duguid WP (1983) A new approach to the induction of ductepithelial hyperplasia and nesidioblastosis by cellophane wrapping of the hamster pancreas. J Surg Res 35: 63-72.
- Rosenberg L (1998) Induction of islet cell neogenesis in the adult pancreas: the partial duct obstruction model. Microsc Res Tech 15 43: 337-346.
- Lee SH, Hao E, Levine F (2011) β-Cell replication and islet neogenesis following partial pancreatectomy. Islets 3:188-195.
- Wang RN, Klöppel G, Bouwens L (1995) Duct- to islet-cell differentiation and islet growth in the pancreas of duct-ligated adult rats. Diabetologia 38: 1405-1411.
- Yonemura Y, Toru Takashima T, Miwa K, Miyazaki I, Yamamoto H, et al. (1984) Amelioration of Diabetes Mellitus in Partially Depancreatized Rats by Poly(ADP-ribose) Synthetase Inhibitors: Evidence of Islet B-Cell Regeneration Diabetes 33: 401-404.
- Xu X, D’Hoker J, Stange G, Bonné S, De Leu N, et al. (2008) Beta cells can be generated from endogenous progenitors in injured adult mouse pancreas. Cell 132: 197-207.
- Hao E, Lee SH, Levine F (2013) Efficient β-cell regeneration by a combination of neogenesis and replication following β-cell ablation and reversal of pancreatic duct ligation. Stem Cells 31: 2388-2395.
- Del Zotto H, Borelli MI, Flores L, García ME, Gómez Dumm CL, et al. (2004) Islet neogenesis: an apparent key component of long-term pancreas adaptation to increased insulin demand. J Endocrinol 183: 321-330.
- Bonner-Weir S, Baxter LA, Schuppin GT, Smith FE (1993) A second pathway for regeneration of adult exocrine and endocrine pancreas. A possible recapitulation of embryonic development. Diabetes 42: 1715-1720.
- Hao E, Tyrberg B, Itkin-Ansari P, Lakey JR, Geron I, et al, (2006) Beta-cell differentiation from nonendocrine epithelial cells of the adult human pancreas. Nat Med 12: 310-316.
- Bonner-Weir S, Taneja M, Weir GC, Tatarkiewicz K, Song KH, et al. (2000) In vitro cultivation of human islets from expanded ductal tissue. Proc Natl Acad Sci 97: 7999-8004.
- Bonner-Weir S1, Inada A, Yatoh S,Li WC, Aye T, et al.(2008) Transdifferentiation of pancreatic ductal cells to endocrine beta-cells. Biochem Soc Trans 36:353-356.
- Bonner-Weir S1, Toschi E, Inada A,Reitz P, Fonseca SY, et al. (2004) The pancreatic ductal epithelium serves as a potential pool of progenitor cells. Pediatr Diabetes 2:16-22.
- Inada A, Nienaber C, Katsuta H,Fujitani Y, Levine J, et al.(2008) Carbonic anhydrase II-positive pancreatic cells are progenitors for both endocrine and exocrine pancreas after birth. Proc Natl Acad Sci USA105:19915-19919.
- Lechner A, Habener JF (2003) Stem/progenitor cells derived from adult tissues: potential for the treatment of diabetes mellitus. Am J Physiol Endocrinol Metab 284: 259-266.
- Davani B, Ariely S, Ikonomou L, Oron Y, Gershengorn MC (2009) Human islet-derived precursor cells can cycle between epithelial clusters and mesenchymal phenotypes.J Cell Mol Med13:2570-2581.
- Watanabe T, Yutaka Y, Yonekura H, Suzuki Y, Miyashita H, et al. (1994) Pancreatic beta cell replication and amelioration of surgical diabetes by Reg protein. Proc. Natl Acad Sci USA 91: 3589-3592.
- Xia F, Cao H, Du J, Liu X, Liu Y, et al. (2016) Reg3g overexpression promotes β cell regeneration and induces immune tolerance in nonobese-diabetic mouse model.J Leukoc Biol99:1131-1140.
- Okamoto H (1999) The Reg gene family and Reg proteins, with special attention to the regeneration of pancreatic beta-cells. J Hepatobiliary Pancreat Surg 6: 254-262.
- Unno M, Itoh T, Watanabe T, Miyashita H, Moriizumi S, et al. (1992) Islet beta-cell regeneration and reg genes. Adv Exp Med Biol 321:61-66.
- Akiyama T, Takasawa S, Nata K, et al. (2001) Activation of Reg gene, a gene for insulin-producing beta -cell regeneration: poly(ADP-ribose) polymerase binds Reg promoter and regulates the transcription by autopoly(ADP-ribosyl)ation. Proc Natl Acad Sci USA98:48-53.
- Aida K,Saitoh S,Nishida Y,Yokota S, Ohno S, et al. (2014) Distinct Cell Clusters Touching Islet Cells Induce Islet Cell Replication in Association with Over-Expression of Regenerating Gene (REG) Protein in Fulminant Type 1 Diabetes. PLoS One 9: e95110.
- Newgard CPA, Hughes S, Chen L, Okamoto H, Milburn JL (1989) The Reg gene is preferentially expressed in the exocrine pancreas during islet regeneration. Diabetes38: 49A.
- Terazono K, Yamamoto H, Takasawa S, Shiga K, Yonemura Y, et al. (1988) A novel gene activated in regenerating islets. J. Biol Chem 263: 2111-2114.
- Terazono K, Uchiyama Y, Ide M, Watanabe T, YonekuraH, et al. (1990) Expression of reg protein in rat regenerating islets and its co- localization with insulin in the beta-cell secretory granules. Diabetologia33: 250-252.
- Miyaura C, Chen L, Appel M, Alam T, Inman L, et al. (1991) Expression of reg/PSP, a pancreatic exocrine gene: relationship to changes in islet beta-cell mass. Mol Endocrinol 5: 226-234.
- Gross DJ, Weiss L, Reibstein I, van den Brand J, Okamoto H, et al. (1998) Amelioration of diabetes in nonobese diabetic mice with advanced disease by linomide-induced immunoregulation combined with Reg protein treatment. Endocrinology139: 2369-2374.
- Ota H, Itaya-Hironaka A, Yamauchi A, Sakuramoto-Tsuchida S, Miyaoka T, et al. (2013) Pancreatic β cell proliferation by intermittent hypoxia via up-regulation of Reg family genes and HGF gene. Life Sci. 93:664-672.
- Wang Y, Jacovetti C, Li B, Siddique T,Siddique T, Xiong X, et al. (2011) Coordinated age-dependent and pancreatic-specific expression of mouse Reg2Reg3α, and Reg3β genes. Growth Factors29:72-81.
- Liu JL, Cui W, Li B, Lu Y (2008) Possible roles of reg family proteins in pancreatic islet cell growth. Endocr Metab Immune Disord Drug Targets8:1-10.
- Chen T1, Wang Y, Gu L, Zhou S, Ye J, et al. (2013) Role of INGAP-pp in the differentiation of hUCMSCs into insulin producing cells. Xi Bao Yu Fen Zi Mian Yi Xue Za Zhi29:141-145.
- Calderari S, Irminger JC, Giroix MH, Ehses JA, Gangnerau MN, et al. (2014) Regenerating 1 and 3b gene expression in the pancreas of type 2 diabetic Goto-Kakizaki (GK) rats. PLoS One 26: e90045.
- Lu Y, Ponton A, Okamoto H, Takasawa S, Herrera PL, et al. (2006) Activation of the Reg family genes by pancreatic-specific IGF-I gene deficiency and after streptozotocin-induced diabetes in mouse pancreas.Am J Physiol Endocrinol Metab 291:E50-E58.
- Huszarik K, Wright B, Keller C, Nikoopour E, Krougly O, et al. (2010) Adjuvant immunotherapy increases beta cell regenerative factor Reg2 in the pancreas of diabetic mice. J Immunol185:5120-5129.
- Rafaeloff R, Qin XF, Barlow SW, Rosenberg L, Vinik AI (1996) Identification of differentially expressed genes induced in pancreatic islet neogenesis. FEBS Lett378:219-223.
- Zenilman ME, Perfetti R, Swinson K.Magnuson T, Shuldiner AR (1996) Pancreatic regeneration (reg) gene expression in a rat model of islet hyperplasia. Surgery119:576-84.
- Dusetti NJ, Mallo GV, Ortiz EM, Keim V, Dagorn JC, et al. (1996) Induction of lithostathine/reg mRNA expression by serum from rats with acute pancreatitis and cytokines in pancreatic acinar AR-42J cells. Biochim Biophys Acta 330: 129-132.
- Kobayashi S, Akiyama T, Nata K, Abe M, Tajima M, et al. (2000) Identification of a receptor for REG (Regenerating gene) protein, a pancreatic beta-cell regeneration factor. J Biol Chem 275: 10723-10726.
- Zenilman ME, Chen J, Magnuson TH (1998) Effect of reg protein on rat pancreatic ductal cells. Pancreas 17:256-261.
- Graf R, Schiesser M, Reding T, Appenzeller P, Sun LK, et al. (2006) Exocrine meets endocrine: pancreatic stone protein and regenerating protein—two sides of the same coin. J Surg Res133:113-120.
- Orelle B, Keim V, Masciotra L, Dagorn JC, Iovanna JL (1992) Human pancreatitis-associated protein: messenger RNA cloning and expression in pancreatic diseases. J Clin Invest90:2284-2291.
- Vasseur S, Folch-Puy E, Hlouschek V, Garcia S, Fiedler F, et al. (2004) p8 improves pancreatic response to acute pancreatitis by enhancing the expression of the anti-inflammatory protein pancreatitis-associated protein I. J Biol Chem 279:7199-7207.
- Zenilman ME, Magnuson TH, Swinson K, Egan J, Perfetti R, et al. (1996) Pancreatic thread protein is mitogenic to pancreatic-derived cells in culture. Gastroenterology110:1208-1214.
- Iovanna J, Orelle B, Keim V, Dagorn JC (1991) Messenger RNA sequence and expression of rat pancreatitis-associated protein, a lectin-related protein overexpressed during acute experimental pancreatitis. J Biol Chem 266:24664-24669.
- Mouse Genomics Informatics. Mus musculus 11 days pregnant adult female ovary and uterus cDNA, RIKEN full-length enriched library, clone:5033401N17 product:regenerating islet-derived 1, full insert sequence.
- Assouline-Thomas B, Ellis D, Petropavlovskaia M, Makhlin J, Ding J, et al. (2015) Islet Neogenesis Associated Protein (INGAP) induces the differentiation of an adult human pancreatic ductal cell line into insulin-expressing cells through stepwise activation of key transcription factors for embryonic beta cell development. Differentiation 90:77-90.
- Levetan C (2010) Distinctions between islet neogenesis and β-cell replication: implications for reversal of Type 1 and 2 diabetes. J Diabetes2:76-84.
- Barbosa HC, Bordin S, Anhê G, Persaud SJ, Bowe J, et al. (2008) Islet neogenesis-associated protein signaling in neonatal pancreatic rat islets: involvement of the cholinergic pathway.J Endocrinol199:299-306.
- Francini F, Del Zotto H, Massa ML, et al, (2009) Selective effect of INGAP-PP upon mouse embryonic stem cell differentiation toward islet cells. Regul Pept153:43-48.
- Madrid V, Borelli MI, Maiztegui B, Flores LE, Gagliardino JJ, et al. (2013) Islet neogenesis-associated protein (INGAP)-positive cell mass, β-cell mass, and insulin secretion: their relationship during the fetal and neonatal periods. Pancreas 42: 422-428.
- De Krijgar RR, Aanstoot HJ, Kranenburg G, Reinhard M, Visser WJ (1992) The midgestational human fetal pancreas contains cells coexpressing islet hormones. Dev Biol 153: 368-375.
- Hamblet NS, Shi W, Vinik AI, Taylor-Fishwick DA (2008) The Reg family member INGAP is a marker of endocrine patterning in the embryonic pancreas. Pancreas36: 1-9.
- Unno M, Nata K, Noguchi N, Narushima Y, Akiyama T, et al. (2002) Production and characterization of REG knockout mice: reduced proliferation of pancreatic beta-cells in REG knockout mice. Diabetes 51: S478-S483.
- Levetan CS, Upham LV, Deng S, Laury-Kleintop L, Kery V, et al., (2008) Discovery of a human peptide sequence signaling islet neogenesis. Endocr Pract 14:1075-1083.
- Li J, Wang Y, Yu X,Wu Y, Han X, et al. (2009) Islet neogenesis-associated protein-related pentadecapeptide enhances the differentiation of islet-like clusters from human pancreatic duct cells.Peptides30:2242-2249.
- Kapur R, Højfeldt TW, Højfeldt TW,Rønn SG, Karlsen AE, et al. (2012) Short-term effects of INGAP and Reg family peptides on the appearance of small β-cells clusters in non-diabetic mice. Islets4:40-48.
- Silva KE, Barbosa HC, Rafacho A, Bosqueiro JR, Stoppiglia LF, et al. (2008) INGAP-PP up-regulates the expression of genes and proteins related to K+ ATP channels and ameliorates Ca2+ handling in cultured adult rat islets. Regul Pept 148:39-45.
- Rosenberg L, Vinik AI (1989) Induction of endocrine cell differentiation: a new approach to management of diabetes. J Lab Clin Med 114: 75-83.
- Lipsett M, Hanley S, Castellarin M,Austin E, Suarez-Pinzon WL, et al. (2007) The role of islet neogenesis-associated protein (INGAP) in islet neogenesis.Cell Biochem Biophys. 48:127-137.
- Taylor-Fishwick DA, Bowman A, Hamblet N,Bernard P, Harlan DM, et al. (2006) Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J Endocrinol190:729-737.
- Barbosa H, Bordin S, Stoppiglia L,Silva K, Borelli M, et al. (2006) Islet Neogenesis Associated Protein (INGAP) modulates gene expression in cultured neonatal rat islets. Regul Pept136:78-84.
- Borelli MI, Stoppiglia LF, Rezende LF, Flores LE, Del Zotto H, et al. (2005) INGAP-related pentadecapeptide: its modulatory effect upon insulin secretion. Regul Pept131:97-102.
- Lipsett M, Hanley S, Radzioch D,Compton C, Wang GS, et al. (2003) INGAP: A critical mediator of islet neogenesis? Diabetes52:A360.
- Rosenberg L, Lipsett M, Yoon JW,Prentki M, Wang R, et al. (2004) A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Ann Surg240:875-884.
- Gagliardino JJ, Del Zotto H, Massa L, LE Flores, MI Borelli (2003) Pancreatic duodenal homeobox-1 and islet neogenesis-associated protein: a possible combined marker of activateable pancreatic cell precursors. J Endocrinol177:249-259.
- Del Zotto H, Massa L, Rafaeloff R, Pittenger GL, Vinik A, et al. (2000) Possible relationship between changes in islet neogenesis and islet neogenesis-associated protein-positive cell mass induced by sucrose administration to normal hamsters. J Endocrinol165:725-733.
- Pittenger GL, Taylor-Fishwick DA, Johns RH, Burcus N, Kosuri S, et al. (2007) Intramuscular injection of islet neogenesis-associated protein peptide stimulates pancreatic islet neogenesis in healthy dogs. Pancreas34:103-111.
- Rosenberg L, Duguid WP, Brown RA, Vinik AI (1988) Induction of islet cell proliferation will reverse diabetes in the Syrian golden hamster. Diabetes 37: 334-334
- Rosenberg L, Lipsett M, Yoon JW,Prentki M, Wang R, et al. (2004) A pentadecapeptide fragment of islet neogenesis-associated protein increases beta-cell mass and reverses diabetes in C57BL/6J mice. Ann Surg 240:875-884.
- Taylor-Fishwick DA, Bowman A, Hamblet N, Bernard P, Harlan DM, et al. (2006) Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J Endocrinol 190: 729-737.
- Pittenger GL, Taylor-Fishwick D, Vinik AI (2009) A role for islet neogenesis in curing diabetes. Diabetologia 52:735-738.
- Rosenberg L, Clas D, Duguid WP (1990) Trophic stimulation of the ductal/islet cell axis: a new approach to the treatment of diabetes. Surgery 108: 191-197.
- Rosenberg L, Dafoe D, Turcotte J (1987) Enhancing hamster pancreatic islet isolation by induction of nesidioblastosis. Transplant Proc19: 907-908.
- Rosenberg L, Duguid WP, Brown RA (1983) Effect of experimental nesidioblastosis on streptozotocin-induced diabetes. Surg. Forum34: 48-51.
- Rosenberg L, Duguid WP, Brown RA, Vinik AIInduction of islet cell proliferation will reverse diabetes in the Syrian golden hamster. Diabetes 37: 334-341.
- Rosenberg L, Vinik AI, Pittenger GL,Rafaeloff R, Duguid WP (1996) Islet-cell regeneration in the diabetic hamster pancreas with restoration of normoglycaemia can be induced by a local growth factor(s). Diabetologia39: 256-262.
- Gagliardino JJ, Del Zotto H, Massa L,LE Flores, MI Borelli (2003) Pancreatic duodenal homeobox-1 and islet neogenesis associated protein: a possible combined marker of activateable pancreatic cell precursors. J Endocrinol 177: 249-259.
- Taylor-Fishwick DA, Bowman A, Hamblet N,Bernard P, Harlan DM, et al. (2006) Islet neogenesis associated protein transgenic mice are resistant to hyperglycemia induced by streptozotocin. J Endocrinol190: 729-737.
- Taylor-Fishwick DA, Shi W, Pittenger GL, Vinik AI (2006) PDX-1 can repress stimulus-induced activation of the INGAP promoter. J Endocrinol 188: 611-621.
- Pittenger GL, Vinik AI, Rosenberg L (1992) The partial isolation and characterization of ilotropin, a novel islet-specific growth factor. Adv Exp Med Biol 321: 123-130.
- Rosenberg L, Vinik AI (1993)In vitro stimulation of hamster pancreatic duct growth by an extract derived from the “wrapped” pancreas. Pancreas8: 255-260.
- Sasahara K, Yamaoka T, Moritani M, Yoshimoto K, Kuroda Y, et al. (2000) Molecular cloning and tissue-specific expression of a new member of the regenerating protein family, islet neogenesis-associated protein-related protein. Biochem Biophys Acta1500:142.
- Ren L, Chen L, Qi H, Li F, Gong F (2014) In vitro differentiation of human adipose tissue-derived stem cells into islet-like clusters promoted by islet neogenesis-associated protein pentadecapeptide.Cells Tissues Organs 199: 329-341.
- Flores LE, Del Zotto H, Fragapane F,Maiztegui B, Román CL, et al. (2014) Islet neogenesis-associated protein (INGAP): the role of its endogenous production as a positive modulator of insulin secretion. Regul Pept193:30-34.
- Chen H, Zhang M, Wang Y, Yu X, Gu Y, et al. (2014) Islet neogenesis-associated protein-related pentadecapeptide improves the function of allograft after islets transplantation. J Pediatr Endocrinol Metab27:1167-1173.
- Zha M, Zhang M, Shan S,Xu KF, Chen H, et al. (2012) Effects of islet neogenesis-associated protein pentadecapeptide on cell mass and insulin secretion of pancreatic β-cells. J Endocrinol Invest35:634-639.
- Chang TJ, Weaver JR, Bowman A,Leone K, Raab R, et al. (2011) Targeted expression of islet neogenesis associated protein to beta cells enhances glucose tolerance and confers resistance to streptozotocin-induced hyperglycemia. Mol Cell Endocrinol335:104-109.
- Madrid V, Del Zotto H, Maiztegui B,Raschia MA, Alzugaray ME, et al. (2009) Islet neogenesis-associated protein pentadecapeptide (INGAP-PP): mechanisms involved in its effect upon beta-cell mass and function. Regul Pept 157:25-31.
- Levine JL, Patel KJ, Zheng Q, Shuldiner AR, Zenilman ME (2000) A recombinant rat regenerating protein is mitogenic to pancreatic derived cells. J Surg Res89:60-65.
- Ortiz EM, Dusetti NJ, Vasseur S,Malka D, Bödeker H, et al. (1998) The pancreatitis-associated protein is induced by free radicals in AR4-2J cells and confers cell resistance to apoptosis. Gastroenterology114:808-816.
- Fleming A, Lawrence Rosenberg L (2007) Prospects and Challenges for Islet Regeneration as a Treatment for Diabetes: A Review of Islet Neogenesis Associated Protein. J Diabetes Sci Technol 1: 231-244.
- Pittenger GL, Taylor-Fishwick D, Vinik AI (2009) The role of islet neogeneis-associated protein (INGAP) in pancreatic islet neogenesis. Curr Protein Pept Sci 10: 37-45.
- McCarthy AN, Mogilner IG, Grigera JR, Borelli MI, Del Zotto H, et al. (2009) Islet neogenesis associated protein (ingap): structural and dynamical properties of its active pentadecapeptide. J Mol Graph Model 27: 701-705.
- Tersey SA, Carter JD, Rosenberg L, Taylor-Fishwick DA, Mirmira RG, et al. (2012) Amelioration of type 1 diabetes following treatment of non-obese diabetic mice with INGAP and lisofylline. J Diabetes Mellitus 2: 251-257.
- Li J, Wang Y, Yu X, Chen H, Wu Y, et al. (2009) Islet neogenesis-associated protein-related pentadecapeptide enhances the differentiation of islet-like clusters from human pancreatic duct cells. Peptides 30: 2242-2249.
- Ratner RE, Feeley D, Buse, JB, Schwartz SL (2005) Double-Blind, Placebo-Controlled Trial of Islet Neogenesis Gene Associated Protein (INGAP) in Type 1 Diabetes (T1D) Subjects.
- Ratner RE, Feeley D, Buse JB, Fischer JS (2005) Double-Blind, Placebo-Controlled Trial of Islet Neogenesis Gene Associated Protein (INGAP) Therapy in Type 2 Diabetes (T2DM) Subjects.
- Dungan KM, Buse JB, Ratner RE (2009) Effects of therapy in type 1 and type 2 diabetes mellitus with a peptide derived from islet neogenesis associated protein (INGAP). Diabetes Metab Res Rev 25: 558-565.
- Guo L (2010) Pancreatic Regeneration after Partial Pancreatectomy (Px) in Mice Mirrors That in Rats with Both Enhanced Replication and Neogenesis.
- Ilic S, Jovanovic L, Wollitzer AO (2010) Is the paradoxical first trimester drop in insulin requirement due to an increase in C-peptide concentration in pregnant Type I diabetic women? Diabetologia 43: 1329-1330.
- Levetan CS, Pierce SM (2013) Distinctions between the islets of mice and men: implications for new therapies for type 1 and 2 diabetes. Endocr Pract 19: 301-312.
- Bairoch A, Boeckmann B (1994) The SWISS-PROT protein sequence data bank: current status. Nucleic Acids Res 22: 3578-3580.
- Rother KI, Brown RJ, Morales MM, Wright E, Duan Z, et al. (2009) Effect of ingested interferon-alpha on beta-cell function in children with new-onset type 1 diabetes. Diabetes Care 32: 1250-1255.
- TODAY Study Group (2012) A Clinical Trial to Maintain Glycemic Control in Youth with Type 2 Diabetes. N Engl J Med 366: 2247-2256.
- Lipska KJ, Ross JS MD, Wang Y, Inzucchi SE, Minges K, et al. (2014) National Trends in US Hospital Admissions for Hyperglycemia and Hypoglycemia Among Medicare Beneficiaries, 1999 to 2011. JAMA Intern Med 174: 1116-1124.
Figure 1: C-peptide rise among ten consecutive pregnant type 1 patients with a mean duration of diabetes for 21.2 years.C-peptide levels were measured before pregnancy in the fasting state and at 10 weeks of pregnancy.There was a rise in C-peptide concentration from a non-detectable concentration pre-pregnancy to a mean concentration of 0.58 ng/ml (0.2 nmol/l) at 10 weeks of gestation.
Figure 2:Three-dimensional modeling of the mammalian Regprotein sequences by SwissProt folding algorithms reveal that the binding region sequence is presented and exposed on the external surface of the protein and not folded within the confines of the protein; thus, it is available for protein-binding interactions with the Reg receptor.
Citation: Levetan C (2017) Islet Neogenesis Therapy from Endogenous Pancreatic Stem Cells without Transplantation: Will Type 1 and Type 2 Diabetes Soon be Diseases of the Past?. J Diabetes Treat 2017: J116.