Vol 75, No 2 (2024)
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The role of genetic risk factors, diet, and gut microbiota in type 1 diabetes mellitus, pancreas and pancreatic islet transplantation

Agnieszka Zawada1, Marzena Skrzypczak-Zielińska2, Sarah Gondek3, Piotr Witkowski3, Anna M. Rychter41, Alicja E. Ratajczak-Pawłowska41, Marek Karczewski5, Agnieszka Dobrowolska1, Iwona Krela-Kaźmierczak41
Pubmed: 38646984
Endokrynol Pol 2024;75(2):140-147.

Abstract

Despite advances in insulin delivery and glucose monitoring technology, prevention of the progression of secondary complications in patients with type 1 diabetes (T1DM) remains a challenge. Beta cell replacement therapy in the form of islet or pancreas transplantation can restore long-term normoglycaemia with sustained periods of insulin independence among T1DM patients.

However, the same genetic, behavioural, or gut microbiota-related factors that promoted autoimmunity and primary islet destruction may also affect the function of transplanted islets and the ultimate results of transplant procedures. In such cases, identifying genetic risk factors and modifying behavioural factors and those related to gut microbiota may be beneficial for the outcomes of transplant procedures.

Herein, we review related literature to the identified current gap in knowledge to be addressed in future clinical trials.

Review

Endokrynologia Polska

DOI: 10.5603/ep.98903

ISSN 0423–104X, e-ISSN 2299–8306

Volume/Tom 75; Number/Numer 2/2024

Submitted: 12.01.2024

Accepted: 13.03.2024

Early publication date: 22.04.2024

The role of genetic risk factors, diet, and gut microbiota in type 1 diabetes mellitus, pancreas and pancreatic islet transplantation

Agnieszka Zawada1Marzena Skrzypczak-Zielińska2Sarah Gondek3Piotr Witkowski3Anna M. Rychter14Alicja E. Ratajczak-Pawłowska14Marek Karczewski5Agnieszka Dobrowolska1Iwona Krela-Kaźmierczak14
1Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
2Institute of Human Genetics, Polish Academy of Sciences, Poznan, Poland
3The Transplantation Institute, University of Chicago, Chicago, United States
4Laboratory of Nutrigenetics, Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poznan, Poland
5Department of General and Transplantation Surgery, Poznan University of Medical Sciences, Poznan, Poland

Agnieszka Zawada and Alicja Ratajczak-Pawłowska, Department of Gastroenterology, Dietetics, and Internal Diseases, Poznan University of Medical Sciences, Poland, tel: (+48) 8691 343; fax: (+48) 8691 686; a.zawada@ump.edu.pl

This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, allowing to download articles and share them with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially

Abstract
Despite advances in insulin delivery and glucose monitoring technology, prevention of the progression of secondary complications in patients with type 1 diabetes (T1DM) remains a challenge. Beta cell replacement therapy in the form of islet or pancreas transplantation can restore long-term normoglycaemia with sustained periods of insulin independence among T1DM patients. However, the same genetic, behavioural, or gut microbiota-related factors that promoted autoimmunity and primary islet destruction may also affect the function of transplanted islets and the ultimate results of transplant procedures. In such cases, identifying genetic risk factors and modifying behavioural factors and those related to gut microbiota may be beneficial for the outcomes of transplant procedures. Herein, we review related literature to the identified current gap in knowledge to be addressed in future clinical trials. (Endokrynol Pol 2024; 75 (2): 140–147)
Key words: pancreatic islets transplantation; genes; gut microbiota; diet; type 1 diabetes

Introduction

Type 1 diabetes mellitus as an autoimmune disease

Type 1 diabetes mellitus (T1DM) is an autoimmune disease in which pancreatic beta cells are selectively destroyed, leading to a deficiency in insulin production in the body and subsequent hyperglycaemia. Despite technological advancement in exogenous insulin supplementation and blood glucose monitoring, the disease still presents a significant clinical challenge, suboptimal blood glucose control, and the development of secondary diabetic complications. Epidemiological data indicate that microangiopathic complications affect approximately 30% of patients with diabetes, and macroangiopathy is still a primary cause of mortality, significantly higher than in the general population. Patients with T1DM have reduced life expectancy and live with significant disabilities and poor quality of life. Increasingly, researchers are looking for alternative ways to treat diabetes in the form of beta cell replacement therapy with islet cell or pancreas transplantation. However, the need for toxic lifelong immunosuppressive medication remains a considerable hurdle precluding the extensive application of this therapy. The review aims to establish the current knowledge about genetic and behavioural determinants, abnormalities in the gut microbiota concerning the severity of diabetic complications, and the outcomes after pancreas and pancreatic islet transplantation.

Genetic factors and progression of secondary complications in patients with T1DM

There seem to be other factors affecting the progression of secondary diabetic complications besides poor blood glucose control. There are patients with similar duration of diabetes and degree of glycaemic control but with very different severity of microangiopathy (particularly diabetic retinopathy and nephropathy) [1, 2]. Hence, it is essential to look for predictors of severe course and progression of complications. The Family Investigation of Nephropathy and Diabetes (FIND-Eye research) found a significant heritability of diabetic retinopathy at 27%, and a study of a group of 8114 DM1 patients among 6707 American families confirmed a serious familial risk of diabetic retinopathy, regardless of disease duration [3, 4]. The literature describes numerous genes potentially related to the progression of diabetic complications, but there is a lack of consistent findings and use of this knowledge in clinical practice [5, 6]. Thus, it is crucial to conduct further molecular genetic studies to define the genetic factors associated with retinopathy and other complications and the severe course of diabetes in these patients. Advanced genetic techniques may help identify patients more prone to develop microangiopathic complications, in whom the use of beta cell replacement therapy may provide more clinical benefit. Based on previous scientific studies, especially genome-wide association studies (GWAS), numerous candidate genes have been identified that may be involved in determining the course of DM1. They are summarised in Table 1.

Table 1. Candidate gene studies in diabetic retinopathy, nephropathy, and neuropathy

Candidate gene

Gene location

OMIM entry

Polymorphism

Effect on T1DM

Reference

Folliculin (FLCN)

17p11.2

607273

rs11867934

Susceptibility to diabetic retinopathy

Skol et al. 2020 [7]

Aldose reductase (AKR1B1)

7q33

103880

rs9640883

rs759853

Protection from diabetic retinopathy

Cao et al. 2018 [8]

Duration of diabetes

Abhary et al. 2010 [6]

Receptor for advanced glycation end product (AGER)

6p21.32

600214

Risk of diabetic retinopathy

Balasubbu et al. 2010 [9]

Vascular endothelial growth factor (VEGFA)

6p21.1

192240

rs3025039

rs25648

rs3025039 rs3025021 rs13207351 rs2146323 rs2010963 rs25648 rs833061 rs2010963

Risk of diabetic retinopathy

Yang et al. 2020 [10]

Susceptibility to diabetic neuropathy.

Politi et al. 2016 [11]

Endothelial nitric oxide synthase (NOS3)

7q36.1

163729

rs270744

rs869109213 rs2070744

Risk of diabetic retinopathy

Midani et al. 2019 [12]

Susceptibility to diabetic neuropathy

Angiotensin I converting enzyme (ACE)

17q23.3

106180

rs1799752

rs1799752 rs4343

Risk of diabetic retinopathy

Luo et al. 2016 [13];

Liang et al. 2013 [14]

Risk of diabetic retinal and renal complications

Marre et al., 1994 [15]

Erythropoietin (EPO)

7q22.1

133170

rs551238

rs1617640

rs507392

Risk of diabetic retinopathy

Fan et al. 2016 [16]; Abhary et al. 2010 [6]; Mankoˇc Ramuš et al. 2021 [17]

Calcium channel voltage dependent beta-2 sub unit (CACNB2)

10p12.33-p12.31

600003

rs202152674 rs137886839

Increased risk of proliferative diabetic retinopathy

Vuori et al. 2019 [18]

Intergenic locus in between AKT3 and ZNF238

1:24401312

-

rs476141

Increased risk of diabetic retinopathy

Grassi et al. 2011 [19]

Calcium/calmodulin-dependent protein kinase IV (CAMK4)

5q22.1

114080

rs2300782

Increased risk of diabetic retinopathy

Fu et al. 2009 [20]

Formin 1 (FMN1)

15q13.3

136535

rs2300782

Increased risk of diabetic retinopathy

Fu et al. 2009 [20]

Growth factor receptor bound 2 (GRB2)

17q25.1

108355

rs9896052

Sight threatening diabetic retinopathy

Burdon et al. 2015 [21]

Valosin-containing protein-like (NVL)

1q42.11

602426

rs142293996

Increased risk of diabetic retinopathy

Pollack et al. 2019 [22]

STT3 Oligosaccharyltransferase complex catalytic subunit B (STT3B)

3p23

608605

rs12630354

Increased risk of diabetic retinopathy

Imamura et al. 2021 [23]

Paralemmin 2 (PALM2AKAP2)

9q31.3

604582

rs140508424

Increased risk of diabetic retinopathy

Mathebula et al. 2015 [24]

Methylenetetrahydrofolate reductase (MTHFR)

1p36.22

607093

rs1801133

Susceptibility to diabetic neuropathy

Politi et al. 2016 [11]

Glyoxalase I (GLO1)

6p21.2

138750

rs2736654

Apolipoprotein E (APOE)

19q13.32

107741

rs429358

Interleukin 4 (IL4)

5q31.1

147780

VNTR (P1/P2 allele)

Glutathione peroxidase 1 (GPX1)

3p21.31

138320

rs1050450

Adrenoceptor alpha 2B (ADRA2B)

2q11.2

104260

rs879255577

MicroRNA 146A

(MIR146A)

5q33.3

610566

rs2910164

Decreased risk of neuropathy

MicroRNA 128A (MIR128A)

2q21.3

611774

rs11888095

Susceptibility to diabetic neuropathy

GDNF family receptor alpha 2 (GFRA2)

8p21.3

601956

rs7428041

Decreased risk of neuropathy

Glutathione S-transferase theta 1 (GSTT1)

22q11.2

600436

wild/nul

Susceptibility to diabetic neuropathy

Transcription factor 7 like 2 (TCF7L2)

10q25.2-q25.3

602228

rs7903146

Beta cell replacement therapies: pancreas and pancreatic islet transplantation in T1DM

Pancreatic transplantation

Pancreas transplantation has been offered to patients with T1DM since 1966 [25]. Metabolic outcomes of the procedure are excellent; the transplant restores proper interaction between beta and alpha cells, resulting in appropriate regulation of insulin and glucagon secretion, optimal blood glucose control, and long-term insulin independence. It also improves lipid profile and normalises glucose production in the liver. Clinically, pancreas transplantation prevents the progression of neuropathy, retinopathy, and nephropathy and even, to some extent, reverses some pathological changes [26]. Unfortunately, despite improved surgical outcomes, the procedure still carries a substantial risk of morbidity, especially in patients with advanced cardiovascular disease. Also, the need for lifelong immunosuppression with related side effects (opportunistic infection, nephrotoxicity, neurotoxicity, hypertension, increased risk of skin cancer, and lymphoproliferative disease) limits pancreas transplantation utility to small patient populations [7]. Most commonly pancreas transplant is offered to patients with end-stage kidney disease who need surgery and immunosuppression for kidney transplantation. A pancreas can be offered at the time of kidney transplant as simultaneous kidney and pancreas transplantation (SPK), or subsequently after kidney transplant as pancreas after kidney transplantation (PAK). Pancreas transplant alone (PTA) is offered only to desperate patients with problematic hypoglycaemia despite optimal insulin treatment (Fig. 1) [27].

178593.png
Figure 1. Pancreas transplant in a patient with type 1 diabetes (T1DM). GC glycemic control; HG hypoglycemia; SPK simultaneous kidney and pancreas transplantation; CKD chronic kidney disease

Microbiota is a factor that significantly influences the human immune system and may also affect the acceptance of the transplant [28, 29]. Pancreas transplantation can also affect patient microbiota by transmitting donor microbiota from donor duodenum transplanted together with the pancreas and by the effect of antibiotics and immunosuppression medication used after the transplant. In addition, the gut microbiota composition of T1DM patients differs from healthy adults [30], which may have an additional effect on the graft. However, it is unknown whether and how gut microbiota affects the post-transplantation clinical course and complications [29]. Despite progression in surgical technique, the 10% risk of early pancreas graft thrombosis and even higher risk of postoperative infection remains a clinical challenge, and microbiota may play a dominant role in these complications.

Because genetic factors may affect the progression of microangiopathy in T1DM before transplant, they may also affect the progression or recovery from those complications after the transplant. However, we have not found any studies shedding any light on this relationship.

Pancreatic islet transplantation

Pancreatic islet transplantation is a minimally invasive alternative to whole pancreas transplantation. Islets are isolated from a deceased donor pancreas, suspended in a special media, and then infused into the patient portal vein via a small catheter placed through the skin under local anaesthesia by an interventional radiologist. Because no surgery is required, the risk of complication is minimal compared to whole pancreas transplantation. The risk of bleeding from the liver requiring blood transfusion is low and below 10%, while the need for surgical intervention to stop bleeding is very rare below 1%. Unfortunately, since islets are allogeneic, patients still require the same lifelong immunosuppression as any other transplant recipients, which limits its utility again to a small population of patients with T1DM. Similarly to whole pancreas transplants, islets are offered to desperate patients with problematic hypoglycaemia (islet transplant alone ITA) or kidney transplant recipients (islet after kidney IAK). The lack of reimbursement for the procedure in the US due to outdated FDA regulations further limits islet transplantation availability [31].

Metabolically, islet transplantation restores endogenous insulin secretion and physiologic blood glucose regulation as whole pancreas transplantation. Five-year insulin independence might be as high as 50–60% in the most experienced centres, with most of the remaining patients maintaining partial islet function, which protects them from severe hypoglycaemic episodes much more effectively than optimal insulin therapy [32, 33]. By providing improved blood glucose control, islet transplantation also prevents the progression of microangiopathy, retinopathy, nephropathy, and macroangiopathy in the carotid artery despite immunosuppression toxicity [34–36].

Moreover, because nutrition is essential in the behavioural management of T1DM, its significance also seems important after islet transplantation. The study of Poggioli et al. showed that anthropometric measures body weight, waist circumference, and fat mass significantly decreased after the procedure. Moreover, the intake of carbohydrates, protein, vitamin B12, B6, zinc, and phosphorus was also lower than before transplantation [37]. Interestingly, zinc can be beneficial posttransplant by improving glucose control and suppressing early graft failure in animal studies, and further studies on humans are warranted to confirm the effect. [38]. Therefore, perioperative management should consider counselling by a qualified dietitian and appropriate nutritional support.

Diet and lifestyle in patients with T1DM

Nutritional therapy and counselling are essential parts of T1DM treatment, and they aim to improve and maintain glycaemic control and prevent chronic complications (or to adjust diet if they occur) [39]. However, several data show that adherence to dietary guidelines may vary considerably among T1DM patients. Results from the non-systematic review of Patton showed that adherence to nutritional recommendations among youths with T1DM varied between 21 and 95%; however, many participants did not adhere to recommended intakes of fruits, vegetables, and whole grains [40]. In the study of Mohammed et al., 55.7% of patients (only 28.7% of participants had T1DM) did not adhere to the recommended dietary approach, and family/friends meetings and eating out were the main reasons [41]. However, attending to nutritional education and diabetes duration significantly increased nutritive adherence. Nutritional education and dietary counselling are essential because other studies have shown that they can also be associated with lower glycosylated haemoglobin (HbA1c) values [42, 43]. However, studies are missing discussing whether adherence to dietary guidelines will delay the development of hypoglycaemia unawareness and the need for transplantation.

Due to limited engraftment and limited islet mass retrieved and transplanted from a deceased donor pancreas, islet transplantation usually provides lower than naturally present pancreas islet mass to the patients. As a result, islet mass, even in insulin-independent patients, is typically only borderline, and islet function can be affected by excessive carbohydrate intake, leading to chronic islet overstimulation, exhaustion, and graft failure. The gradual decline of islet graft function without signs of rejection has been described. Amyloid deposition found in failing islets may indicate misfolding mechanism and faulty protein production instead of insulin resulting from beta cell metabolic stress [44]. Therefore, dietary carbohydrate restrictions and physical activity promote stability of the islet graft and insulin independence and are highly recommended. However, reports with data supporting such recommendations are still lacking.

Because the aetiopathogenesis of T1DM is still not completely understood, it seems thqt environmental and genetic factors play a significant role. The same factors may lead to the reactivation of autoimmunity and ultimately affect the function of transplanted islets. Therefore, an approach that will include proper nutrition and genetic factors is necessary [45, 47]. However, although food compounds potentially modify the expression of genes involved in the immune response which is vital for T1DM patients more studies investigating gene-nutrient interactions are needed beause current evidence regarding nutrigenetics and nutrigenomics are scarce [48, 49].

More studies are needed to evaluate the influence of nutritional factors during peri- and postoperative states on islet transplantation.

Gut microbiota composition in type 1 diabetes after pancreatic and pancreatic islet transplantation

The incidence rate of T1DM is increasing dramatically, but only 10% of genetically susceptible individuals will develop the disease. Therefore, there is no doubt that other factors, such as viral and bacterial infections and environmental factors, also play a role in developing T1D [50]. The microbiome may impact the development and course of this disease due to its proven influence on inflammation and the immune system [51]. Gut microbiota may influence signalling through TLR family receptors that are directly involved in autoimmunity in T1DM [52, 53]. The gut microbiota may also affect the development of type 1 diabetes through short chain fatty acids (SCFAs). An increased abundance of butyrate producing species was associated with an increased risk of T1DM [54, 55]. Other studies show that SCFAs protect genetically susceptible mice from developing diabetes. The epigenetic action of butyrate via histone acetylation at the Foxp3 locus promoter is responsible for differentiating regulatory T cells or inhibiting histone deacetylases in macrophages [56]. However, data on the impact of microbiota are still ambiguous [57]. Modulation of the microbiome leading to improved composition and diversity of the gut microbiota may include early exposure to beneficial bacteria, FMT transplants, dietary modifications, and probiotic and prebiotic supplementation [30]. Probiotic administration in early infancy positively correlated with decreased pancreatic islet specific autoantibodies [58]. Probiotic supplementation immunomodulates pancreatic islet function, which may improve glycaemic control and microflora changes to protect against systemic manifestations of pancreatic islet autoimmunity [59, 60].

The microbiota may also affect glycaemic control and, thus, the development of chronic complications, particularly in patients with already developed chronic kidney disease. In these patients, uraemia exacerbates dysbiosis, and regular use of probiotics improves metabolic control by reducing inflammation and oxidative stress, which improves renal flow.

Based on the current knowledge in the field of gut microbiota research in diabetes, it can be postulated that the understanding of the abnormal composition of the microorganisms inhabiting the gut may contribute to the greater effectiveness of pancreatic islet transplantation. It has been shown that the composition of microbiota in individuals with T1DM is significantly different than in healthy subjects, which may be an important modifiable risk factor for T1DM complications. The number of some bacterial groups (Actinobacteria and Firmicutes) and the ratio of Firmicutes to Bacteroidetes is lower in children with T1DM. However, these individuals have increased amounts of Clostridium, Bacteroides, and Veillonella [61]. In addition to quantitative changes, the microbiome of children with diabetes is also less diverse and relatively less stable [62]. Differences in the gut microbiota may also be observed after pancreatic islet transplantation in people with type 1 diabetes due to the interaction between the gut microbiota and the immune system. Studies in animals and humans have shown differences in gut microbial diversity before and after allogeneic organ transplants (liver, kidney, and haematopoietic stem cell transplantation) (29)but also closely related to the occurrence and development of various diseases. With the development of transplantation technologies, allogeneic transplantation has become an effective therapy for a variety of end-stage diseases. However, complications after transplantation still restrict its further development. Post-transplantation complications are closely associated with a host’s immune system. There is also an interaction between a person’s gut microbiota and immune system. Recently, animal and human studies have shown that gut microbial populations and diversity are altered after allogeneic transplantations, such as liver transplantation (LT. Dysbiosis was also observed to be exacerbated during the occurrence of graft versus host (GVHD) [29]. Moreover, numerous studies confirm that probiotic and prebiotic intake can effectively regulate the intestinal microflora and influence the incidence of posttransplant complications [63, 64]. Fewer complications after organ transplantation were also observed in rats with prior stool transplantation [65]. Precise identification by genetic methods of individuals predisposed to developing chronic complications may guide their further treatment in considering pancreatic islet transplantation. Assessment of differences in the gut microbiome composition in individuals before and after pancreas and pancreatic islet cell transplantation may give us the perspective to introduce new standards in the form of probiotic supplementation or stool transplantation in individuals preparing for or after pancreas or beta-cell transplantation.

178602.png
Figure 2. The complex relationship between pancreatic islet transplantation and standard treatment of type 1 diabetes (T1DM)

Summary

A patient with T1DM has a complex health problem developing early in life. A unique interest in the genetic determinants of the occurrence of chronic complications in diabetes can guide more personalised treatment. Diet and microbiota also have an indispensable influence on this process. Promoting better outcomes after islet and pancreas transplantation will benefit the patient’s subsequent prognosis and survival. Investigating the interplay between these factors requires a great deal of research; nonetheless, it can significantly expand the medical knowledge of doctors and patients with type 1 diabetes, improve clinical outcomes, and ultimately improve quality of life.

Author contributions

Conceptualisation: A.Z. and I.K.-K.; writing original draft preparation: A.Z., M.S.-Z., S.G., P.W., A.M.R., A.E.R.-P., M.K.; critical revision of the manuscript: A.D. and I.K.-K.; supervision: I.K.-K.; acceptance of the final version: all authors. All authors have read and agreed to the published version of the manuscript.

Acknowledgements

1. Ms. Anna Rychter and Ms. Alicja Ratajczak-Pawłowska are the participants of the STER Internationalization of Doctoral Schools Program me from NAWA Polish National Agency for Academic Exchange No. PPI/STE/2020/1/00014/DEC/02.

2. Figures were created with BioRender.

3. We acknowledge support for PW from NIDDK P30 DK020595.

Conflict of interest

Authors declare no conflict of interests.

Funding

Not applicable.

References

  1. Sun JK, Keenan HA, Cavallerano JD, et al. Protection from retinopathy and other complications in patients with type 1 diabetes of extreme duration: the joslin 50-year medalist study. Diabetes Care. 2011; 34(4): 968–974, doi: 10.2337/dc10-1675, indexed in Pubmed: 21447665.
  2. Gao X, Gauderman WJ, Marjoram P, et al. Native American ancestry is associated with severe diabetic retinopathy in Latinos. Invest Ophthalmol Vis Sci. 2014; 55(9): 6041–6045, doi: 10.1167/iovs.14-15044, indexed in Pubmed: 25146985.
  3. Arar NH, Freedman BI, Adler SG, et al. Family Investigation of Nephropathy and Diabetes Research Group. Heritability of the severity of diabetic retinopathy: the FIND-Eye study. Invest Ophthalmol Vis Sci. 2008; 49(9): 3839–3845, doi: 10.1167/iovs.07-1633, indexed in Pubmed: 18765632.
  4. Monti MC, Lonsdale JT, Montomoli C, et al. Familial risk factors for microvascular complications and differential male-female risk in a large cohort of American families with type 1 diabetes. J Clin Endocrinol Metab. 2007; 92(12): 4650–4655, doi: 10.1210/jc.2007-1185, indexed in Pubmed: 17878250.
  5. Bhatwadekar AD, Shughoury A, Belamkar A, et al. Genetics of Diabetic Retinopathy, a Leading Cause of Irreversible Blindness in the Industrialized World. Genes (Basel). 2021; 12(8), doi: 10.3390/genes12081200, indexed in Pubmed: 34440374.
  6. Abhary S, Burdon KP, Laurie KJ, et al. Aldose reductase gene polymorphisms and diabetic retinopathy susceptibility. Diabetes Care. 2010; 33(8): 1834–1836, doi: 10.2337/dc09-1893, indexed in Pubmed: 20424224.
  7. Skol AD, Jung SC, Sokovic AM, et al. DCCT/EDIC Study group. Integration of genomics and transcriptomics predicts diabetic retinopathy susceptibility genes. Elife. 2020; 9, doi: 10.7554/eLife.59980, indexed in Pubmed: 33164750.
  8. Cao M, Tian Z, Zhang L, et al. Genetic association of AKR1B1 gene polymorphism rs759853 with diabetic retinopathy risk: A meta-analysis. Gene. 2018; 676: 73–78, doi: 10.1016/j.gene.2018.07.014, indexed in Pubmed: 30201105.
  9. Balasubbu S, Sundaresan P, Rajendran A, et al. Association analysis of nine candidate gene polymorphisms in Indian patients with type 2 diabetic retinopathy. BMC Med Genet. 2010; 11: 158, doi: 10.1186/1471-2350-11-158, indexed in Pubmed: 21067572.
  10. Yang Q, Zhang Y, Zhang X, et al. Association of VEGF Gene Polymorphisms with Susceptibility to Diabetic Retinopathy: A Systematic Review and Meta-Analysis. Horm Metab Res. 2020; 52(5): 264–279, doi: 10.1055/a-1143-6024, indexed in Pubmed: 32403142.
  11. Politi C, Ciccacci C, D’Amato C, et al. Recent advances in exploring the genetic susceptibility to diabetic neuropathy. Diabetes Res Clin Pract. 2016; 120: 198–208, doi: 10.1016/j.diabres.2016.08.006, indexed in Pubmed: 27596057.
  12. Midani F, Ben Amor Z, El Afrit MA, et al. The Role of Genetic Variants (rs869109213 and rs2070744) Of the Gene and II in the a Subunit of the ab Integrin Gene in Diabetic Retinopathy in a Tunisian Population. Semin Ophthalmol. 2019; 34(5): 365–374, doi: 10.1080/08820538.2019.1632354, indexed in Pubmed: 31257963.
  13. Luo S, Shi C, Wang F, et al. Association between the Angiotensin-Converting Enzyme (ACE) Genetic Polymorphism and Diabetic Retinopathy-A Meta-Analysis Comprising 10,168 Subjects. Int J Environ Res Public Health. 2016; 13(11), doi: 10.3390/ijerph13111142, indexed in Pubmed: 27854313.
  14. Liang S, Pan M, Hu N, et al. Association of angiotensin-converting enzyme gene 2350 G/A polymorphism with diabetic retinopathy in Chinese Han population. Mol Biol Rep. 2013; 40(1): 463–468, doi: 10.1007/s11033-012-2081-2, indexed in Pubmed: 23065222.
  15. Marre M, Bernadet P, Gallois Y, et al. Relationships between angiotensin I converting enzyme gene polymorphism, plasma levels, and diabetic retinal and renal complications. Diabetes. 1994; 43(3): 384–388, doi: 10.2337/diab.43.3.384, indexed in Pubmed: 8314010.
  16. Fan Y, Fu YY, Chen Z, et al. Gene-gene interaction of erythropoietin gene polymorphisms and diabetic retinopathy in Chinese Han. Exp Biol Med (Maywood). 2016; 241(14): 1524–1530, doi: 10.1177/1535370216645210, indexed in Pubmed: 27190272.
  17. Mankoč Ramuš S, Pungeršek G, Petrovič MG, et al. The GG genotype of erythropoietin rs1617640 polymorphism affects the risk of proliferative diabetic retinopathy in Slovenian subjects with type 2 diabetes mellitus: enemy or ally? Acta Ophthalmol. 2021; 99(8): e1382–e1389, doi: 10.1111/aos.14813, indexed in Pubmed: 33599115.
  18. Vuori N, Sandholm N, Kumar A, et al. FinnDiane Study. Is a Novel Susceptibility Gene for Diabetic Retinopathy in Type 1 Diabetes. Diabetes. 2019; 68(11): 2165–2174, doi: 10.2337/db19-0130, indexed in Pubmed: 31439644.
  19. Grassi MA, Tikhomirov A, Ramalingam S, et al. Genome-wide meta-analysis for severe diabetic retinopathy. Hum Mol Genet. 2011; 20(12): 2472–2481, doi: 10.1093/hmg/ddr121, indexed in Pubmed: 21441570.
  20. Fu YP, Hallman DM, Gonzalez VH, et al. Identification of Diabetic Retinopathy Genes through a Genome-Wide Association Study among Mexican-Americans from Starr County, Texas. J Ophthalmol. 2010; 2010, doi: 10.1155/2010/861291, indexed in Pubmed: 20871662.
  21. Burdon KP, Fogarty RD, Shen W, et al. Genome-wide association study for sight-threatening diabetic retinopathy reveals association with genetic variation near the GRB2 gene. Diabetologia. 2015; 58(10): 2288–2297, doi: 10.1007/s00125-015-3697-2, indexed in Pubmed: 26188370.
  22. Pollack S, Igo R, Jensen R, et al. Erratum. Multiethnic Genome-Wide Association Study of Diabetic Retinopathy Using Liability Threshold Modeling of Duration of Diabetes and Glycemic Control. Diabetes 2019;68:441—456. Diabetes. 2020; 69(6): 1306–1306, doi: 10.2337/db20-er06a.
  23. Imamura M, Takahashi A, Matsunami M, et al. International Diabetic Retinopathy and Genetics CONsortium (iDRAGON). Genome-wide association studies identify two novel loci conferring susceptibility to diabetic retinopathy in Japanese patients with type 2 diabetes. Hum Mol Genet. 2021; 30(8): 716–726, doi: 10.1093/hmg/ddab044, indexed in Pubmed: 33607655.
  24. Mathebula S. Polyol pathway: A possible mechanism of diabetes complications in the eye. Afr Vis Eye Health. 2015; 74(1), doi: 10.4102/aveh.v74i1.13.
  25. Gallego Ferrero P, Crespo Del Pozo J. Imaging in pancreas transplantation complications: Temporal classification. J Med Imaging Radiat Oncol. 2018 [Epub ahead of print], doi: 10.1111/1754-9485.12750, indexed in Pubmed: 29808575.
  26. Dholakia S, Royston E, Quiroga I, et al. The rise and potential fall of pancreas transplantation. Br Med Bull. 2017; 124(1): 171–179, doi: 10.1093/bmb/ldx039, indexed in Pubmed: 29088319.
  27. Aref A, Zayan T, Pararajasingam R, et al. Pancreatic transplantation: Brief review of the current evidence. World J Transplant. 2019; 9(4): 81–93, doi: 10.5500/wjt.v9.i4.81, indexed in Pubmed: 31523630.
  28. Dery KJ, Kadono K, Hirao H, et al. Microbiota in organ transplantation: An immunological and therapeutic conundrum? Cell Immunol. 2020; 351: 104080, doi: 10.1016/j.cellimm.2020.104080, indexed in Pubmed: 32139071.
  29. Wang W, Xu S, Ren Z, et al. Gut microbiota and allogeneic transplantation. J Transl Med. 2015; 13: 275, doi: 10.1186/s12967-015-0640-8, indexed in Pubmed: 26298517.
  30. Gradisteanu Pircalabioru G, Corcionivoschi N, Gundogdu O, et al. Dysbiosis in the Development of Type I Diabetes and Associated Complications: From Mechanisms to Targeted Gut Microbes Manipulation Therapies. Int J Mol Sci. 2021; 22(5), doi: 10.3390/ijms22052763, indexed in Pubmed: 33803255.
  31. Witkowski P, Philipson LH, Buse JB, et al. Islets Transplantation at a Crossroads - Need for Urgent Regulatory Update in the United States: Perspective Presented During the Scientific Sessions 2021 at the American Diabetes Association Congress. Front Endocrinol (Lausanne). 2021; 12: 789526, doi: 10.3389/fendo.2021.789526, indexed in Pubmed: 35069442.
  32. Shapiro AM. Islet transplantation in type 1 diabetes: ongoing challenges, refined procedures, and long-term outcome. Rev Diabet Stud. 2012; 9(4): 385–406, doi: 10.1900/RDS.2012.9.385, indexed in Pubmed: 23804275.
  33. Lablanche S, Vantyghem MC, Kessler L, et al. TRIMECO trial investigators. Islet transplantation versus insulin therapy in patients with type 1 diabetes with severe hypoglycaemia or poorly controlled glycaemia after kidney transplantation (TRIMECO): a multicentre, randomised controlled trial. Lancet Diabetes Endocrinol. 2018; 6(7): 527–537, doi: 10.1016/S2213-8587(18)30078-0, indexed in Pubmed: 29776895.
  34. Fensom B, Harris C, Thompson SE, et al. Islet cell transplantation improves nerve conduction velocity in type 1 diabetes compared with intensive medical therapy over six years. Diabetes Res Clin Pract. 2016; 122: 101–105, doi: 10.1016/j.diabres.2016.10.011, indexed in Pubmed: 27825059.
  35. Thompson DM, Meloche M, Ao Z, et al. Reduced progression of diabetic microvascular complications with islet cell transplantation compared with intensive medical therapy. Transplantation. 2011; 91(3): 373–378, doi: 10.1097/TP.0b013e31820437f3, indexed in Pubmed: 21258272.
  36. Danielson KK, Hatipoglu B, Kinzer K, et al. Reduction in carotid intima-media thickness after pancreatic islet transplantation in patients with type 1 diabetes. Diabetes Care. 2013; 36(2): 450–456, doi: 10.2337/dc12-0679, indexed in Pubmed: 23172970.
  37. Poggioli R, Enfield G, Messinger S, et al. Nutritional status and behavior in subjects with type 1 diabetes, before and after islet transplantation. Transplantation. 2008; 85(4): 501–506, doi: 10.1097/TP.0b013e3181629d7b, indexed in Pubmed: 18347527.
  38. Okamoto T, Kuroki T, Adachi T, et al. Effect of zinc on early graft failure following intraportal islet transplantation in rat recipients. Ann Transplant. 2011; 16(3): 114–120, doi: 10.12659/aot.882003, indexed in Pubmed: 21959518.
  39. Gray A, Threlkeld RJ. Nutritional Recommendations for Individuals with Diabetes. In: Feingold KR, Anawalt B, Boyce A. et al. ed. Endotext [Internet]. MDText.com, South Dartmouth (MA) 2000.
  40. Patton SR. Adherence to diet in youth with type 1 diabetes. J Am Diet Assoc. 2011; 111(4): 550–555, doi: 10.1016/j.jada.2011.01.016, indexed in Pubmed: 21443987.
  41. Mohammed MA, Sharew NT. Adherence to dietary recommendation and associated factors among diabetic patients in Ethiopian teaching hospitals. Pan Afr Med J. 2019; 33: 260, doi: 10.11604/pamj.2019.33.260.14463, indexed in Pubmed: 31692826.
  42. Pancheva R, Zhelyazkova D, Ahmed F, et al. Dietary Intake and Adherence to the Recommendations for Healthy Eating in Patients With Type 1 Diabetes: A Narrative Review. Front Nutr. 2021; 8: 782670, doi: 10.3389/fnut.2021.782670, indexed in Pubmed: 34977126.
  43. Powers MA, Gal RL, Connor CG, et al. Eating patterns and food intake of persons with type 1 diabetes within the T1D exchange. Diabetes Res Clin Pract. 2018; 141: 217–228, doi: 10.1016/j.diabres.2018.05.011, indexed in Pubmed: 29772288.
  44. Potter KJ, Abedini A, Marek P, et al. Islet amyloid deposition limits the viability of human islet grafts but not porcine islet grafts. Proc Natl Acad Sci U S A. 2010; 107(9): 4305–4310, doi: 10.1073/pnas.0909024107, indexed in Pubmed: 20160085.
  45. Ortega Á, Berná G, Rojas A, et al. Gene-Diet Interactions in Type 2 Diabetes: The Chicken and Egg Debate. Int J Mol Sci. 2017; 18(6), doi: 10.3390/ijms18061188, indexed in Pubmed: 28574454.
  46. Felisbino K, Granzotti JG, Bello-Santos L, et al. Nutrigenomics in Regulating the Expression of Genes Related to Type 2 Diabetes Mellitus. Front Physiol. 2021; 12: 699220, doi: 10.3389/fphys.2021.699220, indexed in Pubmed: 34366888.
  47. Udogadi N, Abdullahi M. Interplay between nutrigenomics and diabetes: a mini review. J Diab Metab Diso Control. 2020; 7(1): 9–12, doi: 10.15406/jdmdc.2020.07.00194.
  48. Biros E, Jordan MA, Baxter AG. Genes mediating environment interactions in type 1 diabetes. Rev Diabet Stud. 2005; 2(4): 192–207, doi: 10.1900/RDS.2005.2.192, indexed in Pubmed: 17491695.
  49. Patrick C, Wang GS, Lefebvre DE, et al. Promotion of autoimmune diabetes by cereal diet in the presence or absence of microbes associated with gut immune activation, regulatory imbalance, and altered cathelicidin antimicrobial Peptide. Diabetes. 2013; 62(6): 2036–2047, doi: 10.2337/db12-1243, indexed in Pubmed: 23349499.
  50. Achenbach P, Bonifacio E, Koczwara K, et al. Natural History of Type 1 Diabetes. Diabetes. 2005; 54(suppl_2): S25–S31, doi: 10.2337/diabetes.54.suppl_2.s25.
  51. Hooper LV, Littman DR, Macpherson AJ. Interactions between the microbiota and the immune system. Science. 2012; 336(6086): 1268–1273, doi: 10.1126/science.1223490, indexed in Pubmed: 22674334.
  52. Wen Li, Ley RE, Volchkov PYu, et al. Innate immunity and intestinal microbiota in the development of Type 1 diabetes. Nature. 2008; 455(7216): 1109–1113, doi: 10.1038/nature07336, indexed in Pubmed: 18806780.
  53. Alkanani AK, Hara N, Lien E, et al. Induction of diabetes in the RIP-B7.1 mouse model is critically dependent on TLR3 and MyD88 pathways and is associated with alterations in the intestinal microbiome. Diabetes. 2014; 63(2): 619–631, doi: 10.2337/db13-1007, indexed in Pubmed: 24353176.
  54. de Groot PF, Belzer C, Aydin Ö, et al. Distinct fecal and oral microbiota composition in human type 1 diabetes, an observational study. PLoS One. 2017; 12(12): e0188475, doi: 10.1371/journal.pone.0188475, indexed in Pubmed: 29211757.
  55. Brown CT, Davis-Richardson AG, Giongo A, et al. Gut microbiome metagenomics analysis suggests a functional model for the development of autoimmunity for type 1 diabetes. PLoS One. 2011; 6(10): e25792, doi: 10.1371/journal.pone.0025792, indexed in Pubmed: 22043294.
  56. Furusawa Y, Obata Y, Fukuda S, et al. Commensal microbe-derived butyrate induces the differentiation of colonic regulatory T cells. Nature. 2013; 504(7480): 446–450, doi: 10.1038/nature12721, indexed in Pubmed: 24226770.
  57. Morrison DJ, Preston T. Formation of short chain fatty acids by the gut microbiota and their impact on human metabolism. Gut Microbes. 2016; 7(3): 189–200, doi: 10.1080/19490976.2015.1134082, indexed in Pubmed: 26963409.
  58. Uusitalo U, Liu X, Yang J, et al. TEDDY Study Group. Association of Early Exposure of Probiotics and Islet Autoimmunity in the TEDDY Study. JAMA Pediatr. 2016; 170(1): 20–28, doi: 10.1001/jamapediatrics.2015.2757, indexed in Pubmed: 26552054.
  59. Groele L, Szajewska H, Szypowska A. Effects of GG and Bb12 on beta-cell function in children with newly diagnosed type 1 diabetes: protocol of a randomised controlled trial. BMJ Open. 2017; 7(10): e017178, doi: 10.1136/bmjopen-2017-017178, indexed in Pubmed: 29025837.
  60. Vatanen T, Franzosa EA, Schwager R, et al. The human gut microbiome in early-onset type 1 diabetes from the TEDDY study. Nature. 2018; 562(7728): 589–594, doi: 10.1038/s41586-018-0620-2, indexed in Pubmed: 30356183.
  61. Murri M, Leiva I, Gomez-Zumaquero JM, et al. Gut microbiota in children with type 1 diabetes differs from that in healthy children: a case-control study. BMC Med. 2013; 11: 46, doi: 10.1186/1741-7015-11-46, indexed in Pubmed: 23433344.
  62. Giongo A, Gano KA, Crabb DB, et al. Toward defining the autoimmune microbiome for type 1 diabetes. ISME J. 2011; 5(1): 82–91, doi: 10.1038/ismej.2010.92, indexed in Pubmed: 20613793.
  63. Xie L, Hu X, Li W, et al. A retrospective study of end-stage kidney disease patients on maintenance hemodialysis with renal osteodystrophy-associated fragility fractures. BMC Nephrol. 2021; 22(1): 23, doi: 10.1186/s12882-020-02224-7, indexed in Pubmed: 33430788.
  64. Oh PL, Martínez I, Sun Y, et al. Characterization of the ileal microbiota in rejecting and nonrejecting recipients of small bowel transplants. Am J Transplant. 2012; 12(3): 753–762, doi: 10.1111/j.1600-6143.2011.03860.x, indexed in Pubmed: 22152019.
  65. Xie Y, Chen H, Zhu B, et al. Effect of intestinal microbiota alteration on hepatic damage in rats with acute rejection after liver transplantation. Microb Ecol. 2014; 68(4): 871–880, doi: 10.1007/s00248-014-0452-z, indexed in Pubmed: 25004996.