Cognitive Outcome After Islet Transplantation.

Severe or repeated hypoglycemia events may favor memory complaints in type 1 diabetes (T1D). Pancreatic islet transplantation (IT) is an alternative option to exogenous insulin therapy in case of labile T1D, implying a maintenance immunosuppression regimen based on sirolimus or mycophenolate, associated with tacrolimus, that may also have neurological toxicity. The objective of this study was to compare a cognitive rating scale Mini-Mental State Examination (MMSE) between T1D patients with or without IT and to identify parameters influencing MMSE. Methods: This retrospective cross-sectional study compared MMSE and cognitive function tests between islet-transplanted T1D patients and nontransplanted T1D controls who were transplant candidates. Patients were excluded if they refused. Results: Forty-three T1D patients were included: 9 T1D patients before IT and 34 islet-transplanted patients (14 treated with mycophenolate and 20 treated with sirolimus). Neither MMSE score (P = 0.70) nor higher cognitive function differed between islet versus non-islet-transplanted patients, whatever the type of immunosuppression. In the whole population (N = 43), MMSE score was negatively correlated to glycated hemoglobin (r = -0.30; P = 0.048) and the time spent in hypoglycemia on the continuous glucose monitoring (r = -0.32; P = 0.041). MMSE score was not correlated to fasting C-peptide level, time spent in hyperglycemia, average blood glucose, time under immunosuppression, duration of diabetes, or beta-score (success score of IT). Conclusions: This first study evaluating cognitive disorders in islet-transplanted T1D patients argues for the importance of glucose balance on cognitive function rather than of immunosuppressive treatment, with a favorable effect of glucose balance improvement on MMSE score after IT.

Primary Graft Function and 5 Year Insulin Independence After Pancreas and Islet Transplantation for Type 1 Diabetes: A Retrospective Parallel Cohort Study.

In islet transplantation (ITx), primary graft function (PGF) or beta cell function measured early after last infusion is closely associated with long term clinical outcomes. We investigated the association between PGF and 5 year insulin independence rate in ITx and pancreas transplantation (PTx) recipients. This retrospective multicenter study included type 1 diabetes patients who underwent ITx in Lille and PTx in Nantes from 2000 to 2022. PGF was assessed using the validated Beta2-score and compared to normoglycemic control subjects. Subsequently, the 5 year insulin independence rates, as predicted by a validated PGF-based model, were compared to the actual rates observed in ITx and PTx patients. The study enrolled 39 ITx (23 ITA, 16 IAK), 209 PTx recipients (23 PTA, 14 PAK, 172 SPK), and 56 normoglycemic controls. Mean[SD] PGF was lower after ITx (ITA 22.3[5.2], IAK 24.8[6.4], than after PTx (PTA 38.9[15.3], PAK 36.8[9.0], SPK 38.7[10.5]), and lower than mean beta-cell function measured in normoglycemic control: 36.6[4.3]. The insulin independence rates observed at 5 years after PTA and PAK aligned with PGF predictions, and was higher after SPK. Our results indicate a similar relation between PGF and 5 year insulin independence in ITx and solitary PTx, shedding new light on long-term transplantation outcomes.

The challenge of HLA donor specific antibodies in the management of pancreatic islet transplantation: an illustrative case-series.

Islet transplantation is a unique paradigm in organ transplantation, since multiple donors are required to achieve complete insulin-independence. Preformed or de novo Donor Specific Antibodies (DSA) may target one or several donor islets, which adds complexity to the analysis of their impact. Adult patients with type 1 diabetes transplanted with pancreatic islets between 2005 and 2018 were included in a single-center observational study. Thirty-two recipients with available sera tested by solid-phase assays for anti-HLA antibodies during their whole follow-up were analyzed. Twenty-five recipients were islet-transplantation-alone recipients, and 7 islet-after-kidney recipients. Seven recipients presented with DSA at any time during follow-up (two with preformed DSA only, one with preformed and de novo DSA, 4 with de novo DSA only). Only islet-transplantation-alone recipients presented with de novo DSA. Three clinical trajectories were identified according to: 1/the presence of preformed DSA, 2/early de novo DSA or 3/late de novo DSA. Only late de novo DSA were associated with unfavorable outcomes, depicted by a decrease of the ß-score. Islet transplantation with preformed DSA, even with high MFI values, is associated with favorable outcomes in our experience. On the contrary, de novo DSA, and especially late de novo DSA, may be associated with allograft loss.

Impact of Procedure-Related Complications on Long-term Islet Transplantation Outcome.

BACKGROUND: Pancreatic islet transplantation offers a promising biotherapy for the treatment of type 1 diabetes, but this procedure has met significant challenges over the years. One such challenge is to address why primary graft function still remains inconsistent after islet transplantation. Several variables have been shown to affect graft function, but the impact of procedure-related complications on primary and long-term graft functions has not yet been explored. METHODS: Twenty-six patients with established type 1 diabetes were included in this study. Each patient had two to three intraportal islet infusions to obtain 10,000 islet equivalent (IEQ)/kg in body weight, equaling a total of 68 islet infusions. Islet transplantation consisted of three sequential fresh islet infusions within 3 months. Islet infusions were performed surgically or under ultrasound guidance, depending on patient morphology, availability of the radiology suite, and patient medical history. Prospective assessment of adverse events was recorded and graded using "Common Terminology Criteria for adverse events in Trials of Adult Pancreatic Islet Transplantation." RESULTS: There were no deaths or patients dropouts. Early complications occurred in nine of 68 procedures. ß score 1 month after the last graft and optimal graft function (ß score ≥7) rate were significantly lower in cases of procedure-related complications (P = 0.02, P = 0.03). Procedure-related complications negatively impacted graft function (P = 0.009) and was an independent predictive factor of long-term graft survival (P = 0.033) in multivariate analysis. CONCLUSION: Complications occurring during radiologic or surgical intraportal islet transplantation significantly impair primary graft function and graft survival regardless of their severity.

Management of endocrino-metabolic dysfunctions after allogeneic hematopoietic stem cell transplantation.

Allogeneic hematopoietic stem cell transplantation is mainly indicated in bone marrow dysfunction related to blood diseases, but also in some rare diseases (adrenoleucodystrophy, mitochondrial neurogastrointestinal encephalomyopathy or MNGIE...). After decades, this treatment has proven to be efficient at the cost of numerous early and delayed side effects such as infection, graft-versus-host disease, cardiovascular complications and secondary malignancies. These complications are mainly related to the conditioning, which requires a powerful chemotherapy associated to total body irradiation (myelo-ablation) or immunosuppression (non myelo-ablation). Among side effects, the endocrine complications may be classified as 1) hormonal endocrine deficiencies (particularly gonado- and somatotropic) related to delayed consequences of chemo- and above all radiotherapy, with their consequences on growth, puberty, bone and fertility); 2) auto-immune diseases, particularly dysthyroidism; 3) secondary tumors involving either endocrine glands (thyroid carcinoma) or dependent on hormonal status (breast cancer, meningioma), favored by immune dysregulation and radiotherapy; 4) metabolic complications, especially steroid-induced diabetes and dyslipidemia with their increased cardio-vascular risk. These complications are intricate. Moreover, hormone replacement therapy can modulate the cardio-vascular or the tumoral risk of patients, already increased by radiotherapy and chemotherapy, especially steroids and anthracyclins... Therefore, patients and families should be informed of these side effects and of the importance of a long-term follow-up requiring a multidisciplinary approach.

Continuous glucose monitoring after islet transplantation in type 1 diabetes: an excellent graft function (ß-score greater than 7) Is required to abrogate hyperglycemia, whereas a minimal function is necessary to suppress severe hypoglycemia (ß-score greater than 3).

CONTEXT: For the last 10 yr, continuous glucose monitoring (CGM) has brought up new insights into the accuracy of blood glucose analysis. OBJECTIVE: Our objective was to determine how islet graft function was able to influence the various components of dysglycemia after islet transplantation (IT). DESIGN AND SETTING: We conducted a single-arm open-labeled study with a 3-yr follow-up in a referral center (ClinicalTrial.gov identifiers NCT00446264 and NCT01123187). PATIENTS: Twenty-three consecutive patients with type 1 diabetes (14 islet alone, nine islet after kidney) received IT within 3 months using the Edmonton protocol. INTERVENTION: INTERVENTION included 72-h CGM before and 3, 6, 9, 12, 24, and 36 months after transplantation. MAIN OUTCOME MEASURE: Graft function was estimated via ß-score, a previously validated index (range 0-8) based on treatment requirements, C-peptide, blood glucose, and glycated hemoglobin. RESULTS: At the 3-yr visit, graft function persisted in 19 patients (82%), and 10 (43%) remained insulin independent. Glycated hemoglobin decreased in the whole cohort from 8.3% (7.3-9.0%) at baseline to 6.7% (5.9-7.7%) at 3 yr [median (interquartile range), P < 0.01]. Mean glucose, glucose sd, and time spent with glycemia above 10 mmol/liter (hyperglycemia) and below 3 mmol/liter (hypoglycemia) were significantly lower after IT (P < 0.05 vs. baseline). The four CGM outcomes were related to ß-score (P < 0.001). However, partial function (ß-score >3) was sufficient to abrogate hypoglycemia; suboptimal function (ß-score >5) was necessary to significantly improve mean glucose, glucose sd, and hyperglycemia; and optimal function (ß score >7) was necessary to normalize them. CONCLUSION: The four components of dysglycemia were not equally affected by the degree of islet graft function, which could have important implications for future development of ß-cell replacement. A ß-score above 3 dramatically reduced the occurrence of hypoglycemia.

How to diagnose a lipodystrophy syndrome.

The spectrum of adipose tissue diseases ranges from obesity to lipodystrophy, and is accompanied by insulin resistance syndrome, which promotes the occurrence of type 2 diabetes, dyslipidemia and cardiovascular complications. Lipodystrophy refers to a group of rare diseases characterized by the generalized or partial absence of adipose tissue, and occurs with or without hypertrophy of adipose tissue in other sites. They are classified as being familial or acquired, and generalized or partial. The genetically determined partial forms usually occur as Dunnigan syndrome, which is a type of laminopathy that can also manifest as muscle, cardiac, neuropathic or progeroid involvement. Gene mutations encoding for PPAR-gamma, Akt2, CIDEC, perilipin and the ZMPSTE 24 enzyme are much more rare. The genetically determined generalized forms are also very rare and are linked to mutations of seipin AGPAT2, FBN1, which is accompanied by Marfan syndrome, or of BANF1, which is characterized by a progeroid syndrome without insulin resistance and with early bone complications. Glycosylation disorders are sometimes involved. Some genetically determined forms have recently been found to be due to autoinflammatory syndromes linked to a proteasome anomaly (PSMB8). They result in a lipodystrophy syndrome that occurs secondarily with fever, dermatosis and panniculitis. Then there are forms that are considered to be acquired. They may be iatrogenic (protease inhibitors in HIV patients, glucocorticosteroids, insulin, graft-versus-host disease, etc.), related to an immune system disease (sequelae of dermatopolymyositis, autoimmune polyendocrine syndromes, particularly associated with type 1 diabetes, Barraquer-Simons and Lawrence syndromes), which are promoted by anomalies of the complement system. Finally, lipomatosis is currently classified as a painful form (adiposis dolorosa or Dercum's disease) or benign symmetric multiple form, also known as Launois-Bensaude syndrome or Madelung's disease, which are sometimes related to mitochondrial DNA mutations, but are usually promoted by alcohol. In addition to the medical management of metabolic syndrome and the sometimes surgical treatment of lipodystrophy, recombinant leptin provides hope for genetically determined lipodystrophy syndromes, whereas modifications in antiretroviral treatment and tesamorelin, a GHRH analog, is effective in the metabolic syndrome of HIV patients. Other therapeutic options will undoubtedly be developed, dependent on pathophysiological advances, which today tend to classify genetically determined lipodystrophy as being related to laminopathy or to lipid droplet disorders.

Primary graft function, metabolic control, and graft survival after islet transplantation.

OBJECTIVE To investigate the influence of primary graft function (PGF) on graft survival and metabolic control after islet transplantation with the Edmonton protocol. RESEARCH DESIGN AND METHODS A total of 14 consecutive patients with brittle type 1 diabetes were enrolled in this phase 2 study and received median 12,479 islet equivalents per kilogram of body weight (interquartile range 11,072-15,755) in two or three sequential infusions within 67 days (44-95). PGF was estimated 1 month after the last infusion by the beta-score, a previously validated index (range 0-8) based on insulin or oral treatment requirements, plasma C-peptide, blood glucose, and A1C. Primary outcome was graft survival, defined as insulin independence with A1C < or =6.5%. RESULTS All patients gained insulin independence within 12 days (6-23) after the last infusion. PGF was optimal (beta-score > or =7) in nine patients and suboptimal (beta-score < or =6) in five. At last follow-up, 3.3 years (2.8-4.0) after islet transplantation, eight patients (57%) remained insulin independent with A1C < or =6.5%, including seven patients with optimal PGF (78%) and one with suboptimal PGF (20%) (P = 0.01, log-rank test). Graft survival was not significantly influenced by HLA mismatches or by preexisting islet autoantibodies. A1C, mean glucose, glucose variability (assessed with continuous glucose monitoring system), and glucose tolerance (using an oral glucose tolerance test) were markedly improved when compared with baseline values and were significantly lower in patients with optimal PGF than in those with suboptimal PGF. CONCLUSIONS Optimal PGF was associated with prolonged graft survival and better metabolic control after islet transplantation. This early outcome may represent a valuable end point in future clinical trials.

PPARgamma-dependent and -independent effects of rosiglitazone on lipotoxic human pancreatic islets.

We explored the in vitro effects of Rosiglitazone (RZG), a PPARgamma agonist, on human pancreatic islet dysfunctions induced by chronic free fatty acid exposure. We demonstrated that RZG beneficial effects on insulin secretion and apoptosis did not imply PDX-1 or insulin gene modulation. It rather involved, through a PPARgamma-dependent mechanism, a reduction of iNOS overexpressed in lipotoxic islets. This reduction likely led to the restoration of ATP level and insulin secretion as well as the decrease in apoptosis. More interestingly, we also demonstrated that RZG beneficial effects involved PPARgamma-independent mechanisms. RZG treatment led to a limitation of oxidative stress exemplified by an increase of GPx and SOD expression. It also increased UCP2 expression that seemed to display antioxidant action in this model. Thus, RZG did not appear to exert a direct action on insulin expression but rather an indirect action on insulin secretion and apoptosis, through PPARgamma-dependent and -independent mechanisms, via regulation of nitrogen and oxygen reactive species injury.