Clinical Trial Protocol for Porcine Islet Xenotransplantation in South Korea.

Background: Islet transplantation holds promise for treating selected type 1 diabetes mellitus patients, yet the scarcity of human donor organs impedes widespread adoption. Porcine islets, deemed a viable alternative, recently demonstrated successful longterm survival without zoonotic risks in a clinically relevant pig-to-non-human primate islet transplantation model. This success prompted the development of a clinical trial protocol for porcine islet xenotransplantation in humans. Methods: A single-center, open-label clinical trial initiated by the sponsor will assess the safety and efficacy of porcine islet transplantation for diabetes patients at Gachon Hospital. The protocol received approval from the Gachon Hospital Institutional Review Board (IRB) and the Korean Ministry of Food and Drug Safety (MFDS) under the Investigational New Drug (IND) process. Two diabetic patients, experiencing inadequate glycemic control despite intensive insulin treatment and frequent hypoglycemic unawareness, will be enrolled. Participants and their family members will engage in deliberation before xenotransplantation during the screening period. Each patient will receive islets isolated from designated pathogen-free pigs. Immunosuppressants and systemic infection prophylaxis will follow the program schedule. The primary endpoint is to confirm the safety of porcine islets in patients, and the secondary endpoint is to assess whether porcine islets can reduce insulin dose and the frequency of hypoglycemic unawareness. Conclusion: A clinical trial protocol adhering to global consensus guidelines for porcine islet xenotransplantation is presented, facilitating streamlined implementation of comparable human trials worldwide.

Notch1 Has an Important Role in ß-Cell Mass Determination and Development of Diabetes.

BACKGROUND: Notch signaling pathway plays an important role in regulating pancreatic endocrine and exocrine cell fate during pancreas development. Notch signaling is also expressed in adult pancreas. There are few studies on the effect of Notch on adult pancreas. Here, we investigated the role of Notch in islet mass and glucose homeostasis in adult pancreas using Notch1 antisense transgenic (NAS). METHODS: Western blot analysis was performed for the liver of 8-week-old male NAS mice. We also conducted an intraperitoneal glucose tolerance test (IPGTT) and intraperitoneal insulin tolerance test in 8-week-old male NAS mice and male C57BL/6 mice (control). Morphologic observation of pancreatic islet and ß-cell was conducted in two groups. Insulin secretion capacity in islets was measured by glucose-stimulated insulin secretion (GSIS) and perifusion. RESULTS: NAS mice showed higher glucose levels and lower insulin secretion in IPGTT than the control mice. There was no significant difference in insulin resistance. Total islet and ß-cell masses were decreased in NAS mice. The number of large islets (≥250 µm) decreased while that of small islets (<250 µm) increased. Reduced insulin secretion was observed in GSIS and perifusion. Neurogenin3, neurogenic differentiation, and MAF bZIP transcription factor A levels increased in NAS mice. CONCLUSION: Our study provides that Notch1 inhibition decreased insulin secretion and decreased islet and ß-cell masses. It is thought that Notch1 inhibition suppresses islet proliferation and induces differentiation of small islets. In conclusion, Notch signaling pathway may play an important role in ß-cell mass determination and diabetes.

Comparison of the Effects of Liraglutide on Islet Graft Survival Between Local and Systemic Delivery.

Islet transplantation has emerged as a promising treatment for type 1 diabetes mellitus. Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor agonist, protects beta cells after islet transplantation by improving glycemic control through several mechanisms. In this study, we compared the effects of local pretreatment and systemic treatment with liraglutide on islet transplantation in a diabetic mouse model. Streptozotocin (STZ)-induced diabetic C57BL/6 mice were transplanted with syngeneic islets under the kidney capsule. Isolated islets were either locally treated with liraglutide before transplantation or mice were treated systemically by intraperitoneal injection after islet transplantation. Local pretreatment of islets with liraglutide was more effective in increasing body weight, decreasing hemoglobin A1c levels, and lowering blood glucose levels in STZ-diabetic mice transplanted with islets. Local pretreatment was also more effective in increasing insulin secretion and islet survival in STZ-diabetic mice. Histological analysis of the transplantation site revealed fewer apoptotic cells following local pretreatment compared with systemic injection of liraglutide. These findings indicate that liraglutide administered once locally before transplantation might have superior effects on islet preservation than systemic administration.

Diabetes and Cancer: Cancer Should Be Screened in Routine Diabetes Assessment.

Cancer incidence appears to be increased in both type 1 and type 2 diabetes mellitus (DM). DM represents a risk factor for cancer, particularly hepatocellular, hepatobiliary, pancreas, breast, ovarian, endometrial, and gastrointestinal cancers. In addition, there is evidence showing that DM is associated with increased cancer mortality. Common risk factors such as age, obesity, physical inactivity and smoking may contribute to increased cancer risk in patients with DM. Although the mechanistic process that may link diabetes to cancer is not completely understood yet, biological mechanisms linking DM and cancer are hyperglycemia, hyperinsulinemia, increased bioactivity of insulin-like growth factor 1, oxidative stress, dysregulations of sex hormones, and chronic inflammation. However, cancer screening rate is significantly lower in people with DM than that in people without diabetes. Evidence from previous studies suggests that some medications used to treat DM are associated with either increased or reduced risk of cancer. However, there is no strong evidence supporting the association between the use of anti-hyperglycemic medication and specific cancer. In conclusion, all patients with DM should be undergo recommended age- and sex appropriate cancer screenings to promote primary prevention and early detection. Furthermore, cancer should be screened in routine diabetes assessment.

Outcome of Endoscopic Transsphenoidal Surgery for Acromegaly.

OBJECTIVE: Endoscopic transsphenoidal surgery has recently been introduced in pituitary surgery. We investigated outcomes and complications of endoscopic surgery in 2 referral centers in Korea. METHODS: We enrolled 134 patients with acromegaly (microadenomas, n = 15; macroadenomas, n = 119) who underwent endoscopic transsphenoidal surgery at Seoul National University Hospital (n = 74) and Samsung Medical Center (n = 60) between January 2009 and March 2016. Remission was defined as having a normal insulin-like growth factor-1 and a suppressed growth hormone (GH) <1 ng/mL during an oral glucose tolerance test. RESULTS: Remission was achieved in 73.1% of patients, including 13 of 15 microadenoma patients (86.7%) and 86 of 119 macroadenoma patients (72.3%). A multivariate analysis to determine a predictor of biochemical remission demonstrated that absence of cavernous sinus invasion and immediate postoperative GH levels <2.5 ng/dL were significant predictors of remission (adjusted odds ratio [OR], 5.14; 95% confidence interval [CI], 1.52-17.3 and OR, 9.60; 95% CI, 3.41-26.9, respectively). After surgery, normal pituitary function was maintained in 34 patients (25.4%). Sixty-four patients (47.7%) presented complete (n = 59, 44.0%) or incomplete (n = 5, 3.7%) recovery of pituitary function. Hypopituitarism persisted in 20 patients (14.9%) and worsened in 16 patients (11.9%). Postoperatively, transient diabetes insipidus was reported in 52 patients (38.8%) but only persisted in 2 patients (1.5%). Other postoperative complications were epistaxis (n = 2), cerebral fluid leakage (n = 4), infection (n = 1), and intracerebral hemorrhage (n = 1). CONCLUSIONS: Endoscopic transsphenoidal surgery for acromegaly presented high remission rates and a low incidence of endocrine deficits and complications. Regardless of surgical techniques, invasive pituitary tumors were associated with poor outcome.

Is islet transplantation a realistic approach to curing diabetes?

Since the report of type 1 diabetes reversal in seven consecutive patients by the Edmonton protocol in 2000, pancreatic islet transplantation has been reappraised based on accumulated clinical evidence. Although initially expected to therapeutically target long-term insulin independence, islet transplantation is now indicated for more specific clinical benefits. With the long-awaited report of the first phase 3 clinical trial in 2016, allogeneic islet transplantation is now transitioning from an experimental to a proven therapy for type 1 diabetes with problematic hypoglycemia. Islet autotransplantation has already been therapeutically proven in chronic pancreatitis with severe abdominal pain refractory to conventional treatments, and it holds promise for preventing diabetes after partial pancreatectomy due to benign pancreatic tumors. Based on current evidence, this review focuses on islet transplantation as a realistic approach to treating diabetes.

Protective Effects of Vildagliptin against Pioglitazone-Induced Bone Loss in Type 2 Diabetic Rats.

Long-term use of thiazolidinediones (TZDs) is associated with bone loss and an increased risk of fracture in patients with type 2 diabetes (T2DM). Incretin-based drugs (glucagon-like peptide-1 (GLP-1) agonists and dipeptidylpeptidase-4 (DPP-4) inhibitors) have several benefits in many systems in addition to glycemic control. In a previous study, we reported that exendin-4 might increase bone mineral density (BMD) by decreasing the expression of SOST/sclerostin in osteocytes in a T2DM animal model. In this study, we investigated the effects of a DPP-4 inhibitor on TZD-induced bone loss in a T2DM animal model. We randomly divided 12-week-old male Zucker Diabetic Fatty (ZDF) rats into four groups; control, vildagliptin, pioglitazone, and vildagliptin and pioglitazone combination. Animals in each group received the respective treatments for 5 weeks. We performed an intraperitoneal glucose tolerance test (IPGTT) before and after treatment. BMD and the trabecular micro-architecture were measured by DEXA and micro CT, respectively, at the end of the treatment. The circulating levels of active GLP-1, bone turnover markers, and sclerostin were assayed. Vildagliptin treatment significantly increased BMD and trabecular bone volume. The combination therapy restored BMD, trabecular bone volume, and trabecular bone thickness that were decreased by pioglitazone. The levels of the bone formation marker, osteocalcin, decreased and that of the bone resorption marker, tartrate-resistant acid phosphatase (TRAP) 5b increased in the pioglitazone group. These biomarkers were ameliorated and the pioglitazone-induced increase in sclerostin level was lowered to control values by the addition of vildagliptin. In conclusion, our results indicate that orally administered vildagliptin demonstrated a protective effect on pioglitazone-induced bone loss in a type 2 diabetic rat model.

Co-culture with mature islet cells augments the differentiation of insulin-producing cells from pluripotent stem cells.

Islet transplantation has been hampered by the shortage of islet donors available for diabetes therapy. However, pluripotent stem cells (PSCs) can be an alternative source of insulin-producing cells (IPCs) because of their capacity for self-renewal and differentiation. We described a method to efficiently differentiate PSCs into IPCs by co-culturing mature islets with directed-differentiated pancreatic endoderm (PE) cells from mouse and human PSCs. PE cells co-cultured with islet cells or islet cell-derived conditioned medium (CM) showed increased expression levels of ß-cell markers; significantly higher levels of proinsulin- and Newport Green (NG)-positive cells, which revealed the characteristics of insulin producing cells; and increased insulin secretion upon glucose stimulation. Co-culturing human PE cells with islet cells was also effective to differentiate PE cells into IPCs. Diabetic nude mice transplanted with co-cultured cells exhibited restored euglycemia, human C-peptide release, and improved glucose tolerance. Immunohistochemistry revealed that insulin+/C-peptide + cells existed in the grafted tissues. These results suggest that mature islet cells can increase the differentiation efficiency of PE cells into mature IPCs via paracrine effects.

Effectiveness of 3-day continuous glucose monitoring for improving glucose control in type 2 diabetic patients in clinical practice.

BACKGROUND: The aim of this study was to investigate whether adjusting diabetic treatment regimens according to the information obtained from a continuous glucose monitoring system (CGMS) might lead to improved glycemic control in patients with type 2 diabetes. METHODS: We reviewed the medical charts of 172 patients who used the CGMS for 1 year starting in December 2008 and the records of 1,500 patients who visited their regular outpatient clinics during December 2008. Of these patients, a total of 65 CGMS patients and 301 regular outpatients (control group) were enrolled in the study after propensity score matching. There were no differences in baseline glycated hemoglobin (HbA1c), age, and duration of diabetes between the CGMS and the control groups after propensity score matching. The changes in the HbA1c levels from baseline to 6 months were calculated. RESULTS: The CGMS group showed a significant improvement in the HbA1c level compared to the control group at 3 months (7.9%±1.6% vs. 7.4%±1.2%, P=0.001) and at 6 months (7.4%±1.2% vs. 7.9%±1.6%, P=0.010). There were significant differences in the treatment modality changes between the CGMS group and the control group. CONCLUSION: Using a 3-day CGMS was advantageous for improving glucose control in patients with type 2 diabetes and may help these patients to optimize glycemic control in clinical practice.

Benefits of PEGylation in the early post-transplant period of intraportal islet transplantation as assessed by magnetic resonance imaging of labeled islets.

While a few studies have demonstrated the benefit of PEGylation in islet transplantation, most have employed renal subcapsular models and none have performed direct comparisons of islet mass in intraportal islet transplantation using islet magnetic resonance imaging (MRI). In this study, our aim was to demonstrate the benefit of PEGylation in the early post-transplant period of intraportal islet transplantation with a novel algorithm for islet MRI. Islets were PEGylated after ferucarbotran labeling in a rat syngeneic intraportal islet transplantation model followed by comparisons of post-transplant glycemic levels in recipient rats infused with PEGylated (n = 12) and non-PEGylated (n = 13) islets. The total area of hypointense spots and the number of hypointense spots larger than 1.758 mm(2) of PEGylated and non-PEGylated islets were quantitatively compared. The total area of hypointense spots (P < 0.05) and the number of hypointense spots larger than 1.758 mm(2) (P < 0.05) were higher in the PEGylated islet group 7 and 14 days post translation (DPT). These results translated into better post-transplant outcomes in the PEGylated islet group 28 DPT. In validation experiments, MRI parameters obtained 1, 7, and 14 DPT predicted normoglycemia 4 wk post-transplantation. We directly demonstrated the benefit of islet PEGylation in protection against nonspecific islet destruction in the early post-transplant period of intraportal islet transplantation using a novel algorithm for islet MRI. This novel algorithm could serve as a useful tool to demonstrate such benefit in future clinical trials of islet transplantation using PEGylated islets.

Using growth hormone levels to detect macroadenoma in patients with acromegaly.

BACKGROUND: The aim of this study was to assess the clinical differences between acromegalic patients with microadenoma and patients with macroadenoma, and to evaluate the predictive value of growth hormone (GH) levels for early detection of macroadenoma. METHODS: We performed a retrospective analysis of 215 patients diagnosed with a GH-secreting pituitary adenoma. The patients were divided into two groups: the microadenoma group and the macroadenoma group, and the clinical parameters were compared between these two groups. The most sensitive and specific GH values for predicting macroadenoma were selected using receiver operating characteristic (ROC) curves. RESULTS: Compared with the microadenoma group, the macroadenoma group had a significantly younger age, higher body mass index, higher prevalence of hyperprolactinemia and hypogonadism, and a lower proportion of positive suppression to octreotide. However, there were no significant differences in the gender or in the prevalence of diabetes between the two groups. The tumor diameter was positively correlated with all GH values during the oral glucose tolerance test (OGTT). All GH values were significantly higher in the macroadenoma group than the microadenoma group. Cut-off values for GH levels at 0, 30, 60, 90, and 120 minutes for optimal discrimination between macroadenoma and microadenoma were 5.6, 5.7, 6.3, 6.0, and 5.8 ng/mL, respectively. ROC curve analysis revealed that the GH value at 30 minutes had the highest area under the curve. CONCLUSION: The GH level of 5.7 ng/mL or higher at 30 minutes during OGTT could provide sufficient information to detect macroadenoma at the time of diagnosis.

Clinical characteristics, management, and outcome of 22 cases of primary hypophysitis.

BACKGROUND: Primary hypophysitis causes varying degrees of endocrine dysfunction and mass effect. The natural course and best treatment have not been well established. METHODS: Medical records of 22 patients who had been diagnosed with primary hypophysitis between January 2001 and March 2013 were retrospectively reviewed. Based on the anatomical location, we classified the cases as adenohypophysitis (AH), infundibuloneurohypophysitis (INH), and panhypophysitis (PH). Clinical presentation, endocrine function, pathologic findings, magnetic resonance imaging findings, and treatment courses were reviewed. RESULTS: Among 22 patients with primary hypophysitis, 81.8% (18/22) had involvement of the posterior pituitary lobe. Two patients of the AH (2/3, 66.6%) and three patients of the PH (3/10, 30%) groups initially underwent surgical mass reduction. Five patients, including three of the PH (3/10, 33.3%) group and one from each of the AH (1/3, 33.3%) and INH (1/9, 11.1%) groups, initially received high-dose glucocorticoid treatment. Nearly all of the patients treated with surgery or high-dose steroid treatment (9/11, 82%) required continuous hormone replacement during the follow-up period. Twelve patients received no treatment for mass reduction due to the absence of acute symptoms and signs related to a compressive mass effect. Most of them (11/12, 92%) did not show disease progression, and three patients recovered partially from hormone deficiency. CONCLUSION: Deficits of the posterior pituitary were the most common features in our cases of primary hypophysitis. Pituitary endocrine defects responded less favorably to glucocorticoid treatment and surgery. In the absence of symptoms related to mass effect and with the mild defect of endocrine function, it may not require treatment to reduce mass except hormone replacement.

Genetic Analysis of Multiple Endocrine Neoplasia Type 1 (MEN1) Leads to Misdiagnosis of an Extremely Rare Presentation of Intrasellar Cavernous Hemangioma as MEN1.

BACKGROUND: Multiple endocrine neoplasia type 1 (MEN1) is a rare inherited disorder characterized by the simultaneous occurrence of endocrine tumors in target tissues (mainly the pituitary, endocrine pancreas, and parathyroid glands). MEN1 is caused by mutations in the MEN1 gene, which functions as a tumor suppressor and consists of one untranslated exon and nine exons encoding the menin protein. This condition is usually suspected when we encounter patients diagnosed with tumors in multiple endocrine organs, as mentioned above. METHODS: A 65-year-old woman who underwent surgery for a pancreatic tumor (serous cystadenoma) 5 years previously was referred to our hospital due to neurologic symptoms of diplopia and left ptosis. Brain magnetic resonance imaging revealed a 3.4-cm lesion originating from the cavernous sinus wall and extending into the sellar region. It was thought to be a nonfunctioning tumor from the results of the combined pituitary function test. Incidentally, we found that she also had a pancreatic tumor, indicating the necessity of genetic analysis for MEN1. RESULTS: Genomic analysis using peripheral leukocytes revealed a heterozygous c.1621G>A mutation in the MEN1 gene that was previously reported to be either a pathogenic mutation or a simple polymorphism. We pursued a stereotactic approach to the pituitary lesion, and microscopic findings of the tumor revealed it to be an intrasellar cavernous hemangioma, a rare finding in the sellar region and even rarer in relation to oculomotor palsy. The patient recovered well from surgery, but refused further evaluation for the pancreatic lesion. CONCLUSION: There is great emphasis placed on genetic testing in the diagnosis of MEN1, but herein we report a case where it did not assist in diagnosis, hence, further discussion on the role of genetic testing in this disease is needed. Also, in cases of pituitary tumor with cranial nerve palsy, despite its low prevalence, intrasellar cavernous hemangioma could be suspected.

Hemoglobin A1c values are affected by hemoglobin level and gender in non-anemic Koreans.

AIMS/INTRODUCTION: To evaluate whether hemoglobin A1c (HbA1c) levels are affected by hemoglobin level and gender. MATERIALS AND METHODS: A cross-sectional analysis was carried out in a sample of 87,284 non-diabetic Koreans without anemia who participated in comprehensive health check-ups between January and December 2009 at the Kangbuk Samsung Hospital Total Healthcare Center in Seoul, Korea. We categorized men and women separately according to fasting plasma glucose and hemoglobin level to carry out the analysis. RESULTS: HbA1c increased steadily with increasing fasting plasma glucose level. Both men and women with lower hemoglobin had significantly higher HbA1c at a given fasting glucose level, and this result was consistent across the fasting glucose quintiles within the non-diabetic range. Women had a lower mean hemoglobin value compared with men, and women had higher HbA1c levels at a given fasting glucose level consistently across the fasting glucose deciles. There was also a gender-specific association between age and HbA1c (P < 0.001 for interaction). CONCLUSIONS: HbA1c values were affected by hemoglobin level and gender in non-anemic Koreans. Thus, hemoglobin level and gender should be considered in the diagnosis of diabetes using HbA1c.

Predictive factors of durability to sitagliptin: Slower reduction of glycated hemoglobin, older age and higher baseline glycated hemoglobin.

AIMS/INTRODUCTION: The goal of the present study was to evaluate predictive factors for good efficacy and durability to sitagliptin with ongoing metformin or metformin plus glimepiride therapy in a real practice situation. The present observational study was carried out over a 60-week period and involved Korean patients with type 2 diabetes mellitus. MATERIALS AND METHODS: A total of 100 mg of sitagliptin were added once daily to the two most popular therapy regimens (group 1: metformin, group 2: metformin plus glimepiride). Before adding sitagliptin, mean initial glycated hemoglobin (HbA1c) levels were 7.8% (62 mmol/mol) and mean diabetes duration was 8.3 years. RESULTS: After 60 weeks, the mean change in HbA1c from baseline was -0.9% (-10 mmol/mol) in group 1 and -1.0% (-11 mmol/mol) in group 2. Decreased HbA1c levels were significantly associated with higher initial HbA1c and lower log-transformed C-peptide levels in a multivariate regression analysis. Logistic regression analysis showed that a sustained reduction in HbA1c levels after 12 weeks was significantly associated with older age (≥60 years), higher baseline HbA1c (group 1 ≥ 7.0% [53 mmol/mol], group 2 ≥ 7.5% [58 mmol/mol]) and slower reduction of HbA1c (ΔHbA1c <1.0% [11 mmol/mol]) in group 1 and group 2. In group 2, a higher ratio of reduction of postprandial glucose/reduction of fasting plasma glucose (ΔPPG/ΔFPG) during 12 weeks was also associated with a sustained reduction in HbA1c levels after 12 weeks. CONCLUSIONS: The effects of sitagliptin lasted more than 12 weeks in older patients with a higher baseline HbA1c, and slower reduction of HbA1c during 12 weeks.

Glucagon/insulin ratio in preoperative screening before pancreatic surgery: correlation with hemoglobin A1C in subjects with and without pancreatic cancer.

Role of impaired suppression of glucagon secretion in the pathogenesis of pancreatic cancer-associated diabetes has been suggested. We examined the correlation between glucagon/insulin ratio (G/I) after glucose challenge and hemoglobin A1C (A1C) in subjects with and without pancreatic cancer. Data were gathered from a preoperative screening 75-g oral glucose tolerance test in patients who would eventually undergo pancreatic resection. A multiple linear regression analysis was conducted using the following covariates: age, body mass index, hemoglobin, glucose and insulin levels at the corresponding time points, indices of insulin resistance, duration of diabetes, insulinogenic index, and use of glucose-lowering drugs. In subject group with pancreatic cancer (n = 45), but not in subject group without pancreatic cancer (n = 101), participants with A1C ≥ 6.5 % had significantly higher glucagon levels, lower insulin levels, and higher G/I ratios after the glucose challenge than those of the subjects with A1C <5.7 %. In the multiple linear regression analysis, there was an independent correlation between post-challenge G/I ratio and A1C in both groups. Some of the patients without pancreatic cancer had inappropriately elevated G/I ratios despite A1C <6.5 %. These patients were characterized by lower insulinogenic indices (p = 0.004) and less insulin resistance (p = 0.008). In conclusion, post-challenge G/I ratio independently correlated with A1C in patients with pancreatic cancer. Although significant, the degree of correlation was weakened in the subjects without pancreatic cancer because some had lower insulin secretory reserve compensated by less insulin resistance, resulting in inappropriately elevated G/I ratios relative to A1C.

Metformin enhances glucagon-like peptide 1 via cooperation between insulin and Wnt signaling.

One aspect of the effects of metformin on glucagon-like peptide (GLP)-1 might be associated with the mechanism by which the cross talk between insulin and Wnt signaling enhances GLP1 secretion, due to the action of metformin as an insulin sensitizer. However, this remains completely unknown. In this study, we have investigated the mechanisms of the action of metformin on cross talk between insulin and Wnt signaling. GLP1 enhancement by meformin was determined in human NCI-H716 intestinal L-cells and hyperglycemic db/db mice treated with metformin (0.25 and 0.5 mM and/or 12.5 mg/kg body weight) for 24 h and 2 months. Metformin increased GLP1 secretion in L-cells and db/db mice. Metformin stimulated the nuclear translocation of ß-catenin and TOPflash reporter activity, and gene depletion of ß-catenin or enhancement of mutation of transcription factor 7-like 2 binding site offset GLP1. In addition, insulin receptor substrate 2 gene depletion blocked metformin-enhanced ß-catenin translocation. These effects were preceded by an increase in glucose utilization and calcium influx, the activation of calcium-dependent protein kinase, and, in turn, the activation of insulin signaling, and the inhibition of glycogen synthase kinase 3ß, a potent inhibitor of ß-catenin. Furthermore, high blood glucose levels were controlled via GLP1 receptor-dependent insulinotropic pathways in db/db mice, which were evidenced by the increase in GLP1 and insulin levels at 30 min after oral glucose loading and pancreatic insulinotropic gene expression. Our findings indicate that the cooperation between Wnt and its upstream insulin signaling pathways might be a novel and important mechanism underlying the effects of metformin on GLP1 production.

Clinical characteristics and follow-up of Korean patients with adrenal incidentalomas.

BACKGROUND/AIMS: We investigated the clinical characteristics and follow-up findings of subjects with adrenal incidentalomas in a single, tertiary-care hospital in South Korea. METHODS: The study consisted of a retrospective analysis of 282 adrenal incidentaloma patients who underwent radiographic and endocrinological evaluations at Samsung Medical Center in Seoul, South Korea, between January 2004 and July 2011. RESULTS: Most (86.2%) of the subjects were found to have nonfunctioning tumors. Functioning tumors were seen in 39 patients (13.8%). Among them, 28 (9.9%) had subclinical Cushing syndrome (SCS), six (2.1%) had pheochromocytoma, and five (1.8%) had primary hyperaldosteronism. Malignant adrenal tumors were discovered in three cases: two (0.7%) were primary adrenal cancers, and one (0.4%) was a secondary metastasis from a lung cancer. Significant risk factors for functional tumors were female gender (odds ratio [OR], 3.386; 95% confidence interval [CI], 1.611 to 7.117; p = 0.0013) and a noncontrast attenuation value of > 10 Hounsfield units (OR, 2.806; 95% CI, 1.231 to 6.397; p = 0.0141). During follow-up (mean, 22.5 months) of 72 of the patients, three (4.2%) developed hormonal changes due to functional tumors. One was confirmed as pheochromocytoma by histopathology, and the others were diagnosed with SCS and followed routinely without surgical intervention. No malignant transformation was found in these patients. CONCLUSIONS: Based on these findings, initial hormonal and radiographic evaluations for adrenal incidentalomas appear to be more important than follow-up tests because functional or malignant changes are rare.

Reduced food intake is the major contributor to the protective effect of rimonabant on islet in established obesity-associated type 2 diabetes.

PURPOSE: Although the presence of cannabinoid type 1 (CB1) receptor in islets has been reported, the major contributor to the protective effect of rimonabant on islet morphology is unknown. We determined whether the protective effect of rimonabant on pancreatic islet morphology is valid in established diabetes and also whether any effect was independent of decreased food intake. MATERIALS AND METHODS: After diabetes was confirmed, Otsuka Long-Evans Tokushima Fatty rats, aged 32 weeks, were treated with rimonabant (30 mg/kg/d, rimonabant group) for 6 weeks. Metabolic profiles and islet morphology of rats treated with rimonabant were compared with those of controls without treatment (control group), a pair-fed control group, and rats treated with rosiglitazone (4 mg/kg/d, rosiglitazone group). RESULTS: Compared to the control group, rats treated with rimonabant exhibited reduced glycated albumin levels (p<0.001), islet fibrosis (p<0.01), and improved glucose tolerance (p< 0.05), with no differences from the pair-fed control group. The retroperitoneal adipose tissue mass was lower in the rimonabant group than those of the pair-fed control and rosiglitazone groups (p<0.05). Rimonabant, pair-fed control, and rosiglitazone groups showed decreased insulin resistance and increased adiponectin, with no differences between the rimonabant and pair-fed control groups. CONCLUSION: Rimonabant had a protective effect on islet morphology in vivo even in established diabetes. However, the protective effect was also reproduced by pair-feeding. Thus, the results of this study did not support the significance of islet CB1 receptors in islet protection with rimonabant in established obesity-associated type 2 diabetes.

Diabetes-free survival in patients who underwent islet autotransplantation after 50% to 60% distal partial pancreatectomy for benign pancreatic tumors.

BACKGROUND: Several retrospective studies with short-term follow-up have demonstrated a low rate of new-onset diabetes after distal pancreatectomy for benign pancreatic tumors. We sought to determine the long-term diabetes-free survival of patients who underwent islet autotransplantation (IAT) after distal pancreatectomy and to identify any associations between the isolation parameters of autologous islets and diabetes-free survival. METHODS: Among the 37 nondiabetic patients who underwent 50% to 60% partial pancreatectomy, 20 underwent IAT (IAT group; median follow-up period, 61 months). In the IAT group, diabetes-free survival was determined based on annual oral glucose tolerance tests, fasting blood glucose, and hemoglobin A1C. RESULTS: The 7-year diabetes-free survival rate was 51% in the IAT group (median follow-up period, 61 months) and 45% in the 37 study subjects. Diabetes-free survival was significantly prolonged when islet yield per gram of pancreas weight was more than 5154 islet equivalents (IEQ)/g, even in patients with prediabetes and high insulin resistance who had a markedly high rate of diabetes development. The proportion of patients with impaired glucose tolerance at 2 years after distal pancreatectomy was 12 of 16 in the control group, 6 of 7 in patients with islet yields of less than 5154 IEQ/g, and 3 of 11 in patients with islet yields of more than 5154 IEQ/g (P=0.019). CONCLUSIONS: Partial (50%-60%) pancreatectomy for benign pancreatic tumors had a major metabolic consequence, especially in patients with prediabetes and high insulin resistance. In this setting, prolonged diabetes-free survival was observed in patients who underwent IAT when a high islet yield per gram of pancreas was achieved.