Arginine Stimulation Test Research Articles

Utility of arginine stimulation testing in preoperative assessment of children undergoing total pancreatectomy with islet autotransplantation.

Metabolic outcomes after total pancreatectomy with islet autotransplantation (TPIAT) are influenced by the islet mass transplanted. Preclinical and clinical studies indicate that insulin and C-peptide levels measured after intravenous administration of the beta cell secretagogue arginine can be used to estimate the available islet mass. We sought to determine if preoperative arginine stimulation test (AST) results predicted transplanted islet mass and metabolic outcomes in pediatric patients undergoing TPIAT. We evaluated the association of preoperative C-peptide and insulin responses to AST with islet isolation metrics using linear regression, and with postoperative insulin independence using logistic regression. Twenty-six TPIAT patients underwent preoperative AST from 2015 to 2018. The acute C-peptide response to arginine (ACRarg) was correlated with isolated islet equivalents (IEQ; r=0.59, P=0.002) and islet number (IPN; r=0.48, P=0.013). The acute insulin response to arginine (AIRarg) was not significantly correlated with IEQ (r=0.38, P=0.095) or IPN (r=0.41, P=0.071). Neither ACRarg nor AIRarg was associated with insulin use at 6months postoperatively. Preoperative C-peptide response to arginine correlates with islet mass available for transplant in pediatric TPIAT patients. AST represents an additional tool before autotransplant to provide counseling on likely islet mass and to inform quality improvements of islet isolation techniques.

Prevalence of growth hormone (GH) deficiency in previously GH-treated young adults with Prader-Willi syndrome.

ObjectiveSome features of subjects with Prader‐Willi syndrome (PWS) resemble those seen in growth hormone deficiency (GHD). Children with PWS are treated with growth hormone (GH), which has substantially changed their phenotype. Currently, young adults with PWS must discontinue GH after attainment of adult height when they do not fulfil the criteria of adult GHD. Limited information is available about the prevalence of GHD in adults with PWS. This study aimed to investigate the GH/insulin‐like growth factor (IGF‐I) axis and the prevalence of GHD in previously GH‐treated young adults with PWS.DesignCross‐sectional study in 60 young adults with PWS.MeasurementsSerum IGF‐I and IGFBP‐3 levels, GH peak during combined growth hormone‐releasing hormone (GHRH)‐arginine stimulation test.ResultsSerum IGF‐I was <−2 standard deviation scores (SDS) in 2 (3%) patients, and IGFBP‐3 was within the normal range in all but one patient. Median (IQR) GH peak was 17.8 μg/L (12.2; 29.7) [~53.4 mU/L] and below 9 μg/L in 9 (15%) patients. Not one patient fulfilled the criteria for adult GHD (GH peak < 9 μg/L and IGF‐I < −2 SDS), also when BMI‐dependent criteria were used. A higher BMI and a higher fat mass percentage were significantly associated with a lower GH peak. There was no significant difference in GH peak between patients with a deletion or a maternal uniparental disomy (mUPD).ConclusionsIn a large group of previously GH‐treated young adults with PWS, approximately 1 in 7 exhibited a GH peak <9 μg/L during a GHRH‐arginine test. However, none of the patients fulfilled the consensus criteria for adult GHD.

Analysis of the value and correlation of IGF-1 with GH and IGFBP-3 in the diagnosis of dwarfism.

Correlation between the value of insulin-like growth factor-1 (IGF-1) in the diagnosis of dwarfism and the levels of growth hormone (GH) and insulin-like growth factor binding protein-3 (IGFBP-3) was investigated. From April 2014 to June 2017, 122 children with dwarfism who were treated in The Affiliated Wuxi No. 2 People's Hospital of Nanjing Medical University and The First Affiliated Hospital of Xinxiang Medical University were selected as the experimental group, and 51 normal children as the control group. The basic information was recorded in detail; serum GH and IGFBP-3 levels were measured using an arginine stimulation test and an insulin hypoglycemia stimulation test, respectively. According to the peak of GH in the experimental group, there were 65 cases of growth hormone deficiency (GHD) and 57 cases of idiopathic short stature (ISS). The expression levels of IGF-1 of the serum in the experimental and control group were detected by chemiluminescence immunoassay (CLIA). The correlation between IGF-1 and GH, IGF-1 and IGFBP-3 was analyzed. The expression level of serum IGF-1 in GHD group was significantly lower than that in the ISS group (P<0.05). The expression level of serum IGF-1 in GHD group was significantly lower than that in the control group (P<0.05). The expression level of serum IGF-1 in ISS group was significantly lower than that in the control group (P<0.05). The results of partial correlation studies showed that IGF-1 is positively correlated with GH and IGFBP-3. Detection of GH and IGFBP-3 are important for the early diagnosis and comprehensive evaluation of children with dwarfism, and also in the detection of IGF-1 can reflect the therapeutic effect of dwarfism on recombinant human growth hormone (rhGH) treatment, which is worthy of application in clinics.

Contribution of pancreatic α-cell function to insulin sensitivity and glycemic variability in patients with type1 diabetes.

Aims/IntroductionTo evaluate the contribution of pancreatic α‐cell function to the dawn phenomenon, insulin sensitivity, hepatic glucose uptake and glycemic variability in patients with type 1 diabetes.Materials and MethodsIn 40 patients with type 1 diabetes, arginine stimulation tests were carried out, and the area under the curve (AUC) of glucagon was measured using radioimmunoassays (AUC glc RIA) and enzyme‐linked immunosorbent assays (AUC glc ELISA). The ratio of the insulin dose delivered by an artificial pancreas to maintain euglycemia between 04.00 and 08.00 hours or between 00.00 and 04.00 hours was measured as the dawn index. The glucose infusion rate and hepatic glucose uptake were measured using hyperinsulinemic euglycemic clamp and clamp oral glucose loading tests. Glycemic variability in 96 h was measured by continuous glucose monitoring.ResultsThe median dawn index (1.7, interquartile range 1.0–2.8) was not correlated with AUC glc RIA (R 2 = 0.03, P = 0.39) or AUC glc ELISA (R 2 = 0.04, P = 0.32). The median glucose infusion rate (7.3 mg/kg/min, interquartile range 6.4–9.2 mg/kg/min) was significantly correlated with AUC glc RIA (R 2 = 0.20, P = 0.02) and AUC glc ELISA (R 2 = 0.21, P = 0.02). The median hepatic glucose uptake (65.3%, interquartile range 40.0–87.3%) was not correlated with AUC glc RIA (R 2 = 0.07, P = 0.26) or AUC glc ELISA (R 2 = 0.26, P = 0.79). The standard deviation of glucose levels measured by continuous glucose monitoring was significantly correlated with AUC glc RIA (R 2 = 0.11, P = 0.049), but not with AUC glc ELISA (R 2 = 0.01, P = 0.75).ConclusionsPancreatic α‐cell function contributed to insulin sensitivity in patients with type 1 diabetes.

Outpatient versus inpatient mixed meal tolerance and arginine stimulation testing yields comparable measures of variability for assessment of beta cell function.

Standard practice to minimize variability in beta cell function (BCF) measurement is to test in inpatient (IP) settings. IP testing strains trial subjects, investigators, and budgets. Outpatient (OP) testing may be a solution although there are few reports on OP BCF testing variability. We compared variability metrics between OP and IP from a standardized mixed meal tolerance test (MMTT) and arginine stimulation test (AST) in two separate type 2 diabetes (T2DM) cohorts (OP, n = 20; IP n = 22) in test-retest design. MMTT variables included: insulin sensitivity (Si); beta cell responsivity (Φtot); and disposition index (DItot = Si* Φtot) following 470 kCal meal. AST variables included: acute insulin response to arginine (AIRarg) and during hyperglycemia (AIRargMAX).ResultsBaseline characteristics were well-matched. Between and within subject variance for each parameter across cohorts, and intraclass correlation coefficients (ICC-a measure of reproducibility) across parameters were generally comparable for OP to IP. Table summarizes the ICC results for each key parameter and cohort.Test/ParameterOutpatient (95% CI)Inpatient (95% CI)MMTT: Si0.49(0,0.69)0.28(0,0.60)MMTT: Φtot0.65(0.16,0.89)0.81(0.44,0.93)MMTT: DI0.67(0,0.83)0.36(0,0.69) AST: AIR Arg0.96(0.88,0.98)0.84(0.59,0.94)AST: AIR Arg Max0.97(0.90,0.99)0.95(0.86,0.97)AST: ISR0.93(0.77,0.97)0.93(0.82,0.96)In conclusion, the variability (reproducibility) of BCF measures from standardized MMTT and AST is comparable between OP and IP settings. These observations have significant implications for complexity and cost of metabolic studies.

Deregulation of the growth hormone/insulin-like growth factor-1 axis in adults with cystic fibrosis.

Patients with cystic fibrosis (CF) present with signs and symptoms that overlap with those of adult growth hormone deficiency (GHD) syndrome: loss of muscle mass, bone fragility and lower stress tolerance. In literature, the prevalence of GHD in pediatric CF patients is higher than general population, but these studies have been performed on children with growth delay. To our knowledge, there are no studies on adult patients. The aim of this paper is to evaluate GH-IGF1 axis in an adult CF population. Fifty clinically stable adult patients, 30 males; age 36±2years; BMI 21.39±0.22kg/m2 and FEV1 67±4% were studied. Data regarding glycometabolic status and results of pituitary, thyroid, parathyroid, gonadal and adrenal function tests were recorded. All patients underwent a GH releasing hormone (GHRH)+Arginine stimulation test to confirm a GHD. GHRH+Arginine test revealed the presence of GHD in 16 patients (32%); specifically 7 patients had a severe deficiency and 9 a partial deficiency. Adult patients with CF may show GHD. These patients should be followed over time to assess if the GHD could impact the clinical progression of CF.

The prevalence of growth hormone deficiency in survivors of subarachnoid haemorrhage: results from a large single centre study

ObjectiveThe variation in reported prevalence of growth hormone deficiency (GHD) post subarachnoid haemorrhage (SAH) is mainly due to methodological heterogeneity. We report on the prevalence of GHD in a large cohort of patients following SAH, when dynamic and confirmatory pituitary hormone testing methods are systematically employed.DesignIn this cross-sectional study, pituitary function was assessed in 100 patients following SAH. Baseline pituitary hormonal profile measurement and glucagon stimulation testing (GST) was carried out in all patients. Isolated GHD was confirmed with an Arginine stimulation test and ACTH deficiency was confirmed with a short synacthen test.ResultsThe prevalence of hypopituitarism in our cohort was 19% and the prevalence of GHD was 14%. There was no association between GHD and the clinical or radiological severity of SAH at presentation, treatment modality, age, or occurrence of vasospasm. There were statistically significant differences in terms of Glasgow Outcome Scale (GOS; p = 0.03) between patients diagnosed with GHD and those without. Significant inverse correlations between GH peak on GST with body mass index (BMI) and waist hip ratio (WHR) was also noted (p < 0.0001 and p < 0.0001 respectively).ConclusionUsing the current testing protocol, the prevalence of GHD detected in our cohort was 14%. It is unclear if the BMI and WHR difference observed is truly due to GHD or confounded by the endocrine tests used in this protocol. There is possibly an association between the development of GHD and worse GOS score. Routine endocrine screening of all SAH survivors with dynamic tests is time consuming and may subject many patients to unnecessary side-effects. Furthermore the degree of clinical benefit derived from growth hormone replacement in this patient group, remains unclear. Increased understanding of the most appropriate testing methodology in this patient group and more importantly which SAH survivors would derive most benefit from GHD screening is required.

Gender has to be taken into account in diagnosing adult growth hormone deficiency by the GHRH plus arginine test

ObjectiveData on the effect of gender on the interpretation of the GHRH plus arginine stimulation test (GHRH+ARG test) is controversial. We validated the GHRH+ARG stimulation test in control subjects and patients with organic or idiopathic pituitary disease and a suspicion of adult growth hormone deficiency (AGHD) using the Immulite 2000 XPi GH assay. DesignWe studied 126 apparently healthy adults (median age 38.8years) and 34 patients with a suspicion of AGHD (median age 42.2years). Identification of AGHD with the GHRH+ARG test was investigated with commonly accepted BMI-related consensus cut-off limits for peak GH concentrations. Serum samples collected during the GHRH+ARG test were analysed for GH in 2014–2015. Serum IGF-1 concentrations were studied as a reference. ResultsIn 14 of 65 (22%) control males the GH peak value was below the BMI-related cut-off limits for GH sufficiency indicating a false diagnosis of AGHD. All control females had a normal GHRH+ARG response. Median peak GH response was significantly (p<0.001) higher in female (39.3μg/L) than in male controls (21μg/L). According to consensus cut-offs all but one young female patient had a deficient response compatible with a diagnosis of AGHD. ConclusionsThe GH response to stimulation by GHRH+ARG is gender-dependent, being lower in healthy males than in females. Gender should be considered when defining cut-off limits for peak GH concentrations in the GHRH+ARG test. The presently used BMI-related cut-off levels will lead to a significant misclassification of males as GH deficient.

Effects of semaglutide on beta cell function and glycaemic control in participants with type 2 diabetes: a randomised, double-blind, placebo-controlled trial

Aims/hypothesisSemaglutide is a glucagon-like peptide-1 analogue in development for the treatment of type 2 diabetes. Its effects on first- and second-phase insulin secretion and other measures of beta cell function and glycaemic control were assessed.MethodsIn this single-centre, double-blind, placebo-controlled, parallel-group trial, conducted at the Profil Institut für Stoffwechselforschung, Germany, 75 adult (aged 18–64 years) participants with type 2 diabetes (eligibility: HbA1c of 6.5–9.0% (47.5–74.9 mmol/mol); BMI 20.0–35.0 kg/m2; and treatment with diet and exercise and/or metformin monotherapy with a dose unchanged in the 30 days prior to screening) were randomised (1:1) to once-weekly s.c. semaglutide 1.0 mg (0.25, 0.5, 1.0 mg escalated) or placebo for 12 weeks. Co-primary endpoints were changes from baseline to end of treatment in the first (AUC0–10 min) and second (AUC10–120 min) insulin secretion phases, as measured by the IVGTT. An arginine stimulation test (AST) and a 24 h meal stimulation test were also conducted. A graded glucose infusion test (GGIT) assessed insulin secretion rate (ISR) in treated participants and a group of untreated healthy participants. Safety endpoints were also assessed.ResultsIn total, 37 participants received semaglutide and 38 received placebo. Following IVGTT, for insulin, both AUC0−10min and AUC10−120min were significantly increased with semaglutide (estimated treatment ratio [95% CI] 3.02 [2.53, 3.60] and 2.10 [1.86, 2.37], respectively; p < 0.0001). The 24 h meal test showed reduced fasting, postprandial and overall (AUC0–24h) glucose and glucagon responses with semaglutide (p < 0.0001). The AST showed that maximal insulin capacity increased following semaglutide treatment. During GGIT, semaglutide significantly increased ISR to levels similar to those in healthy participants. Semaglutide was well tolerated.Conclusions/interpretationTwelve weeks of once-weekly treatment with semaglutide significantly improved beta cell function and glycaemic control in participants with type 2 diabetes.Trial registration:ClinicalTrials.gov NCT02212067Funding:The study was funded by Novo Nordisk A/S.

Growth hormone/IGF-1 axis longitudinal evaluation in clinically isolated syndrome patients on interferon β-1b therapy: stimulation tests and correlations with clinical and radiological conversion to multiple sclerosis.

Growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis abnormalities in multiple sclerosis (MS) suggest their role in its pathogenesis. Interferon β (IFN-β) efficacy could be mediated also by an increase of IGF-1 levels. A 2-year longitudinal study was performed to estimate the prevalence of GH and/or IGF-1 deficiency in clinically isolated syndrome (CIS) patients and their correlation with conversion to MS in IFN treated patients. Clinical and demographic features of CIS patients were collected before the start of IFN-β-1b. IGF-1 levels and GH response after arginine and GH releasing hormone + arginine stimulation tests were assessed. Clinical and magnetic resonance imaging evaluations were performed at baseline, 1 year and 2 years. Thirty CIS patients (24 female) were enrolled. At baseline, four patients (13%) showed a hypothalamic GH deficiency (GHD), whilst no one had a pituitary GHD. Baseline demographic, clinical and radiological data were not related to GHD, whilst IGF-1 levels were inversely related to age (P < 0.001) and GH levels (P = 0.03). GH and IGF-1 serum mean levels were not significantly modified after 1 and 2 years of treatment in the whole group, although 3/4 GHD patients experienced a normalization of GH levels, whilst one dropped out. After 2 years of treatment 13/28 (46%) patients converted to MS. The presence of GHD and GH and IGF-1 levels were not predictive of relapses, new T2 lesions or conversion occurrence. Growth hormone/IGF-1 axis function was found to be frequently altered in CIS patients, but this was not related to MS conversion. Patients experienced an improvement of GHD during IFN therapy. Longer follow-up is necessary to assess its impact on disease progression.

Outcomes of Pancreatic Islet Allotransplantation Using the Edmonton Protocol at the University of Chicago.

ObjectiveThe aim of this study was to assess short-term and long-term results of the pancreatic islet transplantation using the Edmonton protocol at the University of Chicago.Materials and MethodsNine patients underwent pancreatic islet cell transplantation using the Edmonton Protocol; they were followed up for 10 years after initial islet transplant with up to 3 separate islet infusions. They were given induction treatment using an IL-2R antibody and their maintenance immunosuppression regimen consisted of sirolimus and tacrolimus.ResultsNine patients received a total of 18 islet infusions. Five patients dropped out in the early phase of the study. Greater than 50% drop-out and noncompliance rate resulted from both poor islet function and recurrent side effects of immunosuppression. The remaining 4 (44%) patients stayed insulin free with intervals for at least over 5 years (cumulative time) after the first transplant. Each of them received 3 infusions, on average 445 000 islet equivalent per transplant. Immunosuppression regimen required multiple adjustments in all patients due to recurrent side effects. In the long-term follow up, kidney function remained stable, and diabetic retinopathy and polyneuropathy did not progress in any of the patients. Patients' panel reactive antibodies remained zero and anti-glutamic acid decarboxylase 65 antibody did not rise after the transplant. Results of metabolic tests including hemoglobin A1c, arginine stimulation, and mixed meal tolerance test were correlated with clinical islet function.ConclusionsPancreatic islet transplantation initiated according to Edmonton protocol offered durable long-term insulin-free glycemic control in only highly selected brittle diabetics providing stable control of diabetic neuropathy and retinopathy and without increased sensitization or impaired renal function. Immunosuppression adjustments and close follow-up were critical for patient retention and ultimate success.

Standardized Mixed-Meal Tolerance and Arginine Stimulation Tests Provide Reproducible and Complementary Measures of β-Cell Function: Results From the Foundation for the National Institutes of Health Biomarkers Consortium Investigative Series.

Standardized, reproducible, and feasible quantification of β-cell function (BCF) is necessary for the evaluation of interventions to improve insulin secretion and important for comparison across studies. We therefore characterized the responses to, and reproducibility of, standardized methods of in vivo BCF across different glucose tolerance states. Participants classified as having normal glucose tolerance (NGT; n = 23), prediabetes (PDM; n = 17), and type 2 diabetes mellitus (T2DM; n = 22) underwent two standardized mixed-meal tolerance tests (MMTT) and two standardized arginine stimulation tests (AST) in a test-retest paradigm and one frequently sampled intravenous glucose tolerance test (FSIGT). From the MMTT, insulin secretion in T2DM was >86% lower compared with NGT or PDM (P < 0.001). Insulin sensitivity (Si) decreased from NGT to PDM (∼50%) to T2DM (93% lower [P < 0.001]). In the AST, insulin secretory response to arginine at basal glucose and during hyperglycemia was lower in T2DM compared with NGT and PDM (>58%; all P < 0.001). FSIGT showed decreases in both insulin secretion and Si across populations (P < 0.001), although Si did not differ significantly between PDM and T2DM populations. Reproducibility was generally good for the MMTT, with intraclass correlation coefficients (ICCs) ranging from ∼0.3 to ∼0.8 depending on population and variable. Reproducibility for the AST was very good, with ICC values >0.8 across all variables and populations. Standardized MMTT and AST provide reproducible and complementary measures of BCF with characteristics favorable for longitudinal interventional trials use.

Long-term follow-up results of growth hormone therapy for patients with adult growth hormone deficiency.

We evaluated the long-term effects of growth hormone (GH) on markers of quality of life, glucose metabolism, and lipid metabolism to validate the adequacy of long-term GH replacement therapy for adult GH deficiency (AGHD). Eighty-three of 100 sequentially followed patients who received GH therapy were selected for this study. Forty-nine were men aged 26 to 78 years (mean, 52 years) and 34 were women aged 20 to 78 years (mean, 56 years). The GH-releasing peptide-2 stimulation test and arginine stimulation test were used to diagnose AGHD. The adult hypopituitarism questionnaire (AHQ) and biochemical parameters such as cholesterol (TC), triglyceride (TG), high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol, and gyrated hemoglobin (HbA1c) were determined before treatment, at 6 months of treatment, and at 1, 2, 3, 4, 5, 6, 7, and 8 years of treatment. Considering age and sex as factors potentially influencing the effect of GH therapy, the patients were divided into age groups of <60 and ≥60 years and sex groups of men and women. Repeated measured analysis of variance (ANOVA) was employed. ANOVA demonstrated significant changes in mean AHQ scores during follow-up. Comparison of individual AHQ scores with baseline values revealed sequential improvements, stabilization, and decline in QOL. A significant elevation in HbA1c level was demonstrated. LDL-C and HDL-C levels changed significantly upon GH treatment regardless of sex or age. Levels of glucose, TC or TG did not change significantly. The effect of GH therapy on QOL showed sequential improvements and stabilization until 6-year follow-up.

Case of aniridia with a heterozygous PAX6 mutation in which the glucagon response to arginine was evaluated.

Pax6 is a highly evolutionally conserved transcription factor involved in the development of the eye and pancreatic islets. In humans, a heterozygous PAX6 mutation causes aniridia and mild glucose intolerance with impaired insulin secretion1. However, there have been no reports evaluating pancreatic α-cell function in aniridia patients with heterozygous PAX6 mutations. We herein present the first case of an aniridia patient with a heterozygous PAX6 mutation in which pancreatic α-cell function was evaluated. A 40-year-old woman with aniridia and obesity (165 cm, 86 kg, body mass index 31.6 kg/m2) was admitted to the Department of Metabolic Medicine, Osaka Hospital, Suita, Japan, for an endocrine examination. In childhood, she was diagnosed with aniridia, and at 28 years-of-age, it was found that she had a heterozygous PAX6 mutation (c.969C>T) leading to a truncated protein lacking a transactivation domain. The mutant PAX6 protein in the patient did not exert any transcriptional activity1. On admission, a 75-g oral glucose tolerance test showed impaired glucose tolerance (IGT) with impaired insulin secretion (Table​(Table1).1). On an arginine stimulation test (a 10% L-arginine hydrochloride solution [300 mL] was given intravenously over 30 min), the area under the concentration–time curve for the immunoreactive glucagon (AUCIRG) between time 0 and 120 min was calculated by means of the trapezoidal rule. The serum glucagon concentration was measured by RIA (SRL, Tokyo, Japan) similar to that in non-diabetic Japanese controls2. As a result, AUCIRG in the present case was comparable with that in non-diabetic Japanese controls (25.9 pg/mL/min × 103 vs 25.20 ± 7.76 pg/mL/min × 103)2. Table 1 Results of 75-g oral glucose tolerance test in the patient Recently, the involvement of glucagon in the pathogenesis of diabetes has drawn much attention. Pax6 is a transcription factor involved in the development of pancreatic α- and β-cells. Mice with a targeted disruption of Pax6 die soon after birth with an absence of glucagon-producing α-cells and a marked reduction of insulin producing β-cells. In heterozygous Pax6 mutant mice lacking a transactivation domain similar to the present case, α- and β-cells are reduced to 25 and 40% of wild type3. In contrast, aniridia patients with heterozygous PAX6 mutations had mild glucose intolerance with impaired insulin secretion1. However, secretory properties of glucagon in those patients were unclear. The present case showed impaired insulin secretion, whereas her glucagon response to arginine was comparable with those in non-diabetic control subjects. Although we could not conclude, because we failed to assess the glucagon responses to arginine in the control subjects with obese and IGT, and the other subjects with PAX6 mutation, this result might not necessarily show that her glucagon capacity is normal. This is because it has been shown that glucagon response to arginine in patients with IGT and/or obesity, as well as the present case, is exaggerated. Therefore, the result that her glucagon secretory capacity was not exaggerated despite her obesity and IGT could suggest her impaired glucagon secretory capacity. To the best of our knowledge, the present case is the first report to evaluate pancreatic α-cell function in a patient with a heterozygous PAX6 mutation. In addition, interestingly, recent studies have shown that blocking glucagon action prevents diabetes4. Considering these results, the cause of a mild degree of glucose intolerance in patients with heterozygous PAX6 mutations might be partially because of decreased glucagon secretion. In conclusion, we presented the first case of an aniridia patient with a heterozygous PAX6 mutation in which the glucagon response to arginine was evaluated. Further human studies are required to show the association of PAX6 mutations with glucagon secretion.

Effect of intensive insulin therapy on first-phase insulin secretion in newly diagnosed type 2 diabetic patients with a family history of the disease.

Intensive insulin treatment is known to improve β-cell function in the majority of patients with newly diagnosed type 2 diabetes mellitus (T2DM), and family history (FH) is known to be an important independent risk factor for T2DM. Thus, the aim of the present study was to investigate the difference in first-phase insulin secretion and the effect of intensive insulin therapy on the improvement of β-cell function between T2DM patients with and without a FH of diabetes. Patients with newly diagnosed T2DM and healthy controls were divided into groups according to their FH of diabetes. Improvement in β-cell function was evaluated with an arginine stimulation test after two weeks of continuous subcutaneous insulin infusion (CSII). Compared with the control group, the level of fasting insulin and the homeostasis model assessment of insulin resistance (HOMA2-IR) were higher in the DM group, while the homeostasis model assessment of β-cell insulin secretion (HOMA2-%β) and the first-phase peak ratio were lower (P<0.05). In addition, the first-phase peak ratio in the FH- control group was higher compared with that in the FH+ control group (P=0.023). Following CSII, all the patients achieved excellent blood glucose control in 6.2±3.6 days, without severe adverse effects. In the DM groups, the fasting insulin level and HOMA2-IR were lower, while the HOMA2-%β and first-phase peak ratio were higher, when compared with the values prior to treatment, particularly in the FH- DM group. The HOMA2-%β in the FH+ DM group was lower compared with the FH- DM group (P=0.027). Therefore, T2DM patients with and without a FH of the disease were shown to have a good response to CSII in the improvement of insulin resistance and β-cell function; however, the improvements were less significant in patients with a FH compared with patients without a FH of diabetes.

Assessment of β-cell mass and α- and β-cell survival and function by arginine stimulation in human autologous islet recipients.

We used intravenous arginine with measurements of insulin, C-peptide, and glucagon to examine β-cell and α-cell survival and function in a group of 10 chronic pancreatitis recipients 1–8 years after total pancreatectomy and autoislet transplantation. Insulin and C-peptide responses correlated robustly with the number of islets transplanted (correlation coefficients range 0.81–0.91; P < 0.01–0.001). Since a wide range of islets were transplanted, we normalized the insulin and C-peptide responses to the number of islets transplanted in each recipient for comparison with responses in normal subjects. No significant differences were observed in terms of magnitude and timing of hormone release in the two groups. Three recipients had a portion of the autoislets placed within their peritoneal cavities, which appeared to be functioning normally up to 7 years posttransplant. Glucagon responses to arginine were normally timed and normally suppressed by intravenous glucose infusion. These findings indicate that arginine stimulation testing may be a means of assessing the numbers of native islets available in autologous islet transplant candidates and is a means of following posttransplant α- and β-cell function and survival.

Alteration of the Glucagon Axis in GPR120 (FFAR4) Knockout Mice: A ROLE FOR GPR120 IN GLUCAGON SECRETION

GPR40 (FFAR1) and GPR120 (FFAR4) are G-protein-coupled receptors (GPCRs) that are activated by long chain fatty acids (LCFAs). GPR40 is expressed at high levels in islets and mediates the ability of LCFAs to potentiate glucose-stimulated insulin secretion (GSIS). GPR120 is expressed at high levels in colon, adipose, and pituitary, and at more modest levels in pancreatic islets. The role of GPR120 in islets has not been explored extensively. Here, we confirm that saturated (e.g. palmitic acid) and unsaturated (e.g. docosahexaenoic acid (DHA)) LCFAs engage GPR120 and demonstrate that palmitate- and DHA-potentiated glucagon secretion are greatly reduced in isolated GPR120 KO islets. Remarkably, LCFA potentiated glucagon secretion is similarly reduced in GPR40 KO islets. Compensatory changes in mRNA expression of GPR120 in GPR40 KO islets, and vice versa, do not explain that LCFA potentiated glucagon secretion seemingly involves both receptors. LCFA-potentiated GSIS remains intact in GPR120 KO islets. Consistent with previous reports, GPR120 KO mice are hyperglycemic and glucose intolerant; however, our KO mice display evidence of a hyperactive counter-regulatory response rather than insulin resistance during insulin tolerance tests. An arginine stimulation test and a glucagon challenge confirmed both increases in glucagon secretion and liver glucagon sensitivity in GPR120 KO mice relative to WT mice. Our findings demonstrate that GPR120 is a nutrient sensor that is activated endogenously by both saturated and unsaturated long chain fatty acids and that an altered glucagon axis likely contributes to the impaired glucose homeostasis observed in GPR120 KO mice.

Endocrine Secretory Reserve and Proinsulin Processing in Recipients of Islet of Langerhans Versus Whole Pancreas Transplants

OBJECTIVEβ-Cells have demonstrated altered proinsulin processing after islet transplantation. We compare β-cell metabolic responses and proinsulin processing in pancreas and islet transplant recipients with respect to healthy control subjects.RESEARCH DESIGN AND METHODSWe studied 15 islet and 32 pancreas transplant recipients. Islet subjects were subdivided into insulin-requiring (IR-ISL, n = 6) and insulin-independent (II-ISL, n = 9) groups. Ten healthy subjects served as control subjects. Subjects were administered an intravenous arginine stimulation test, and insulin, C-peptide, total proinsulin, intact proinsulin, and proinsulin fragment levels were determined from serum samples. Acute insulin response (AIR) and proinsulin processing rates were calculated.RESULTSWe found that basal insulin and C-peptide levels were higher in the pancreas group than in all other groups. II-ISL patients had basal insulin and C-peptide levels similar to healthy control subjects. The IR-ISL group had significantly lower AIRs than all other groups. Basal processing rates were higher in the pancreas and II-ISL groups than in healthy control subjects and the IR-ISL group. After arginine stimulation, all groups had elevated processing rates, with the exception of the IR-ISL group.CONCLUSIONSOur data suggest that II-ISL transplant recipients can maintain basal metabolic parameters similar to healthy control subjects at the cost of a higher rate of proinsulin processing. IR-ISL transplant recipients, on the other hand, demonstrate both lower insulin response and lower basal rates of proinsulin processing even after arginine stimulation.

Quantification of Islet Loss and Graft Functionality During Immune Rejection by 3-Tesla MRI in a Rat Model

Because metabolic markers are not suitable for early diagnosis of islet graft dysfunction, magnetic resonance imaging (MRI) has been used to study islets that were labeled pretransplantation with superparamagnetic iron oxide nanoparticles. However, the relation between graft functionality assessed by glycemia, and MRI signal remains unclear. We transplanted hyperglycemic rats intraportally with 2500 ferucarbotran-labeled syngeneic (n=10) or allogeneic (n=12) islet equivalents or normoglycemic rats with 5000 xenogeneic human islet equivalents. Images were acquired on a clinical 3-Tesla MRI scanner. When rejection occurred on days 4 and 8 in xenogeneic and allogeneic recipients, 60% (57-68) and 55% (46-73) of the initial signal remained compared to 93% (71-104) and 82% (59-90) in syngeneic controls (P=0.006 and 0.03). With a cutoff value of 84% on day 4 for the diagnosis of allogeneic rejection, sensitivity of 91% and specificity of 70% were obtained. Based on MRI signal on day 4, treatment with antilymphocytic serum from day 4 allowed graft rescue in 75% of recipients. In this model, MRI of pretransplantation superparamagnetic iron oxide nanoparticle-labeled islet grafts allows timely diagnosis of immune rejection.

Assessment of beta‐cell function in young patients with type 2 diabetes: arginine‐stimulated insulin secretion may reflect beta‐cell reserve

Simple methods for the evaluation of dynamic b-cell function in epidemiological and clinical studies of patients with type 2 diabetes (T2D) are needed. The aim of this study was to evaluate the dynamic beta-cell function in young patients with T2D with different disease durations and treatments. Overall, 54 subjects with T2D from the Diabetes Incidence Study in Sweden (DISS) and 23 healthy control participants were included in this cross-sectional study. Beta-cell function was assessed by intravenous (i.v.) administration of arginine followed by i.v. glucose. The acute insulin and C-peptide responses to arginine (AIRarg and Ac-pepRarg, respectively) and to glucose (AIRglu and Ac-pepRglu, respectively)were estimated.Homeostasis model assessment of b-cell function(HOMA-b) andCpeptide assessments were also used for comparisons between patients with T2D and control participants. AIRarg and Ac-pepRarg, but not AIRglu and Ac-pepRglu, could differentiate between patients with different disease durations. AIRglu values were 89% (P < 0.001) lower and AIRarg values were 29% (P < 0.01) lower in patients with T2D compared with control participants. HOMA-b and fasting plasma C-peptide levels did not differ between the T2D and control groups. In young patients with T2D, the insulin secretory response to i.v. glucose is markedly attenuated, whereas i.v. arginine-stimulated insulin release is better preserved and can distinguish between patients with different disease duration and antidiabetic therapies. This suggests that the i.v. arginine stimulation test may provide an estimate of functional beta-cell reserve.