Β-cell Function Research Articles

β-cell dedifferentiation in HOMA-βlow and HOMA-βhigh subjects.

β-cell dedifferentiation ratio is increased in type 2 diabetes; but its direct link to in vivo β-cell function in human remains unclear. The present study was designed to investigate whether β-cell dedifferentiation in situ was closely associated with β-cell function in vivo and to identify targets crucial for β-cell dedifferentiation/function in human. We acquired HOMA-β values, calculated the number of hormone-negative endocrine cells and evaluated important markers and novel candidates for β-cell dedifferentiation/function on paraneoplastic pancreatic tissues from 13 patients with benign pancreatic cystic neoplasm (PCN) or intrapancreatic accessory spleen. Both β-cell dedifferentiation ratio and dedifferentiation marker (Aldh1a3) were inversely related with in vivo β-cell function (HOMA-β) and in situ β-cell functional markers Glut2 and Ucn3 in human. Moreover, the islets from HOMA-βlow subjects were manifested as 1) increased β-cell dedifferentiation ratio, 2) enriched dedifferentiation maker Aldh1a3, and 3) lower expression of Glut2 and Ucn3, compared to those from HOMA-βhigh subjects. We found that basic leucine zipper transcription factor 2 (Bach2) expression was significantly induced in islets from HOMA-βlow patients and was positively correlated with the ratio of β-cell dedifferentiation in human. Our findings emphasize the contribution of β-cell dedifferentiation to β-cell dysfunction in human. The Bach2 induction in β-cells with higher frequency of dedifferentiation observed in HOMA-βlow subjects reinforce its distinctive role as a pharmaceutical target of β-cell dedifferentiation for the treatment of human diabetes.

Therapeutic Potential of Blocking Nephrin Phosphorylation to Improve Pancreatic β-cell Function.

The phosphorylation of the transmembrane protein nephrin has been shown to play an important role in signaling in kidney podocytes, and it has now been shown to also play a key role in regulating pancreatic β-cell function. Williamson et al have recently shown that the loss of nephrin tyrosine phosphorylation on its 3 cytoplasmic YDxV motifs can enhance insulin release in aged female mice. These studies suggest that blocking nephrin phosphorylation may be an effective treatment option for improving β-cell function.

Associations of adipose insulin resistance index with pancreatic β cell function (inverse) and glucose excursion (positive) in young Japanese women

The relationship of adipose tissue insulin resistance (AT-IR, a product of fasting insulin and free fatty acids) and homeostasis-model assessment-insulin resistance (HOMA-IR) to β-cell function was studied cross-sectionally in the setting of subtle glucose dysregulation. Associations of AT-IR and HOMA-IR with fasting and post-glucose glycemia and β-cell function inferred from serum insulin kinetics during a 75 g oral glucose tolerance test were studied in 168 young female Japanese students. β-cell function was evaluated by disposition index calculated as a product of the insulinogenic index (IGI) and Matsuda index. AT-IR, not HOMA-IR, showed positive associations with post-glucose glycemia and area under the glucose response curve although both indices were associated with fasting glycemia. HOMA-IR, not AT-IR, was associated positively with log IGI whereas both indices were inversely associated with Matsuda index. AT-IR, not HOMA-IR, showed inverse associations with log disposition index. Associations of adipose tissue insulin resistance with β-cell function (inverse) and glucose excursion in young Japanese women may suggest that lipotoxicity to pancreatic β-cells for decades may be associated with β cell dysfunction found in Japanese patients with type 2 diabetes. Positive association of HOMA-IR with insulinogenic index may be associated with compensatory increased insulin secretion.

β-cell function and long-term glycemic control in patients newly diagnosed with type 2 diabetes with moderate hyperglycemia after a 6-month course of basal insulin therapy

AimsTo evaluate whether treatment with insulin is advantageous compared with oral anti-diabetic drugs (OAD) for patients newly diagnosed with type 2 diabetes with moderate hyperglycemia. MethodsPatients newly diagnosed with type 2 diabetes with moderate hyperglycemia were recruited and randomized to receive insulin, metformin or sitagliptin treatment. The oral glucose tolerance test (OGTT) was performed before treatment and 6 months thereafter. The primary outcome was the glycohemoglobin (HbA1c) level change. For the secondary efficacy analysis, the β-cell function and insulin sensitivity were calculated from the OGTT, as was the proportion of subjects who reached the treatment target (HbA1c level < 7.0 % or < 6.5 %) at 6 months. ResultsWe randomized 50 patients to the three groups and 32 patients who received the allocated treatment were analyzed. The change of HbA1c level in the insulin, metformin, and sitagliptin groups was − 2.06 ± 1.37 %, −0.43 ± 0.32 %, and − 1.62 ± 0.92 %, respectively. This change was smallest in the metformin group. There was no significant difference in the changes or final HbA1c levels between the insulin and sitagliptin groups. The treat-to-target (HbA1c level < 7.0 %) rates in the insulin, metformin and sitagliptin were 75 %, 50 % and 100 %, respectively. The treat-to-target rates were not significantly different among the three groups. The insulin secretion indices, including the Matsuda index and HOMA-IR, indicated that the groups did not differ after 6 months of therapy. ConclusionA 6-month course of basal insulin therapy did not benefit patients newly diagnosed with diabetes with moderate hyperglycemia in terms of insulin sensitivity or insulin secretion.

Insulin-based or non-insulin-based insulin resistance indicators and risk of long-term cardiovascular and all-cause mortality in the general population: A 25-year cohort study

ObjectiveAlthough insulin resistance (IR) has been recognized to be a causal component in various diseases, current information on the relationship between IR and long-term mortality in the general population is limited and conclusions varied among different IR indicators and different populations. We aimed to assess associations between different measurements of IR with long-term all-cause mortality and cardiovascular mortality risk for the general population. Research design and methodsWe included 13,909 individuals from the Third National Health and Nutrition Examination Survey. Mortality was identified via National Death Index information until December 31, 2019. IR was measured using fasting insulin, homeostasis model assessment of IR (HOMA-IR), homeostasis model assessment of β-cell function, quantitative insulin sensitivity check index (QUICKI), insulin-to-glucose ratio (IGR), triglyceride glucose (TyG) index, TyG-body mass index (TyG-BMI), and hypertriglyceridemic-waist phenotype. ResultsDuring median 25-year follow-up, 5,306 all-cause mortality events occurred. After multivariate adjustment, variables significantly associated with elevated all-cause mortality risk were (hazard ratio [95 % confidence interval]): higher insulin (1.07 [1.02;1.13]); HOMA-IR (1.08 [1.03;1.13]); IGR (1.05 [1.00;1.11]); TyG (1.07 [1.00;1.14]); TyG-BMI (1.24 [1.02;1.51]); lower QUICKI (0.91 [0.86–0.96]). After stratification by diabetes status, higher insulin, HOMA-IR, TyG-BMI and lower QUICKI were significantly associated with increased risk of all-cause mortality in both diabetes and non-diabetes populations (all P for interaction > 0.05). Higher TyG (adjusted HR 1.17 [1.09;1.26], P for interaction = 0.018) and hypertriglyceridemic-waist phenotype (adjusted HR 1.26 [1.08;1.46], P for interaction = 0.047) were significantly associated with increased risk of all-cause mortality in patients with diabetes, however, these associations could not be seen in people without diabetes. Similar results were observed between the above-mentioned IR indicators and cardiovascular death. ConclusionsFasting insulin, HOMA-IR, TyG-BMI, and QUICKI may indicate mortality risk in diabetes and non-diabetes populations, with TyG and the hypertriglyceridemic-waist phenotype showing particular relevance for individuals with diabetes. Further studies are needed to validate these findings and determine their broader applicability.

Revisiting the pattern of loss of β-cell function in preclinical Type 1 Diabetes.

Type 1 diabetes (T1D) results from beta cell destruction due to autoimmunity. It has been proposed that beta cell loss is relatively quiescent in the early years after seroconversion to islet antibody positivity (stage 1) with accelerated beta cell loss only developing around 6-18 months prior to clinical diagnosis. This construct implies that immunointervention in this early stage will be of little benefit since there is little disease activity to modulate. Here we argue that the apparent lack of progression in early stage disease may be an artefact of the modality of assessment used. When substantial β-cell function remains, the standard assessment - the oral glucose tolerance test - represents a submaximal stimulus and underestimates the residual function. By contrast, around the time of diagnosis, glucotoxicity exerts a deleterious effect on insulin secretion giving the impression of disease acceleration. Once glucotoxicity is relieved by insulin therapy, β-cell function partially recovers ("the honeymoon effect"). However, evidence from recent trials suggests that glucose control has little effect on the underlying disease process. We therefore hypothesise that the autoimmune destruction of β-cells actually progresses at a more or less constant rate through all phases of T1D and that early stage immunointervention will be both beneficial and desirable.

Deciphering the role of classical oestrogen receptor in insulin resistance and type 2 diabetes mellitus: From molecular mechanism to clinical evidence

The biological actions of oestrogen are mediated by the oestrogen receptor α or β (ERα or ERβ), which are members of a broad nuclear receptor superfamily. Numerous in vivo and in vitro studies have demonstrated that loss of circulating oestrogen modulated by classical ERα and ERβ led to rapid changes in pancreatic β-cell and islet function, GLUT4 expression, insulin sensitivity and glucose tolerance, dysfunctional lipid homeostasis, oxidative stress, and inflammatory cascades. Remarkably, 17β-oestradiol (E2) can completely reverse these effects. This review evaluates the current understanding of the protective role of classical ER in critical pathways and molecular mechanisms associated with insulin resistance and type 2 diabetes mellitus (T2DM). It also examines the effectiveness of menopausal hormone therapy (MHT) in reducing the risk of developing T2DM in menopausal women. Clinical trials have shown the protective effects of MHT on glucose metabolism, which may be useful to treat T2DM in perimenopausal women. However, there are concerns about E2's potential side effects of obesity and hyperlipidaemia in menopausal women. Further studies are warranted to gain understanding and find other oestrogen alternatives for treatment of insulin resistance and T2DM in postmenopausal women.

Patients with type 2 diabetes who achieve reduced postprandial glucose levels during insulin intensive therapy may have a better recovery of β-cell function

ObjectivesTo explore parameters that may determine the improvement in C-peptide levels in patients with type 2 diabetes (T2D) receiving continuous subcutaneous insulin infusion (CSII) therapy. MethodsThe trial included a lead-in period for collecting baseline parameters and correcting hyperglycemia, a 4-day CGM period, and a 2–3 weeks treatment period. After screening, patients were hospitalized and randomized to the metformin add-on NovoRapid group or the Prandilin group. Once the glycemic target was reached, all patients underwent a 4-day CGM, with treatments maintained for 2–3 weeks. OGTTs were performed at baseline and endpoint. The primary endpoint was identifying factors contributing to better β-cell function recovery after CSII therapy. ResultsA total of 99 recruited patients were admitted as inpatients and achieved glycemic control within 3.8 ± 1.1 days. Of these, 83 (84 %) patients showed improvement in C-peptide levels, while 16 (16 %) did not show any change in C-peptide levels at the endpoint. Pearson analysis showed a negative correlation between the incremental AUC of glucose concentration (from 0700 to 1000) and the increase in incremental AUC of C-peptide levels (r = −0.199, P < 0.05). ConclusionsDrug-naïve T2D patients with lower postprandial glucose concentration during CSII therapy exhibit better β-cell function recovery.

Potential of Fasting C-peptide to Glucose Ratio and Triglyceride Glucose Index as Markers for β-Cell Dysfunction and Insulin Resistance in Patients With Type 2 Diabetes on Insulin Therapy.

Pathogenesis of type 2 diabetes mellitus (T2DM) is combined from initial insulin resistance (IR) and subsequent β-cell dysfunction. Insulin therapy can replace β-cell function in advanced stages. However excessive insulin therapy increases IR and may expose the patients to risk of cardiovascular disease. We aim to assess β-cell function and IR in patients with type 2 diabetes on insulin therapy by fasting C-peptide to glucose ratio (FCPGR), and triglyceride glucose (TyG) index respectively to support treatment plans. A cross-sectional study was conducted at the Galiawa Diabetes and Endocrinology Teaching Center in Erbil City, Iraq,from June 2023 to January 2024. A convenient sample of 100 patients with T2DM on insulin-based therapy were included after obtaining informed written consent and excluding conditions such as acute illness,uncertain type of diabetes, etc. Each patient was evaluated for anthropometric parameters and current treatment details. Biochemical tests were then carried out to calculate metabolic syndrome (MetS) index score, FCPGR, and TyG index. Finally, patients were divided into four subgroups according to their FCPGR and TyG index and the data were analyzed statistically. The data showed those patients with sufficient β-cell function were 60(60%), and patients withhigh TyG index were 95 (95%). There was a significant negative correlation betweenFCPGR and hemoglobin A1c (HbA1c) (p-value=0.001), while there was a positive correlation between TyG index and HbA1C (p-value=0.001). None of these markers were correlated with BMI (p-value=0.297, and 0.976), duration of T2DM (p-value=0.258, and 0.458), and dose of insulin therapy (p-value=0.901, and 0.477). Patients with sufficient β-cell function and high TyG index had the lowest HbA1C. The study provides valuable insights into the utility of FCPGR and TyG index as biomarkers for β-cell function and insulin resistance in T2DM patients on insulin therapy. The significant correlation with HbA1C underscores their potential in clinical practice. However, the lack of correlation with BMI, disease duration, and insulin dose suggests that further investigation is needed to fully understand these biomarkers' implications across diverse patient profiles.

EXTOD-Immune: a randomised controlled trial to investigate whether a remotely monitored, home-based exercise intervention can reduce disease activity in people with type 1 diabetes

Type 1 diabetes (T1D) is a chronic autoimmune disease in which the adaptive immune system targets insulin-producing β-cells of pancreatic islets, leading to dependence on exogenous insulin therapy. Cytotoxic (CD8+)...

Increased Genetic Risk for β-Cell Failure Is Associated With β-Cell Function Decline in People With Prediabetes.

Partitioned polygenic scores (pPS) have been developed to capture pathophysiologic processes underlying type 2 diabetes (T2D). We investigated the influence of T2D pPS on diabetes-related traits and T2D incidence in the Diabetes Prevention Program. We generated five T2D pPS (β-cell, proinsulin, liver/lipid, obesity, lipodystrophy) in 2,647 participants randomized to intensive lifestyle, metformin or placebo arms. Associations were tested using general linear models and Cox regression adjusted for age, sex, and principal components. Sensitivity analyses included adjustment for BMI. Higher β-cell pPS was associated with lower insulinogenic index and corrected insulin response at one year follow-up adjusted for baseline measures (effect per pPS standard deviation (SD) -0.04, P=9.6 x 10-7; -8.45 uU/mg, P=5.6 x 10-6, respectively) and with increased diabetes incidence adjusted for BMI at nominal significance (HR 1.10 per SD, P=0.035). The liver/lipid pPS was associated with reduced one-year baseline-adjusted triglyceride levels (effect per SD -4.37, P=0.001). There was no significant interaction between T2D pPS and randomized groups. The remaining pPS were associated with baseline measures only. We conclude that despite interventions for diabetes prevention, participants with a high genetic burden of the β-cell cluster pPS had worsening in measures of β-cell function.

CREB activates the MafA promoter through proximal E-boxes and a CCAAT motif in pancreatic β-cells.

MafA is a key transcriptional regulator of pancreatic islet β-cell function. Its target genes include those encoding preproinsulin and the glucose transporter Glut2 (Slc2a2); thus, MafA function is essential for glucose-stimulated insulin secretion. Expression levels of MafA are reduced in β-cells of diabetic mouse models and human subjects, suggesting that β-cell dysfunction associated with type 2 diabetes is attributable to the loss of MafA. On the other hand, MafA is transcriptionally upregulated by incretin hormones through activation of CREB and its co-activator CRTC2. β-cell-specific expression of MafA relies on a distal enhancer element. However, the precise mechanism by which CREB-CRTC2 regulates the enhancer and proximal promoter regions of MafA remains unclear. In this report, we analyzed previously published ChIP-seq data and found that CREB and NeuroD1, a β-cell-enriched transactivator, bound to both the promoter and enhancer regions of human MAFA. A series of reporter assays revealed that CREB activated the enhancer through a conserved cAMP-responsive element (CRE) but stimulated MAFA promoter activity even when the putative CRE was deleted. Two E-box elements and a CCAAT motif, which bind NeuroD1 and ubiquitous NF-Y transcription factors, respectively, were necessary for transcriptional activation of the MAFA promoter by CREB. Genome-wide analysis of CREB-bound loci in β-cells revealed that they were enriched with CCAAT motifs. Furthermore, promoter analysis of the Isl1 gene encoding a β-cell-enriched transcription factor revealed that a CRE-like element and two CCAAT motifs, but not the E-box, were necessary for activation by CREB. These results provide clues to elucidate the detailed mechanism by which CREB regulates MafA as well as β-cell-specific genes.

Clinical characteristics and complication risks in data-driven clusters among Chinese community diabetes populations.

Novel diabetes phenotypes were proposed by the Europeans through cluster analysis, but Chinese community diabetes populations might exhibit different characteristics. This study aims to explore the clinical characteristics of novel diabetes subgroups under data-driven analysis in Chinese community diabetes populations. We used K-means cluster analysis in 6369 newly diagnosed diabetic patients from eight centers of the REACTION (Risk Evaluation of cAncers in Chinese diabeTic Individuals) study. The cluster analysis was performed based on age, body mass index, glycosylated hemoglobin, homeostatic modeled insulin resistance index, and homeostatic modeled pancreatic β-cell functionality index. The clinical features were evaluated with the analysis of variance (ANOVA) and chi-square test. Logistic regression analysis was done to compare chronic kidney disease and cardiovascular disease risks between subgroups. Overall, 2063 (32.39%), 658 (10.33%), 1769 (27.78%), and 1879 (29.50%) populations were assigned to severe obesity-related and insulin-resistant diabetes (SOIRD), severe insulin-deficient diabetes (SIDD), mild age-associated diabetes mellitus (MARD), and mild insulin-deficient diabetes (MIDD) subgroups, respectively. Individuals in the MIDD subgroup had a low risk burden equivalent to prediabetes, but with reduced insulin secretion. Individuals in the SOIRD subgroup were obese, had insulin resistance, and a high prevalence of fatty liver, tumors, family history of diabetes, and tumors. Individuals in the SIDD subgroup had severe insulin deficiency, the poorest glycemic control, and the highest prevalence of dyslipidemia and diabetic nephropathy. Individuals in MARD subgroup were the oldest, had moderate metabolic dysregulation and the highest risk of cardiovascular disease. The data-driven approach to differentiating the status of new-onset diabetes in the Chinese community was feasible. Patients in different clusters presented different characteristics and risks of complications.

Effect of ghrelin on glucose tolerance, gut hormones, appetite, and food intake after sleeve gastrectomy.

Ghrelin is an appetite-stimulating hormone secreted from the gastric mucosa in the fasting state, and secretion decreases in response to food intake. After sleeve gastrectomy (SG), plasma concentrations of ghrelin decrease markedly. Whether this affects appetite and glucose tolerance postoperatively is unknown. We investigated the effects of ghrelin infusion on appetite and glucose tolerance in individuals with obesity before and 3 mo after SG. Twelve participants scheduled for SG were included. Before and 3 mo after surgery, a mixed-meal test followed by an ad libitum meal test was performed with concomitant infusions of acyl-ghrelin (1 pmol/kg/min) or placebo. Infusions began 60 min before meal intake to reach a steady state before the mixed-meal and were continued throughout the study day. Two additional experimental days with 0.25 pmol/kg/min and 10 pmol/kg/min of acyl-ghrelin infusions were conducted 3 mo after surgery. Both before and after SG, postprandial glucose concentrations increased dose dependently during ghrelin infusions compared with placebo. Ghrelin infusions inhibited basal and postprandial insulin secretion rates, resulting in lowered measures of β-cell function, but no effect on insulin sensitivity was seen. Ad libitum meal intake was unaffected by the administration of ghrelin. In conclusion, ghrelin infusion increases postprandial plasma glucose concentrations and impairs β-cell function before and after SG but has no effect on ad libitum meal intake. We speculate that the lower concentration of ghrelin after SG may impact glucose metabolism following this procedure.NEW & NOTEWORTHY Ghrelin's effect on glucose tolerance and food intake following sleeve gastrectomy (SG) was evaluated. Acyl-ghrelin was infused during a mixed-meal and ad libitum meals before and 3 mo after surgery. Postprandial glucose concentrations increased during ghrelin infusions, both before and after surgery, while insulin production was inhibited. However, ad libitum meal intake did not differ during ghrelin administration compared with placebo. The decreased ghrelin concentration following SG may contribute to the glycemic control after surgery.

Mitochondrial diabetes in mice expressing a dominant-negative allele of nuclear respiratory factor-1 (Nrf1) in pancreatic β-cells

Genetic polymorphisms in nuclear respiratory factor-1 (Nrf1), a key transcriptional regulator of nuclear-encoded mitochondrial proteins, have been linked to diabetes. Homozygous deletion of Nrf1 is embryonic lethal in mice. Our goal was to generate mice with β-cell-specific reduction in NRF1 function to investigate the relationship between NRF1 and diabetes. We report the generation of mice expressing a dominant-negative allele of Nrf1 (DNNRF1) in pancreatic β-cells. Heterozygous transgenic mice had high fed blood glucose levels detected at 3 wks of age, which persisted through adulthood. Plasma insulin levels in DNNRF1 transgenic mice were reduced, while insulin sensitivity remained intact in young animals. Islet size was reduced with increased numbers of apoptotic cells, and insulin content in islets by immunohistochemistry was low. Glucose-stimulated insulin secretion in isolated islets was reduced in DNNRF1-mice, but partially rescued by KCl, suggesting that decreased mitochondrial function contributed to the insulin secretory defect. Electron micrographs demonstrated abnormal mitochondrial morphology in β-cells. Expression of NRF1 target genes Tfam, Tfb1m and Tfb2m, and islet cytochrome c oxidase and succinate dehydrogenase activities were reduced in DNNRF1-mice. Rescue of mitochondrial function with low level activation of transgenic c-Myc in β-cells was sufficient to restore β-cell mass and prevent diabetes. This study demonstrates that reduced NRF1 function can lead to loss of β-cell function and establishes a model to study the interplay between regulators of bi-genomic gene transcription in diabetes.

High glutamic acid decarboxylase antibody titers may be associated with a decline in β-cell function over time and future insulin deficiency in latent autoimmune diabetes in adults

AimsLatent autoimmune diabetes in adults (LADA) is characterized by positive islet-associated autoantibodies including glutamic acid decarboxylase antibody (GADA), and gradual decline in insulin secretion, progressing to insulin dependency. This cross-sectional study aimed to determine whether GADA by enzyme-linked immunosorbent assay (GADA-ELISA) titer of ≥180 U/mL could be associated with decline in β-cell function in participants with LADA. MethodsSixty-three participants with LADA were recruited and an association between insulin secretion capacity and disease duration was investigated. Insulin peptide-specific inflammatory immunoreactivity was investigated to determine the disease’s activity. ResultsThere was a significant inverse correlation between disease duration and C-peptide index in participants with GADA-ELISA titer of ≥180 U/mL (Spearman’s r (rs) = –0.516, p < 0.01). The positivity rate of insulin peptide-specific inflammatory immunoreactivity was significantly higher in those with ≥180 U/mL than in those with <180 U/mL (p < 0.05). In participants with human leukocyte antigen (HLA)-DRB1*04:05, a significant inverse correlation was observed between disease duration and C-peptide index in those with ≥180 U/mL (rs = −0.751, p < 0.01). ConclusionsGADA-ELISA titer of ≥180 U/mL, especially with HLA-DRB1*04:05, might reflect higher disease activity and may be associated with decline in β-cell function over time and future insulin dependency in LADA.

Ustekinumab for type 1 diabetes in adolescents: a multicenter, double-blind, randomized phase 2 trial

Immunotherapy targeting the autoimmune process in type 1 diabetes (T1D) can delay the loss of β-cells but needs to have minimal adverse effects to be an adjunct to insulin in the management of T1D. Ustekinumab binds to the shared p40 subunit of interleukin (IL)-12 and IL-23, targeting development of T helper 1 cells and T helper 17 cells (TH1 and TH17 cells) implicated in the pathogenesis of T1D. We conducted a double-blind, randomized controlled trial of ustekinumab in 72 adolescents aged 12–18 years with recent-onset T1D. Treatment was well tolerated with no increase in adverse events. At 12 months, β-cell function, measured by stimulated C-peptide, was 49% higher in the intervention group (P = 0.02), meeting the prespecified primary outcome. Preservation of C-peptide correlated with the reduction of T helper cells co-secreting IL-17A and interferon-γ (TH17.1 cells, P = 0.04) and, in particular, with the reduction in a subset of TH17.1 cells co-expressing IL-2 and granulocyte–macrophage colony-stimulating factor (IL-2+ GM-CSF+ TH17.1 cells, P = 0.04). A significant fall in β-cell-targeted (proinsulin-specific) IL-17A-secreting T cells was also seen (P = 0.0003). Although exploratory, our data suggest a role for an activated subset of TH17.1 cells in T1D that can be targeted with minimal adverse effects to reduce C-peptide loss, which requires confirmation in a larger study. (International Standard Randomised Controlled Trial Number Registry: ISRCTN 14274380).

Increase in the Expression of Glucose Transporter 2 (GLUT2) on the Peripheral Blood Insulin-Producing Cells (PB-IPC) in Type 1 Diabetic Patients after Receiving Stem Cell Educator Therapy.

Multicenter international clinical trials demonstrated the clinical safety and efficacy by using stem cell educator therapy to treat type 1 diabetes (T1D) and other autoimmune diseases. Previous studies characterized the peripheral blood insulin-producing cells (PB-IPC) from healthy donors with high potential to give rise to insulin-producing cells. PB-IPC displayed the molecular marker glucose transporter 2 (GLUT2), contributing to the glucose transport and sensing. To improve the clinical efficacy of stem cell educator therapy in the restoration of islet β-cell function, we explored the GLUT2 expression on PB-IPC in recent onset and longstanding T1D patients. In the Food and Drug Administration (FDA)-approved phase 2 clinical studies, patients received one treatment with the stem cell educator therapy. Peripheral blood mononuclear cells (PBMC) were isolated for flow cytometry analysis of PB-IPC and other immune markers before and after the treatment with stem cell educator therapy. Flow cytometry revealed that both recent onset and longstanding T1D patients displayed very low levels of GLUT2 on PB-IPC. After the treatment with stem cell educator therapy, the percentages of GLUT2+CD45RO+ PB-IPC were markedly increased in these T1D subjects. Notably, we found that T1D patients shared common clinical features with patients with other autoimmune and inflammation-associated diseases, such as displaying low or no expression of GLUT2 on PB-IPC at baseline and exhibiting a high profile of the inflammatory cytokine interleukin (IL)-1β. Flow cytometry demonstrated that their GLUT2 expressions on PB-IPC were also markedly upregulated, and the levels of IL-1β-positive cells were significantly downregulated after the treatment with stem cell educator therapy. Stem cell educator therapy could upregulate the GLUT2 expression on PB-IPC and restore their function in T1D patients, leading to the improvement of clinical outcomes. The clinical data advances current understanding about the molecular mechanisms underlying the stem cell educator therapy, which can be expanded to treat patients with other autoimmune and inflammation-associated diseases.

Low muscle mass is associated with low insulin sensitivity, impaired pancreatic β cell function, and high glucose excursion in nondiabetic nonobese Japanese women

AimWe tested whether skeletal muscle mass is associated with insulin sensitivity, pancreatic β-cell function, and postglucose glycemia. MethodsAppendicular skeletal muscle mass (ASM) (relative to body size, %ASM) by DXA, surrogate measures of insulin sensitivity, insulin secretion and the disposition index (insulin sensitivity adjusted insulin secretion: a product of the insulinogenic index and Matsuda insulin sensitivity index) inferred from serum insulin kinetics during a 75 g oral glucose tolerance test (OGTT) were evaluated in 168 young and 65 middle-aged women, whose BMI averaged <23.0 kg/m2 and HbA1c ≦ 5.5 %. ResultsIn two groups of women, %ASM was associated negatively with homeostasis model assessment insulin resistance (HOMA-IR) and 2-h insulin (both p < 0.01 or less). In middle-aged women not in young women, %ASM was associated inversely with the Matsuda index (p < 0.001). In middle-aged women only, it also showed a positive association with the disposition index (p = 0.02) and inverse associations with 1-h and 2-h glucose (both p < 0.01) and area under the glucose concentration curve during OGTT (p = 0.006). On multivariate linear regression analyses, 2-h insulin emerged as a determinant of %ASM independently of HOMA-IR in young women (standardized β: 0.287, p < 0.001, R2 = 0.077). In middle-aged women, the Matsuda index emerged as a determinant of %ASM (standardized β: 0.476, p < 0.001) independently of HOMA-IR, log ODI and AUCg and explained 21.3 % of %ASM variability. Post-glucose glycemia and AUCg were higher and log ODI was lower in middle-aged women with low compared with high %ASM. ConclusionLow skeletal muscle mass (relative to body size) was associated with low insulin sensitivity in young and middle-aged Japanese women who were neither obese nor diabetic. Middle-aged women with low muscle mass had low disposition index, an early marker of inadequate pancreatic β-cell compensation, and hence high glucose excursion. Low skeletal muscle mass may be associated with the development of type 2 diabetes at a much lower BMI in Japanese people.

Effects of licorice extract in combination with a low-calorie diet on obesity indices, glycemic indices, and lipid profiles in overweight/obese women with polycystic ovary syndrome (PCOS): a randomized, double-blind, placebo-controlled trial

BackgroundPolycystic ovary syndrome (PCOS) is the most common ovarian dysfunction. Recent studies showed the effectiveness of licorice on metabolic profiles with inconsistent findings. So, we investigated the effect of licorice on obesity indices, glycemic indices, and lipid profiles in women with PCOS.MethodsThis randomized, double-blind, placebo-controlled trial was performed on 66 overweight/obese women with PCOS. The participants were randomly assigned to receive either 1.5 gr/day licorice extract plus a low-calorie diet (n = 33) or placebo plus a low-calorie diet (n = 33) for 8 weeks. Participants’ anthropometric indices and body composition were assessed using standard protocols. Fasting blood sugar (FBS), insulin levels, low-density lipoprotein-cholesterol (LDL-C), total cholesterol (TC), triglyceride (TG), and high-density lipoprotein-cholesterol (HDL-C) were measured using enzymatic kits. The homeostasis model assessment-insulin resistance (HOMA-IR) and HOMA of β-cell function (HOMA-B) were calculated using valid formulas.ResultsBetween-group comparisons demonstrated significant differences between the groups in terms of obesity indices (body weight, BMI, and body fat), lipid profiles (TG, TC, LDL-C, and HDL-C), FBS and insulin levels, HOMA-IR, and HOMA-B at the end of the study (P < 0.05). Supplementation with licorice plus a low-calorie diet was also more effective in improving all parameters than a low-calorie diet alone after adjusting for confounders (baseline values, age, weight changes, and physical activity changes) (P < 0.05).ConclusionThe findings showed that licorice consumption leads to improvements in obesity indices, glucose homeostasis, and lipid profiles compared to placebo. Due to possible limitations of the study, further research is needed to confirm these findings.