Eco-friendly Nanoparticles Synthesized from Salvia sclarea Ethanol Extract Protect against STZ-induced Diabetic Nephropathy in Rats via Antioxidant, Anti-inflammatory, and Apoptosis Mechanisms.

Recent global scientific attention has been directed towards eco-friendly synthesis and versatile applications of silver nanoparticles (AgNPs) due to their effectiveness against specific cells and tissues. This study aimed to develop a green synthesis method for AgNPs using ethanolic extract from Salvia sclarea aerial parts, and to assess their protective efficacy against streptozotocin (STZ)-induced diabetic nephropathy in rats. Additionally, antioxidant, anti-inflammatory, and apoptosis studies were conducted to understand their mode of action. Characterization via ultraviolet-visible (UV-Vis) spectroscopy, infrared (IR) spectroscopy, and X-ray diffraction (XRD) confirmed the formation of ethanol extract of Salvia sclarea silver nanoparticles (EESS AgNPs), with a distinctive absorption peak at 400 nm. Scanning electron microscopy (SEM) analysis revealed predominantly spherical and quasi-spherical shapes of the synthesized nanoparticles. The treatment procedure spanned for a period of 12 weeks in diabetic rats and were evaluated for inflammatory markers (tumor necrosis factor-α, antioxidant markers (superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH) and apoptosis markers (Bcl-2, Bax, cleaved-caspase-3). Results demonstrated that treatment with EESS AgNPs significantly reduced blood glucose levels compared to the diabetic group. Additionally, EESS AgNPs treatment led to a significant decrease in levels of pro-inflammatory cytokines TNF-α, IL-1ß, and PKC-ꞵ in renal cells. Furthermore, EESS AgNPs effectively modulated antioxidant enzyme concentrations, including GSH, SOD, GPx, and CAT, bringing them to acceptable levels. Administration of EESS AgNPs also resulted in a significant decrease in protein levels of Bax and activated caspase-3, while increasing expression of the anti-apoptotic protein Bcl-2 in renal cells of STZ-induced diabetic rats. In conclusion, EESS AgNPs demonstrate potent anti-hyperglycemic effects, potentially mitigating diabetic nephropathy by suppressing hyperglycemiainduced oxidative stress, apoptosis, and inflammation in renal cells of diabetic rats.

The phenotype and related gene expressions of macrophages in adipose tissue of T2D mice following MSCs infusion.

BACKGROUND: Infusion of mesenchymal stem cells (MSCs) induces polarization of M2 macrophages in adipose tissue of type 2 diabetes (T2D) mice. Studies have shown that M2 macrophages were divided into four sub-phenotypes (M2a, M2b, M2c and M2d) with different functions, and manuscripts have also confirmed that macrophages co-cultured with MSCs were not matched with known four phenotype macrophages. Therefore, our study explored the phenotype and related gene expressions of macrophages in the adipose tissue of T2D mice with/without MSCs infusion. METHODS: We induced a T2D mouse model by using high-fat diets and streptozotocin (STZ) injection. The mice were divided into three groups: the control group, the T2D group, and the MSCs group. MSCs were systemically injected once a week for 6 weeks. The phenotype of macrophages in adipose tissue was detected via flow cytometric analysis. We also investigated the gene expression of macrophages in different groups via SMART-RNA-sequencing and quantitative real-time reverse transcriptase polymerase chain reaction (qRT-PCR). RESULTS: The present study found that the macrophages of adipose tissue in the MSCs group were polarized to the M2 phenotype mixed with four sub-phenotypes. Besides, M2a and M2c held a dominant position, while M2b and M2d (tumor-associated macrophages, TAMs) exhibited a decreasing trend after infusion of MSCs. Moreover, the MSCs group did not appear to express higher levels of tumor-associated, inflammation-associated, or fibrosis-associated genes in comparison to the T2D group. CONCLUSION: The present results unveiled that the macrophage phenotype was inclined to be present in a hybridity state of four M2 sub-phenotypes and the genes related to tumor-promoting, pro-inflammation and pro-fibrosis were not increased after MSCs injection.

Application Effect of Bladder Function Training Combined with Kangaiping Pills on Permanent Bladder Stoma after Radical Prostatectomy.

Objective: To investigate the application effect of bladder function training combined with Kangaiping pills on permanent bladder stoma after radical prostatectomy (RP). Methods: The clinical data of 80 patients with a permanent bladder stoma after RP in our hospital from December 2018 to December 2019 were retrospectively analyzed, and they were equally split into the experimental group (EG) and control group (CG) according to the odd and even hospitalization numbers. EG received bladder function training combined with Kangaiping pills while CG received routine nursing for permanent bladder stomas to compare the urodynamic indexes and quality of life (QOL) scores after intervention between the two groups. Results: Compared with CG, EG after intervention achieved an obviously higher number of patients with bladder function grade I (∗), higher urodynamic indexes (P < 0.001), a higher SF-36 score (P < 0.001), a lower LUTS score (P < 0.001), and a lower total incidence of postoperative adverse reactions (P < 0.05). Conclusion: Bladder function training combined with Kangaiping pills is a reliable method to improve the bladder function of patients with a permanent bladder stoma after RP. This intervention method greatly enhances the QOL of patients and reduces the risk of postoperative adverse reactions, which is recommended for clinical application.

Human umbilical cord-derived mesenchymal stem cells alleviate insulin resistance in diet-induced obese mice via an interaction with splenocytes.

BACKGROUND: Previous research has demonstrated that the spleen plays an important role in mesenchymal stem cell (MSC)-mediated alleviation of acute inflammation, as MSC infusion increases the spleen-derived anti-inflammatory cytokine interleukin 10 (IL-10) levels. However, studies on splenic involvement in MSC-induced protection against chronic inflammatory diseases are limited. Obesity is characterized by chronic low-grade inflammation, a key driver of insulin resistance. This study aims to evaluate the effects of MSCs on obesity-related insulin resistance and explore the underlying mechanism, particularly regarding splenic involvement. METHODS: We induced obesity in mice by feeding them high-fat diets for 20 weeks. Human umbilical cord-derived MSCs (UC-MSCs) were systemically infused into the obese mice once per week for 6 weeks. Systemic glucose metabolic homeostasis and insulin sensitivity in epididymal adipose tissue (EAT) were evaluated. Then, we conducted in vivo blockade of IL-10 during UC-MSC infusion by intraperitoneally administrating an IL-10-neutralizing antibody twice per week. We also investigated the therapeutic effects of UC-MSCs on obese mice after removal of the spleen by splenectomy. RESULTS: UC-MSC infusions improved systemic metabolic homeostasis and alleviated insulin resistance in EAT but elicited no change in weight. Despite rare engraftment of UC-MSCs in EAT, UC-MSC infusions attenuated insulin resistance in EAT by polarizing macrophages into the M2 phenotype, coupled with elevated serum IL-10 levels. In vivo blockade of IL-10 blunted the effects of UC-MSCs on obese mice. Furthermore, UC-MSCs overwhelmingly homed to the spleen, and the ability of UC-MSCs to elevate serum IL-10 levels and alleviate insulin resistance was impaired in the absence of the spleen. Further in vivo and in vitro studies revealed that UC-MSCs promoted the capacity of regulatory T cells (Treg cells) to produce IL-10 in the spleen. CONCLUSIONS: Our results demonstrated that UC-MSCs elevated serum IL-10 levels and subsequently promoted macrophage polarization, leading to alleviation of insulin resistance in EAT. The underlying mechanism was that UC-MSCs improved the capacity of Treg cells to produce IL-10 in the spleen. Our findings indicated that the spleen played a critical role in amplifying MSC-mediated immunomodulatory effects, which may contribute to maximizing MSC efficacy in clinical applications in the future.

Reversion of early- and late-stage ß-cell dedifferentiation by human umbilical cord-derived mesenchymal stem cells in type 2 diabetic mice.

BACKGROUND AIMS: The authors aimed to observe ß-cell dedifferentiation in type 2 diabetes mellitus (T2DM) and investigate the reversal effect of umbilical cord-derived mesenchymal stem cells (UC-MSCs) on early- and late-stage ß-cell dedifferentiation. METHODS: In high-fat diet (HFD)/streptozotocin (STZ)-induced T2DM mice, the authors examined the predominant role of ß-cell dedifferentiation over apoptosis in the development of T2DM and observed the reversion of ß-cell dedifferentiation by UC-MSCs. Next, the authors used db/db mice to observe the progress of ß-cell dedifferentiation from early to late stage, after which UC-MSC infusions of the same amount were performed in the early and late stages of dedifferentiation. Improvement in metabolic indices and restoration of ß-cell dedifferentiation markers were examined. RESULTS: In HFD/STZ-induced T2DM mice, the proportion of ß-cell dedifferentiation was much greater than that of apoptosis, demonstrating that ß-cell dedifferentiation was the predominant contributor to T2DM. UC-MSC infusions significantly improved glucose homeostasis and reversed ß-cell dedifferentiation. In db/db mice, UC-MSC infusions in the early stage significantly improved glucose homeostasis and reversed ß-cell dedifferentiation. In the late stage, UC-MSC infusions mildly improved glucose homeostasis and partially reversed ß-cell dedifferentiation. Combining with other studies, the authors found that the reversal effect of UC-MSCs on ß-cell dedifferentiation relied on the simultaneous relief of glucose and lipid metabolic disorders. CONCLUSIONS: UC-MSC therapy is a promising strategy for reversing ß-cell dedifferentiation in T2DM, and the reversal effect is greater in the early stage than in the late stage of ß-cell dedifferentiation.

Low-Dose Decitabine Assists Human Umbilical Cord-Derived Mesenchymal Stem Cells in Protecting ß Cells via the Modulation of the Macrophage Phenotype in Type 2 Diabetic Mice.

BACKGROUND: Progressive ß-cell dysfunction, a major characteristic of type 2 diabetes (T2D), is closely related to the infiltration of inflammatory macrophages within islets. Mesenchymal stem cells (MSCs) have been identified to alleviate ß-cell dysfunction by modulating macrophage phenotype in T2D, but the restoration of ß-cells by a single MSC infusion is relatively transient. Decitabine (DAC) has been reported to polarize macrophages towards the anti-inflammatory phenotype at low doses. We therefore investigated whether low-dose decitabine could enhance the antidiabetic effect of MSCs and further promote the restoration of ß-cell function. METHODS: We induced a T2D mice model by high-fat diets and streptozotocin (STZ) injection. Mice were divided into five groups: the normal group, the T2D group, the DAC group, the MSC group, and the MSC plus DAC group (MD group). We examined the blood glucose and serum insulin levels of mice 1, 2, and 4 weeks after MSC and/or DAC treatment. Dynamic changes in islets and the phenotype of intraislet macrophages were detected via immunofluorescence. In vitro, we explored the effect of MSCs and DAC on macrophage polarization. RESULTS: The blood glucose and serum insulin levels revealed that DAC prolonged the antidiabetic effect of MSCs to 4 weeks in T2D mice. Immunofluorescence staining demonstrated more sustainable morphological and structural amelioration in islets of the MD group than in the MSC group. Interestingly, further analysis showed more alternatively activated macrophages (M2, anti-inflammatory) and fewer classically activated macrophages (M1, proinflammatory) in islets of the MD group 4 weeks after treatment. An in vitro study demonstrated that DAC together with MSCs further polarized macrophages from the M1 to M2 phenotype via the PI3K/AKT pathway. CONCLUSION: These data unveiled that DAC prolonged the antidiabetic effect of MSCs and promoted sustainable ß-cell restoration, possibly by modulating the macrophage phenotype. Our results offer a preferable therapeutic strategy for T2D.

M1 macrophages accelerate renal glomerular endothelial cell senescence through reactive oxygen species accumulation in streptozotocin-induced diabetic mice.

Cellular senescence is a fundamental aging mechanism leading to tissue dysfunction. Accumulation of senescent cells is observed in the context of diabetes, which plays an important role in the pathogenesis of diabetes and its complications. Macrophages, the most prevalent leucocytes found in diabetic kidney, have been implicated in the modulation of cellular senescence; however, their role and mechanism in cellular senescence of diabetic kidney have not been determined. In this study, we found trends of cellular senescence in the glomeruli of streptozotocin-induced diabetic mice. The onset of glomerular senescence was confirmed by increased SA-ß-gal staining, the upregulation of p16INK4a, p21, and p53 protein levels and the increased expression of SASP RNA. The senescent cells in the glomeruli were mainly endothelial cells. We next confirmed that M1 macrophages accumulated in the glomeruli, occurred just shortly before glomerular senescence. Therefore, we examined whether M1 macrophage accumulation is associated with glomerular endothelial cell senescence. Thus, an in vitro co-culture model was established using human renal glomerular endothelial cells (HRGECs) and M1-polarized THP-1 macrophages. Indeed, M1 macrophages induced senescence in HRGECs. Furthermore, intracellular ROS levels and p38 MAPK signalling activation were significantly increased in HRGECs and reducing ROS generation significantly abolished M1 macrophage-mediated endothelial senescence and p38 MAPK activation, suggesting that M1 macrophage-mediated endothelial senescence is largely dependent on ROS. Thus, our results demonstrate that kidney M1 macrophage accumulation is in connection with endothelial cell senescence and strategy to modulate M1 macrophages accumulation is promising to be a new target for immunotherapy for diabetic kidney disease and other age-related diseases.

Treatment with adipose tissue-derived mesenchymal stem cells exerts anti-diabetic effects, improves long-term complications, and attenuates inflammation in type 2 diabetic rats.

BACKGROUND: Long-term diabetes-associated complications are the major causes of morbidity and mortality in individuals with diabetes. These diabetic complications are closely linked to immune system activation along with chronic, non-resolving inflammation, but therapies to directly reverse these complications are still not available. Our previous study demonstrated that mesenchymal stem cells (MSCs) attenuated chronic inflammation in type 2 diabetes mellitus (T2DM), resulting in improved insulin sensitivity and islet function. Therefore, we speculated that MSCs might exert anti-inflammatory effects and promote the reversal of diabetes-induced kidney, liver, lung, heart, and lens diseases in T2DM rats. METHODS: We induced a long-term T2DM complication rat model by using a combination of a low dose of streptozotocin (STZ) with a high-fat diet (HFD) for 32 weeks. Adipose-derived mesenchymal stem cells (ADSCs) were systemically administered once a week for 24 weeks. Then, we investigated the role of ADSCs in modulating the progress of long-term diabetic complications. RESULTS: Multiple infusions of ADSCs attenuated chronic kidney disease (CKD), nonalcoholic steatohepatitis (NASH), lung fibrosis, and cataracts; improved cardiac function; and lowered serum lipid levels in T2DM rats. Moreover, the levels of inflammatory cytokines in the serum of each animal group revealed that ADSC infusions were able to not only inhibit pro-inflammatory cytokines IL-6, IL-1ß, and TNF-α expression but also increase anti-inflammatory cytokine IL-10 systematically. Additionally, MSCs reduced the number of iNOS(+) M1 macrophages and restored the number of CD163(+) M2 macrophages. CONCLUSIONS: Multiple intravenous infusions of ADSCs produced significant protective effects against long-term T2DM complications by alleviating inflammation and promoting tissue repair. The present study suggests ADSCs may be a novel, alternative cell therapy for long-term diabetic complications.

Decitabine assists umbilical cord-derived mesenchymal stem cells in improving glucose homeostasis by modulating macrophage polarization in type 2 diabetic mice.

BACKGROUND: Mesenchymal stem cells (MSCs) have emerged as a promising therapy for type 2 diabetes (T2D). Mechanistic researches demonstrate that the anti-diabetic effect of MSCs is partially mediated by eliciting macrophages into an anti-inflammatory phenotype thus alleviating insulin resistance. However, single MSC infusion is insufficient to ameliorate sustained hyperglycemia or normalize blood glucose levels. In this study, we used decitabine (DAC), which is involved in the regulation of macrophage polarization, to test whether MSCs combined with decitabine can prolong and enhance the anti-diabetic effect in T2D mice. METHODS: High-fat diet (HFD) and streptozocin (STZ) were given to induce T2D mouse model. Successfully induced T2D mice were randomly divided into four groups: T2D group, MSC group, DAC group, and MSC + DAC group. Blood glucose was monitored, and glucose tolerance and insulin sensitivity were evaluated during the entire analysis period. Epididymal fat was extracted for analysis of macrophage phenotype and inflammation in adipose tissue. In vitro, we examined the effect of MSC + DAC on macrophage polarization in bone marrow-derived macrophages (BMDMs) and explore the possible mechanism. RESULTS: MSC infusion effectively improved insulin sensitivity and glucose homeostasis in T2D mice within 1 week, whereas combination therapy of MSCs + DAC extended the anti-diabetic effects of MSCs from 1 to 4 weeks (the end of the observation). Correspondingly, more M2 macrophages in adipose tissue were observed in the combination therapy group over the entire study period. In vitro, compared with the MSC group, MSCs combined with decitabine more effectively polarized M1 macrophages to M2 macrophages. Further analysis showed that the effect of MSC + DAC on macrophage polarization was largely abrogated by the peroxisome proliferator-activated receptor gamma (PPARγ) antagonist GW9662. CONCLUSIONS: Our data suggest that MSCs combined with decitabine can more effectively alleviate insulin resistance and prolong and enhance the anti-diabetic effect of MSCs in T2D mice in part by prompting M2 polarization in a PPARγ-dependent manner. Thus, decitabine may be an applicable addition to MSCs for diabetes therapy. UC-MSCs combined with decitabine activate the IL4R/STAT6/STAT3/PPARγ axis to further promote M2 macrophage polarization in adipose tissue, reduce inflammation, improve insulin sensitivity, and lead to better glucose metabolism and long-term hypoglycemic effects.

Cardiovascular disease outcomes in metabolically healthy obesity in communities of Beijing cohort study.

OBJECTIVE: The objective of this study was to investigate the association between metabolically healthy obese (MHO) phenotype and the risk of cardiovascular disease (CVD). METHODS: A total of 9393 subjects aged ≥40 years were enrolled in the cohort study (2011-2015). The participants were stratified by body mass index category and metabolic risk at baseline, and incidence of CVD was ascertained at follow-up. RESULTS: The MHO accounted for 6.7%. Compared with the metabolically healthy normal weight (MHNW) group, MHO subjects demonstrated increased risk of CVD events (HR = 1.91; 95% CI, 1.13-3.24). In people with obesity, there was no significant difference on increasing risk of incidence of CVD in the metabolically unhealthy individuals compared with metabolically healthy individuals (HR = 1.19; 95% CI, 0.74-1.91). Female (OR = 1.97; 95% CI, 1.06-3.64), smoking (OR = 2.09; 95% CI, 1.06-4.10), a larger waist circumference (OR = 1.07; 95% CI, 1.03-1.10) and higher LDL cholesterol levels (OR = 1.55; 95% CI, 1.20-2.00) were independent risk factors of the development of the MHO to the metabolically unhealthy obese (MUO) phenotype. CONCLUSIONS: The risk of CVD events of MHO phenotypes is similar to MUO phenotypes; both are higher than the MHNW phenotypes.

Human umbilical cord-derived mesenchymal stem cells direct macrophage polarization to alleviate pancreatic islets dysfunction in type 2 diabetic mice.

Progressive pancreatic ß-cell dysfunction is recognized as a fundamental pathology of type 2 diabetes (T2D). Recently, mesenchymal stem cells (MSCs) have been identified in protection of islets function in T2D individuals. However, the underlying mechanisms remain elusive. It is widely accepted that ß-cell dysfunction is closely related to improper accumulation of macrophages in the islets, and a series of reports suggest that MSCs possess great immunomodulatory properties by which they could elicit macrophages into an anti-inflammatory M2 state. In this study, we induced a T2D mouse model with a combination of high-fat diet (HFD) and low-dose streptozotocin (STZ), and then performed human umbilical cord-derived MSCs (hUC-MSCs) infusion to investigate whether the effect of MSCs on islets protection was related to regulation on macrophages in pancreatic islets. hUC-MSCs infusion exerted anti-diabetic effects and significantly promoted islets recovery in T2D mice. Interestingly, pancreatic inflammation was remarkably suppressed, and local M1 macrophages were directed toward an anti-inflammatory M2-like state after hUC-MSC infusion. In vitro study also proved that hUC-MSCs inhibited the activation of the M1 phenotype and induced the generation of the M2 phenotype in isolated mouse bone marrow-derived macrophages (BMDMs), peritoneal macrophages (PMs) and in THP-1 cells. Further analysis showed that M1-stimulated hUC-MSCs increased the secretion of interleukin (IL)-6, blocking which by small interfering RNA (siRNA) largely abrogated the hUC-MSCs effects on macrophages both in vitro and in vivo, resulting in dampened restoration of ß-cell function and glucose homeostasis in T2D mice. In addition, MCP-1 was found to work in accordance with IL-6 in directing macrophage polarization from M1 to M2 state. These data may provide new clues for searching for the target of ß-cell protection. Furthermore, hUC-MSCs may be a superior alternative in treating T2D for their macrophage polarization effects.

The homing of human umbilical cord-derived mesenchymal stem cells and the subsequent modulation of macrophage polarization in type 2 diabetic mice.

Umbilical cord-derived mesenchymal stem cells (UC-MSCs), with both immunomodulatory and pro-regenerative properties, are promising for the treatment of type 2 diabetes mellitus (T2DM). As efficient cell therapy largely relies on appropriate homing to target tissues, knowing where and to what extent injected UC-MSCs have homed is critically important. However, bio-distribution data for UC-MSCs in T2DM subjects are extremely limited. Beneficial effects of UC-MSCs on T2DM subjects are associated with increased M2 macrophages, but no systemic evaluation of M2 macrophages has been performed in T2DM individuals. In this study, we treated T2DM mice with CM-Dil-labelled UC-MSCs. UC-MSC infusion not only exerted anti-diabetic effects but also alleviated dyslipidemia and improved liver function in T2DM mice. To compare UC-MSC migration between T2DM and normal subjects, a collection of normal mice also received UC-MSC transplantation. UC-MSCs homed to the lung, liver and spleen in both normal and T2DM recipients. Specifically, the spleen harbored the largest number of UC-MSCs. Unlike normal mice, a certain number of UC-MSCs also homed to pancreatic islets in T2DM mice, which suggested that UC-MSC homing may be closely related to tissue damage. Moreover, the number of M2 macrophages in the islets, liver, fat and muscle significantly increased after UC-MSC infusion, which implied a strong link between the increased M2 macrophages and the improved condition in T2DM mice. Additionally, an M2 macrophage increase was also observed in the spleen, suggesting that UC-MSCs might exert systemic effects in T2DM individuals by modulating macrophages in immune organs.

M2 macrophages infusion ameliorates obesity and insulin resistance by remodeling inflammatory/macrophages' homeostasis in obese mice.

OBJECTIVE: The role of M2 macrophages infusion in dealing with obesity is still little known. In this study, the therapeutic effects of M2 macrophages infusion were investigated. METHODS: High fat diet (HFD) was used to induce obesity in C57BL/6N mice. 5 × 105 M2 macrophages, derived from the bone marrow, were injected into obese mice through the tail vein twice with an interval of one week. RESULTS: One week after the second injection, weight of inguinal adipose pad was significantly decreased. Accordingly, the adipocyte size of epididymal and inguinal adipose tissue (EAT and INAT) shrank. To our interest, we found that the infused M2 macrophages were homed to EAT, reversing the disturbed homeostasis of high M1 to low M2 in obese mice. Meanwhile, EAT with remodeled macrophages' homeostasis expressed less MCP-1, accompanying with decreased recruitment of inflammatory CCR2+CX3CR1lowLy6C+ monocytes from the blood in M2 infusion group. Further, increased M2 in EAT contribute to enhanced expression of UCP1 expression in EAT, which helped to ameliorate insulin resistance and, subsequently, improve the serum level of triglycerides (TG) and low density lipoprotein cholesterol (LDL-c). CONCLUSIONS: These findings highlighted that M2 macrophages infusion could ameliorate obesity as well as obesity-related insulin resistance, suggesting an effective and healthy weight loss strategy.

The impact of a family history of type 2 diabetes on insulin secretion and insulin sensitivity in individuals with varying glucose tolerance.

INTRODUCTION: This study was performed to investigate the impact of a family history of type 2 diabetes (T2DM) on insulin resistance and beta-cell dysfunction in populations with varying glucose tolerance. METHODS: Among the total of 142 participants, 73 subjects with no family history of T2DM (FH-) included 42 with normal glucose tolerance (NGT/FH-) and 31 with impaired glucose tolerance (IGT/FH-); and 69 first-degree relatives of patients with T2DM (FH+) included 36 with NGT (NGT/FH+) and 33 with IGT (IGT/FH+). Insulin resistance was evaluated by Insulin Sensitivity Index (ISI) based on the euglycemic hyperinsulinemic clamp. Islet beta-cell function was assessed by disposition index (DI) for the acute insulin response to glucose (AIRg) using intravenous glucose tolerance test. Metabolic data were compared between groups after adjustment for age, sex, body mass index and waist-to-hip ratio. RESULTS: The NGT/FH+ group showed lower level of ISI (P = 0.023) than the NGT/FH- group, whereas no difference was found in AIRg or DI between these 2 subgroups. In the FH- individuals, both ISI and DI of the IGT/FH- group decreased compared with the NGT/FH- group (both P < 0.05). In the FH+ individuals, no difference was found in ISI between the IGT/FH+ and NGT/FH+ groups, whereas the IGT/FH+ group had a lower level of AIRg and DI than the NGT/FH+ group (both P < 0.0001). CONCLUSIONS: This study showed that the pathophysiological changes were different between individuals with and without a family history of T2DM during the glucose tolerance aggravation.