Prophylactic fenbendazole therapy does not affect the incidence and onset of type 1 diabetes in non-obese diabetic mice

Fenbendazole (FBZ) is a common, highly efficacious broad-spectrum anthelmintic drug used to treat and limit rodent pinworm infections. However, the effect of its prophylactic use on the immune response of rodents is largely undefined. The non-obese diabetic (NOD) mouse is a model commonly used to study type 1 diabetes (T1D). Parasitic infections will inhibit diabetes development in NOD mice; thus, in the presence of contamination, prophylactic treatment with anthelmintics must be considered to maintain experimental research. Herein, we investigated the prophylactic use of FBZ in NOD mice to determine its effect on the incidence and onset of diabetes, lymphocyte sub-populations and T cell proliferative responses. NOD mice were separated into control and treatment groups. The treatment group received a diet containing FBZ. Animals were monitored for the incidence and onset of T1D. At matched time points, diabetic and non-diabetic mice were killed and splenic lymphocytes analyzed for various cell sub-populations and mitogen-induced proliferative responses using flow cytometry. Treated and control mice were monitored >23 weeks with no detectable effects on the incidence or onset of diabetes. Moreover, no significant differences were detected in lymphocyte sub-populations and mitogen-induced CD4(+) and CD8(+) proliferative responses between control and treatment groups. These results suggest that prophylactic FBZ treatment does not significantly alter the incidence or onset of diabetes in NOD mice. The prophylactic use of FBZ, therefore, presents a viable approach for the prevention of pinworm infection in precious experimental animals with substantial scientific and economic benefits.     

Genetic deletion of granzyme B does not confer resistance to the development of spontaneous diabetes in non‐obese diabetic mice

Granzyme B (GzmB) and perforin are proteins, secreted mainly by natural killer cells and cytotoxic T lymphocytes that are largely responsible for the induction of apoptosis in target cells. Because type 1 diabetes results from the selective destruction of β cells and perforin deficiency effectively reduces diabetes in non‐obese diabetic (NOD) mice, it can be deduced that β cell apoptosis involves the GzmB/perforin pathway. However, the relevance of GzmB remains totally unknown in non‐obese diabetic (NOD) mice. In this study we have focused on GzmB and examined the consequence of GzmB deficiency in NOD mice. We found that NOD.GzmB^–/– mice developed diabetes spontaneously with kinetics similar to those of wild‐type NOD (wt‐NOD) mice. Adoptive transfer study with regulatory T cell (T_reg)‐depleted splenocytes (SPCs) into NOD‐SCID mice or in‐vivo T_reg depletion by anti‐CD25 antibody at 4 weeks of age comparably induced the rapid progression of diabetes in the NOD.GzmB^–/– mice and wt‐NOD mice. Expression of GzmA and Fas was enhanced in the islets from pre‐diabetic NOD.GzmB^–/– mice. In contrast to spontaneous diabetes, GzmB deficiency suppressed the development of cyclophosphamide‐promoted diabetes in male NOD mice. Cyclophosphamide treatment led to a significantly lower percentage of apoptotic CD4⁺, CD8⁺ and CD4⁺CD25⁺ T cells in SPCs from NOD.GzmB^–/– mice than those from wt‐NOD mice. In conclusion, GzmB, in contrast to perforin, is not essentially involved in the effector mechanisms for β cell destruction in NOD mice.     

Immune responses to glutamic acid decarboxylase and insulin in patients with gestational diabetes

Pregnancy is a natural state of immunoprotection and tolerance. We studied subjects with gestational diabetes (GDM) to evaluate the influence of pregnancy on the humoral immune response to the autoantigen GAD and to injected insulin. Antibodies against glutamic acid decarboxylase (GADA) subclasses and epitope reactivity were determined in 34 GADA-positive pregnant patients with GDM, in 20 GADA-positive relatives of people with TID and in 25 GADA-positive patients with newly diagnosed TID. Partum levels of insulin antibodies (IA), IgG1- and IgG4-IA were measured in 131 women with GDM treated with human insulin from the time of diabetes diagnosis (including 22 with GADA) and were compared to 19 patients with TID after 3 months of insulin treatment. GADA titre and subclasses were similar among all groups. GADA in GDM patients bound fewer epitopes than GADA in relatives of patients with TID (all epitopes being present in 23%versus 65%, P < 0.01). In particular, antibodies to the minor GADA epitopes GAD6596-249, GAD651-100 and GAD67 were less frequent in patients with GDM compared to relatives (P < 0.01). Antibodies to insulin (IA) were found in 17% of patients with GDM. They were more frequent in GDM patients with GADA compared to GADA-negative patients (41%versus 12%, P < 0.005). IgG1 was the dominant insulin antibody subclass response in both patients with GDM and TID but levels of IgG1-IA and IgG4-IA were significantly lower in patients with GDM compared to patients with TID (P < 0.004). Antibody responses in women with gestational diabetes appear to be dampened and restricted, but without change in subclass usage.     

Short-term subcutaneous insulin treatment delays but does not prevent diabetes in NOD mice

Despite encouraging results in the NOD mouse, type 1 diabetes prevention trials using subcutaneous insulin have been unsuccessful. To explain these discrepancies, 3-week-old NOD mice were treated for 7 weeks with subcutaneous insulin at two different doses: a high dose (0.5 U/mouse) used in previous mouse studies; and a low dose (0.005 U/mouse) equivalent to that used in human trials. Effects on insulitis and diabetes were monitored along with immune and metabolic modifications. Low-dose insulin did not have any effect on disease incidence. High-dose treatment delayed but did not prevent diabetes, with reduced insulitis reappearing once insulin discontinued. This effect was not associated with significant immune changes in islet infiltrates, either in terms of cell composition or frequency and IFN-γ secretion of islet-reactive CD8(+) T cells recognizing the immunodominant epitopes insulin B(15-23) and islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP)(206-214). Delayed diabetes and insulitis were associated with lower blood glucose and endogenous C-peptide levels, which rapidly returned to normal upon treatment discontinuation. In conclusion, high- but not low-dose prophylactic insulin treatment delays diabetes onset and is associated with metabolic changes suggestive of β-cell "rest" which do not persist beyond treatment. These findings have important implications for designing insulin-based prevention trials.     

C肽联合胰岛素对糖尿病小白鼠肾脏的影响

目的研究C肽联合胰岛素治疗对糖尿病小白鼠肾脏病变的改善作用。方法选取小白鼠50只，分为正常对照组（NC组）、糖尿病组（DM组），糖尿病组用链脲佐菌素诱发小白鼠成模后，随机分为三组：糖尿病对照组（DC组）、胰岛素组（IG组）和胰岛素＋C肽组（ICG组）。治疗8周后测定各组小白鼠24小时尿白蛋白排泄率（UAER）、肾重／体重，并观察糖尿病小白鼠肾脏超微结构变化。结果胰岛素＋C肽组肾重／体重比值低于糖尿病组（P〈0．05），与胰岛素组和正常对照组差异无显著性。胰岛素＋C肽组小白鼠肾小球体积明显小于糖尿病组（P〈0．05），与胰岛素组和正常对照组无显著性差异（P〉0．05）。24小时尿白蛋白排泄率糖尿病组明显升高，胰岛素组低于糖尿病组，但差异无显著性，胰岛素＋C肽组与正常对照组相似。结论C肽联合胰岛素治疗可明显改善糖尿病小白鼠肾脏病变。     

Coxsackievirus immunization delays onset of diabetes in non-obese diabetic mice

Enteroviruses may be involved in the pathogenesis of Type 1 diabetes through different mechanisms including triggering of autoimmunity. The effect of immunization with coxsackievirus B4-E2 on diabetes incidence was studied in the non-obese diabetic mice, an animal model for human autoimmune insulin-dependent diabetes mellitus. The immunization delayed the onset of diabetes in the mice, and the effect was mediated at least partially by virus immunization-activated splenocytes as demonstrated by adoptive transfer experiments. Immunization resulted in a strong humoral immune response against the immunizing virus, formalin-inactivated coxsackievirus B4-E2. Cell-mediated immune response to virus antigen was characterised by interferon gamma and interleukin 10 secretion. The immunization also resulted in increased antibody levels against several beta-cell autoantigens. By using epitope mapping we were able to show that in addition to reactivity with the known epitopes of viral proteins and tyrosine phosphatase IA-2 or heat shock protein 60, responses to some other regions of autoantigens were enhanced. In preproinsulin, the response was restricted against an antigenic region earlier identified as DR4-dependent epitope. This reactivity can not be explained by homologous amino acid sequences and it is possible that enterovirus immunization might change the autoantigen specific TH1/TH2 balance in non-obese diabetic mice. In conclusion, our results suggest that coxsackievirus immunization increased humoral immune response to beta cell autoantigens and this was associated with a less destructive pathology for spontaneous diabetes in non-obese diabetic mice.     

Longitudinal study of islet cell antibodies and insulin autoantibodies and development of diabetes in non-obese diabetic (NOD) mice.

We have previously shown the presence of circulating islet cell cytoplasmic antibodies (ICA) and insulin autoantibodies (IAA) in the NOD mouse before onset of insulin-dependent diabetes mellitus (IDDM). Here we have determined the levels of the two autoantibodies in 28 female NOD mice longitudinally from approximately day 40 to day 250, to examine their ontogeny, association and predictive value for diabetes. All animals (11 diabetic, 17 non-diabetic) showed varying levels of ICA at some stage, while IAA activity was found in 21 out of 28 mice. Expression of both the markers was seen in more than half of the animals by day 60, with higher levels and rates occurring subsequently in both diabetic and non-diabetic groups. The expression of ICA did not always correlate with that of IAA. There was no apparent difference in the ontogeny of ICA and IAA between the two groups. During the study period the number of animals with ICA was similar in the two groups, while the number of those with IAA was higher in the diabetic animals. In this group declining and rising levels of ICA were seen just before clinical diabetes with frequent peaks of IAA. In the same animals, eight out of 11 mice showed co-expression of high levels of both markers either intermittently or persistently prior to onset, whereas only one non-diabetic animal showed this. We conclude that the ontogeny and serum level of ICA or IAA alone could not be used to predict the clinical onset of diabetes in these animals. However, co-expression of high levels of both markers prior to onset may suggest a strong predisposition to clinical diabetes. This may have relevance to attempts to predict the onset of IDDM in humans who have one or both of these immunological markers.     

Maternal respiratory sensitization and gestational allergen exposure does not affect subsequent pup responses to homologous or heterologous allergen

Evidence suggests that the predisposition towards atopy begins early in life. Maternal allergy has been associated with an increased risk of the development of allergic disease in offspring. Some studies suggest that the development of childhood atopy may also be influenced by prenatal allergen exposure. In this study, a respiratory allergen exposure model was used to determine the impact of maternal sensitization (with or without additional exposures during pregnancy) on subsequent pup responses to homologous or heterologous allergen. Female BALB/c mice received two intratracheal aspiration (IA) exposures to Metarhizium anisopliae crude antigen (MACA) or Hank’s buffered salt solution (HBSS) prior to breeding. Some mice also received three additional exposures during pregnancy. Control mothers did not receive treatment. Young adult offspring received three IA exposures to MACA, house dust mite extract (HDM) or HBSS. Offspring sensitized as young adults to either HDM or MACA developed an airway inflammatory response, including increased bronchoalveolar lavage fluid lactate dehydrogenase activity, total protein and total and differential cell counts compared to offspring exposed to HBSS. Increased airway responsiveness to methacholine was observed in pups treated with HDM but not with MACA. Maternal sensitization status (with or without gestational allergen exposure) had no effect on offspring response to either MACA or HDM. In conclusion, this study demonstrates that IA administration of MACA or HDM extract to young adult BALB/c mice induces the development of an inflammatory airway response. In contrast to previous reports, neither maternal sensitization nor gestational allergen exposure could be demonstrated to have a clear effect on offspring sensitization. This discrepancy may be a function of the respiratory sensitization and exposure protocol used in this study, which mimics natural sensitization more closely than do parenteral routes of exposure.     

The effect of gestation and fetal mismatching on the development of autoimmune diabetes in non-obese diabetic mice

The impact of gestation and fetal-maternal interactions on pre-existent autoimmune beta cell destruction is widely unknown. The aim of this study was to investigate the influence of gestation per se and fetal mismatching on the onset of autoimmune diabetes in female non-obese diabetic (NOD) mice. We examined cumulative diabetes frequencies of NOD dams mated to syngeneic NOD, haploidentical CByB6F1/J and fully mismatched C57BL/6J male mice. Pregnancy from NOD males neither increased nor accelerated the diabetes onset of NOD dams (71% by age 28 weeks) compared to unmated female NOD mice (81% by age 28 weeks; P = 0·38). In contrast, delayed diabetes onset was observed when NOD dams were mated at 10 weeks of age with major histocompatibility complex (MHC) haploidentical CByB6F1/J male mice (38% at age 28 weeks; P = 0·01). Mating with fully MHC mismatched C57BL/6J male mice (72% diabetes by age 28 weeks; P = 0·22) or mating with the haploidentical males at the later time-point of age 13 weeks (64% versus 91% in unmated litter-matched controls; P = 0·13) did not delay diabetes significantly in NOD females. Because infusion of haploidentical male mouse splenocytes was found previously to prevent diabetes in NOD mice we looked for, but found no evidence of, persistent chimeric lymphocytes from haploidentical paternal origin within the dams' splenocytes. Gestation per se appears to have no aggravating or ameliorating effects on pre-existent autoimmune beta cell destruction, but pregnancy from MHC partially mismatched males delays diabetes onset in female NOD mice.     

B10 细胞与非肥胖型糖尿病小鼠自身免疫性糖尿病发生的关系研究

目的：研究B10细胞与非肥胖型糖尿病小鼠自身免疫性糖尿病发生的关系。方法：选择20只6周龄NOD/LT雌性小鼠进行常规培养至30周龄,根据小鼠血糖、血肌酐和体重情况将小鼠分为自身免疫性糖尿病未发生组和发生组。利用酶联吸附反应检测两组小鼠脾脏组织中IL-10水平。利用流式细胞分选术检测两组小鼠脾脏组织汇总B10细胞比例。将40只6周龄NOD/LT雌性小鼠分为对照组和B10组,B10组小鼠接种分离得到的B10细胞,每周一次,对照组接种同等体积生理盐水,分别于第10、15、20、25、30周龄时检测小鼠自身免疫性糖尿病发生情况。结果：发生组小鼠血糖和血肌酐水平显著高于未发生组（ P ＜0.05）,体重水平显著低于未发生组（ P ＜0.05）。发生组小鼠脾脏组织中IL-10水平显著高于未发生组。自身免疫性糖尿病发生组小鼠脾脏组织中B10细胞含量显著高于未发生组。当小鼠处于第10、15周龄时,B10组小鼠中自身免疫性糖尿病发生率显著低于对照组,但第20、25、30周时,B10组小鼠中自身免疫性糖尿病发生率显著高于对照组。结论： B10细胞的过度积累,可能是进一步诱发NOD小鼠自身免疫性糖尿病发生的原因之一。     

IgE-mediated allergy to recombinant human insulin in a diabetic

A 63-year-old nonatopic female suffering from type II diabetes with severe local and systemic immediate-type allergic reactions to injections of different recombinant human insulin products has been reported. Skin testing as well as IgE measurements not only proved immediate-type sensitization to human insulin but also to porcine and bovine insulin which had never been administered and indicated immunological cross-reactivity. Cross-reactivity was proved by an IgE inhibition test. Independent of this reaction, the patient showed IgE-mediated sensitization to protamine.     

小檗碱对非肥胖性糖尿病小鼠1型糖尿病的预防作用

目的探讨小檗碱对非肥胖性糖尿病(NOD)小鼠1型糖尿病的影响及其可能的分子机制。方法40只4周龄NOD雌性小鼠随机分为小檗碱干预组(Ber,20只)和生理盐水对照组(NS,20),监测血糖,记录糖尿病发病率,40周后处死小鼠,分别应用Western blot方法与real time PCR方法检测两组小鼠胰腺内Fas、iNOS、bcl-2、SOD蛋白与mRNA的表达水平。结果小檗碱干预组NOD小鼠1型糖尿病发生率较对照组明显降低(4/20,20%;18/20,90%),平均发病时间也明显延缓。与对照组相比,小檗碱干预组NOD小鼠胰腺组织Fas、iNOS的蛋白与mRNA表达水平明显下调,Bcl-2、SOD的蛋白与mRNA表达水平明显上调,P0.05。结论小檗碱预防NOD鼠糖尿病的发生可能与上调胰腺组织Fas、iNOS的蛋白表达,下调Bcl-2、SOD的蛋白表达相关。     

Dynamics of insulin secretion in dogs with alloxan diabetes

Hypoinsulinemia in the superior pancreatico-duodenal vein and depression of the first phase of insulin secretion by the pancreas, characteristic of alloxan diabetes of different degrees of severity, are not observed in the femoral vein. The results of an investigation of the dynamics of the insulin and glucose concentrations in the superior pancreatico-duodenal vein emphasize the dominant role of the pancreatic factor in the pathogenesis of alloxan diabetes in dogs. Data obtained by the study of these indices in the peripheral femoral vein do not reflect this state of affairs adequately.Laboratory of Pathological Physiology, Institute of Experimental Endocrinology and Hormone Chemistry, Academy of Medical Sciences of the USSR, Moscow. Department of Normal Physiology, North-Ossetian Medical Institute, Ordzhonikidze. (Presented by Academician of the Academy of Medical Sciences of the USSR N. A. Fedorov.) Translated from Byulleten' Éksperimental'noi Biologii i Meditsiny, Vol. 85, No. 3, pp. 278–281. March, 1978.     

Studies of autoantibodies reactive with thyroid membrane antigens and insulin in non obese diabetic mice.

Enzyme-linked immunosorbent assay (ELISA) was used to study the temporal relationship between the appearance of murine autoantibodies reactive to insulin and thyroid membrane antigens (TMA) and the development of diabetes and thyroiditis in the non obese diabetic (NOD) mouse. Overall, 28% of NOD mice had antibodies specific for mouse thyroid membrane antigens (MTMA), 30% had antibodies to human thyroid membrane antigens (HTMA) and 23% of NOD mice had insulin autoantibodies (IAA), in at least one of their serial monthly blood samples. Non autoimmune BALB/c mice did not develop antibodies to these antigens. Presence of IAA was associated with the development of diabetes and in 87% of cases such antibodies were detected before the diabetes was diagnosed. IAA were usually demonstrated before insulitis. No association between thyroiditis and IAA was noted. Anti-MTMA and anti-HTMA antibodies were detected more frequently in NOD mice with thyroiditis than in those without thyroid inflammation. No significant association was noted between detection of serum anti-TMA antibodies and the development of diabetes. In young mice, anti-TMA antibodies were not detected in the absence of thyroiditis. Western blot analysis of NOD sera positive for MTMA by ELISA revealed a heterogeneous pattern of reactivity. The significance of these findings with respect to the pathogenesis of diabetes and thyroiditis and their association, is discussed.     

NFkappaB1 gene does not affect type 1 diabetes predisposition in a Spanish population

The chromosomal location of the NFkappaB1 gene on 4q, a region linked to type 1 diabetes (T1D), together with the observed resistance to T1D of NFkappaB1-deficient mice, suggests its potential role as candidate gene increasing diabetes predisposition. Previous association studies in diverse populations yielded inconclusive results. Two polymorphisms in the promoter region of the NFkappaB1 gene have been studied: a functional -94ins/delATTG regulating the gene expression and a very informative CA-repeat microsatellite. A strong association with the latter was reported in British population but could not be replicated in Danish families. No evidence of association was detected for those genetic markers in 270 Spanish T1D patients and 484 healthy ethnically matched controls. Therefore, it seems that this gene plays no major role in T1D predisposition.     

Modulation of diabetes in NOD mice by GAD65-specific monoclonal antibodies is epitope specific and accompanied by anti-idiotypic antibodies

Type 1 diabetes is caused by the autoimmune destruction of pancreatic beta cells. Here we show that administration of a human monoclonal antibody (b96.11) specific to the 65-kDa isoform of glutamate decarboxylase (GAD65) to prediabetic non-obese diabetic (NOD) mice significantly delays the onset of autoimmune diabetes. We found this effect to be epitope-specific, as only b96.11 showed this therapeutic property, while a GAD65-specific human monoclonal control antibody (b78) derived from the same patient, but specific to a different determinant of GAD65, had no significant effect on the progression of disease. Administration of b96.11 or b78 to NOD mice was accompanied by the generation of anti-idiotypic antibodies. Importantly, the induced anti-idiotypic antibodies were specific for the immunizing antibody and blocked the binding of GAD65 by the respective antibody. These findings suggest a potential role for the internal image of the GAD65 determinant recognized by b96.11 in the anti-idiotypic antibody, supporting an immunomodulatory role for GAD65-specific autoantibodies, as originally postulated by Jerne.     

Inhibition of type 1 diabetes in filaria‐infected non‐obese diabetic mice is associated with a T helper type 2 shift and induction of FoxP3+ regulatory T cells

We sought to determine whether Litomosoides sigmodontis, a filarial infection of rodents, protects against type 1 diabetes in non‐obese diabetic (NOD) mice. Six‐week‐old NOD mice were sham‐infected or infected with either L3 larvae, adult male worms, or adult female worms. Whereas 82% of uninfected NOD mice developed diabetes by 25 weeks of age, no L. sigmodontis‐infected mice developed disease. Although all mice had evidence of ongoing islet cell inflammation by histology, L. sigmodontis‐infected mice had greater numbers of total islets and non‐infiltrated islets than control mice. Protection against diabetes was associated with a T helper type 2 (Th2) shift, as interleukin‐4 (IL‐4) and IL‐5 release from α‐CD3/α‐CD28‐stimulated splenocytes was greater in L. sigmodontis‐infected mice than in uninfected mice. Increased circulating levels of insulin‐specific immunoglobulin G1, showed that this Th2 shift occurs in response to one of the main autoantigens in diabetes. Multicolour flow cytometry studies demonstrated that protection against diabetes in L. sigmodontis‐infected NOD mice was associated with significantly increased numbers of splenic CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells. Interestingly, injection of crude worm antigen into NOD mice also resulted in protection against type 1 diabetes, though to a lesser degree than infection with live L. sigmodontis worms. In conclusion, these studies demonstrate that filarial worms can protect against the onset of type 1 diabetes in NOD mice. This protection is associated with a Th2 shift, as demonstrated by cytokine and antibody production, and with an increase in CD4⁺ CD25⁺ FoxP3⁺ regulatory T cells.     

A single night of partial sleep loss impairs fasting insulin sensitivity but does not affect cephalic phase insulin release in young men

The present study sought to investigate whether a single night of partial sleep deprivation (PSD) would alter fasting insulin sensitivity and cephalic phase insulin release (CPIR) in humans. A rise in circulating insulin in response to food‐related sensory stimulation may prepare tissues to break down ingested glucose, e.g. by stimulating rate‐limiting glycolytic enzymes. In addition, given insulin's anorexigenic properties once it reaches the brain, the CPIR may serve as an early peripheral satiety signal. Against this background, in the present study 16 men participated in two separate sessions: one night of PSD (4.25 h sleep) versus one night of full sleep (8.5 h sleep). In the morning following each sleep condition, subjects’ oral cavities were rinsed with a 1‐molar sucrose solution for 45 s, preceded and followed by blood sampling for repeated determination of plasma glucose and serum insulin concentrations (?3, +3, +5, +7, +10 and +20 min). Our main result was that PSD, compared with full sleep, was associated with significantly higher peripheral insulin resistance, as indicated by a higher fasting homeostasis model assessment of insulin resistance index (+16%, P = 0.025). In contrast, no CPIR was observed in any of the two sleep conditions. Our findings indicate that a single night of PSD is already sufficient to impair fasting insulin sensitivity in healthy men. In contrast, brief oral cavity rinsing with sucrose solution did not change serum insulin concentrations, suggesting that a blunted CPIR is an unlikely mechanism through which acute sleep loss causes metabolic perturbations during morning hours in humans.     

Association of a type 2 diabetes genetic risk score with insulin secretion modulated by insulin sensitivity among Chinese Hans

Type 2 diabetes (T2D) is characterized by insulin resistance and impaired insulin secretion. The present study aimed to identify the influence of insulin sensitivity on the genetic risk of impaired insulin secretion among a Chinese Han population. For 3229 controls and 1994 treatment‐naïve T2D, single nucleotide polymorphisms (SNPs) from 24 T2D‐related genomic loci were genotyped and a genetic risk score (GRS) was constructed. Results showed that GRS was associated with insulin secretion and disposition indices in both controls and treatment‐naïve T2Ds. Upon stratifying the participants into tertiles by the Matsuda index, we observed an inhibitory relationship between the GRS and insulin secretion in low insulin sensitive but not in high insulin sensitive controls and treatment‐naïve T2Ds. Moreover, low insulin sensitive individuals exhibited more severe impairment in insulin secretion and beta cell response to insulin sensitivity with an increase in risk alleles. Our findings identified that the association of GRS with insulin secretion was strongly modulated by insulin sensitivity in both controls and T2Ds of Chinese Han. It indicates that insulin sensitization should be emphasized in prevention and treatment of T2D for beta cell protection.