diabetes mellitus is a growing public health concern in the united states , presently affecting 25.8 million or 8.3% of the american population . the medical costs associated with this disease , which include drug therapy and surgical treatment , are tremendous . diabetes is a complex metabolic disorder characterized by abnormalities in insulin secretion and action , which leads to hyperglycemia . type 1 diabetes ( t1d ) is a t - cell - mediated autoimmune disease leading to the destruction of pancreatic -cells , whereas type 2 diabetes ( t2d ) is due to a combination of peripheral insulin resistance and loss of functional -cell mass [ 47 ] . therefore , in both t1d and t2d , inadequate -cell mass and -cell dysfunction leading to impaired insulin secretion are central to the deterioration of glycemic control . thus , the search for novel and cost - effective agents that can enhance -cell function and preserve -cell mass is important to provide effective treatment for diabetes . scutellariae baicalensis georgi ( sbg ) , a medicinal plant , grows in some asian countries including siberia , far east of russia , mongolia , china , and some other eastern asian countries . the root of sbg has been used as an ingredient in traditional chinese medicine formulations for thousands of years . according to chinese medicine there have been 295 compounds isolated from sbg , more than 40 of which are flavonoids [ 11 , 12 ] . baicalein , baicalin , wogonin , and wogonoside are presumably the main bioactive components in sbg , which account for 5.41% , 10.11% , 1.3% , and 3.55% , respectively , of the dry material . recently , baicalein and its glucuronide baicalin have drawn wide attention due to their possible health effects . a recent study showed that oral administration of baicalin for 30 days reduced hyperglycemia - induced mitochondrial damage in -cells in diabetic rats . another study reported that long - term administration of baicalin reduced high - fat diet- ( hfd- ) induced body weight gain , circulating cholesterol and free fatty acid levels , lipid deposits in the liver , and systemic inflammation markers . baicalein was reported to have beneficial effects in diabetes - associated health complications [ 1417 ] , cancers [ 18 , 19 ] , cardiovascular disease , inflammation , bacterial infections [ 22 , 23 ] , and oxidative stress [ 2426 ] , although some of the claimed benefits remain controversial and the mechanisms of these effects are unclear . in addition , it is unknown whether baicalein has an antidiabetic effect . moreover , whether this compound exerts a beneficial effect on pancreatic -cells is unclear . as aforementioned , loss of functional -cell mass and -cell dysfunction thus , agents that can increase -cell mass and/or enhance -cell function can provide effective treatment for diabetes and thereby decrease the burden of morbidity from diabetes and related complications . in the present study , we evaluated the antidiabetic potential of baicalein in two mouse models and further determined its effects on pancreatic -cells . we found for the first time that baicalein improves hyperglycemia and glucose tolerance , promotes insulin secretion , and preserves islet mass by inhibiting apoptosis in middle - aged obese diabetic mice . rpmi-1640 media ( rpmi ) were purchased from sigma - aldrich ( st . louis , mo ) ; cmrl-1066 media ( cmrl ) were purchased from mediatech ( holly hill , fl ) ; heat - inactivated fetal bovine serum ( fbs ) was obtained from hyclone ( logan , ut ) . baicalein ( 98% pure ) for in vitro studies was purchased from sigma - aldrich ( st louis , mo ) . stock solutions of baicalein at 20  mm were dissolved in sterilized dimethyl sulfoxide ( dmso ) and stored at 80c before use . baicalein ( 98% pure by hplc ) for in vivo studies was purchased from xi'an yile bio - tech company , china ; ultrasensitive rat insulin enzyme - linked immunosorbent assay ( elisa ) kits were obtained from mercodia ( winston - salem , nc ) ; the active form of the caspase-3 antibody was from bd biosciences ( san jose , ca ) ; the rabbit polyclonal anti - insulin antibody was from abcam ( cambridge , ma ) ; the immpress anti - rabbit ig ( peroxidase ) polymer detection kit , vector novared peroxidase substrate kit , and vector sg peroxidase substrate kits were from vector laboratories ( burlingame , ca ) ; cell viability assay kits were from promega ( madison , wi ) ; and the brdu elisa kit for the cell proliferation assay was from roche applied sciences ( indianapolis , in ) . eight - month - old male c57bl/6 mice ( national cancer institute , frederick , md ) were individually housed in an animal room maintained on a 12 h light / dark cycle under constant temperature ( 2225c ) with ad libitum access to food and water . after 1  wk of environment acclimation , the following two animal studies were performed . the animal study protocols were reviewed and approved by the institutional animal care and use committee at virginia tech . for the first animal study , mice were divided into 3 groups ( n = 10 ) and fed either a standard diet ( sd ) with 10% of calories derived from fat , a high - fat diet ( hf ; research diets inc . , new brunswick , nj ) with 58% of calories from fat , or hf supplemented with baicalein ( 0.5  g / kg diet ) for 8  wks . the fasting blood glucose levels in tail vein blood samples were measured using a glucometer ( roche ) every 4  wk . after 7  wk of dietary baicalein supplementation , body composition was evaluated using an lf-90 instrument ( bruker optics , inc . the lf-90 body composition instrument is based on time domain nuclear magnetic resonance ( td - nmr ) technology which provides an in vivo measurement of lean tissue , body fat , and body fluid in live mice without anesthesia . at the end of 8  wk of dietary treatment , glucose tolerance and mice were fasted for 12  h and injected intraperitoneally ( ip ) with a single bolus of glucose ( l  g / kg  bw ) . glucose levels were measured at time points of 0 , 15 , 30 , 60 , and 120  min , and plasma insulin concentrations were measured at 0 and 30  min , after glucose administration . for the insulin tolerance test , mice were injected i.p . with insulin ( 0.75 units / kg  bw ) , and blood glucose levels were measured at 0 , 15 , 30 , 60 , and 120  min after insulin administration . area under the curve ( auc ) was calculated using the trapezoidal rule . at the end of the study , blood samples were collected from overnight - fasted mice ; plasma insulin concentration was measured using an ultrasensitive mouse / rat insulin elisa kit ; fasting plasma total cholesterol and triacylglycerols were measured in triplicate by enzymatic methods using a pointer 180 analyzer ( pointe scientific , canton , mi ) as described . for this study , mice were divided into 6 groups ( n = 10 mice / group ) with initial fasting blood glucose and body weights balanced among groups . mice were then fed a sd diet , a hf diet ( 58  kcal% fat ) , or hf diet containing 0.25  g or 0.5  g baicalein / kg diet . after 4  wk of treatment , mice received ip injection of stz dissolved in 0.1  m cold sterile sodium citrate buffer ( ph 4.5 ) at 40  mg / kg daily for 3 consecutive days . following stz injection , the levels of nonfasting blood glucose were measured weekly to assess the onset of hyperglycemia ( nonfasting blood glucose > 250  mg / dl ) . plasma insulin concentration measurements and glucose tolerance and insulin tolerance tests were performed as stated above . at the end of experiment , mice were euthanized , and the pancreata were dissected and fixed in 4% ( vol / vol ) formaldehyde buffer ( ph 7.2 ) . a series of tissue sections ( 5  m thickness ) were prepared by aml laboratory ( baltimore , md ) . for determining -cell mass , tissue sections mounted on glass slides were immunofluorescently stained with insulin antibody as we previously described . the -cell mass was calculated by dividing the area of insulin - positive cells by the total area of pancreatic tissue and multiplying by the pancreas weight . the double labelling against the activated caspase-3 and insulin as a measure of -cell apoptosis was performed using an immpress detection system according to the manufacturer 's protocol . in brief , tissue sections were deparaffinized in xylene and rehydrated through a graded series of alcohol washes . antigen retrieval was carried out by boiling sections for 10  min in 0.01  m citrate buffer ( ph 6.0 ) , cooled at room temperature for 30  min , and then blocked with 2.5% normal horse serum in pbs for 20  min . sections were then incubated with a rabbit - anti - mouse caspase-3 antibody detecting the activated form of caspase-3 ( 1  :  200 dilution ) at room temperature for 1  h. visualization was performed using a novared peroxidase substrate kit . the slides were subsequently processed for double immunostaining for insulin using the same approach , and insulin was visualized using a sg peroxidase substrate kit . five pancreatic sections from each mouse with 6 mice per group were costained with activated caspase-3 and insulin . photographs of immune - stained pancreatic sections were captured using an olympus phase contrast microscope . christopher newgard at duke university ) were cultured in rpmi medium containing 11.1  mm glucose and supplemented with 10% fbs , 1  mm sodium pyruvate , 10  mm hepes , 2  g / l sodium bicarbonate , 50  m -mercaptoethanol , 100  u / ml penicillin , and 100  g / ml streptomycin as previously described . human islets were isolated from cadaver organ donors by the islet cell resource centers administered by the southern california resources center & southern california islet consortium at the national medical center ( duarte , ca ) . ins382/13 cells were cultured in 96-well plates in rpmi medium containing 11.1  mm glucose and 10% fbs at 37c until the cells became 50%60% confluent . the cultures were then switched to rpmi medium containing 3  mm glucose and 2% fbs for 12  h. for determining the effect of baicalein on glucose - stimulated insulin secretion ( gsis ) , cells and human islets were washed with krebs - ringer bicarbonate ( krb ) buffer ( 129  mm  nacl , 4.8  mm  kcl , 1.2  mm  mgso4 , 1.2  mm  kh2po4 , 2.5  mm  cacl2 , 5  mm  nahco3 , 0.1% bsa , and 10  mm hepes , ph 7.4 ) followed by incubation in krb buffer containing 3  mm or 20  mm glucose in the presence or absence of 0.1 , 1 , 5 , 10 , or 20  m baicalein at 37c for 30  min . human islets ( 100 islets / tube ) were incubated in 3 or 20  mm glucose with or without various concentrations of baicalein in a 37c water bath with gentle shaking for 30  min . insulin in the supernatants was measured by elisa and normalized to protein content in the same sample . our preliminary experiments showed that exposure of the cells to baicalein for 30  min had no effect on insulin or protein content . ins382/13 cells or human islets were incubated with various concentrations of baicalein or vehicle in rpmi medium containing 5.5  mm glucose and 2% fbs at 37c . 48  h later , the cultures were continued for an additional 4  h in the presence of 3-(4,5-dimethylthiazol-2-yl)-5-(3-carboxymethoxyphenyl)-2-(4-sulfophenyl)-2h - tetrazolium ( mts ) , a formazan compound , which was reduced by cells into a colored formazan product that was soluble in culture medium . cell viability was assessed by the absorbance measurements at 490  nm with a plate reader . to determine whether baicalein has a protective effect on -cells exposed to chronic hyperlipidemia , ins382/13 cells or human islets ( 150 islets / well ) were cultured in rpmi medium containing 0.5  mm palmitate or vehicle with or without various concentrations of baicalein for 4 d , with ins382/13 cells were incubated with various concentrations of baicalein or vehicle in rpmi medium containing 5.5  mm glucose and 2% fbs at 37c . 24  h later , the cultures were continued for an additional 4  h in the presence of bromodeoxyuridine ( brdu ) , an analog of thymidine which incorporates into newly synthesized dna , thereby labeling replicating cells . cell proliferation was assessed by brdu incorporation measurements with an elisa cell proliferation assay kit as previously described . all data were analyzed with one - way anova or student 's t - test using the sigmaplot ( systat software ) program . the hf diet decreased the accumulative average food intake , but baicalein supplementation for 8 consecutive wk did not alter the food consumption pattern compared with hf diet - fed mice ( figure 1(a ) ) . four wk of consuming hf diet significantly increased bw of mice . however , dietary intake of baicalein at 0.5  g / kg diet had no effect on hf diet - induced bw gain ( figure 1(b ) ) . baicalein treatment also had no effects on the weights of the heart , pancreas , spleen , liver , or kidney as compared to weights of hf mice ( data not shown ) . consistently , baicalein treatment did not alter body composition of obese mice as determined by measuring their relative percentage of fat ( figure 1(c ) ) and muscle mass ( figure 1(d ) ) . fasting blood levels of cholesterol ( figure 1(e ) ) and hdl - cholesterol ( figure 1(f ) ) were increased in hf diet - fed obese mice , but they were not significantly altered by dietary intake of baicalein . fasting plasma triglyceride concentrations ( figure 1(g ) ) were not significantly altered by hf feeding or baicalein treatment . after 4  wk of hf diet consumption , mice displayed significantly elevated fasting blood glucose concentrations compared with animals that consumed the sd diet . baicalein supplementation at this point did not affect the hf diet - induced rise in blood glucose . however , after 8  wks of baicalein supplementation , fasting blood glucose levels were significantly lower ( 30% reduction ) than those in hf - fed mice ( figure 2(a ) ) . insulin resistance is important to the etiology of t2d and usually occurs in obesity . to determine if dietary intake of baicalein improves insulin sensitivity in obese mice , we performed an intraperitoneal insulin tolerance test . as expected , hf diet treatment impaired peripheral insulin sensitivity . however , there were little differences in plasma glucose levels ( figure 2(b ) ) and the auc ( figure 2(c ) ) postinsulin injection between hf mice and mice given the hf diet supplemented with baicalein . these results suggest that the improvement in glucose tolerance in baicalein - treated mice is likely not due to an improvement in insulin sensitivity . we next performed a glucose tolerance test to evaluate if the improved glycemic control in mice that consumed baicalein - supplemented diets is via protecting pancreatic -cell function . data showed that baicalein improved glucose tolerance as demonstrated by significantly lower blood glucose levels at 30 and 60  min ( figure 2(d ) ) as well as reduced auc ( figure 2(e ) ) following intraperitoneal glucose injection compared to hf - fed mice . these results suggest that baicalein may promote pancreatic -cell insulin secretory function in response to glucose challenge . we then measured plasma insulin levels after overnight fasting and during intraperitoneal injection of glucose . we observed that fasting plasma insulin levels in hf mice were almost threefold of those in mice that received the sd diet , suggesting that obese mice are insulin resistant ( figure 3(a ) ) . baicalein treatment had no effect on fasting plasma insulin levels ( figure 3(a ) ) but significantly increased blood insulin concentrations following glucose injection ( figure 3(b ) ) indicating that the improvement in glucose tolerance in baicalein - treated mice may be the result of greater insulin secretion from pancreatic -cells . we further assessed whether baicalein can prevent or ameliorate diabetes via promoting pancreatic -cell function in a t2d mouse model that was generated through a combination of hf diet feeding and three consecutive injections of low - doses of stz . regarding this , c57bl/6 mice ( male , 8 months old ) were fed the sd , a hf , or hf containing 0.25  g , 0.5  g , or 1.0  g / kg baicalein . treatment with baicalein for 4  wk had no effect on body weight gain , fasting blood glucose levels , or food intake of mice fed the hf diet ( data not shown ) , consistent with the observations from the animal study described above . after 4  wk of dietary treatment , stz ( 40  mg / kg  bw ) was administrated ( ip ) for 3 consecutive days to induce mild to moderate diabetes mediated by a destruction of islet -cells in mice . our data showed that baicalein significantly ameliorated stz - induced hyperglycemia in diabetic mice fed 0.25 and 0.5  g / kg baicalein , with 0.5  g / kg baicalein producing the maximal protective effect ( figure 4(a ) ) . consistently , dietary ingestion of 0.25 and 0.5  g / kg baicalein ameliorated the loss of bw secondary to the development of diabetes   ( figure 4(b ) ) , whereas food intake was not affected in diabetic mice ( data not shown ) . in addition , insulin tolerance was not altered by baicalein treatment ( data not shown ) , further confirming that this compound has no effect on insulin sensitivity . to determine if the improved glycemic control in mice that were fed the baicalein - supplemented diets is the result of improved islet function , we measured insulin levels in the plasma of control and baicalein - fed mice . as shown in figure 4(c ) , plasma insulin levels in mice fed diets containing 0.25 and 0.5  g / kg baicalein were significantly greater as compared to those in nontreated diabetic mice , suggesting that baicalein may ameliorate hyperglycemia primarily through preserving islet -cell function . since stz causes diabetes by destroying islet -cells , and the results from our first animal study showed that baicalein might improve -cell function , we then examined whether baicalein treatment preserved -cell mass in diabetic mice by using an immunohistochemical technique . we found that stz administration severely decreased -cell mass and insulin content and disrupted the islet architecture ( figures 5(a ) and 5(b ) ) . however , dietary provision of baicalein significantly improved islet -cell mass and preserved its structure in diabetic mice ( figures 5(a ) and 5(b ) ) . consistently , baicalein - treated diabetic mice displayed fewer apoptotic -cells than untreated mice ( figure 5(c ) ) , as determined by double immunolabeling of the activated caspase-3 , a key protease involved in the terminal steps of cell apoptosis . our animal study showed that baicalein preserves functional -cell mass . to investigate the mechanism underlying this protective action of baicalein , we assessed whether baicalein affects the viability of insulin - secreting cells and human islets . our results showed that baicalein dose - dependently increased both ins382/13 cell ( figure 6(a ) ) and human islet ( figure 6(b ) ) viability , with 520  m exerting a protective action . to further determine whether baicalein is a survival factor for -cells , we evaluated whether baicalein protects clonal -cells and islets exposed to chronic hyperlipidemia . incubation of ins382/13 cells ( figure 6(c ) ) or human islets ( figure 6(d ) ) with palmitate ( 0.5  mm ) for 4  d significantly reduced cell viability . addition of baicalein negated palmitate - induced reductions in cell viability , with 10  m baicalein , completely abolished this detrimental effect of palmitate on the cells , suggesting that this compound may be capable of protecting against hyperlipidemia - induced -cell toxicity . however , our results showed that baicalein at 0.1  m to 20  m concentrations had no effect on -cell proliferation as determined by a brdu incorporation assay ( data not shown ) . in the animal study , we found that baicalein may promote -cell function and insulin secretion in response to glucose . to examine whether baicalein directly enhances gsis in -cells , we first cultured ins832/13 cells in basal ( 3  mm ) or high ( 20  mm ) glucose in the presence or absence of baicalein for 30  min . as shown in figure 7(a ) , high glucose significantly induced insulin secretion and baicalein further dose - dependently augmented gsis , with a maximal increase observed at a 10  m concentration ( figure 7(a ) ) . we then tested whether baicalein has a similar effect on insulin secretion in pancreatic islets . as shown in figure 7(b ) , baicalein had no effect on basal insulin secretion but significantly augmented gsis in human islets , suggesting that these in vitro findings may have physiological relevance . recent studies showed that baicalin , the glucuronide form of baicalein , may exert beneficial effects on diabetes mellitus or diabetes - related complications [ 1416 ] . however , whether and how baicalein exerts an antidiabetic effect is unclear . in the present study , we tested the antidiabetic potential of this natural compound using two mouse models , and we found that dietary intake of baicalein can improve glucose tolerance in middle - aged obese mice induced to become obese by hf diet feeding and ameliorate hyperglycemia in stz - induced diabetic mice by preserving -cell mass and protecting its function . while peripheral insulin resistance is common during obesity and aging in mice and humans , its progression to t2d is largely due to insulin secretory dysfunction and significant apoptosis of functional -cells [ 5 , 3437 ] , leading to an inability to compensate for insulin resistance . indeed , those with t2d always manifest increased -cell apoptosis and reduced -cell mass [ 35 , 36 , 38 ] . in this context , it is tempting to speculate that baicalein may be a plant - derived novel antidiabetic compound by protecting -cell mass and function , given that promotion or preservation of -cell mass has been shown to be effective in preventing and treating diabetes [ 5 , 34 , 3942 ] . in our animal studies , we used near middle - aged mice , because t2d usually occurs at middle and older ages in humans . we observed that baicalein treatment for 8  wks improved fasting blood glucose levels in obese mice . however , the mechanism by which baicalein treatment ameliorates fasting hyperglycemia is unclear , given that neither fasting plasma insulin levels nor peripheral insulin sensitivity was significantly modulated . a growing body of evidence indicates that obesity causes hepatic insulin resistance , leading to impaired regulation of glycogenolysis and gluconeogenesis by insulin , thereby increasing hepatic glucose production and output [ 43 , 44 ] . previous studies found that some of the flavonoids can reduce hepatic glucose production by suppressing the expression and enzymatic activities of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase [ 4548 ] , two critical enzymes for gluconeogenesis in the liver . it is unknown whether flavonoid baicalein also has this effect , which is currently under investigation in this laboratory . in this study , we also found that baicalein treatment improved glucose tolerance in obese mice , which should primarily reflect a direct response of -cells to circulating glucose , since whole body insulin sensitivity was not altered by baicalein treatment . indeed , mice given baicalein displayed greater circulating insulin levels following ip injection of glucose compared to controls , suggesting that baicalein treatment may directly improve insulin secretion from pancreatic islets in response to a glucose challenge . we further explored whether baicalein directly protects pancreatic -cell function by using a nongenetic mouse model of t2d , that was generated by employing a combination of feeding a hf diet and administering three mild doses ( 40  mg / kg ) of stz that does not cause diabetes in chow - fed mice , as demonstrated in our previous study . this nongenetic diabetic mouse model manifests the metabolic characteristics of human t2d , including moderate levels of hyperglycemia , hyperlipidemia , insulin resistance , impaired insulin secretion , and reduced -cell mass . the use of low - doses of stz also minimizes the variability of diet - induced diabetes development and thus provides better experimental controls for evaluating the antidiabetic effects of this compound . the results in the present study show that baicalein protected against stz - induced -cell apoptosis , thereby leading to the improved -cell mass in obese diabetic mice , which could be primarily attributable to its antidiabetic action , given that baicalein treatment did not alter other metabolic parameters such as insulin resistance , bw , or food intake . consistent with the animal data , we demonstrated that baicalein promoted insulin - secreting cell and pancreatic islet viability and insulin secretory function in vitro . our results showing that 5  m baicalein can improve the viability of ins1 and human islet cells and stimulate insulin secretion might be of biological relevance , given that this dose of baicalein used in the present study may overlap with the physiologically achievable levels in the plasma following dietary intake . it was reported that baicalein can be absorbed from the stomach and the small intestine due to its high lipophilicity and low molecular weight [ 49 , 50 ] . in fact , it was found that after oral administration of baicalein to rodents , the plasma concentrations of total baicalein peaked at 10  m and can be maintained at a 1  m concentration for 36  h [ 51 , 52 ] . collectively , these results obtained from both in vivo and in vitro experiments strongly suggest that baicalein may act directly on the pancreatic -cell to enhance its function , thereby exerting an antidiabetic effect . however , the exact mechanism underlying such a cytoprotective effect of this compound on -cells is presently unknown . 12/15-lipoxygenase ( lo ) is a member of the lo family that catalyzes conversion of arachidonic acid to 12-hydroperoxyeicosatetraenoic acid , which is subsequently reduced to 12-hydroxyeicosatetraenoic acid , an inflammatory mediator . 12/15-lo is expressed in both rodent and human islets and its expression and activity are upregulated in hf diet - induced obese mice . recent studies have shown that 12-lo knockout mice are resistant to islet -cell damage induced by hf feeding   or low - dose stz administration , suggesting that this enzyme plays a crucial role in mediating metabolic stress - induced pancreatic -cell damage . therefore , it is intriguing to speculate that baicalein treatment may prevent islet -cells from hf feeding and stz - induced damage , which is an ongoing investigation in this laboratory . our results show that baicalein could significantly stimulate insulin secretion in -cell lines and human islets . it is well characterized that glucose induces insulin secretion through glycolysis and mitochondrial oxidation in -cells . these events cause an increase in the intracellular atp / adp ratio , which sequentially leads to closure of katp channels , depolarization of the cell membranes , ca influx , and ultimate exocytosis of insulin - containing granules . our in vitro study showed that baicalein treatment increases the viability of clonal -cells and human islets . increased cell viability could produce more nicotinamide adenine dinucleotide ( nadh ) and nicotinamide adenine dinucleotide phosphate ( nadph ) , leading to enhanced mitochondrial function to increase atp production , which may in turn enhance insulin secretion in -cells therefore , the effect of baicalein on insulin secretion may be mediated through improving mitochondrial metabolism , thereby increasing atp generation in -cells . there is also the possibility that baicalein stimulates insulin secretion through a camp - mediated mechanism . it was reported that genistein , a flavonoid from soybean , acutely stimulated insulin secretion in pancreatic -cells via a camp - dependent protein kinase pathway . however , it is unknown whether baicalein can activate the camp / pka pathway in -cells , leading to insulin secretion . in summary , this is the first report to our knowledge that dietary supplementation of baicalein significantly ameliorated hyperglycemia and increased blood insulin levels , concomitant with improved functional islet mass , in obese diabetic mice . in addition , baicalein directly improved -cell and human islet viability and insulin secretion , suggesting that this natural compound may have a novel antidiabetic action . future study should be directed at elucidating the molecular mechanism by which baicalein stimulates insulin secretion and promotes -cell survival .
in both type 1 ( t1d ) and type 2 diabetes ( t2d ) , the deterioration of glycemic control over time is primarily caused by an inadequate mass and progressive dysfunction of -cell , leading to the impaired insulin secretion . 
 here , we show that dietary supplementation of baicalein , a flavone isolated from the roots of chinese herb scutellaria baicalensis , improved glucose tolerance and enhanced glucose - stimulated insulin secretion ( gsis ) in high - fat diet ( hfd- ) induced middle - aged obese mice . 
 baicalein had no effect on food intake , body weight gain , circulating lipid profile , and insulin sensitivity in obese mice . using another mouse model of type 2 diabetes generated by high - fat diet ( hfd ) feeding and low doses of streptozotocin injection 
 , we found that baicalein treatment significantly improved hyperglycemia , glucose tolerance , and blood insulin levels in these middle - aged obese diabetic mice , which are associated with the improved islet -cell survival and mass . in the in vitro studies 
 , baicalein significantly augmented gsis and promoted viability of insulin - secreting cells and human islets cultured either in the basal medium or under chronic hyperlipidemic condition . 
 these results demonstrate that baicalein may be a naturally occurring antidiabetic agent by directly modulating pancreatic -cell function .