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A Hydroxychalcone Derived from Cinnamon Functions as a Mimetic for Insulin in 3T3-L1 Adipocytes
Abstract
These studies investigated the ability of a hydroxychalcone from cinnamon to function as an insulin mimetic in 3T3-LI adipocytes.
Comparative experiments were performed with the cinnamon methylhydroxychalcone polymer and insulin with regard to glucose uptake, glycogen synthesis. phosphatidylinositol-3-kinase dependency, glycogen synthase activation and glycogen synthase kinase-3beta activity. The phosphorylation state of the insulin receptor was also investigated.
MHCP treatment stimulated glucose uptake and glycogen synthesis to a similar level as insulin. Glycogen synthesis was inhibited by both wortmannin and LY294002, inhibitors directed against the PI-3-kinase. In addition, MHCP treatment activated glycogen synthase and inhibited glycogen synthase kinase-3beta activities, known effects of insulin treatment. Analysis of the insulin receptor demonstrated that the receptor was phosphorylated upon exposure to the MHCP. This supports that the insulin cascade was triggered by MHCP. Along with comparing MHCP to insulin, experiments were done with MHCP and insulin combined. The responses observed using the dual treatment were greater than additive, indicating synergism between the two compounds.
Together, these results demonstrate that the MHCP is an effective mimetic of insulin. MHCP may be useful in the treatment of insulin resistance and in the study of the pathways leading to glucose utilization in cells.
... Cinnamon stimulates glucose uptake through regulating the expression of GLUT4 and through acting as an insulin mimetic that leads to the stimulation of the translocation of GLUT4, therefore causing a reduction in blood glucose levels [52,53]. Moreover, polyphenols, found in cinnamon, have been shown to improve insulin sensitivity. ...
... Jarvill et al. concluded that cinnamon extracts activate insulin receptor kinase and inhibit the dephosphorylation of insulin receptors, thus causing the maximal phosphorylation of the insulin receptors. This phosphorylation is associated with improved insulin sensitivity, and has been linked to improved lipid profiles and glycemic responses [53]. Moreover, cinnamon has the ability to inhibit hepatic reductase activity, hence lowering lipid profile levels [54]. ...
... Similarly, Anderson et al. reported that 500 mg of water extract supplementation with cinnamon for 6 weeks lowered the fasting blood glucose, total cholesterol, and LDL levels, and enhanced the insulin sensitivity of diabetic individuals [58]. The findings from Jarvill et al. and Anderson et al. are in agreement with the findings of the current research study [53,58]. Previous study findings agree with the findings of the current study when administrated in similar dosages and durations. ...
Non-communicable diseases (NCDs) place a significant burden on global health and the healthcare systems which support it. Metabolic syndrome is a major risk factor for a large number of NCDs; however, treatments remain limited. Previous research has shown the protective benefits of edible dietary spices on key components of metabolic syndrome. Therefore we performed a 12-week double-blind, placebo-controlled, randomized, clinical trial to evaluate the effect of ginger (Zingiber officinale), cinnamon (Cinnamomum), and black seed (Nigella sativa) consumption on blood glucose, lipid profiles, and body composition in 120 participants with, or at risk of, metabolic syndrome. Each participant consumed 3 g/day of powder (spice or placebo). Data related to different parameters were collected from participants at the baseline, midpoint, and endpoint of the intervention. Over the 12-week interventions, there was an improvement in a number of biochemical indices of metabolic syndrome, including fasting blood glucose, HbA1c, LCL, and total cholesterol associated with supplementation with the spices when compared to a placebo. This study provides evidence to support the adjunct use of supplementation for those at risk of metabolic syndrome and its sequelae.
... galactomannans decrease blood glucose concentration [57] 4hydroxyisoleucine [58] saponins - [59] trigonelline + nicotinic acid + [60] Ceylon cinnamon Cinnamomum zeylanicum J.Presl methylhydroxychal cone polymer elevation in plasma insulin; hypoglycaemic; hypocholesterolemic; stimulate glucose uptake by adipocytes; [61] cinnamaldehyde [62,63] eugenol [64] Ginger Zingiber officinale Rosc. shogaol increase insulin level; decrease fasting glucose level [65,66] gingerol [66,67] ...
... Studies have also demonstrated that cinnamon bark in doses of 1-6 g per day causes a reduction in TG, TC, and LDL fraction in patients with type 2 diabetes [63]. This is probably caused by the presence of a methylhydroxychalcone polymer (MHCP) stimulating, almost like insulin, glucose uptake by adipocytes [61]. In the study by Jarvill-Taylor et al. [61], MHCP activated insulin receptor autophosphorylation and, thus, glucose uptake and glycogen synthesis. ...
... This is probably caused by the presence of a methylhydroxychalcone polymer (MHCP) stimulating, almost like insulin, glucose uptake by adipocytes [61]. In the study by Jarvill-Taylor et al. [61], MHCP activated insulin receptor autophosphorylation and, thus, glucose uptake and glycogen synthesis. Thus, a synergism between MHCP and insulin was observed since the concurrent application of both substances induced a considerably better response than the sum of responses resulting from their separate application. ...
Diabetes is a metabolic disease that affected 9.3% of adults worldwide in 2019. Its co-occurrence is suspected to increase mortality from COVID-19. The treatment of diabetes is mainly based on the long-term use of pharmacological agents, often expensive and causing unpleasant side effects. There is an alarming increase in the number of pharmaceuticals taken in Europe. The aim of this paper is to concisely collect information concerning the few antidiabetic or hypoglycaemic raw plant materials that are present in the consciousness of Europeans and relatively easily accessible to them on the market and sometimes even grown on European plantations. The following raw materials are discussed in this mini-review: Morus alba L., Cinnamomum zeylanicum J.Presl, Trigonella foenum-graecum L., Phaseolus vulgaris L., Zingiber officinale Rosc., and Panax ginseng C.A.Meyer in terms of scientifically tested antidiabetic activity and the presence of characteristic biologically active compounds and their specific properties, including antioxidant properties. The characteristics of these raw materials are based on in vitro as well as in vivo studies: on animals and in clinical studies. In addition, for each plant, the possibility to use certain morphological elements in the light of EFSA legislation is given.
... Cinnamon bark has gained prominence as a natural anti-diabetic agent due to its ability to regulate blood glucose levels, enhance insulin sensitivity and improve pancreatic function (Anderson et al., 2019). Methyl hydroxychalcone polymer (MHCP) in common and cassia cinnamon was found to be an effective mimetic of insulin (Jarvill-Taylor et al., 2001). MHCP demonstrated in vitro activation of glycogen synthase and inhibition of glycogen synthase kinase-3b as well as insulin receptor phosphorylation homologous to the effects of insulin in 3T3-LI adipocytes (Jarvill-Taylor et al., 2001). ...
... Methyl hydroxychalcone polymer (MHCP) in common and cassia cinnamon was found to be an effective mimetic of insulin (Jarvill-Taylor et al., 2001). MHCP demonstrated in vitro activation of glycogen synthase and inhibition of glycogen synthase kinase-3b as well as insulin receptor phosphorylation homologous to the effects of insulin in 3T3-LI adipocytes (Jarvill-Taylor et al., 2001). High doses of cinnamon, particularly Cinnamomum aromaticum, showed effectiveness in lowering fasting glucose, total cholesterol, and LDL while increasing HDL in DM2 patients (Silva et al., 2021). ...
Diabetes mellitus (DM) is a metabolic disorder characterized by high blood glucose levels due to insulin resistance or impaired insulin secretion. While conventional treatments help manage DM, natural remedies like amla (Emblica officinalis) and cinnamon (Cinnamomum spp.) have shown promising antidiabetic effects. Amla, rich in polyphenols and antioxidants, protects pancreatic -cells, enhances insulin secretion and improves glucose metabolism. Cinnamon contains bioactive compounds like cinnamaldehyde, which mimics insulin action, enhances glucose uptake and lowers blood sugar levels. Studies suggest that both amla and cinnamon effectively reduce fasting blood glucose and cholesterol levels, making them potential adjunct therapies for diabetes management. Further research is needed to confirm their long-term safety and efficacy. ABSTRACT Introduction
... One compound with potential use as a natural growth promoter in the fish diet is cinnamaldehyde (CIN). It is the main component of cinnamon and an aromatic aldehyde organic compound that maintains insulin hormones by lowering blood sugar and lipid levels, and it can maintain healthy liver activity as an insulin mimetic (Hosni et al., 2021;Jarvill-Taylor et al., 2001). CIN can also increase fat metabolism and antioxidant activity (Jayaprakasha and Rao, 2011). ...
... By contrast, the present study revealed that CIN did not affect protease and lipase activity. The polyphenols in cinnamon stimulate glucose metabolism as insulin mimetics (Jarvill-Taylor et al., 2001). CIN supplementation has been demonstrated to improve glucose and lipid homeostasis in diabetic animals. ...
Cinnamaldehyde is an active organic compound and an aromatic aldehyde substance found in cinnamon oil. It is a new feed supplement for animals that can improve growth, nutrient digestion and absorption, lipid use, and immunity. The present study evaluated the effects of dietary trans-cinnamaldehyde 98 % (CIN) on nutrient utilization, antioxidant capacity, and growth performance in Nile tilapia (Oreochromis niloticus). Juveniles used was weighing at about 19.77 ± 0.10 g received dietary CIN at different doses (0, 0.25, 0.5, 0.75, and 1.0 g/kg feed). The fish were maintained in a glass aquarium of 95 × 45 × 35 cm 3 in size at a stocking density of 20 fish per aquarium and fed three times a day to clear satiation. Dietary carbohydrate digestion and absorption were significantly improved in fish fed 0.75 g/kg CIN, as indicated by increased amylase activity and glucose tolerance test. The latter was subsequently confirmed by increases in relative ir, glut4, hx and gs expression that indicated the increase in glucose absorption led to an increase in glucose utilization as an energy source and the synthesis of glycogen as an energy reserve. Interestingly, dietary CIN supplementation also resulted in the downregulation of fas, which facilitates the conversion of glucose to fatty acids, and the upregulation of cpt1a and hsl, indicating increased fatty acid oxidation for energy. CIN at a range of 0.5-0.75 g/kg improved the antioxidant status in the liver, as illustrated by elevated glutathione peroxidase and superoxide dismutase activities (both P < 0.05). Final weight, feed consumption, the specific growth rate, feed efficiency, and protein retention increased were significantly in all CIN groups, with the highest values reached in the 0.5 g/kg CIN (all P < 0.05). Based on a polynomial orthogonal analysis of the fish-specific growth rate, the optimum dosage of CIN inclusion is 0.42 g/ kg.
... 3 Both in vitro and in vivo studies have shown that cinnamon is one such dietary component that contains biologically active substances with insulin-mimetic properties. 4,5 Cinnamon increases glucose absorption by stimulating insulin receptor kinase activity, autophosphorylation, and glycogen synthase activity. The active substances in cinnamon regulate histological, and gene expression profiles due to its low coumarin content compared to other species. ...
... The active substances in cinnamon regulate histological, and gene expression profiles due to its low coumarin content compared to other species. 4 ...
INTRODUCTION: Cinnamon zeylanicum (CZ) bark is widely used as supplement for diabetic management, there are concerns about its safety and potential toxicity at high doses, and limited evidence to support its efficacy. To investigate this further, this study examines the effects of Cinnamon zeylanicum aqueous extract (CZAE) on various factors in diabetic rats, including body weight, blood glucose level, biochemical parameters, histological changes, and gene expression. MATERIALS AND METHODS: In the study, 30 male Sprague Dawley rats were divided into five groups of six animals each. Type 2 diabetes mellitus (T2DM) was induced in all groups except the negative control by a single intraperitoneal injection of streptozotocin (STZ). The rats in the intervention groups (Groups C, D, and E) were given CZAE at 1000, 1500, and 2000 mg/kg, dose respectively, for 28 days. The body weight and fasting blood glucose were monitored weekly, and their liver and renal profiles were analyzed. Histology was assessed with hematoxylin and eosin stain, and apoptotic gene expression was examined in liver and renal tissues. RESULTS: The body weight of rats in intervention groups increased compared to the control group. There was a significant decrease (P<0.001) in blood glucose levels. The extract significantly reduced (P<0.05) liver biochemical markers in the intervention groups compared to the control group. The histology of the liver & kidney improved (p<0.001) with upregulated Bcl-2 and down-regulated BAX genes in preventing apoptosis in the intervention groups. CONCLUSIONS: High doses of CZAE are safe and effective for T2DM.
... It is a type of polyphenol or flavonoid, and a water-soluble compound that cannot be found in spice oils sold as food additives (33). (34) reported that methyl hydroxy chalcone polymer, found in cinnamon, acts as an insulin-mimetic in 3T3-L1 adipocytes. The absorption of 2-deoxy D-[1,2-3 H] glucose was evaluated for uptake after the 60-minute time point. ...
... For the in vitro studies, cell viability assays were performed by (34) to make sure that the aqueous cinnamon extract at a concentration ranging from 1-25 µg/mL was not cytotoxic to H4IIE rat hepatoma cells. It was then found that there was no cytotoxicity with the use of the cinnamon extract treatment. ...
Research regarding the enormous potential of medicinal plants for the development of new drugs and the efficient treatment of diabetes mellitus is increasing due to the harmful effects that synthetic drugs may bring such as severe hypoglycemia, abdominal discomfort, lactic acidosis, and more. Cinnamomum sp. (cinnamon) extracts have shown to have significant anti-diabetic effects on type 2 diabetes mellitus in experimental rodent animals in a dose-dependent manner. There are different possible mechanisms of action involved in its anti-diabetic activities. The efficacy of cinnamon extract as an anti-diabetic agent in type 1 diabetes mellitus experimental rodent animal studies explored in this study.
... Cinnamaldehyde content helps stimulate an increase in glycogen and glucose. Moreover, cinnamon stimulates glucose uptake, glycogen synthesis, and active glycogen synthase in 3T3-L1 adipocytes (Jarvill-Taylor, Anderson, & Graves, 2001;Bernardo et al., 2015). ...
... On the other hand, the glucose improvement is assumed to be caused by the presence of the glucose transporter, other studies suggest that cinnamon has been shown to increase in vitro glucose uptake and glycogen synthesis and increase insulin receptor phosphorylation (Khan et al., 2003;Couturier et al., 2010). Additionally, previous studies stated that this cinnamon extract tends to help trigger the insulin cascade system (Jarvill-Taylor et al., 2001;Shen et al., 2012). Since insulin also plays a key role in lipid metabolism, we postulate that cinnamon consumption will increase blood glucose and lipids in vivo. ...
Weightlifting is a type of sport that demands beneficial complementary supplements. This is because of the highly intensive training and tight schedules, which requires the body to be maintained at the prime condition to avoid injury. Furthermore, supplements and natural products are needed to accelerate athletes' recovery and avoid doping. Cinnamon is a good natural product that contains phenol and cinnamaldehyde antioxidant content. This study used a double-blind one-way crossover design approach on 16 male athletes with the lowest experience competing in Southeast Asia. The athletes consumed 500 mg of cinnamon extract for 8 weeks and entered a 4 and 8 week washout phase and placebo, respectively. The performance tests were conducted by match simulations, such as snatch and clean and jerk. Creatine kinase (CK), C-reactive protein (CRP), and lactate were tested to determine fatigue levels and accelerate recovery. According to the results, significant changes occurred for CK and CRP of p<0.005, glucose p<0.048, and lactate at p<0.012 with no effects on performance. Conclusion: Cinnamon extract significantly affects CK, CRP, lactate, and glucose without any notable effects on performance.
... These benefits include antimicrobial properties (Dusan et al., 2006), insecticidal effects (Park et al., 2005), acaricidal effects (Fichi et al., 2007), antityrosinase effects (Marongiu et al., 2007), antioxidant effects, and insulin-mimicking effects (Broadhurst et al., 2000). Moreover, cinnamon extracts have been shown to enhance insulin receptor functions in cells (Jarvill-Taylor et al., 2001) and may hold promise in cancer treatments (Dutta & Chakraborty, 2018). ...
The Cinnamomum zeylanicum Blume is a spice crop native to Sri Lanka, also known as true cinnamon or Ceylon cinnamon. For almost four centuries, Sri Lankans have been using a traditional method introduced by the Dutch for bundling and peeling cinnamon. While countries produce Chinese cinnamon (Cinnamomum cassia), they do not use intensive labour for quill-making. Cinnamon is primarily used as an aromatic condiment and flavouring agent in traditional and modern medicines. The world cinnamon market is currently dominated by cassia cinnamon due to its high coumarin content (up to 1%). However, Ceylon cinnamon is superior because it has a low coumarin content (less than 0.004%), a unique aroma, and a sweet and spicy flavour profile. A scientific study was conducted on samples peeled with three different methods: traditional peeling, peeling without rubbing and scraping, and peeling with rubbing and scraping. The study aimed to find out the effects on bark oil content and chemical composition, including α-pinene, camphene, β-pinene, α-phellandrene, α-terpinene, D-limonene, β-phellandrene, p-cymene, β-linalool, β-caryophyllene, α-terpineol, 3-phenylpropanoid, cis-cinnamaldehyde, trans-cinnamaldehyde, cinnamyl acetate, eugenol, cinnamyl alcohol, and benzyl benzoate. The standard deviation was calculated for each chemical constituent. Cinnamon bark samples were peeled from approximately two-and-a-half-year-matured trees, and bark oils were obtained using hydro-distillation of bark samples by a Clevenger-type apparatus. Qualitative and quantitative analyses were conducted using GC-MS and GC-FID. The study found that the locations do not significantly affect oil yield, as p>0.05 (p = 0.39). Neither treatment significantly affected the oil yields, p>0.05 (p = 0.84). The study also found that different peeling methods or regions do not significantly affect the oils' chemical composition or physical parameters (p>0.05). Therefore, the study concluded that we could shift from the traditional high-cost peeling method to the low-cost peeling technique without rubbing and scraping without diminishing the final quality of the cinnamon bark products.
... Some meta-analysis also indicated that cinnamon powder intake decreased fasting blood glucose and HbA1c [144]. Methylhydroxychalcone polymer (MHCP) in cinnamon bark reported as effective mimetic of insulin which could activate glycogen synthase and inhibit actions of glycogen synthase kinase-3b as well as insulin receptor phosphorylation homologous [145]. ...
Phytotherapy is attracting increased interest for several reasons. It differs from medical procedures in that it uses the whole herb, although there is often only one component of the plant that works effectively to manage the problem. Plants contain many natural chemicals or phytochemicals that interact with the active ingredient and help prevent any side effects. Medicinal herbs and spices are investigated for their suitability in daily diets for maintaining general wellness or preventing disease. In the past decade, natural health products, dietary supplements, foods with added value, or nutraceuticals have emerged due to the increasing demand for non-pharmaceutical healthcare products. Medical herbs and spices are potential sources for developing new, effective, and safe ingredients to capture a rapidly expanding opportunity in global marketplaces. This book presents up-to-date information on the chemical, pharmacological, and nutritional uses of medicinal herbs and spices in folk medicine, pharmaceuticals, the food industry, veterinary practice, and gastronomy.
... To prevent the varieties of other Diabetes related problems because no were cure has been identified. Hence, management of Diabetes with diet exercise and drug has been established [37]. Aegle marmelosis widely used Ayurvedic medicine for the treatment of diabetes mellitus [38]. ...
... To prevent the varieties of other Diabetes related problems because no were cure has been identified. Hence, management of Diabetes with diet exercise and drug has been established [37]. Aegle marmelosis widely used Ayurvedic medicine for the treatment of diabetes mellitus [38]. ...
... Increasing the expression of proteins involved in glucose transport, insulin signaling pathway, and dyslipidemia is another mechanism by which bioactive compounds of cinnamon administer their antidiabetic efects. Cinnamon extracts could induce the enzymes involved in glycogen synthase, increase glucose uptake primarily by stimulating glucose transporter 4 (GLUT4), and inhibit glycogen synthase kinase-3β [41][42][43]. Furthermore, oxidative stress and consequent tissue damage are the main reasons for insulin resistance and T2D. ...
Type 2 diabetes (T2D) is known as a major public health problem with a noticeable adverse impact on quality of life and health
expenditures worldwide. Despite using routine multiple pharmacological and nonpharmacological interventions, including diet therapy and increasing physical activity, controlling this chronic disease remains a challenging issue, and therapeutic goals are often not achieved. Berefore, recently, other therapeutic procedures, such as using herbal products and functional foods as complementary or alternative medicine (CAM), have received great attention as a new approach to managing T2D complications, according to the literature. We reviewed the existing evidence that supports using various fundamental medicinal herbs, including cinnamon, sa;ron, ginger, jujube, turmeric, and barberry, as CAM adjunctive therapeutic strategies for T2D patients. 3e current review addressed di;erent aspects of the potential impact of the abovementioned herbal products in improving glycemic indices and lipid pro<les, including the e;ect size reported in the studies, their e;ective dose, possible side e;ects, herbs-drug interactions, and their potential action mechanisms.
... Increasing the expression of proteins involved in glucose transport, insulin signaling pathway, and dyslipidemia is another mechanism by which bioactive compounds of cinnamon administer their antidiabetic efects. Cinnamon extracts could induce the enzymes involved in glycogen synthase, increase glucose uptake primarily by stimulating glucose transporter 4 (GLUT4), and inhibit glycogen synthase kinase-3β [41][42][43]. Furthermore, oxidative stress and consequent tissue damage are the main reasons for insulin resistance and T2D. ...
Type 2 diabetes (T2D) is known as a major public health problem with a noticeable adverse impact on quality of life and health expenditures worldwide. Despite using routine multiple pharmacological and nonpharmacological interventions, including diet therapy and increasing physical activity, controlling this chronic disease remains a challenging issue, and therapeutic goals are often not achieved. Therefore, recently, other therapeutic procedures, such as using herbal products and functional foods as complementary or alternative medicine (CAM), have received great attention as a new approach to managing T2D complications, according to the literature. We reviewed the existing evidence that supports using various fundamental medicinal herbs, including cinnamon, saffron, ginger, jujube, turmeric, and barberry, as CAM adjunctive therapeutic strategies for T2D patients. The current review addressed different aspects of the potential impact of the abovementioned herbal products in improving glycemic indices and lipid profiles, including the effect size reported in the studies, their effective dose, possible side effects, herbs-drug interactions, and their potential action mechanisms.
... One of the active ingredients derived from cinnamon is a polymer called methyl hydroxychalcone, which acts like insulin [39]. Cinnamon polyphenols stimulate glucose uptake like insulin and stimulate glycogen biosynthesis by activating the glycogen synthetase and inhibiting the action of glycogen synthetase kinase [40]. Peng et al. (2008) stated that the polyphenols of cinnamon prevent the formation of glycosylated end-products in the serum [41]. ...
Objective
Numerous studies have reported the beneficial effects of exercise and the use of herbal supplements in improving type 2 diabetes and insulin resistance. However, there are still many unanswered questions about the effects of cold and hot water, exercise, and herbal supplements on meteorine-like protein (METRNL), which is considered one of the key factors influencing insulin resistance improvement in this condition. Hence, the current study aimed to address these knowledge gaps and investigate the effects of 8 weeks of warm and cold-water swimming exercise with cinnamon consumption on serum levels of METRNL, histone deacetylase-5 (HDAC5), and insulin resistance in diabetic male rats.
Methods
For this purpose, 70 diabetic male rats were randomly divided into seven groups (10 rats in each group) H ealthy control (HC) , Diabetic control , swimming training in cold water (temperature 5 °C) , swimming training at 5 °C + cinnamon consumption (200 mg/kg body weight) , swimming training in warm water (temperature 36-35 °C) , swimming training in warm water (temperature 36-35 °C) + consumption of cinnamon, and consumption of cinnamon only.
Results
The present study revealed a significant increase in serum METRNL concentration in the cold-water swimming + cinnamon consumption group (p < 0.05). However, no significant changes were observed in insulin levels and HOMA-IR across the different groups (p > 0.05). Additionally, noteworthy findings included a significant reduction in HDAC5 levels in both the cold-water swimming group and the cold-water swimming + cinnamon consumption group, as well as a significant decrease in fasting blood sugar (FBS) levels in all groups compared to the HC group (p < 0.05).
Conclusions
The results of the present study demonstrate that the combination of cold-water swimming exercises and cinnamon extract consumption led to notable increases in serum METRNL concentration. Additionally, significant reductions were observed in HDAC5 and FBS levels. These findings highlight the potential effectiveness and benefits of the combination of cold-water swimming exercises and cinnamon extract consumption as an approach to improve diabetes-related indices.
... Initially, methyl hydroxy chalcone polymer (MHCP) (Figure 3) was identified as the component responsible for reducing blood glucose levels, possibly by acting as a molecular mimic. In the laboratory, MHCP has been shown to activate cell receptors, potentially including insulin receptors (Jarvill-Taylor et al., 2001). However, recent suggestions propose that the polyphenols present in cinnamon, particularly polyphenol A, may also play a role in lowering blood glucose levels (Davis & Yokoyama, 2011). ...
We reported the systematic review of anti-diabetic herbal medicine from Indonesia by integrating herbal medicine databases and summarized the anti-diabetic compounds in Indonesian plants. We used data sources from Pubmed and local Indonesian databases such as Portal Garuda and Basis Data Tanaman Obat Indonesia (BDTOI) to elucidate anti-diabetic candidate herbal medicine. We found 927 articles (PubMed) and 70 articles (Portal Garuda) based on the criteria of anti-diabetic properties. After thoroughly assessing those publications, 38 articles on controlling blood glucose were identified. Moreover, we utilized ClinicalTrial.gov to map the evidence. Five species (Abelmoschus esculentus, Allium sativum L, Cinnamomum cassia, Citrullus colocynthis, and Punica granatum L) passed the clinical trial, three of which were intended for use in treating other diseases, and eight of which lacked clinical evidence. Additionally, over 30 compounds were elucidating from those herbs, including quercetin and allicin. In conclusion, we successfully retrieved anti-diabetic herbal medicine from Indonesia by integrating public databases. The molecular docking study was employed to predict and optimize the anti-diabetic outcomes.
... Some meta-analysis also indicated that cinnamon powder intake decreased fasting blood glucose and HbA1c [144]. Methylhydroxychalcone polymer (MHCP) in cinnamon bark reported as effective mimetic of insulin which could activate glycogen synthase and inhibit actions of glycogen synthase kinase-3b as well as insulin receptor phosphorylation homologous [145]. ...
Herbs and spices have been used as therapeutic agents in traditional medicine due to the presence of bioactive compounds including flavonoids, polyphenols, alkaloids, carotenoids, organosulfur compounds, glucosinolates etc. As a result, they are associated with various functional properties such as digestive stimulant, antioxidant, anti-inflammatory anticancer, anti-diabetic, cardioprotective, neuroprotective, and antimicrobial activities. However, the bioefficacy of different spices are affected by the bioavailabilties of their bioactive compounds and depends on various factors such bioaccessibility, molecular structures, composition of food matrices, and metabolizing enzymes. In this chapter we discuss on major phytochemical compounds of some selected spices including turmeric, garlic, ginger, onion, cinnamon, chili pepper, and black pepper including their bio accessibilities, bioavailabilities and their health beneficial effects. The knowledge of bioaccessibility and bioavailability of spices bioactive compounds will give a better understanding towards the development of strategies to optimize the positive health benefits of spices.
... Previous studies suggested that Dglucose is mediated by the stimulation of the lateral part of the dorsal parabrachial nucleus (LPBD) enhancing glucagon release and suppression insulin secretion leading to hyperglycemia. Dglucose affects the suprachiasmatic nucleus (SCN) and β -adrenergic mechanisms that are involved in the hyperglycemic response to (LPBD) stimulation [16] . Pretreatment with oral cinnamon extract had a weak and delayed hypoglycemic effect which was significant 6 hour after treatment. ...
... The mechanism by which cinnamon and its bioactive components regulate insulin signaling includes the activation of intracellular cascade events. Thus, the extract of this plant and its isolated compounds (hydroxychalcone) seem to stimulate the insulin tyrosine kinase receptor (IR), tyrosine auto-phosphorylation [53], and then, the insulin receptor substrate molecules (IRS) [54]. The IRS-2 phosphorylation results in the activation of phosphatidylinositol 3-kinase (PI3K), which is responsible for the activation of phosphoinositide-dependent protein kinase (PDK1). ...
The scientific evidence that cinnamon may exert beneficial effects on type 2 diabetes mellitus due to the biological activity of its bioactive compounds has been increasing in recent years. This review provides an overview of the effects of cinnamon on clinical parameters of diabetes and summarizes the molecular mechanisms of action of cinnamon on glucose and lipid metabolism. Search criteria include an electronic search using PubMed, Medline, and Cochrane Library databases. English literature references from 2000 up to 2022 were included. Following title and abstract review, full articles that met the inclusion criteria were included. The results from the available evidence revealed that cinnamon improved glycemic and lipidemic indicators. Clinical trials clarified that cinnamon also possesses an anti-inflammatory effect, which may act beneficially in diabetes. Based on in vitro and in vivo studies, cinnamon seems to elicit the regulation of glucose metabolism in tissues by insulin-mimetic effect and enzyme activity improvement. Furthermore, cinnamon seems to decrease cholesterol and fatty acid absorption in the gut. The current literature search showed a considerable number of studies on diabetic subjects. Some limitations in comparing published data should be highlighted, including variability in doses, extracts and species of cinnamon, administration forms, and antidiabetic therapy.
... Cinnamon with scientific name "Cinnamomum zeylanicum "increases glucose consumption and glycogen production and also phosphorylation of insulin receptor that ultimately leads to increased insulin sensitivity (26). ...
Objective: The use of medicinal plants in diabetic patients is rising, it is essential to increase knowledge about the effects of medicinal plants and subsequently perform evidence-based action, so, review studies are a helpful way for the present purpose. Current study was conducted to investigate the clinical trials of medicinal plants used in the treatment of diabetes in Iran.
Materials and Methods: Articles published online between 2010 - 2020 were googled in Magiran, SID, Scopus, and, Iran Medex with Persian keywords such as “type 2 diabetes”, “medicinal herbs”, “healing herbs” “herbs”, “medicinal plants” and “clinical trial”. The inclusion criteria for articles were conducting in the form of a clinical trial, conducting in Iran, publishing in Persian language and having at least a score of 3 based on the Jadad scale.
Results: 20 clinical trial studies were extracted. Five studies were conducted on cinnamon and two studies on cumin and the rest of the plants were examined just in one study. Although some trials showed positive effects of the medicinal plants on reducing fasting blood sugar (FBS) and glycosylated hemoglobin (HbA1c), some others demonstrated that medicinal plants had no effect on important variables in diabetes control.
Conclusion: Conclusions about the benefits of plants should be made with caution, safety and efficacy of plants in the treatment of diabetes should be investigated further. It is essential that patients take any herbal supplements under physician’s supervision and after receiving the necessary advice.
... Cinnamaldehyde, the main constituent of bark essential oil of cinnamon, is reported to have antidiabetic property [24]. Further, methylhydroxychalcone, polyphenol Type-A polymers and naphalenemethyl ester of 3,4-dihydroxycinnamic acid from cinnamon are reported to have insulin mimicking and antidiabetic properties respectively [25][26][27]. Apart from these isolated molecules from cinnamon species, extracts from other commercially important cinnamon species, namely, C. cassia and C. tamala and a few wild species, namely, C. bejolghota, C. loureirii, and C. osmophloeum have also been reported to possess antidiabetic activities [28,29]. Recently, a few wild Cinnamomum species, namely, C. chemungianum, C. litseifolium, C. walaiwarense, and C. wightii have been investigated by us for their antidiabetic potential [30][31][32][33]. ...
This study reports antidiabetic activity of leaf essential oil (EO) of Cinnamomum travancoricum from the Western Ghats, India via in vitro, in vivo and in silico methods. EO was characterized by GC-MS and GC-FID. Essential oil nanoemulsions (EN) were prepared and characterized. Antidiabetic potential was evaluated through in vitro assays namely, α-amylase and α-glucosidase inhibition, glucose uptake and insulin secretion assays. In vivo study was conducted on STZ-induced diabetic Wistar rats. Molecular docking was conducted to find the lead antidiabetic compounds. Of the 42 compounds identified in the EO, α-phellandrene (5.9%), β-phellandrene (12.6%), linalool (23.6%), safrole (6.8%) and shyobunol (5.1%) were major constituents. Of the two ENs formulated, 1:2 ratio (EO to surfactants) was better in zeta size (51.4 nm) and potential (-30.9). In vitro results were impressive. EN lowered elevated blood glucose level to normal (p < 0.01) and improved the insulin secretion (p < 0.01) in diabetic rats. Further, serum AST, ALT, ALP, triglyceride and pancreatic β-cell damage were seen reduced (p < 0.05). Molecular docking studies showed minor constituents of EO, namely, δ-cadinene, elemol, spathulenol and α-copaen-11-ol playing active role in antidiabetic activity through α-amylase, α-glucosidase, insulin receptor, and insulin secretion proteins.
... Cinnamaldehyde, cinnamic acid, eugenol and coumarin, which have a wide range of medicinal properties such as antioxidant, anti-inflammatory and anti-diabetic activities, are the main phytochemicals of cinnamon (Broadhurst et al., 2000). In addition, cinnamon increases the activity of triacylglycerol lipase, increases glycogen synthesis in the liver, increases glucose uptake and insulin receptor auto phosphorylation (Jarvill-Taylor et al., 2001). Despite extensive studies on the role of cinnamon in improving glucose metabolism (Khadem et al., 2011;Khan et al., 2003;Qin et al., 2010), there are few studies on its role in lipid metabolism in obese individuals and insulin resistance. ...
Obesity is a health and medical problem and is known as the accumulation of fat that increases the risk of cardiovascular, type 2 diabetes mellitus, and infertility. Cinnamon is a spice that is used mainly as a flavoring additive and folk remedies to treat diabetes. Molecular mechanisms of its effects on hepatic lipogenesis and beta‐oxidation, inflammation, and oxidative damage are not fully understood. Therefore, the aim of this study was to evaluate the protective and therapeutic effect of different doses of cinnamon in obese male rats. Forty‐eight adult male Wister rats were randomly assigned into eight controlled and treated groups. Serum levels of lipid, glucose, and insulin profiles were measured along with liver levels of antioxidant enzymes, MDA and TNF‐α. Hepatic expression of genes involved in beta‐oxidation, lipogenesis, oxidative stress, and inflammation was also evaluated. Hepatic levels of oxidative and inflammatory biomarkers and serum levels of glucose, liver enzymes, insulin, and lipid profiles increased significantly in obese rats. Moreover, hepatic expression of SREBP‐1c and NF‐κB increased, and PPAR‐alpha, CD36, FAS, CPT‐1, and Nrf‐2 decreased in obese rats. However, pretreatment and treatment with different doses of cinnamon in obese rats could significantly ameliorate them in obese rats. It can be concluded that cinnamon could improve hepatic steatosis caused by a high‐fat diet via enhancing hepatic beta‐oxidation and inhibiting hepatic lipogenesis, oxidative damage, and inflammation in male rats.
Practical applications
Obesity as a medical and psychiatric problem is seen in more than a third of the world's population. Obesity leads to cardiovascular disease, diabetes, and in some cases even death. Cinnamon as a spice and folk remedy has long been used as a treatment for obesity and liver disease. Cinnamon has received a great of attention from the past to the present due to its pharmacological properties and in addition to its availability, cheapness and low side effects. Cinnamon can prevent dyslipidemia, hyperglycemia, oxidative damage, and inflammation by modulating multiple signaling pathways. Our results showed that cinnamon could improve hepatic steatosis caused by HFD via enhancing hepatic beta‐oxidation and inhibiting hepatic lipogenesis, oxidative damage, and inflammation. Therefore, it can be recommended that cinnamon and its products can be used as a very suitable option for the production of pharmaceutical supplements for the prevention and treatment of metabolic diseases.
... The content of these compounds differs according to the form in which cinnamon is used. Both in vitro and in vivo animal studies have shown insulin-enhancing or insulin-like effects after cinnamon administration [365][366][367]. Several clinical trials have been conducted since the 2000s that administered cinnamon as extracts, capsules or supplements at varying amounts ranging from 0.5 g to 6 g per day, in subjects with T2DM. ...
As years progress, we are found more often in a postprandial than a postabsorptive state. Chrononutrition is an integral part of metabolism, pancreatic function, and hormone secretion. Eating most calories and carbohydrates at lunch time and early afternoon, avoiding late evening dinner, and keeping consistent number of daily meals and relative times of eating occasions seem to play a pivotal role for postprandial glycemia and insulin sensitivity. Sequence of meals and nutrients also play a significant role, as foods of low density such as vegetables, salads, or soups consumed first, followed by protein and then by starchy foods lead to ameliorated glycemic and insulin responses. There are several dietary schemes available, such as intermittent fasting regimes, which may improve glycemic and insulin responses. Weight loss is important for the treatment of insulin resistance, and it can be achieved by many approaches, such as low-fat, low-carbohydrate, Mediterranean-style diets, etc. Lifestyle interventions with small weight loss (7–10%), 150 min of weekly moderate intensity exercise and behavioral therapy approach can be highly effective in preventing and treating type 2 diabetes. Similarly, decreasing carbohydrates in meals also improves significantly glycemic and insulin responses, but the extent of this reduction should be individualized, patient-centered, and monitored. Alternative foods or ingredients, such as vinegar, yogurt, whey protein, peanuts and tree nuts should also be considered in ameliorating postprandial hyperglycemia and insulin resistance. This review aims to describe the available evidence about the effects of diet, chrononutrition, alternative dietary interventions and exercise on postprandial glycemia and insulin resistance.
... It shows that cinnamon has high polyphenol contents [16]. There are two types of anthocyanidins present in cinnamon which are A and B procyanidins [17,18]. PAs are oligomeric and polymeric flavan-3-ols: a type of tannin while procyanidin contains (+) -catechin and (-) epicatechin [19]. ...
In recent decades, natural phytochemicals gained much attention due to antioxidant and antimicrobial potential. Previously, synthetic preservatives widely used in meat industry to control pathogenic bacterial and to inhibit the lipid peroxidation in order to extend the shelf life and to improve the acceptability of meat and meat products. Due to consumer's awareness and demand and ban on synthetic additives in Europe, demand of plant derived natural products increased. Cinnamon is a wonderful spice that has been used from ancient's time to improve food flavor and sensory and organoleptic characteristics. Due to antioxidant and anti-microbial behavior potential of cinnamon bioactives, the natural antioxidants have been found effective in extending the shelf life and to increase the acceptability of meat by the consumers. Due to non-toxic, natural, residue free and easy availability of natural products make them highly acceptable as food additive and preservative. Cinnamon have been reported precious spice due to various beneficial effects like increased digestive enzymes, appetizer, immune stimulant, antioxidant, anti-microbial and anti-viral activities. Cinnamon is most widely used spice in poultry industry due to its vital phytochemicals and safe use.
... It shows that cinnamon has high polyphenol contents [16]. There are two types of anthocyanidins present in cinnamon which are A and B procyanidins [17,18]. PAs are oligomeric and polymeric flavan-3-ols: a type of tannin while procyanidin contains (+) -catechin and (-) epicatechin [19]. ...
In recent decades, natural phytochemicals gained much attention due to antioxidant and antimicrobial potential. Previously, synthetic preservatives widely used in meat industry to control pathogenic bacterial and to inhibit the lipid peroxidation in order to extend the shelf life and to improve the acceptability of meat and meat products. Due to consumer's awareness and demand and ban on synthetic additives in Europe, demand of plant derived natural products increased. Cinnamon is a wonderful spice that has been used from ancient's time to improve food flavor and sensory and organoleptic characteristics. Due to antioxidant and anti-microbial behavior potential of cinnamon bioactives, the natural antioxidants have been found effective in extending the shelf life and to increase the acceptability of meat by the consumers. Due to non-toxic, natural, residue free and easy availability of natural products make them highly acceptable as food additive and preservative. Cinnamon have been reported precious spice due to various beneficial effects like increased digestive enzymes, appetizer, immune stimulant, antioxidant, anti-microbial and anti-viral activities. Cinnamon is most widely used spice in poultry industry due to its vital phytochemicals and safe use.
In recent years, the popularity of herbal medicine has grown significantly, particularly for managing chronic illnesses like diabetes mellitus, due to their natural properties and low side effects. India, often referred to as the "botanical garden of the world," boasts over 2,500 species of medicinal plants, many of which are integral to traditional health practices like Rasayana. Diabetes mellitus is a rising global issue, impacting millions, with India facing particularly high rates. By 2021, around 101 million Indians were diagnosed with diabetes, and an additional 136 million were at risk due to pre-diabetes. The surge in diabetes cases, especially type 2, is associated with increasing obesity and sedentary habits. Notably, type 2 diabetes is also common among individuals with a normal body mass index, with regions such as Goa and Kerala reporting higher incidences. The global rise in diabetes has led to a growing interest in herbal treatments for managing the condition. Various factors, including genetics, age, obesity, and poor lifestyle choices, play a role in the development of the disease. This review highlights the critical need for public health strategies and research into herbal medicines to effectively manage and prevent diabetes.
Diabetes Mellitus (DM) receives significant attention from most scientists due to being a major global public health threat. Diabetes is considered one of the leading causes of death due to its micro and macrovascular complications. This insidious killer is estimated to reach a staggering number of 578 million (700 million by 2045) cases by 2030.
In this book, utilizing the disciplines of clinical sciences, various contemporary topics related to diabetes are extensively discussed. These include the classification of diabetes, underlying causes, epidemiology, pathogenesis, impact on sexual functions, association with cancer, clinical manifestations, diagnostic methods, complications, and treatment options. Furthermore, intriguing and current subjects such as ""antidiabetic phytotherapy"" and ""the relationship between oral health and diabetes"" are also covered. By doing so, readers will acquire comprehensive and detailed knowledge about the clinical management of diabetes. Thus, this book not only serves those who seek to understand the scientific aspects of diabetes but also proves to be a valuable resource for healthcare professionals, researchers, and students in a clinical setting. We believe that this book will contribute to understanding the complexity of diabetes and provide beneficial solutions while shedding light on future studies.
Based on the wide range of pharmacological aspects related to organophosphates, a new type of chalcone‐phosphonate containing derivatives were synthesized by the reaction of dialkyl phosphite and substituted chalcones using anhydrous Mg(ClO4)2 at 80 °C under solvent‐free conditions. The resulting compounds were evaluated for anti‐proliferative activity in vitro against a panel of three human cancer cell lines: MCF7, HeLa, and A549 cell lines. Compound 3 l, 3 m, and 3 p exhibited anti‐proliferative activity against MCF7 and HeLa, with IC50 values of 1.12 μM, 1.63 μM, 1.09 μM and 1.29 μM, 1.44 μM, 2.40 μM respectively. The molecular docking study showed that the synthesized derivatives have good binding ability in the active site of the Vaccinia H1‐related (VHR) phosphatase (PDB: 3F81), PI3‐ kinase (PDB: 3R7Q), androgen receptor (PDB: 3V49) and VEGFR2 kinase (PDB: 3VHE). Finally, in silico pharmacokinetic (ADME) and toxicity studies revealed that compounds have the drug‐like feature for the favourable bioavailability. In conclusion, this work confirmed the potency of chalcone‐phosphonates derivatives for the further optimization of potential anti‐ proliferative agents.
Background: The Mediterranean Diet (MedDiet) is the dietary pattern par excellence for managing and preventing metabolic diseases, such as Type 2 Diabetes (T2DM). The MedDiet incorporates spices and aromatic herbs, which are abundant sources of bioactive compounds. The aim of this study was to analyze the effect of all aromatic herbs and spices included in the MedDiet, such as black cumin, clove, parsley, saffron, thyme, ginger, black pepper, rosemary, turmeric, basil, oregano, and cinnamon, on the glycemic profile in T2DM subjects. Methods: PubMed, Web of Science, and Scopus databases were searched for interventional studies investigating the effect of these aromatic herbs and spices on the glycemic profile in T2DM subjects. Results: This systematic review retrieved 6958 studies, of which 77 were included in the qualitative synthesis and 45 were included in the meta-analysis. Our results showed that cinnamon, turmeric, ginger, black cumin, and saffron significantly improved the fasting glucose levels in T2DM subjects. The most significant decreases in fasting glucose were achieved after supplementation with black cumin, followed by cinnamon and ginger, which achieved a decrease of between 27 and 17 mg/dL. Conclusions: Only ginger and black cumin reported a significant improvement in glycated hemoglobin, and only cinnamon and ginger showed a significant decrease in insulin.
Based on the wide range of pharmacological aspects related to organophosphates, a novel type of compound, containing chalcones-phosphonates derivative was synthesized by the reaction of dialkyl phosphite and substituted chalcones using anhydrous Mg(ClO 4 ) 2 at 80 °C under solvent-free conditions. All the obtained structures were confirmed by IR, ¹ H NMR ¹³ C NMR, and HRMS techniques. The synthesized compounds were tested in vitro against a panel of three human cancer cell lines against MCF7, HeLa, and A549 cell lines. As compared to the reference drug Doxorubicin (IC 50 = 4.17, 3.31, 6.61 µM against MCF7, HeLa, and A549 cell lines, respectively), most of the synthesized derivatives exhibited moderate to good antiproliferative activity. The structure-activity relationship of synthesized compounds is discussed. To speculate on the mechanism of anticancer activity, a molecular docking study was carried out. The molecular docking investigation indicates that all of the synthesized derivatives have good binding ability in the active site of the Vaccinia H1-related (VHR) phosphatase (PDB: 3F81), PI3- kinase (PDB: 3R7Q), androgen receptor (PDB: 3V49) and VEGFR2 kinase (PDB: 3VHE). Furthermore, all compounds were screened for in silico drug-likeness, and all were found to have drug-like properties, following the Lipinski rule of 5, with no PAINS alarms. Thus, the in vitro inhibitory activity and in silico molecular studies confirmed the potency of the chalcone-phosphonate derivatives for anti-proliferative activity.
Background:
Metabolic syndrome (MetS), also known as syndrome X or insulin resistance, is a complex disorder characterized by multiple risk factors. It is caused by insulin resistance, which is accompanied by abnormal accumulation and dysfunction of adipose tissue.
Introduction:
Recently, several studies have evaluated the efficacy of herbs on MetS. The purpose of this meta-analysis is the comprehensive assessment of the impact of cardamom, cinnamon, saffron, purslane and ginger on the parameters of MetS in patients with MetS.
Methods:
A systematic search was performed based on the English language reports of literature from databases including PubMed, Scopus, Cochrane, and Web of Science and 29 RCT (randomized clinical trial) studies were included in the meta-analysis. This meta-analysis was registered in PROSPERO.
Results:
The results showed significant beneficial effects of cardamom on Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) and waist circumference (WC), cinnamon on diastolic blood pressure (DBP) and weight, ginger on fasting blood sugar (FBS), Hemoglobin A1c HbA1c and HOMA-IR and purslane on triglyceride (TG), total cholesterol (TC), body mass index (BMI) and FBS compared to the placebo; thus, they can be useful in the management of patients with MetS.
Conclusion:
It is suggested that more RCT studies should be performed on the factors affecting the efficacy of these plants on the parameters of the MetS.
This study was conducted to compare the impact of cinnamon silver nanoparticles (C-Ag-NPs) and cinnamon aqueous extract (CAE) on the total body weight (TBW), body weight gain (BWG), blood count (BC), fasting blood glucose (FBG), triglycerides (TGs), total cholesterol (TC), low-density (LDL-C) and high-density (HDL-C) lipoprotein cholesterol, liver function enzymes, superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx) of normal and streptozotocin (STZ) diabetic rats. The CAE was administered to rats at different doses (50.0 and 100.0 mg/kg bw), whereas the C-Ag-NPs were ingested at doses of 25.0 and 50.0 mg/kg bw for 30 days. At the end of the experiment, the administration of high or low dosages of CAE or C-Ag-NPs to diabetic rats significantly reduced the FBG, TC, TG, and LDL-C and significantly increased the HDL-C compared with the diabetic control rats. The highest dose (50.0 mg/kg bw) of the C-Ag-NPs was the most efficient at significantly reducing (P < 0.05) the levels of all the analyzed parameters compared with the CAE. However, the treated and normal rats did not show any hypoglycemic activity after ingesting the CAE or C-Ag-NPs. Such effects were associated with considerable increases in their BWG. The diabetic rats that ingested the CAE or C-Ag-NPs showed a gradual decrease in their FBG, TC, LDL, and TG levels, but they were still higher than those in the normal rats. Furthermore, the C-Ag-NPs and CAE considerably enhanced the hepatic (GPT, GOT, ALP, and GGT) and antioxidant biomarker enzyme activities (SOD, CAT, and GPx) in diabetic rats. Relative to the untreated diabetic control, the C-Ag-NPs were more effective than the CAE in the diabetic rats. The C-Ag-NPs exhibited a protective role against hyperglycemia and hyperlipidemia in the diabetic rats and modulated their liver function enzyme biomarkers and antioxidant enzyme activities more than the CAE.
Metabolic syndrome (MetS) therapy with phytochemicals is an emerging field of study with therapeutic potential. Obesity, insulin resistance, high blood pressure, and abnormal lipid profiles are all components of metabolic syndrome, which is a major public health concern across the world. New research highlights the promise of phytochemicals found in foods, including fruits, vegetables, herbs, and spices, as a sustainable and innovative method of treating this illness. Anti-inflammatory, antioxidant, and insulin-sensitizing qualities are just a few of the many positive impacts shown by bioactive substances. Collectively, they alleviate the hallmark symptoms of metabolic syndrome by modulating critical metabolic pathways, boosting insulin sensitivity, decreasing oxidative stress, and calming chronic low-grade inflammation. In addition, phytochemicals provide a multimodal strategy by targeting not only adipose tissue but also the liver, skeletal muscle, and vascular endothelium, all of which have a role in the pathogenesis of MetS. Increasing evidence suggests that these natural chemicals may be useful in controlling metabolic syndrome as a complementary treatment to standard medication or lifestyle changes. This review article emphasizes the therapeutic potential of phytochemicals, illuminating their varied modes of action and their ability to alleviate the interconnected causes of metabolic syndrome. Phytochemical-based interventions show promise as a novel and sustainable approach to combating the rising global burden of metabolic syndrome, with the ultimate goal of bettering public health and quality of life.
The potential role of natural compounds, including spices, and herbs on human health is now a leading field of research. Several studies have stated natural compounds to have anti-inflammatory, antioxidative, and antimicrobial properties. Clinical trials have examined and reported beneficial impacts of these compounds on conditions like metabolic syndrome, cancer, and osteoporosis. For example, in cancer treatment, natural compounds have been mentioned as a combination therapy by promoting apoptosis, targeting the DNA repair pathways, and suppressing the proliferation of cancer cells. In the field of cardiometabolic risk factors, Rhus coriaria L., or “sumac,” is a widely grown plant with a significant effect on lowering serum insulin, homeostatic model assessment of insulin resistance (HOMA-IR), and oxidative stress-related compounds, including malondialdehyde (MDA) and high sensitive C-reactive protein (hs-CRP) in patients with type 2 diabetes mellitus (T2DM). Supplementation with sumac also decreases liver fibrosis, alanine aminotransferase, aspartate aminotransferase, fasting glucose, insulin, hemoglobin A1c (HbA1c), HOMA-IR, MDA, and hs-CRP in nonalcoholic fatty liver disease patients. Clinical studies have reported the properties of other herbs, including cinnamon and ginger, on improving glycemic status in T2DM patients. Polycystic ovary syndrome (PCOS) is another metabolic disorder with oxidative stress and inflammatory condition. Clinical studies have shown that patients with PCOS may benefit from the antioxidant characteristics of curcumin supplementation, a phytochemical in turmeric, by its role in increasing gene expression of peroxisome proliferator-activated receptor γ coactivator 1α (PGC1α) and activity of the glutathione peroxidase (Gpx). Bringing together, upon considering safety, the application of natural components as a complementary therapy in modern medicine may provide a potent strategy in managing diseases, especially those related to inflammatory and oxidative conditions.KeywordsNatural compoundsCurcuminGingerSumacLemon BalmCinnamonRheum ribesUrtica Dioica
A group of metabolic diseases are collectively called diabetes mellitus. Various pharmaceutical interventions and animal models have been used to investigate the genetic, environmental, and etiological aspects of diabetes and its effects. In recent years for the development of ant-diabetic remedies, numerous novel genetically modified animals, pharmaceutical substances, medical techniques, viruses, and hormones have been developed to screen diabetic complications. A unique disease-treating drug with new properties is still being sought after. The current review tried to include all published models and cutting-edge techniques. Experimental induction of diabetes mellitus in animal models and in vitro methods are essential for advancing our knowledge, a thorough grasp of pathophysiology, and the creation of novel therapeutics. Animal models and in vitro techniques are necessary to develop innovative diabetic medications. New approaches and additional animal models are required for diabetes research to advance. This is particularly true for models produced via dietary modifications, which have various macronutrient compositions. In this article, we review the rodent models of diet-induced diabetic peripheral neuropathy, diabetic retinopathy, and diabetic nephropathy and critically compare the key characteristics of these micro-vascular complications in humans and the diagnostic criteria with the parameters used in preclinical research using rodent models, taking into consideration the potential need for factors that can accelerate or aggravate these conditions.
The aim of this work is the synthesis of a number of substituted E‑1-(2-amino‑5-R1-phenyl)-3-(4-R2-phenyl)prop‑2-en‑1-ones (2-aminochalcones) as precursors for obtaining new derivatives of 7-R1–5-[2-R2-phenylvinyl]-1,4-benzodiazepin‑2-ones. Starting 5-substituted 2-aminoacetophenones with bromo and nitro group were synthesized from 2-aminoacetophenone by bromination of the latter with N‑bromosuccinimide in acetonitrile and nitration of 2-acetaminoacetophenone with a nitrating mixture followed by removal of acetyl protection. 2-Aminochalcones were synthesized according to standard methods during the interaction of a number of 5-substituted 2-aminoacetophenones with para-substituted benzaldehydes under basic catalysis conditions. The target products turned out to be brightly colored compounds with low melting points, their isolation and purification did not cause any difficulties. According to the data of 1H NMR spectroscopy, all synthesized 2-aminochalcones were individual trans isomers, which was also confirmed by X‑ray structural analysis of one of the obtained 2-aminochalcones. A number of new substituted E‑1-(2-amino‑5R1-phenyl)-3-(4-R2-phenylprop‑2-en‑1-ones) were synthesized – compounds with amino and ketofunctions and are precursors for obtaining of a new series of 5-substituted 1,4-benzodiazepines with various arylvinyl groups. 2-aminoacetophenone, 2-amino‑5-bromoacetophenone, and 2-amino‑5-nitroacetophenone were selected as substrates for this series. The methyl groups of these acetophenones were condensed according to Claisen-Schmidt with parasubstituted benzaldehydes. Condensation was carried out under alkaline conditions in an aqueous solution. Yields of aminochalcones reached 60–85%. The methyl group of 2-aminoacetophenones smoothly reacted with aromatic aldehydes to form the corresponding 2-aminophenylchalcones. The structure of the obtained compounds was confirmed by mass spectrometry and 1H NMR spectroscopy. The structure of one of the chalcones was proved by X‑ray structural analysis. The obtained compounds can be used for the synthesis of 1,4-benzodiazepines with 5-arylvinyl substituents.
Coffee, cinnamon, and ginger are natural products rich in bioactive compounds that have led to renewed interest to validate their health benefits through in vitro and in vivo studies. This chapter describes several mechanisms of action to understand their antioxidant, antidiabetic, anti‐inflammatory, cardioprotective, and hepatoprotective effects observed in preclinical and clinical studies. Coffee, ginger, and cinnamon were selected for this chapter because coffee is one of the most consumed beverages in the world, and ginger rhizome and cinnamon bark are among the most commonly used spices for their flavor and medicinal properties. All contain bioactive substances responsible for or attributable to their beneficial health effects, among which are caffeine and gallic acid from coffee, gingerols, shogaols, and paradols from ginger, cinnamaldehyde, cinnamate, and cinnamic acid of cinnamon among others phytochemicals. The molecular mechanisms involved in the antioxidant effects are associated with the activation of Keap1‐Nrf2 pathway that enhances the expression and activation of cytoprotective proteins to prevent oxidative stress. The molecular mechanisms involved in the antidiabetic potential are related to the modulation of glucose metabolism enzymes, increase of glucose tolerance, and insulin sensitivity through the action signaling pathways such as AMPK, PI3K/Akt, NF‐κB, and the family of proliferator‐activated receptor (PPAR) proteins. Cardiovascular protection capacity has been attributed to modulating the expression of Sirtuin 1 (SIRT1), carbohydrate response element binding protein (ChREBP), cholesterol and fatty acid synthesis enzymes, sterol regulatory Element‐Binding Protein 1 (SREBP‐1), the Liver X Receptor alpha, PPARα, and PPARγ. The hepatoprotective benefits of coffee have been associated with TGFβ and JNK modulation, fibrogenic genes suppression, and of NFκβ and MAPK pathways modulation, whereas ginger and cinnamon reduce the expression of different proteins involved in lipid metabolism; in addition, ginger increases liver antioxidant capacity and cinnamon reduces proinflammatory proteins. Finally, the molecular signaling of anti‐inflammatory effects occurs through activation of the TLR4/MyD88/NF‐κβ, JNK/AP‐1, PI3K/Akt, and ERK/MAPK signaling pathways and the subsequent downregulation of proinflammatory cytokines. The available scientific evidence indicates that they are potential natural sources for the development of functional foods and new drugs with greater efficacy and safety.
This is an Open Access Journal / article distributed under the terms of the Creative Commons Attribution License (CC BY-NC-ND 3.0) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. All rights reserved. Despite their extensive use as diabetic therapies in traditional medicine across the world, few secondary metabolites have been proved to fulfil the standards of scientific study. Because of the enormous hikes in the occurrence of DM-2 in our culture, there is a growing demand for alternative diabetes preventive and treatment methods. The creation and study of newer bioactive anti-diabetic substances is underway. In this review, we have attempted to bring together all of the previously described in vivo and in vitro models for antidiabetic medication testing, as well as the numerous in vitro testing methods, such as inhibiting alpha-amylase and beta-glucosidase activities, as well as the glucose absorption assay. The induction of diabetes mellitus through study utilising animal models and in vitro approaches is critical for expanding our knowledge, gaining a better understanding of diabetogenic pathways, and developing new therapies. The utilisation of animal models and in vitro processes are both critical components in developing a new diabetic therapy. The goal of this article is to provide an overview of the relevance of the animal models that are presently accessible for antidiabetic activity screening.
Cinnamon is a spice that has been used in various cultures for centuries for its potential health benefits. While there are health claims for a variety of health conditions, it has continuously been explored for its ability to improve glucose handling in diabetes. Cinnamon is a very popular supplement used by patients with diabetes to help normalize blood glucose levels. A systematic review of the literature was conducted to assess the available evidence evaluating effects on diabetes and glucose handling with the use of various species of cinnamon. The intention was to summarize the existing evidence for cinnamon's effects on blood glucose, both for safety and efficacy, to help guide providers and consumers alike. Reviewing the available literature for the different types of cinnamon and their effects on the diabetes disease process, there are multiple proposed mechanisms for how cinnamon could improve diabetes, including increasing insulin sensitivity by multiple receptor signaling pathways, reducing inflammation, enhancing glucose uptake by effects on glucose transporter proteins, and effects on gastric emptying, and blocking glucose absorption. There appears to be conflicting evidence on whether cinnamon produces any significant effect on glucose parameters, and the extent of these effects. There are several variables that could explain these conflicting data, such as patient sample size, doses and formulations of cinnamon used, baseline patient characteristics, and study duration. A more in-depth evaluation and rating of the available evidence could help clarify this, but data suggest that in some circumstances, cinnamon may have modest effects on improving glucose handling in adults. The safety profile also has been demonstrated to be extremely favorable, with very few adverse events reported in the active treatment groups across all studies. Based upon these data, clinicians should consider cinnamon to be a potential adjunctive therapy to traditional diabetes treatments, and should be open to discussing this with patients expressing interest in the supplement.
This reference summarizes recent advancements in knowledge about cardiovascular disease and pharmacology. The goal of the book is to inform readers about recent findings on cardiovascular therapeutics and how to conduct experiments to evaluate natural products. It presents 10 chapters that cover basic clinical research on cardiovascular diseases and therapeutic agents derived from natural sources. The book concludes with a series of experiments that demonstrate the methods to test the ameliorative effects of 3 phytochemicals: Biochanin A (red clover), Zingiberene (ginger oil) and Betaine (sugar beet).
Key Features
- 10 chapters that highlight recent research cardiovascular medicine and pharmacology
- Covers knowledge about basic cardiovascular physiology, congestive heart failure treatment and the treatment of heart inflammation.
- Covers uses, benefits, and drawbacks of numerous rodent and non-rodent animal models for studying CVD
- Updates readers about 21st-century CRISPR-cas9 technology and its uses in CVD.
- Covers the significance of Indian Ayurvedic techniques on the cardiovascular system,
- Covers information about nutraceuticals for CVD therapy
- Includes experiments to evaluate 3 phytochemicals for the treatment of different heart diseases such as hypertension, obesity-cardiomyopathy and the mitigation of inflammatory cytokines in myocardial infarction.
This book is an informative resource for cardiologists, and researchers working in the field of cardiovascular pharmacology. It also helps readers to understand the benefits of herbal medications that are commonly available for consumption in homes.
A two-way experimental design, comprising a total of 180 growing commercial cross-bred 30-day-old rabbits were assigned to five groups (36 kits in each group equally distributed between the sexes, with twelve replicates of 3 rabbits) was adopted to investigate the effects of dietary treatment (cinnamon and cloves supplemented at 150 and 250 mg/kg diet each) and sex on rabbit growth performance, carcass characteristics, hematological and biochemical indices. The first group was given a basal diet with no supplements as the control, the second and third groups were given cinnamon at 150 and 250 mg/kg diet, respectively. In turn, the fourth and fifth groups were administered cloves at 150 and 250 mg/kg diet, respectively. Treatment with cinnamon and clove powder supplements significantly increased live body weight (LBW), live body weight gain (LBWG) and feed consumption (FC). Also, it significantly increased red blood cell count (RBC), white blood cell count (WBC), plasma total protein, albumin and globulin levels. The treatment with both supplements led to a significant decrease in feed conversion ratio (FCR), as well as levels of glucose, cholesterol, triglycerides, aspartate aminotransferase (AST) and alanine aminotransferase (ALT). Rabbits fed 250 mg cinnamon/kg diet had the highest LBW, LBWG, FC, dressing percentage, meatiness and plasma total protein, but had lowest levels of glucose, cholesterol, triglycerides, AST and ALT compared to the other groups. It was concluded that cinnamon supplement at 250 mg /kg diet may be an effective method to improve growth, carcass characteristics and health in both sexes of growing rabbits thanks to its advantageous effect on blood picture and biochemical constituents and consequently may be the primary factor promoting abundant production.
We designed a novel series of bifunctional inhibitors of α-glucosidase and aldose reductase (ALR2) based on the structure of hydroxychalcone. The two enzymes relate to blood glucose level and anomalously elevated polyol pathway of glucose metabolism under hyperglycemia, respectively. Most compounds in the series exhibited a potent inhibitory activity for both enzymes, and a significant antioxidant property was shown. Further in vivo studies of 11j and 14d using streptozotocin (STZ)-induced diabetic rats as a model found that 11j achieved not only good antihyperglycemic and glucose tolerance effect in a dose-dependent manner (p < 0.01) but also showed effective inhibition of polyol pathway. 14d significantly suppressed the maltose-induced postprandial glucose elevation. Additionally, they effectively improved lipid metabolisms and restored an antioxidant ability. Therefore, the two compounds may be promising agents for the prevention and treatment of diabetic complications.
Medications in treatment and control of diabetes can be costly for pediatric patients and families. Therefore, individuals may seek complementary and alternative therapies, such as cinnamon, in addition to traditional treatments. The objective of this study was to determine acceptability of using cinnamon in treatment of diabetes in a pediatric population with diabetes. Seventy-six pediatric diabetes patients at a diabetes clinic participated in a one-time telephone interview using an 18-item, validated questionnaire. Descriptive statistics were utilized to determine cinnamon acceptability and preferences. The majority of the subjects were between 16-18 years (43%, n = 33), Caucasian (62%, n = 47), and female (67%, n = 51). More than three-fourths were overweight or at risk of being overweight (80%, n = 60). Seventy-six percent stated that they would be willing to try cinnamon for treatment of their diabetes, whereas 14.5% were undecided and 9.2% unwilling. Most (n = 56, 52.5%) were willing to take the cinnamon supplement 1-2 times per day. The greatest concerns expressed by subjects were side effects, interaction with current medications, and physician’s willingness to approve and prescribe. This research suggests that in consultation with health professionals, diabetic youth are willing to try cinnamon supplementation in the treatment.
Chalcones(1, 3, diaryl-2-propen-1-ones) are prominent compounds and therefore, various procedures have been worked out for their synthesis. This review highlights the synthesis and pharmacological properties of chalcone derivatives. Chalcones belong to the flavonoid family and have been widely explored for their various pharmaceutical, biological activities. These chalcone derivatives have shown important antimalarial, anticancer, antimicrobial, anti-inflammatory, antioxidant, antituberculosis, anticonvulsant, antileishmanial and anti-HIV properties. The new structural classes of compounds may prove as lead molecules and good candidates for future investigations.
Context:
Diabetes is a metabolic disorder related to blood insulin deficiency and high glucose level. Cinnamaldehyde is an important component of cinnamon and has an effect on blood glucose.
Objective:
It was aimed to investigate the the effect of cinnamaldehyde on the liver glutathione (GSH), glucose-6-phosphate dehidrogenase (G6PD) activity, blood glucose, protein, lipid and erythrocyte parameters, live weight in diabetic rats.
Material and methods:
Rat used for this research were divided 4 group as control, diabetic, cinnamaldehyde and diabetic + cinnamaldehyde group. The live weight and fasting blood glucose level, taken from tail vein were recorded every ten days. End of the trail the blood samples were taken from rats. Biochemical parameters with autoanalyzer and hematological parameters with blood cell counter were determined in blood. The activity of G6PD and GSH amounts were measured with ELISA in the liver tissues.
Results:
Blood sugar, triglyceride, total cholesterol, VLDL, LDL, and urea levels increased in diabetic rats, and cinnemaldehyde significantly decreased these parameters. Cinnemaldehyde also showed a positive effect on body weight, blood total protein, and mean corpuscular volume in diabetes. A decrease in HbA1c and an increase in liver G6PD, GSH activity were found in treatment group, but these changes were not statistically significant.
Conclusion:
In conclusion, the antidiabetic, hypolipidemic and antioxidant effects of cinnamaldehyde were determined. It has also been shown to improve anemia, ürea levels and weight loss.
The current studies investigated the contribution of phosphatidylinositol 3-kinase (PI3-kinase) isoforms to insulin-stimulated glucose uptake and glucose transporter 4 (GLUT4) translocation. Experiments involving the microinjection of antibodies specific for the p110 catalytic subunit of class I PI3-kinases demonstrated an absolute requirement for this form of the enzyme in GLUT4 translocation. This finding was confirmed by the demonstration that the PI3-kinase antagonist wortmannin inhibits GLUT4 and insulin-responsive aminopeptidase translocation with a dose response identical to that required to inhibit another class I PI3-kinase-dependent event, activation of pp70 S6-kinase. Interestingly, wortmannin inhibited insulin-stimulated glucose uptake at much lower doses, suggesting the existence of a second, higher affinity target of the drug. Subsequent removal of wortmannin from the media shifted this dose-response curve to one resembling that for GLUT4 translocation and pp70 S6-kinase. This is consistent with the lower affinity target being p110, which is irreversibly inhibited by wortmannin. Wortmannin did not reduce glucose uptake in cells stably expressing Myr-Akt, which constitutively induced GLUT4 translocation to the plasma membrane; this demonstrates that wortmannin does not inhibit the transporters directly. In addition to elucidating a second wortmannin-sensitive pathway in 3T3-L1 adipocytes, these studies suggest that the presence of GLUT4 on the plasma membrane is not sufficient for activation of glucose uptake.
Growth factor-dependent survival of a variety of mammalian cells is dependent on the activation of phosphatidylinositol (PI)
3-kinase and its downstream effector, the protein kinase Akt. Glycogen synthase kinase-3 (GSK-3) has been previously identified
as a physiological target of Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell
survival. Overexpression of catalytically active GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dominant-negative
GSK-3 prevented apoptosis following inhibition of PI 3-kinase. GSK-3 thus plays a critical role in regulation of apoptosis
and represents a key downstream target of the PI 3-kinase/Akt survival signaling pathway.
Following the differentiation of 3T3-L1 preadipocytes insulin acutely activates the rate of 2-deoxy-[1-14C]glucose uptake in the mature 3T3-L1 adipocyte by 15- to 20-fold. Phenylarsine oxide, a trivalent arsenical that forms stable ring complexes with vicinal dithiols, prevents insulin-activated hexose uptake in a concentration-dependent manner (Ki = 7 microM) but has no inhibitory effect on basal hexose uptake. 2,3-Dimercaptopropanol at a level nearly stoichiometric to that of phenylarsine oxide prevents or rapidly reverses the inhibition of hexose uptake; 2-mercaptoethanol, even in high stoichiometric excess over the arsenical, does not reverse inhibition of hexose uptake. When phenylarsine oxide is added after adipocytes have been fully activated by insulin, 2-deoxy-[1-14C]glucose uptake rate decays slowly at a rate corresponding to that caused by the withdrawal of insulin (t1/2 = 10 min). Using the same conditions under which phenylarsine oxide blocked activation, the Km for deoxyglucose uptake, the rate at which 125I-insulin became cell-associated, and the 125I-insulin binding isotherm for solubilized insulin receptor were not affected by phenylarsine oxide. These results support the transporter translocation model for insulin-activated hexose transport and implicate vicinal sulfhydryl groups in a post-insulin binding event essential for the translocation of glucose transporters to the plasma membrane.
Insulin stimulates the activity of mitogen-activated protein kinase (MAPK) via its upstream activator, MAPK kinase (MEK), a dual specificity kinase that phosphorylates MAPK on threonine and tyrosine. The potential role of MAPK activation in insulin action was investigated with the specific MEK inhibitor PD98059. Insulin stimulation of MAPK activity in 3T3-L1 adipocytes (2.7-fold) and L6 myotubes (1.4-fold) was completely abolished by pretreatment of cells with the MEK inhibitor, as was the phosphorylation of MAPK and pp90Rsk, and the transcriptional activation of c-fos. Insulin receptor autophosphorylation on tyrosine residues and activation of phosphatidylinositol 3'-kinase were unaffected. Pretreatment of cells with PD98059 had no effect on basal and insulin-stimulated glucose uptake, lipogenesis, and glycogen synthesis. Glycogen synthase activity in extracts from 3T3-L1 adipocytes and L6 myotubes was increased 3-fold and 1.7-fold, respectively, by insulin. Pretreatment with 10 microM PD98059 was without effect. Similarly, the 2-fold activation of protein phosphatase 1 by insulin was insensitive to PD98059. These results indicate that stimulation of the MAPK pathway by insulin is not required for many of the metabolic activities of the hormone in cultured fat and muscle cells.
Insulin resistance is very common in the elderly, and may be associated with glucose intolerance or frank diabetes. In previous studies we demonstrated that insulin resistance in old Wistar rats is associated with decreased autophosphorylation and activation of the hepatic insulin receptor kinase (IRK) in vivo. We now show that this defect can be reproduced in vitro, where the extent of insulin-induced activation of IRK in liver membranes of old rats was decreased by approximately 50% compared with young controls. The defect could be largely abolished after solubilization of the membranes with Triton X-100. We also show that: (a) the viscosity of membranes from the old rats was significantly (P < 0.001, n = 4) higher (by 15%) compared with young controls; (b) incubation of plasma membranes from old animals with lecithin liposomes, which lowered their cholesterol levels, partially abolished the defect in IRK activation; and (c) Triton extracts of liver membranes prepared from old rats did not interfere with the activation of IRK derived from young controls. Additionally, non-membrane components did contribute to the development of this defect. We observed a significant (approximately 30%) (P < 0.001, n = 18) elevation of cytosolic protein tyrosine phosphatase (PTP) activity directed against the beta subunit of the insulin receptor in livers of old rats. No such elevation of PTP activity could be demonstrated with synthetic substrates. Our findings are consistent with a model in which increased membrane viscosity as well as enhancement of a cytosolic PTP activity both markedly inhibit the activation in vivo of the hepatic IRK in old animals.
A novel phosphoinositolglycan-peptide (PIG-P) from the yeast Saccharomyces cerevisiae potently mimicks insulin action on glucose transport and metabolism in rat muscle and adipose tissue. The aim of the present study was to elucidate the cellular signalling pathways of this insulin-mimetic compound. Rapid onset and reversibility of PIG-P action on glucose transport were observed in isolated adipocytes with a half-time of transport stimulation of 6-8 min (insulin less than 5 min). Combined treatment with PIG-P and insulin indicated additive stimulation of glucose transport at submaximal concentrations and non-additive action of both agents at maximal doses. The tyrosine phosphorylation of insulin receptor substrate-1 (IRS-1) was markedly increased in response to PIG-P in rat cardiomyocytes without any effect on the tyrosine phosphorylation of the insulin receptor beta-subunit. PIG-P action in these cells was accompanied by phosphorylation/dephosphorylation of several proteins with molecular masses of 15-30 kDa, a response not detected with insulin. Downstream signalling of IRS-1 was then analysed by monitoring IRS-1-associated phosphatidylinositol 3-kinase (PI 3-kinase) activity in cardiomyocytes. A stable (2 and 15 min incubation with PIG-P) 7-fold stimulation corresponding to about 50% of insulin action could be detected. Increased tyrosine phosphorylation of IRS-1 and enhanced PI 3-kinase activity in response to PIG-P independent of the insulin receptor was also observed in isolated adipocytes. Involvement of PI 3-kinase in PIG-P action was subsequently confirmed by the dose-dependent inhibition of PIG-P-activated glucose transport in rat diaphragm and adipocytes by the PI 3-kinase inhibitors wortmannin and LY294002. These data suggest divergent upstream signalling by insulin and PIG-P involving phosphoproteins not affected by insulin. However, PIG-P and insulin action converge at the level of IRS-1 inducing insulin-independent PI 3-kinase-mediated signalling to glucose transport.
The effects of insulin and platelet-derived growth factor (PDGF) on glycogen synthase activation were compared in 3T3-L1 fibroblasts and adipocytes. In the fibroblasts, PDGF elicited a stronger phosphorylation of mitogen-activated protein kinase (MAPK) and AKT than did insulin. Both agents caused a comparable stimulation of receptor autophosphorylation, MAPK, and phosphatidylinositol 3-kinase (PI3-K) activation in the adipocytes. However, adipogenesis resulted in the uncoupling of PI3-K activation by PDGF from subsequent AKT phosphorylation. The relative contributions of glycogen synthase kinase-3 (GSK-3) inactivation and protein phosphatase-1 (PP1) activation in the regulation of glycogen synthase in both cell types were evaluated. Insulin and PDGF caused a small increase in glycogen synthase a activity in the fibroblasts. Additionally, both agents caused a similar inhibition of GSK-3, while having no effect on PP1 activity. Following differentiation, insulin treatment resulted in a 5-fold stimulation of glycogen synthase, whereas PDGF was without effect. Both agents caused a comparable inhibition of GSK-3 activity in the adipocytes, whereas only insulin activated PP1. Finally, wortmannin completely blocked the stimulation of PP1 by insulin in 3T3-L1 adipocytes, indicating that PI3-K inhibition can impinge on PP1 activation. Cumulatively these results suggest that the weak activation of glycogen synthase in 3T3-L1 fibroblasts is mediated by GSK-3 inactivation, whereas in the more metabolically active adipocytes, the insulin-specific activation of glycogen synthase is mediated by PP1 activation.
Phosphoinositolglycan molecules isolated from insulin-sensitive mammalian tissues have been demonstrated in numerous in vitro studies to exert partial insulin-mimetic activity on glucose and lipid metabolism in insulin-sensitive cells. However, their ill-defined structures, heterogeneous nature, and limited availability have prohibited the analysis of the underlying molecular mechanism. Phosphoinositolglycan-peptide (PIG-P) of defined and homogeneous structure prepared in large scale from the core glycan of a glycosyl-phosphatidylinositol-anchored membrane protein from Saccharomyces cerevisiae has recently been shown to stimulate glucose transport as well as a number of glucose-metabolizing enzymes and pathways to up to 90% (at 2 to 10 microns) of the maximal insulin effect in isolated rat adipocytes, cardiomyocytes, and diaphragms (G. Müller et al., 1997, Endocrinology 138: 3459-3476). Consequently, we used this PIG-P for the present study in which we compare its intracellular signaling with that of insulin. The activation of glucose transport by both PIG-P and insulin in isolated rat adipocytes and diaphragms was found to require stimulation of phosphatidylinositol (PI) 3-kinase but to be independent of functional p70S6kinase and mitogen-activated protein kinase. The increase in glycerol-3-phosphate acyltransferase activity in rat adipocytes in response to PIG-P and insulin was dependent on both PI 3-kinase and p70S6kinase. This suggest that the signaling pathways for PIG-P and insulin to glucose transport and metabolism converage at the level of PI 3-kinase. A component of the PIG-P signaling pathway located up-stream of PI 3-kinase was identified by desensitization of isolated rat adipocytes for PIG-P action by combined treatment with trypsin and NaCl under conditions that preserved cell viability and the insulin-mimetic activity of sodium vanadate but completely blunted the insulin response. Incubation of the cells with either trypsin or NaCl alone was ineffective. The desensitized adipocytes were reconstituted for stimulation of lipogenesis by PIG-P by addition of the concentrated trypsin/salt extract. The reconstituted adipocytes exhibited 65-75% of the maximal PIG-P response and similar EC50 values for PIG-P (2 to 5 microns) compared with control cells. A proteinaceous N-ethylmaleimide (NEM)-sensitive component contained in the trypsin/salt extract was demonstrated to bind in a functional manner to the adipocyte plasma membrane of desensitized adipocytes via bipolar interactions. An excess of trypsin/salt extract inhibited PIG-P action in untreated adipocytes in a competitive fashion compatible with a receptor function for PIG-P of this protein. The presence of the putative PIG-P receptor protein in detergent-insoluble complexes prepared from isolated rat adipocytes suggests that caveolae/detergent-insoluble complexes of the plasma membrane may play a role in insulin-mimetic signaling by PIG-P. Furthermore, treatment of isolated rat diaphragms and adipocytes with PIG-P as well as with other agents exerting partially insulin-mimetic activity, such as PI-specific phospholipase C (PLC) and the sulfonylurea glimepiride, triggered tyrosine phosphorylation of the caveolar marker protein caveolin, which was apparently correlated with stimulation of lipogenesis. Strikingly, in adipocytes subjected to combined trypsin/salt treatment, PIG-P, PI-specific PLC, and glimepiride failed completely to provoke insulin-mimetic effects. A working model is presented for a signaling pathway in insulin-sensitive cells used by PIG(-P) molecules which involves GPI structures, the trypsin/salt- and NEM-sensitive receptor protein for PIG-P, and additional proteins located in caveolae/detergent-insoluble complexes.
During the assembly of cell surface receptors, insulin proreceptors are sometimes joined to insulin-like growth factor (IGF) receptor precursors to form covalently linked hybrid receptors. To address the biological consequences of hybrid receptor formation, we studied 3T3-L1 cells known to undergo a 50-70-fold increase in insulin binding while maintaining nearly constant levels of IGF-I binding during differentiation from preadipocytes into adipocytes. The presence of insulin/IGF receptor hybrids in 3T3-L1 adipocytes was demonstrated by the immunoprecipitation of phosphorylated receptors and a novel enzyme-linked immunoassay. Hybrid receptor levels were very low in the early stages of differentiation and increased rapidly between days 4 and 6, reaching a level about 100-fold higher in the mature adipocyte. Coincident with the hybrid assembly, the formation of archetypal (alpha2,beta2) IGF receptors decreased. In fully differentiated adipocytes, virtually all of the IGF receptors were in hybrid form. Stimulation by IGF-I of receptors isolated from mature adipocytes caused autophosphorylation of IGF receptor beta subunits in hybrid complexes, whereas autophosphorylated IGF holoreceptors were not demonstrable. Insulin and IGF-I were equipotent in stimulating glucose uptake in the differentiated adipocytes, leading to the conclusion that hybrid insulin/IGF receptors can transduce a transmembrane signal when activated by IGF-I. We conclude that hybrid formation constitutes a novel post-translational mechanism whereby increased synthesis of insulin receptors limits the cell surface expression of the homologous IGF receptor. Furthermore, biological actions in 3T3-L1 adipocytes, previously attributed to archetypal IGF receptors, are in fact mediated through hybrid receptors.
Insulin plays a key role in regulating a wide range of cellular processes. However, until recently little was known about the signalling pathways that are involved in linking the insulin receptor with downstream responses. It is now apparent that the activation of class 1a phosphoinositide 3-kinase (PI 3-kinase) is necessary and in some cases sufficient to elicit many of insulin's effects on glucose and lipid metabolism. The lipid products of PI 3-kinase act as both membrane anchors and allosteric regulators, serving to localize and activate downstream enzymes and their protein substrates. One of the major ways these lipid products of PI 3-kinase act in insulin signalling is by binding to pleckstrin homology (PH) domains of phosphoinositide-dependent protein kinase (PDK) and protein kinase B (PKB) and in the process regulating the phosphorylation of PKB by PDK. Using mechanisms such as this, PI 3-kinase is able to act as a molecular switch to regulate the activity of serine/threonine-specific kinase cascades important in mediating insulin's effects on endpoint responses.
To characterize the contribution of glycogen synthase kinase 3beta (GSK3beta) inactivation to insulin-stimulated glucose metabolism, wild-type (WT-GSK), catalytically inactive (KM-GSK), and uninhibitable (S9A-GSK) forms of GSK3beta were expressed in insulin-responsive 3T3-L1 adipocytes using adenovirus technology. WT-GSK, but not KM-GSK, reduced basal and insulin-stimulated glycogen synthase activity without affecting the -fold stimulation of the enzyme by insulin. S9A-GSK similarly decreased cellular glycogen synthase activity, but also partially blocked insulin stimulation of the enzyme. S9A-GSK expression also markedly inhibited insulin stimulation of IRS-1-associated phosphatidylinositol 3-kinase activity, but only weakly inhibited insulin-stimulated Akt/PKB phosphorylation and glucose uptake, with no effect on GLUT4 translocation. To further evaluate the role of GSK3beta in insulin signaling, the GSK3beta inhibitor lithium was used to mimic the consequences of insulin-stimulated GSK3beta inactivation. Although lithium stimulated the incorporation of glucose into glycogen and glycogen synthase enzyme activity, the inhibitor was without effect on GLUT4 translocation and pp70 S6 kinase. Lithium stimulation of glycogen synthesis was insensitive to wortmannin, which is consistent with its acting directly on GSK3beta downstream of phosphatidylinositol 3-kinase. These data support the hypothesis that GSK3beta contributes to insulin regulation of glycogen synthesis, but is not responsible for the increase in glucose transport.
The roles of Akt (protein kinase B) and the atypical lambda isoform of protein kinase C (PKClambda), both of which act downstream of phosphoinositide 3-kinase, in the activation of glycogen synthase and phosphorylation of 4E-BP1 (PHAS-1) in response to insulin were investigated. A mutant Akt (Akt-AA) in which the phosphorylation sites targeted by growth factors are replaced by alanine was shown to inhibit insulin-induced activation of both Akt and glycogen synthase in L6 myotubes. Expression of a mutant Akt in which Lys179 in the kinase domain was replaced by aspartate also inhibited insulin-induced activation of glycogen synthase but had no effect on insulin activation of endogenous Akt. A kinase-defective mutant of PKClambda (lambdaDeltaNKD), which prevents insulin-induced activation of PKClambda, did not affect the activation of glycogen synthase by insulin. Insulin-induced phosphorylation of 4E-BP1 was inhibited by Akt-AA in Chinese hamster ovary cells. However, lambdaDeltaNKD had no effect on 4E-BP1 phosphorylation induced by insulin. These data suggest that Akt, but not PKClambda, is required for insulin activation of glycogen synthase and for insulin-induced phosphorylation of 4E-BP1.
The causes and control of type 2 diabetes mellitus are not clear, but there is strong evidence that dietary factors are involved in its regulation and prevention. We have shown that extracts from cinnamon enhance the activity of insulin. The objective of this study was to isolate and characterize insulin-enhancing complexes from cinnamon that may be involved in the alleviation or possible prevention and control of glucose intolerance and diabetes. Water-soluble polyphenol polymers from cinnamon that increase insulin-dependent in vitro glucose metabolism roughly 20-fold and display antioxidant activity were isolated and characterized by nuclear magnetic resonance and mass spectroscopy. The polymers were composed of monomeric units with a molecular mass of 288. Two trimers with a molecular mass of 864 and a tetramer with a mass of 1152 were isolated. Their protonated molecular masses indicated that they are A type doubly linked procyanidin oligomers of the catechins and/or epicatechins. These polyphenolic polymers found in cinnamon may function as antioxidants, potentiate insulin action, and may be beneficial in the control of glucose intolerance and diabetes.
In most cases, the genetic susceptibility to Type 2 diabetes fails to follow simple Mendelian inheritance, consistent with the dogma that the common forms of Type 2 diabetes are polygenic with superimposed environmental influences. Now Withers et al. demonstrate that a single gene defect can compromise both insulin action and the ability of β cells to compensate with hyperplasia and hypersecretion of insulin, suggesting a possible single molecular cause for the two key components in the pathogenesis of Type 2 diabetes. The anticlimax is that the specific genes causing the vast majority of cases of human diabetes remain unknown. This could be due to the fact that (1) interactions between two or more genes are required and are difficult to uncover with current genetic approaches, (2) additional important molecules in insulin action are yet to be discovered, and/or (3) the focus for identification of candidate genes has been on the wrong site, i.e., the primary defect leading to insulin resistance may not be in classic insulin target tissues. Generation of signals or biochemical molecules that predispose to diabetes may originate in the brain; a likely example is insulin resistance in the db/db (leptin receptor mutant) mouse. Efforts to identify diabetogenes are now taking a broader focus extending to secretory products of adipocytes (leptin, TNF) and neuropeptides. Thorough testing for concurrent mutations in several candidate genes, albeit a major undertaking, could pay off, expecially when paired with specific biochemical or physiologic subphenotypes. Transgenic models in which one or more candidate genes are manipulated either singly or in combination will continue to be a valuable approach to identifying new susceptibility loci, uncovering synergy between two subclinical defects, testing the impact of superimposed metabolic and lifestyle variations (e.g., diet, inactivity, stress), and developing new strategies for the prevention and treatment of diabetes and its complications.
We examined the activities of particulate and cytosolic phosphotyrosine phosphatase (PTPase) and phosphoserine phosphatase (PSPase) in adipocytes and livers of diabetic rats. PTPase activity was assessed with [32P]tyrosine-phosphorylated insulin receptor (IR), whereas PSPase activity was assayed with [32P]serine-phosphorylated glycogen synthase. Diabetes increased adipocyte particulate PTPase activity and enhanced IR dephosphorylation by 75% on the 2nd, 93% on the 14th, and 108% on the 30th day. In contrast, cytosolic PTPase activity decreased by 78% on the 14th and 45% on the 30th day (no change on the 2nd day). Similar changes were observed with PSPase (increased activity in particulate and decreased in cytosolic). Insulin therapy for 14 or 30 days restored PTPase and PSPase activities in both fractions. Vanadate, despite rapid normalization of glycemia, restored these activities only after 30 days of therapy. Diabetes-related changes in liver PTPase activity were observed on the 14th day only. At this time, it was increased in both particulate and cytosolic fractions. There was spontaneous normalization of the liver PTPase activity at 30 days of diabetes. In contrast, liver cytosolic PSPase activity was significantly inhibited and not normalized by the 30th day of disease without therapy. In summary, diabetes appears to induce tissue-specific changes in PTPase and PSPase activities resulting in significant alterations in dephosphorylation of IR and glycogen synthase. Moreover, there appears to be a differential regulation of PTPase and PSPase activities in diabetes, particularly in the liver.
An unidentified factor that potentiates the action of insulin in glucose metabolism was investigated in selected foods and spices. Chromium content of these foods and spices was also determined. Foods and spices were extracted with 0.1N NH4OH (1:20, w/v) and the supernatants assayed for insulin potentiation activity in the rat epididymal fat cell assay. Among the selected foods, tuna fish, peanut butter, and vanilla ice cream had some insulin potentiating activity. Among the spices, apple pie spice, cinnamon, cloves, bay leaves, and turmeric potentiated insulin activity more than three-fold. Chromium concentration of foods ranged from 1 to 145 ng/g, and spices ranged from 4 to 1818 ng/g. Insulin potentiating activity of foods and spices did not correlate with total chromium. Spices are generally used for flavor and taste in food preparations, but cinnamon, cloves, bay leaves, and turmeric may have an additional role in glucose metabolism.
Chromium was determined in foods and in extracts of selected samples of foods using modification of the colorimetric procedure to stabilize color development. Extracts were prepared both by hydrolysis of samples to obtain total chromium and by alcohol extraction. Biological activities of these extracts were determined using the glucose oxidation procedure in the presence of insulin. No significant relationship was found between total chromium and biological activity. However, there was a significant relationship for chromium in alcohol extracts of meats, fungi, seeds, and seafoods, excluding fruits and vegetables. A proposed evaluation of the foods was based on these data.
An extensive review of the biogeochemistry of chromium is presented. Topics dealt with in detail include: the chemistry of chromium, its occurrence in nature, chromium's interactions with proteins, nucleic acids, bacteria, yeasts and red blood cells, the biochemical aspects of low-chromium states, the effects of chromium on life span, growth, and survival, the mode and site of action in biological systems, the metabolism (including absorption, distribution, excretion, and toxicology) the effects of chromium's chemical form on biological activity, chromium nutrition in man, and the effects of chromium supplementation in man). 265 references, 12 figures, 8 tables.
A modified method for enzymic synthesis of UDP-14C-glucose in high yield is described. Labeled UDPglucose is isolated by high-voltage paper electrophoresis after an alkaline phosphatase treatment of the reaction products. The synthesis gives high yields and is reproducible, and the isolation of radioactive UDPglucose from the electrophoresis is quantitative.A new assay for UDPglucose: glycogen α-4-glucosyltransferase (EC 2.4.1.11) is also described. Enzyme reaction mixtures are spotted directly on filter paper squares and washed with 66% () ethanol, and 14C-glycogen is counted in a liquid scintillation spectrometer. The method is accurate for all transferase preparations tested if corrections are applied for sample quenching. Assay time is greatly reduced and large numbers of assays can be processed with very little increase in assay time. The assay is also readily applicable to the determination of transferase-I kinase activity.It was also found that stopping the transferase-catalyzed reaction by precipitation of trichloroacetic acid insoluble protein resulted in a loss of radioactive glycogen. When crude preparations of transferase were assayed, up to 20% of the radioactivity bound to glycogen was precipitated by 6% trichloroacetic acid.
This review summarizes the results of 15 controlled studies supplementing defined Cr(III) compounds to subjects with impaired glucose tolerance. Three of these (3-4 mumol Cr/d for > 2 mo) produced no beneficial effects: serum glucose, insulin and lipid concentrations remained unchanged. The remaining 12 interventions improved the efficiency of insulin or the blood lipid profile of subjects (ranging from malnourished children and healthy middle-aged individuals to insulin-requiring diabetics). In addition, three cases of impaired glucose tolerance after long-term total parenteral alimentation responding to Cr supplementation have been reported. Chromium potentiates the action of insulin in vitro and in vivo; maximal in vitro activity requires a special chemical form, termed Glucose Tolerance Factor and tentatively identified as a Cr-nicotinic acid complex. Its complete structural identification is a major challenge to chromium research. The development and validation of a procedure to diagnose chromium status is the second challenge. Such a test would allow the assessment of incidence and severity of deficiency in the population and the selection of deficiency in the population and the selection of chromium-responsive individuals. The third challenge is the definition of chromium's mode of action on parameters of lipid metabolism that have been reported from some studies but not others. Future research along these lines might establish whether chromium deficiency is a factor in the much discussed "Syndrome X" of insulin resistance.
The phosphorylation of insulin receptor substrate 1 (IRS-1) on tyrosine residues by the insulin receptor (IR) tyrosine kinase is involved in most of the biological responses of insulin. IRS-1 mediates insulin signaling by recruiting SH2 proteins through its multiple tyrosine phosphorylation sites. The phosphorylation of IRS-1 on serine/threonine residues also occurs in cells; however, the particular protein kinase(s) promoting this type of phosphorylation are unknown. Here we report that glycogen synthase kinase 3 (GSK-3) is capable of phosphorylating IRS-1 and that this modification converts IRS-1 into an inhibitor of IR tyrosine kinase activity in vitro. Expression of wild-type GSK-3 or an "unregulated" mutant of the kinase (S9A) in CHO cells overexpressing IRS-1 and IR, resulted in increased serine phosphorylation levels of IRS-1, suggesting that IRS-1 is a cellular target of GSK-3. Furthermore, insulin-induced tyrosine phosphorylation of IRS-1 and IR was markedly suppressed in cells expressing wild-type or the S9A mutant, indicating that expression of GSK-3 impairs IR tyrosine kinase activity. Taken together, our studies suggest a new role for GSK-3 in attenuating insulin signaling via its phosphorylation of IRS-1 and may provide new insight into mechanisms important in insulin resistance.
1. Resistance to insulin-mediated glucose transport and metabolism has been identified as a primary mechanism in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM) and as a target for drug development. The aetiology of insulin resistance is likely to be multifactorial, but the present review focuses on candidate post-receptor mechanisms of insulin resistance, particularly protein kinase C (PKC), and the metabolic and genetic significance of β3-adrenoceptors (β3-AR) in adipose tissue.
2. Multiple lines of evidence suggest that isoform-selective activation of PKC phosphorylates and down-regulates one or more substrates involved in glucose transport and metabolism (e.g. glycogen synthase and the insulin receptor) and recent studies have shown increased expression of calcium-independent isozymes (PKC-ε and PKC-θ) in the membrane fraction of skeletal muscle in fructose- and fat-fed rat models of insulin resistance. In addition, there is separate evidence that glucose-induced PKC activation plays an important role in the micro-and macrovascular complications of diabetes.
3. New pharmacological approaches to NIDDM and obesity have focused on insulin-sensitizing agents (e.g. troglitazone), β3-AR agonists, anti-lipolytic drugs (e.g. the adenosine A1 receptor agonist GR79236) and selective inhibitors of PKC isoforms (e.g. the inhibitor of PKC-β LY333531). Experimental studies with GR79236 show that this drug ameliorates the hypertriglyceridaemia induced by fructose feeding and that the reduction in fatty acid levels is associated with secondary improvements in glucose tolerance.
4. Recent insights into the pathogenesis of NIDDM and its associated complications have been used to develop a range of new therapeutic agents that are currently showing promise in clinical and preclinical development.
To examine the role of clathrin-dependent insulin receptor internalization in insulin-stimulated signal transduction events, we expressed a dominant-interfering mutant of dynamin (K44A/dynamin) by using a recombinant adenovirus in the H4IIE hepatoma and 3T3L1 adipocyte cell lines. Expression of K44A/dynamin inhibited endocytosis of the insulin receptor as determined by both cell surface radioligand binding and trypsin protection analysis. The inhibition of the insulin receptor endocytosis had no effect on either the extent of insulin receptor autophosphorylation or insulin receptor substrate 1 (IRS1) tyrosine phosphorylation. In contrast, expression of K44A/dynamin partially inhibited insulin-stimulated Shc tyrosine phosphorylation and activation of the mitogen-activated protein kinases ERK1 and -2. Although there was an approximately 50% decrease in the insulin-stimulated activation of the phosphatidylinositol 3-kinase associated with IRS1, insulin-stimulated Akt kinase phosphorylation and activation were unaffected. The expression of K44A/dynamin increased the basal rate of amino acid transport, which was additive with the effect of insulin but had no effect on the basal or insulin-stimulated DNA synthesis. In 3T3L1 adipocytes, expression of K44A/dynamin increased the basal rate of glucose uptake, glycogen synthesis, and lipogenesis without any significant effect on insulin stimulation. Together, these data demonstrate that the acute actions of insulin are largely independent of insulin receptor endocytosis and are initiated by activation of the plasma membrane-localized insulin receptor.
Growth factor-dependent survival of a variety of mammalian cells is dependent on the activation of phosphatidylinositol (PI) 3-kinase and its downstream effector, the protein kinase Akt. Glycogen synthase kinase-3 (GSK-3) has been previously identified as a physiological target of Akt, which is inhibited by phosphorylation, so we have investigated the role of GSK-3 in cell survival. Overexpression of catalytically active GSK-3 induced apoptosis of both Rat-1 and PC12 cells, whereas dominant-negative GSK-3 prevented apoptosis following inhibition of PI 3-kinase. GSK-3 thus plays a critical role in regulation of apoptosis and represents a key downstream target of the PI 3-kinase/Akt survival signaling pathway.
Bioactive compound(s) extracted from cinnamon potentiate insulin activity, as measured by glucose oxidation in the rat epididymal fat cell assay. Wortmannin, a potent PI 3'-kinase inhibitor, decreases the biological response to insulin and bioactive compound(s) from cinnamon similarly, indicating that cinnamon is affecting an element(s) upstream of PI 3'-kinase. Enzyme studies done in vitro show that the bioactive compound(s) can stimulate autophosphorylation of a truncated form of the insulin receptor and can inhibit PTP-1, a rat homolog of a tyrosine phosphatase (PTP-1B) that inactivates the insulin receptor. No inhibition was found with alkaline phosphate or calcineurin suggesting that the active material is not a general phosphatase inhibitor. It is suggested, then, that a cinnamon compound(s), like insulin, affects protein phosphorylation-dephosphorylation reactions in the intact adipocyte. Bioactive cinnamon compounds may find further use in studies of insulin resistance in adult-onset diabetes.
Insulin elicits a spectrum of biological responses by binding to its cell surface receptor. In a screen for small molecules
that activate the human insulin receptor tyrosine kinase, a nonpeptidyl fungal metabolite (L-783,281) was identified that
acted as an insulin mimetic in several biochemical and cellular assays. The compound was selective for insulin receptor versus
insulin-like growth factor I (IGFI) receptor and other receptor tyrosine kinases. Oral administration of L-783,281 to two
mouse models of diabetes resulted in significant lowering in blood glucose levels. These results demonstrate the feasibility
of discovering novel insulin receptor activators that may lead to new therapies for diabetes.
Insulin resistance, a major factor in the pathogenesis of type 2 diabetes mellitus, is due mostly to decreased stimulation of glycogen synthesis in muscle by insulin. The primary rate-controlling step responsible for the decrease in muscle glycogen synthesis is not known, although hexokinase activity and glucose transport have been implicated.
We used a novel nuclear magnetic resonance approach with carbon-13 and phosphorus-31 to measure intramuscular glucose, glucose-6-phosphate, and glycogen concentrations under hyperglycemic conditions (plasma glucose concentration, approximately 180 mg per deciliter [10 mmol per liter]) and hyperinsulinemic conditions in six patients with type 2 diabetes and seven normal subjects. In vivo microdialysis of muscle tissue was used to determine the gradient between plasma and interstitial-fluid glucose concentrations, and open-flow microperfusion was used to determine the concentrations of insulin in interstitial fluid.
The time course and concentration of insulin in interstitial fluid were similar in the patients with diabetes and the normal subjects. The rates of whole-body glucose metabolism and muscle glycogen synthesis and the glucose-6-phosphate concentrations in muscle were approximately 80 percent lower in the patients with diabetes than in the normal subjects under conditions of matched plasma insulin concentrations. The mean (+/-SD) intracellular glucose concentration was 2.0+/-8.2 mg per deciliter (0.11+/-0.46 mmol per liter) in the normal subjects. In the patients with diabetes, the intracellular glucose concentration was 4.3+/-4.9 mg per deciliter (0.24+/-0.27 mmol per liter), a value that was 1/25 of what it would be if hexokinase were the rate-controlling enzyme in glucose metabolism.
Impaired insulin-stimulated glucose transport is responsible for the reduced rate of insulin-stimulated muscle glycogen synthesis in patients with type 2 diabetes mellitus.