Lactate downregulates the glycolytic enzymes hexokinase and phosphofructokinase in diverse tissues from mice

We examined the effects of lactate on the enzymatic activity of hexokinase (HK), phosphofructokinase (PFK) and pyruvate kinase (PK) in various mouse tissues. Our results showed that lactate inhibited PFK activity in all the analyzed tissues. This inhibitory effect was observed in skeletal muscle even in the presence of insulin. Lactate directly inhibited the phosphorylation of PFK tyrosine residues in skeletal muscle, an important mechanism of the enzyme activation. Moreover, lactate indirectly inhibited HK activity, which resulted from its cellular redistribution, here attributed to alterations of HK structure. PK activity was not affected by lactate. The activity of HK and PFK is directly related to glucose metabolism. Thus, it is conceivable that lactate exposure can induce inhibition of glucose consumption in tissues.     

Two Weeks of Metformin Treatment Enhances Mitochondrial Respiration in Skeletal Muscle of AMPK Kinase Dead but Not Wild Type Mice

Metformin is used as an anti-diabetic drug. Metformin ameliorates insulin resistance by improving insulin sensitivity in liver and skeletal muscle. Reduced mitochondrial content has been reported in type 2 diabetic muscles and it may contribute to decreased insulin sensitivity characteristic for diabetic muscles. The molecular mechanism behind the effect of metformin is not fully clarified but inhibition of complex I in the mitochondria and also activation of the 5′AMP activated protein kinase (AMPK) has been reported in muscle. Furthermore, both AMPK activation and metformin treatment have been associated with stimulation of mitochondrial function and biogenesis. However, a causal relationship in skeletal muscle has not been investigated. We hypothesized that potential effects of in vivo metformin treatment on mitochondrial function and protein expressions in skeletal muscle are dependent upon AMPK signaling. We investigated this by two weeks of oral metformin treatment of muscle specific kinase dead α₂ (KD) AMPK mice and wild type (WT) littermates. We measured mitochondrial respiration and protein activity and expressions of key enzymes involved in mitochondrial carbohydrate and fat metabolism and oxidative phosphorylation. Mitochondrial respiration, HAD and CS activity, PDH and complex I-V and cytochrome c protein expression were all reduced in AMPK KD compared to WT tibialis anterior muscles. Surprisingly, metformin treatment only enhanced respiration in AMPK KD mice and thereby rescued the respiration defect compared to the WT mice. Metformin did not influence protein activities or expressions in either WT or AMPK KD mice.We conclude that two weeks of in vivo metformin treatment enhances mitochondrial respiration in the mitochondrial deficient AMPK KD but not WT mice. The improvement seems to be unrelated to AMPK, and does not involve changes in key mitochondrial proteins.     

Seasonal changes in the activities of glycolytic enzymes from liver and skeletal muscle of Rana perezi

Glycogen phosphorylase (GP), Hexokinase (HK), Phosphofructokinase (PFK), Pyruvate kinase (PK) and Lactate dehydrogenase (LDH) activities from skeletal muscle and liver were measured in Rana perezi for the four seasons of the year. Skeletal muscle showed a decrease in PFK, PK and LDH activity during winter and summer. Liver displayed an increase in GP activity in spring and in PK and LDH in autumn.     

Histochemical profiles of motoneurons innervating muscle fibres with different activity patterns in the zebrafish, Brachydanio rerio.

Summary Enzyme histochemical profiles of spinal motoneurons in the zebrafish were determined. Five enzymes of glucose metabolism were chosen: glucose-6-phosphate dehydrogenase (G6PDH), hexokinase (HK), phosphofructokinase (PFK), succinate dehydrogenase (SDH) and NADH tetrazolium reductase (NADH-TR). Motoneurons were traced with Fluorogold and classified as those that innervate white muscle fibres (W-MNs) and those that innervate red and intermediate muscle fibres (R/ I-MNs). The average enzyme activities per volume of tissue in the somata of both populations differed at most by 25%. Both the average soma volume and the average number of muscle fibres innervated are three times larger for the W-MNs than for the a/I-MNs. This suggests that the total amount of enzyme activity within a neuron soma matches target size.In the R/I-MNs, the activities of SDH and NADH-TR were closely correlated (correlation coefficient, r=0.99;p<0.05) and HK activity correlated well with G6PDH activity (r=0.94;p<0.05), butnot with PFK (r=0.64;p>0.05). In the W-MNs, there was no correlation between SDH and NADH-TR (r=–0.59;p>0.05) or between HK and G6PDH (r=0.50;p>0.05) and the correlation coefficient between HK and PFK activity was close to zero (r=0.04;p>0.05).It was concluded that in the R/I-MNs gwhich are continuously ctive, firing activity is fuelled by oxidative metabolsm. We suggest that in the W-MNs glucose is stored in the form of glycogen and that, despite high levels of NADH-TR present, the energy for intermittent firing activity is provided by glycolysis.     

Increased renal semicarbazide-sensitive amine oxidase activity and methylglyoxal levels in aristolochic acid-induced nephrotoxicity

Aims

Aristolochic acid (AA) nephrotoxicity is related to accumulation of methylglyoxal (MGO) and N^ε-(carboxymethyl)lysine (CML) in the mouse kidney. We studied the activity of renal semicarbazide-sensitive amine oxidase (SSAO), a key enzyme involved in MGO generation, in AA-treated mice, and investigated nephroprotective effects produced by metformin, a MGO scavenger.

Methods

Mice were orally administered water or metformin for 15 days (12 or 24 mg kg^− 1 day^− 1), and injected AA (5 mg kg^− 1 day^− 1) intraperitoneally for 8 days starting on day 8. Renal function was studied, and histopathological examination, determination of renal SSAO activity, and measurement of MGO levels were performed.

Key findings

Compared to control mice, AA-injected mice showed significant renal damage and approximately 2.7-fold greater renal SSAO activity (p < 0.05). Further, compared to control treatment, administration of 12 mg/kg metformin inhibited formation of renal lesions, and significantly decreased renal MGO levels (37.33 ± 9.78 vs. 5.89 ± 2.64 μg/mg of protein, respectively, p < 0.01). In the AA-treated mice, metformin also inhibited the accumulation of CML in renal tubules, but did not affect SSAO activity.

Significance

This study is the first to show elevated renal SSAO activity in AA-treated mice, which could be involved in MGO accumulation. Moreover, MGO scavenging by metformin reduces AA nephrotoxicity. These findings suggest that reducing MGO accumulation produces nephroprotection, revealing new therapeutic strategies for the management. SSAO is a key enzyme involved in MGO generation, and consequently, inhibition of renal SSAO activity is worth investigating in AA nephrotoxicity and other renal pathologies further.     

Phosphofructo-1-Kinase Deficiency Leads to a Severe Cardiac and Hematological Disorder in Addition to Skeletal Muscle Glycogenosis

Mutations in the gene for muscle phosphofructo-1-kinase (PFKM), a key regulatory enzyme of glycolysis, cause Type VII glycogen storage disease (GSDVII). Clinical manifestations of the disease span from the severe infantile form, leading to death during childhood, to the classical form, which presents mainly with exercise intolerance. PFKM deficiency is considered as a skeletal muscle glycogenosis, but the relative contribution of altered glucose metabolism in other tissues to the pathogenesis of the disease is not fully understood. To elucidate this issue, we have generated mice deficient for PFKM (Pfkm^−/−). Here, we show that Pfkm^−/− mice had high lethality around weaning and reduced lifespan, because of the metabolic alterations. In skeletal muscle, including respiratory muscles, the lack of PFK activity blocked glycolysis and resulted in considerable glycogen storage and low ATP content. Although erythrocytes of Pfkm^−/− mice preserved 50% of PFK activity, they showed strong reduction of 2,3-biphosphoglycerate concentrations and hemolysis, which was associated with compensatory reticulocytosis and splenomegaly. As a consequence of these haematological alterations, and of reduced PFK activity in the heart, Pfkm^−/− mice developed cardiac hypertrophy with age. Taken together, these alterations resulted in muscle hypoxia and hypervascularization, impaired oxidative metabolism, fiber necrosis, and exercise intolerance. These results indicate that, in GSDVII, marked alterations in muscle bioenergetics and erythrocyte metabolism interact to produce a complex systemic disorder. Therefore, GSDVII is not simply a muscle glycogenosis, and Pfkm^−/− mice constitute a unique model of GSDVII which may be useful for the design and assessment of new therapies.     

Lactococcus lactis as a cell factory: a twofold increase in phosphofructokinase activity results in a proportional increase in specific rates of glucose uptake and lactate formation

Despite the fact that the area of glycolysis in Lactococcus lactis has been intensively studied, only a limited number of studies have been focused on the regulation of uptake of glucose itself. Using the tool of the glucostat fed-batch mode of culture, it was demonstrated in our earlier work that the concentration of glucose regulates its uptake rate and that the control of the glycolytic flux resides to a large extent in processes outside the pathway itself, like glucose transport and the ATP consuming reactions, while allosteric properties of key enzymes like phosphofructokinase (PFK) have a significant influence on the control. Extending our work, we report here the results of fermentations with engineered L. lactis strains with altered PFK activity in which the pfkA gene from Aspergillus niger, and its truncated version pfk13 that encodes a shorter PFK1 fragment were cloned. The results in this study suggest that, under the optimum for the microorganism applied microaerobic conditions, the glycolytic capacity of L. lactis was significantly increased in engineered strains with increased PFK activity. The transformant strain in which the truncated pfk13 gene of A. niger was expressed performed more efficiently as it was able to grow successfully in glucostat cultures with 277 mM glucose - while the optimum glucose concentration for the parental strain was 55 mM. The present work demonstrates the direct effect of PFK activity on the glycolytic flux in L. lactis since a twofold increase in specific PFK activity (from 7.1 to 14.5 U/OD₆₀₀) resulted in a proportional increase of the maximum specific rates of glucose uptake (from 0.8 to 1.7 μM s⁻¹ g CDW⁻¹) and lactate formation (from 15 to 22.8 g lactate (g CDW)⁻¹ h⁻¹).     

Serotonin regulates 6-phosphofructo-1-kinase activity in a PLC–PKC–CaMK II- and Janus kinase-dependent signaling pathway

Serotonin (5-HT) is a hormone that has been implicated in the regulation of many physiological and pathological events. One of the most intriguing properties of this hormone is its ability to up-regulate mitosis. Moreover, 5-HT stimulates glucose uptake and up-regulates PFK activity through the 5-HT_2A receptor, resulting in the phosphorylation of a tyrosine residue of PFK and the intracellular redistribution of PFK within skeletal muscle. The present study investigated some of the signaling intermediates involved in the effects of 5-HT on 6-phosphofructo-1-kinase (PFK) regulation from skeletal muscle using kinetic assessments, immunoprecipitation, and western blotting assays. Our results demonstrate that 5-HT stimulates PFK from skeletal muscle via phospholipase C (PLC). The activation of PLC in skeletal muscle leads to the recruitment of protein kinase C (PKC) and calmodulin and the stimulation of calmodulin kinase II, which associates with PFK upon 5-HT action. Alternatively, 5-HT loses its ability to up-regulate PFK activity when Janus kinase is inhibited, suggesting that 5-HT is able to control glycolytic flux in the skeletal muscle of mice by recruiting different pathways and controlling PFK activity.     

Lack of REDD1 reduces whole body glucose and insulin tolerance,and impairs skeletal muscle insulin signaling

A lack of the REDD1 promotes dysregulated growth signaling, though little has been established with respect to the metabolic role of REDD1. Therefore, the goal of this study was to determine the role of REDD1 on glucose and insulin tolerance, as well as insulin stimulated growth signaling pathway activation in skeletal muscle. First, intraperitoneal (IP) injection of glucose or insulin were administered to REDD1 wildtype (WT) versus knockout (KO) mice to examine changes in blood glucose over time. Next, alterations in skeletal muscle insulin (IRS-1, Akt, ERK 1/2) and growth (4E-BP1, S6K1, REDD1) signaling intermediates were determined before and after IP insulin treatment (10 min). REDD1 KO mice were both glucose and insulin intolerant when compared to WT mice, evident by higher circulating blood glucose concentrations and a greater area under the curve following IP injections of glucose or insulin. While the REDD1 KO exhibited significant though blunted insulin-stimulated increases (p < 0.05) in Akt S473 and T308 phosphorylation versus the WT mice, acute insulin treatment has no effect (p < 0.05) on REDD1 KO skeletal muscle 4E-BP1 T37/46, S6K1 T389, IRS-1 Y1222, and ERK 1/2 T202/Y204 phosphorylation versus the WT mice. Collectively, these novel data suggest that REDD1 has a more distinct role in whole body and skeletal muscle metabolism and insulin action than previously thought.     

Suppression of MAPKAPK2 during mammalian hibernation

Metabolic signaling coordinates the transition by hibernating mammals from euthermia into profound torpor. Organ-specific responses by activated p38 mitogen activated protein kinase (MAPK) are known to contribute to this transition. Therefore, we hypothesized that the MAPK-activated protein kinase-2 (MAPKAPK2), a downstream target of p38 MAPK, would also be active in establishing the torpid state. Kinetic parameters of MAPKAPK2 from skeletal muscle of Richardson’s ground squirrels, Spermophilus richardsonii, were analyzed using a fluorescence assay. MAPKAPK2 activity was 27.4 ± 1.27 pmol/min/mg in muscle from euthermic squirrels and decreased by ∼63% during cold torpor, while total protein levels were unchanged (as assessed by immunoblotting). In vitro treatment of MAPKAPK2 via stimulation of endogenous phosphatases and addition of commercial alkaline phosphatase decreased enzyme activity to only ∼3–5% of its original value in muscle extracts from both euthermic and hibernating squirrels suggesting that posttranslational modification suppresses MAPKAPK2 during the transition from euthermic to torpid states. Enzyme S_0.5 and n_H values for ATP and peptide substrates changed significantly between euthermia and torpor, and also between assays at 22 versus 10 °C but, kinetic parameters were actually closely conserved when values for the euthermic enzyme at 22 °C were directly compared with the hibernator enzyme at 10 °C. Arrhenius plots showed significantly different activation energies of 40.8 ± 0.7 and 54.3 ± 2.7 kJ/mol for the muscle enzyme from euthermic versus torpid animals, respectively but MAPKAPK2 from the two physiological states showed no difference in sensitivity to urea denaturation. Overall, the results show that total activity of MAPKAPK2 is in fact reduced, despite previous findings of p38 MAPK activation, and kinetic parameters are altered when ground squirrels enter torpor but protein stability is not apparently changed. The data suggest that MAPKAPK2 suppression may have a significant role in the differential regulation of muscle target proteins when ground squirrels enter torpor.     

Fructose-2,6-bisphosphate counteracts guanidinium chloride-, thermal-, and ATP-induced dissociation of skeletal muscle key glycolytic enzyme 6-phosphofructo-1-kinase: A structural mechanism for PFK allosteric regulation

Rabbit muscle 6-phosphofructo-1-kinase (PFK) is the key glycolytic enzyme being regulated by diverse molecules and signals. This enzyme may undergo a reversible dissociation from a fully active homotetramer to a quite inactive dimer. There are evidences that some positive and negative modulators of PFK, such as ADP and citrate, may interfere with the enzyme oligomeric structure shifting the tetramer-dimer equilibrium towards opposite orientations, where the negative modulators favor the dissociation of tetramers into dimers and vice versa. PFK is allosterically inhibited by ATP at its physiological range of concentration, an effect counteracted by fructose-2,6-bisphosphate (F2,6BP). However, the structural molecular mechanism by which ATP and F2,6BP regulate PFK is hitherto demonstrated. The present paper aimed at demonstrating that either the ATP-induced inhibition of PFK and the reversion of this inhibition by F2,6BP occur through the same molecular mechanism, i.e., the displacement of the oligomeric equilibrium of the enzyme. This conclusion is arrived assessing the effects of ATP and F2,6BP on PFK inactivation through two distinct ways to dissociate the enzyme: (a) upon incubation at 50 °C, or (b) incubating the enzyme with guanidinium hydrochloride (GdmCl). Our results reveal that temperature- and GdmCl-induced inactivation of PFK prove remarkably more effective in the presence 5 mM ATP than in the absence of additives. On the other hand, the presence of 100 nM F2,6BP attenuate the effects of both high-temperature exposition and GdmCl on PFK, even in the simultaneous presence of 5 mM ATP. These data support the hypothesis that ATP shifts the oligomeric equilibrium of PFK towards the smaller conformations, while F2,6BP acts in the opposite direction. This conclusion leads to important information about the molecular mechanism by which PFK is regulated by these modulators.     

麦红吸浆虫不同滞育期四种糖代谢酶活力分析

海藻糖是麦红吸浆虫Sitodiplosis mosellana (Gehin)滞育期间储藏能量的主要物质,为弄清其在滞育期的积累机理,本文测定了麦红吸浆虫滞育前后和滞育期糖原磷酸化酶（Gpase）、己糖激酶（HK）、磷酸果糖激酶（PFK）和醛缩酶（ALD）这4种糖代谢酶活力的变化。结果表明: 麦红吸浆虫滞育前后这些糖代谢酶活力明显不同,滞育后Gpase 活力显著提高,糖酵解有关酶HK,PFK和ALD活力降低;滞育解除后,Gpase 活力降低,HK,PFK和ALD活力升高。滞育期间,4种糖代谢酶的活力均与滞育发育有关;同时Gpase 和PFK的活力也与环境温度有关,即夏、冬季高于春、秋季;同期不同滞育状态幼虫比较,裸露幼虫HK,PFK和ALD活力总是略高于结茧幼虫,Gpase则相反。滞育当年与第2年同期幼虫4种糖代谢酶的活力无显著差异。     

Activities of hexokinase,phosphofructokinase and pyruvate kinase in the body wall,pyloric caeca and tube feet of Asterias vulgaris: Evidence of body wall as a major source of glycolytic activity

• 1.1. The activities of hexokinase (HK) and pyruvate kinase (PK) were significantly higher than the activity of phosphofructokinase (PFK) in the body wall, pyloric caeca and tube feet.
• 2.2. When expressed as a function of wet weight, the specific activity of HK was highest in the pyloric caeca. When expressed as a function of cytosolic protein, the specific activity of HK was highest in the body wall.
• 3.3. Specific activities PFK and PK, expressed as functions of cytosolic protein, were highest in the tube feet. These enzyme activities should reflect the high energetic requirements of the tube feet.
• 4.4. Highest total activity of PFK was found in the body wall. These results support the conclusion that the body wall is a metabolically active organ and that the energetic requirement of the body wall is a significant component of the energetic requirements of the organism.

     

Epigallocatechin gallate promotes GLUT4 translocation in skeletal muscle

In this study, we investigated whether epigallocatechin gallate (EGCg) affects glucose uptake activity and the translocation of insulin-sensitive glucose transporter (GLUT) 4 in skeletal muscle. A single oral administration of EGCg at 75 mg/kg body weight promoted GLUT4 translocation in skeletal muscle of rats. EGCg significantly increased glucose uptake accompanying GLUT4 translocation in L6 myotubes at 1 nM. The translocation of GLUT4 was also observed both in skeletal muscle of mice and rats ex vivo and in insulin-resistant L6 myotubes. Wortmannin, an inhibitor of phosphatidylinositol 3′-kinase, inhibited both EGCg- and insulin-increased glucose uptakes, while genistein, an inhibitor of tyrosine kinase, failed to inhibit the EGCg-increased uptake. Therefore, EGCg may improve hyperglycemia by promoting GLUT4 translocation in skeletal muscle with partially different mechanism from insulin.     

Fuel use in hawkmoth (Amphion floridensis) flight muscle: enzyme activities and flux rates

The fuels used by the hawkmoth Amphion floridensis to power flight are determined by nectar-feeding, with fed moths using primarily carbohydrate and unfed moths using primarily fat. To investigate the metabolic pathways underlying fuel-use flexibility in this species, we measured the maximal activities of several key metabolic enzymes in the flight muscle of fed and unfed individuals, for which metabolic rates and fuel utilization had been previously determined. Hexokinase (HK) and phosphofructokinase (PFK) occur at high activities and, during carbohydrate-fueled flight, are estimated to operate at fractional velocities comparable to those of exclusively carbohydrate-utilizing insects. Females exhibited higher glycolytic enzyme activities than did males, and males regulated PFK activity according to nectar feeding. Although beta-hydroxyacyl-CoA dehydrogenase (HOAD) was found at high activities, carnitine palmitoyl transferase (CPT) was not detectable, suggesting that fatty acids may be utilized via a carnitine-independent pathway during flight. Principal component analysis revealed a tendency for the activities of citrate synthase, HK, PFK, and HOAD to be positively correlated among individuals, as well as a lesser tendency for the activities of glycolytic vs. mitochondrial enzymes to be negatively correlated with each other. However, the principal components did not correlate with variation in either oxygen consumption rate or fuel use in vivo, suggesting that variation in enzyme concentration did not determine differences among individuals in metabolic performance during flight. J. Exp. Zool. 290:108-114, 2001.     

Inhibition of xanthine oxidase reduces oxidative stress and improves skeletal muscle function in response to electrically stimulated isometric contractions in aged mice

Oxidative stress is a putative factor responsible for reducing function and increasing apoptotic signaling in skeletal muscle with aging. This study examined the contribution and functional significance of the xanthine oxidase enzyme as a potential source of oxidant production in aged skeletal muscle during repetitive in situ electrically stimulated isometric contractions. Xanthine oxidase activity was inhibited in young adult and aged mice via a subcutaneously placed time-release (2.5 mg/day) allopurinol pellet, 7 days before the start of in situ electrically stimulated isometric contractions. Gastrocnemius muscles were electrically activated with 20 maximal contractions for 3 consecutive days. Xanthine oxidase activity was 65% greater in the gastrocnemius muscle of aged mice compared to young mice. Xanthine oxidase activity also increased after in situ electrically stimulated isometric contractions in muscles from both young (33%) and aged (28%) mice, relative to contralateral noncontracted muscles. Allopurinol attenuated the exercise-induced increase in oxidative stress, but it did not affect the elevated basal level of oxidative stress that was associated with aging. In addition, inhibition of xanthine oxidase activity decreased caspase-3 activity, but it had no effect on other markers of mitochondrial-associated apoptosis. Our results show that compared to control conditions, suppression of xanthine oxidase activity by allopurinol reduced xanthine oxidase activity, H₂O₂ levels, lipid peroxidation, and caspase-3 activity; prevented the in situ electrically stimulated isometric contraction-induced loss of glutathione; prevented the increase in catalase and copper-zinc superoxide dismutase activities; and increased maximal isometric force in the plantar flexor muscles of aged mice after repetitive electrically evoked contractions.     

Large enhancement of skeletal muscle cell glucose uptake and suppression of hepatocyte glucose-6-phosphatase activity by weak uncouplers of oxidative phosphorylation

Background

Perturbation of energy homeostasis in skeletal muscle and liver resulting from a transient inhibition of mitochondrial energy transduction can produce effects of relevance for the control of hyperglycemia through activation of the AMP-activated protein kinase, as exemplified by the antidiabetic drug metformin. The present study focuses on uncoupling of oxidative phosphorylation rather than its inhibition as a trigger for such effects.

Methods

The reference weak uncoupler 2,4-dinitrophenol, fourteen naturally-occurring phenolic compounds identified as uncouplers in isolated rat liver mitochondria, and fourteen related compounds with little or no uncoupling activity were tested for enhancement of glucose uptake in differentiated C2C12 skeletal muscle cells following 18 h of treatment at 25-100 μM. A subset of compounds were tested for suppression of glucose-6-phosphatase (G6Pase) activity in H4IIE hepatocytes following 16 h at 12.5-25 μM. Metformin (400 μM) was used as a standard in both assays.

Results

Dinitrophenol and nine of eleven compounds that induced 50% or more uncoupling at 100 μM in isolated mitochondria enhanced basal glucose uptake by 53 to 269%; the effect of the 4′-hydroxychalcone butein was more than 6-fold that of metformin; negative control compounds increased uptake by no more than 25%. Dinitrophenol and four 4′-hydroxychalconoids also suppressed hepatocyte G6Pase as well as, or more effectively than metformin, whereas the unsubstituted parent compound chalcone, devoid of uncoupling activity, had no effect.

Conclusions

Activities key to glycemic control can be induced by a wide range of weak uncouplers, including compounds free of difficult-to-metabolize groups typically associated with uncouplers.

General significance

Uncoupling represents a valid and possibly more efficient alternative to inhibition for triggering cytoprotective effects of therapeutic relevance to insulin resistance in both muscle and liver. Identification of actives of natural origin and the insights into their structure-activity relationship reported herein may lead to alternatives to metformin.     

Hypoglycemic activities of A- and B-type procyanidin oligomer-rich extracts from different Cinnamon barks

Procyanidin oligomers in Cinnamon are thought to be responsible for the biological activity in the treatment of diabetes mellitus (DM). To clarify types of procyanidin oligomers in different Cinnamon species and investigate their different effects, the present study investigated procyanidin oligomers in polyphenolic oligomer-rich extracts of three Cinnamon samples by LC-MS methods, and their hypoglycemic activities were detected in vivo and in vitro. The results showed that two of the three samples from Cinnamomum cassia were rich in B-type procyanidin oligomers, and the other sample was rich in A-type procyanidin oligomers. The Cinnamon extracts were administered at doses of 200 and 300 mg/kg body wt. in high-fat diet-fed and low-dose streptozotocin (STZ)-induced diabetic mice for 14 days. The results showed that blood glucose concentrations were significantly decreased in all Cinnamon extract groups compared with the control group (p < 0.05). Administration of the Cinnamon extracts significantly increased the consumption of extracellular glucose in insulin-resistant HepG2 cells and normal HepG2 cells compared with the control group. These results suggest that both A- and B-type procyanidin oligomers in different Cinnamon species have hypoglycemic activities and may improve insulin sensitivity in type 2 DM.