Insulin Potentiating Activity Research Articles

Rationale and design of Short-Term EXenatide therapy in Acute ischaemic Stroke (STEXAS): a randomised, open-label, parallel-group study

IntroductionBoth hyperglycaemia and hypoglycaemia in acute ischaemic stroke (AIS) are associated with increased infarct size and worse functional outcomes. Thus, therapies that can maintain normoglycaemia during stroke are clinically important....

Cinnamon extract lowers glucose, insulin and cholesterol in people with elevated serum glucose

Cinnamon (肉桂 ròu guì) has in vitro insulin potentiating activity, and proanthocyanidins from cinnamon prevent in vitro formation of advanced glycation end products. Some human studies were equivocal, but several have shown beneficial effects of cinnamon supplementation on circulating glucose, lipids, and/or insulin. This placebo-controlled double-blind trial tested the effects of a dried water extract of cinnamon (Cinnamomum cassia) on circulating glucose, lipids, insulin, and insulin resistance. Men and women from Beijing and Dalian, China, were invited to participate if they had fasting serum glucose >6.1 mmol/L or 2-h glucose >7.8 mmol/L. Participants, (173 were enrolled and 137 completed the study) were randomly assigned to receive either a spray-dried, water extract of cinnamon (CinSulin®), 250 mg/capsule, or a placebo, twice a day for two months. Mean ± SEM age of participants was 61.3 ± 0.8 years, BMI was 25.3 ± 0.3 and M/F ratio was 65/72. After 2 mo, fasting glucose decreased (p < 0.001) in the cinnamon extract-supplemented group (8.85 ± 0.36 to 8.19 ± 0.29 mmol/L) compared with the placebo group (8.57 ± 0.32 to 8.44 ± 0.34 mmol/L, p = 0.45). Glucose 2 h after a 75 g carbohydrate load, fasting insulin, and HOMA-IR also decreased with cinnamon extract compared with placebo. Total and LDL-cholesterol decreased with cinnamon extract and HDL-cholesterol decreased in both the cinnamon-extract and placebo groups. In conclusion, supplementation with 500 mg of water-extract of cinnamon for two months reduced fasting insulin, glucose, total cholesterol, and LDL cholesterol and enhanced insulin sensitivity of subjects with elevated blood glucose.

Enhanced anti-diabetic activity of polyphenol-rich de-coumarinated extracts of Cinnamomum cassia

Although the insulin potentiating activity of Cinnamomum cassia extracts has been studied in detail, no systematic investigations have so far been reported to standardize those extracts with respect to their bioactive polyphenol and toxic coumarin contents. Moreover, no process has been reported for the preparation of de-coumarinated water-soluble polyphenol-rich extracts of cinnamomum species. In the present contribution, we describe the preparation of de-coumarinated polyphenol-rich extracts of Cinnamomum cassia containing 45 and 70% gallic acid equivalents of polyphenol content and their characterization by tandem mass spectrometry. These extracts were investigated for their relative anti-hyperglycaemic effects in comparison with a standard aqueous extract containing 18% polyphenol content and 0.8% coumarin. De-coumarinated extracts were found to be safe and showed 3.4 fold enhancements in relative lowering of blood sugar levels as compared to the standard cinnamon extract, when administered to streptozotocin-induced diabetic rats at 200 mg/kg body weight for 30 days.

Mechanisms of action of islet neogenesis-associated protein: comparison of the full-length recombinant protein and a bioactive peptide

Islet neogenesis-associated protein (INGAP) was discovered in the partially duct-obstructed hamster pancreas as a factor inducing formation of new duct-associated islets. A bioactive portion of INGAP, INGAP(104-118) peptide (INGAP-P), has been shown to have neogenic and insulin-potentiating activity in numerous studies, including recent phase 2 clinical trials that demonstrated improved glucose homeostasis in both type 1 and type 2 diabetic patients. Aiming to improve INGAP-P efficacy and to understand its mechanism of action, we cloned the full-length protein (rINGAP) and compared the signaling events induced by the protein and the peptide in RIN-m5F cells that respond to INGAP with an increase in proliferation. Here, we show that, although both rINGAP and INGAP-P signal via the Ras/Raf/ERK pathway, rINGAP is at least 100 times more efficient on a molar basis than INGAP-P. For either ligand, ERK1/2 activation appears to be pertussis toxin sensitive, suggesting involvement of a G protein-coupled receptor(s). However, there are clear differences between the peptide and the protein in interactions with the cell surface and in the downstream signaling. We demonstrate that fluorescent-labeled rINGAP is characterized by clustering on the membrane and by slow internalization (≤5 h), whereas INGAP-P does not cluster and is internalized within minutes. Signaling by rINGAP appears to involve Src, in contrast to INGAP-P, which appears to activate Akt in addition to the Ras/Raf/ERK1/2 pathway. Thus our data suggest that interactions of INGAP with the cell surface are important to consider for further development of INGAP as a pharmacotherapy for diabetes.

Effect of Pro- and Antioxidants on Insulin Sensitivity and Glucose Tolerance

We studied the correlation between the effect of α-lipoic acid, emoxipin, reamberin, and mexidol on LPO in vitro and the action of these drugs on insulin sensitivity and tolerance to glucose load in vivo. It was found that the preparations producing prooxidant effect in vitro (α-lipoic acid and reamberin) are characterized by pronounced insulin-potentiating activity, but only slightly increase (α-lipoic acid) or even decrease (reamberin) tolerance to glucose load. 3-Hydroxypyridine derivatives (emoxipin and mexidol) producing an antioxidant effect in vitro increase glucose tolerance, but exhibit relatively weak insulin-potentiating activity. These results suggest that differential use of the studied drugs in patients with diabetes mellitus depending on the type of the disease and individual insulin requirement is a promising trend in medical studies.

Cinnamon extract lowers blood glucose in hyperglycemic subjects

Based on insulin potentiating activity of cinnamon, effects of a water extract of cinnamon were tested in a 2‐mo double‐blind placebo trial with 137 participants in China. Mean±SEM age was 61.3 ± 0.8 years, BMI was 25.3 ± 0.3 and M/F ratio was 65/72. A placebo capsule or a 250 mg dried water‐extract cinnamon (CinSulin) capsule was given twice per day. At baseline, homeostasis model assessment‐estimated insulin resistance (HOMA‐IR) was significantly correlated with diastolic blood pressure (r=0.23) postprandial glucose (r=0.45) and insulin (r=0.42), triglycerides (r=0.29), fructosamine (0.23), BMI (r=0.29) and negatively correlated with HDLC (r=0.37). After 2 mo, fasting glucose decreased (p&lt;0.001) in the aqua‐cinnamon‐supplemented group (8.85 ± 0.36 to 8.19 ± 0.29 mmol/L) compared with 8.57 ± 0.32 to 8.44 ± 0.34 mmol/L in the placebo group (p=0.45). Glucose 2 h after a 75 g carbohydrate load also decreased (p&lt;0.0001) with CinSulin (15.09 ± 0.57 to 13.30 ± 0.55 mmol/L) compared to 14.18 ± 0.60 to 13.74 ± 0.58 mmol/L with placebo. Insulin concentrations and HOMA‐IR tended to be improved by aqua‐cinnamon supplements but differences were not significant. In summary, supplementation of a water extract of cinnamon had beneficial effects in subjects with hyperglycemia. (Supported by USDA‐ARS, Tang‐An Medical &amp; Oklahoma State Univ).

GHTD-amide: A naturally occurring beta cell-derived peptide with hypoglycemic activity

In the early 1970s, a peptide fraction with insulin potentiating activity was purified from human urine but the identity and origins of the active constituent remained unknown. Here we identify the active component and characterize its origins. The active peptide was identified as an alpha amidated tetrapeptide with the sequence GHTD-amide. The peptide was synthesized and tested for stimulation of glycogen synthesis and insulin potentiation by insulin tolerance testing in insulin-deficient rats, which confirmed GHTD-amide as the active peptide. Tissue localization using a peptide-specific anti-serum and epifluorescent and confocal microscopy showed decoration of pancreatic islets but not other tissues. Confocal microscopy revealed co-localization with insulin and immunogold and electron microscopy showed localization to dense core secretory granules. Consistent with these observations GHTD-amide was found in media conditioned by MIN6 islet beta cells. Sequence database searching found no annotated protein in the human proteome encoding a potential precursor for GHTD-amide. We conclude that the insulin potentiating activity originally described in human urine is attributable to the tetrapeptide GHTD-amide. GHTD-amide is a novel peptide produced by pancreatic beta cells and no precursor protein is present in the annotated human proteome. Stimulation of glycogen synthesis and co-localization with insulin in beta cells suggest that GHTD-amide may play a role in glucose homeostasis by enhancing insulin action and glucose storage in tissues.

Effects of short‐term cinnamon ingestion on in vivo glucose tolerance

Various spices display insulin-potentiating activity in vitro, and in particular, cinnamon spice and its phenolic extracts have been shown to exhibit these capabilities. In vivo study shows that cinnamon may have beneficial effects on glucose homeostasis; therefore the aim of this study was to further investigate this phenomenon in humans. Seven lean healthy male volunteers, aged 26 +/- 1 years, body mass index 24.5 +/- 0.3 kg/m(2) (mean +/- s.e.m.), underwent three oral glucose tolerance tests (OGTT) supplemented with either a 5 g placebo (OGTT(control)), 5 g of cinnamon (OGTT(cin)), or 5 g of cinnamon taken 12 h before (OGTT(cin12hpre)) in a randomized-crossover design. Cinnamon ingestion reduced total plasma glucose responses (AUC) to oral glucose ingestion [-13% and -10% for OGTT(cin) (p < 0.05) and OGTT(cin12hpre) (p < 0.05), respectively], as well as improving insulin sensitivity as assessed by insulin sensitivity index measures based on Matsuda's model in both OGTT(cin) (p < 0.05) and OGTT(cin12hpre) (p < 0.05) trials compared with OGTT(control). These data illustrate that cinnamon spice supplementation may be important to in vivo glycaemic control and insulin sensitivity in humans, and not only are its effects immediate, they also appear to be sustained for 12 h.

Insulin Potentiating Factor (IPF) Present in Foods, Species and Natural Products

Control of diabetes by diet and natural products is more appropriate and economical in developing countries, hence fruits, vegetables, tea, spices and homeopathic drugs were investigated for their insulin potentiating function in glucose metabolism in rat epididymal fat cells assay. Dried flesh and seed of jamon fruit (Eugenia jambulina), fresh and dried flesh and seed of bitter gourd (Momordica charantia), fresh and dried chaunga (Carulina tuberculate) and powdered fenugreek (Trigonella foenum-graecum) were extracted with 0.1 N NH OH or boiling water (1:20 w/v). Black, decaffeinated and green tea (Thea sp.) were prepared 4 without milk and with milk. Sugar was not added to the tea. The supernatants of the extracts and the different prepared tea samples were used for insulin potentiation in the rat epididymal fat cells assay. Homeopathic drugs, diabene and diacure were tested for insulin potentiating activity in the above assay. Dried flesh of jamon fruit potentiated insulin 6.7 fold when boiled with water and 6.1 fold when extracted with 0.1N NH OH. 4 Dried jamon seed potentiated insulin 2 and 5 fold when extracted with water and 0.1N NH OH respectively. 4 Insulin potentiating activity was found in the dried seed of bitter ground but not in the fresh and dried flesh portion. Chaunga did not show any insulin potentiating activity. The water extract of fenugreek showed some activity. Black tea potentiated 5.2 fold insulin function in glucose metabolism and this activity was reduced to 3.7 fold with decaffeinating of tea. Green tea potentiated insulin 2 fold in glucose metabolism. Addition of milk to tea inhibited the insulin potentiating function of tea. Both the homeopathic drugs did not show any insulin potentiating activity. The result indicated that both flesh and seed of dried jamon fruit and tea had very good insulin potentiating function. In the light of these data, based on the vitro model of insulin function, the diabetic patients are advised to use both the flesh and seed of jamon fruit and tea without milk and sugar for their diabetic control.

Role of Diet, Nutrients, Spices and Natural Products in Diabetes Mellitus

Diabetes mellitus is a global disease, prevails all over the world, though the prevalence rate differs from country to country. Diabetes, a disorder of carbohydrate metabolism, is characterized by high blood glucose level and glycosuria resulting from dysfunction of pancreatic beta cells and insulin resistance. In advance stages of diabetes, metabolism of protein and lipid is also altered. Many factors like heredity, age, obesity, diet, sex, sedentary life style, socio economic status, hypertension and various stresses are involved in the etiology of diabetes mellitus. Drug, diet and recently spices therapies are the major approaches used for treatment and control of diabetes mellitus. In drug therapy, hypoglycemic medicines and insulin are used. In diet therapy, diet composition, amount, distribution and time of food intake are important factors. The diet must be acceptable, must supply adequate amount of nutrients, and be formulated in a way to normalize body weight. The diet for diabetic children should have sufficient calories for adequate nutrition, normal weight gain and growth. The diet should be high in complex carbohydrate, low in simple carbohydrate, low in fat and high in mono-unsaturated fatty acid. High fiber diets are beneficial for treatment of diabetes. Soluble fibers are more effective than insoluble fibers. Chromium is important for diabetes and functions in carbohydrate and lipid metabolism primarily via its role in potentiating insulin action in carbohydrate metabolism. In the spices therapy, cinnamon, cloves, bay leaves and turmeric have an insulin potentiating activity and are beneficial for diabetic individuals. Cinnamon is effective in reducing glucose level in type 2 diabetic individuals. The effective ingredient in cinnamon for hypoglycemic function has been identified as methyl hydroxy chalcone polymers. Other plant products have also hypoglycemic activities and may have beneficial role in treatment of diabetes mellitus. Cinnamon should be a part of diabetic diets for its hypoglycemic effect in diabetic individuals.

Tea enhances insulin activity.

The most widely known health benefits of tea relate to the polyphenols as the principal active ingredients in protection against oxidative damage and in antibacterial, antiviral, anticarcinogenic, and antimutagenic activities, but polyphenols in tea may also increase insulin activity. The objective of this study was to determine the insulin-enhancing properties of tea and its components. Tea, as normally consumed, was shown to increase insulin activity >15-fold in vitro in an epididymal fat cell assay. Black, green, and oolong teas but not herbal teas, which are not teas in the traditional sense because they do not contain leaves of Camellia senensis, were all shown to increase insulin activity. High-performance liquid chromatography fractionation of tea extracts utilizing a Waters SymmetryPrep C18 column showed that the majority of the insulin-potentiating activity for green and oolong teas was due to epigallocatechin gallate. For black tea, the activity was present in several regions of the chromatogram corresponding to, in addition to epigallocatechin gallate, tannins, theaflavins, and other undefined compounds. Several known compounds found in tea were shown to enhance insulin with the greatest activity due to epigallocatechin gallate followed by epicatechin gallate, tannins, and theaflavins. Caffeine, catechin, and epicatechin displayed insignificant insulin-enhancing activities. Addition of lemon to the tea did not affect the insulin-potentiating activity. Addition of 5 g of 2% milk per cup decreased the insulin-potentiating activity one-third, and addition of 50 g of milk per cup decreased the insulin-potentiating activity approximately 90%. Nondairy creamers and soy milk also decreased the insulin-enhancing activity. These data demonstrate that tea contains in vitro insulin-enhancing activity and the predominant active ingredient is epigallocatechin gallate.

Role of glucose in chronic desensitization of isolated rat islets and mouse insulinoma (betaTC-3) cells to glucose-dependent insulinotropic polypeptide.

It is well documented that the release of insulin from isolated perifused islets attenuates over time, despite a continued glucose stimulation. In the current study we have shown that potentiation of insulin release by the intestinal hormone glucose-dependent insulinotropic polypeptide (GIP) is also attenuated after its continuous application. In less than 20 h of maintained stimulus with either hyperglycaemia (11.0 mM glucose) or GIP (10 nM) under hyperglycaemic conditions, insulin release returned to basal values. This was not due to loss of islet viability or reduction in the releasable pool of insulin granules, as 1 mM isobutylmethylxanthine was able to stimulate equivalent insulin release under both conditions. Further examination of chronic GIP desensitization was examined in cultured mouse insulinoma (betaTC-3) cells. GIP-stimulated cAMP production was not greatly affected by the prevailing glucose conditions, suggesting that the glucose dependence of GIP-stimulated insulin release occurs distally to the increase in intracellular cAMP in betaTC-3 cells. The GIP-stimulated cAMP response curve after desensitization was of similar magnitude at all glucose concentrations, but GIP pretreatment did not affect forskolin-stimulated cAMP production. Desensitization of the cAMP response in betaTC-3 cells was shown not to involve induction of dipeptidyl peptidase IV or pertussis toxin-sensitive G-proteins, activation of protein kinase C or protein kinase A, or modulation of phosphodiesterase activity. Homologous desensitization of the insulin-potentiating activity of GIP was found to affect both GIP-stimulated and forskolin-stimulated insulin release, indicating desensitization of distal steps in the stimulus-exocytosis cascade.

Glucose tolerance factor potentiation of insulin action in adipocytes from rats raised on a torula yeast diet cannot be attributed to a deficiency of chromium or glucose tolerance factor activity in the diet.

The nature of the dietary component responsible for adipocytes having the ability to respond to Glucose Tolerance Factor (GTF) was investigated. Rats were raised on either a control diet or one of three diets differing only in the protein source (torula yeast, brewer's yeast, or casein). Only in adipocytes from rats fed the torula yeast diet did a GTF fraction prepared from brewer's yeast potentiate the action of suboptimal concentrations of insulin in the incorporation of label from D-[1-14C]-glucose and D-[U-14C]-glucose into CO2 and fatty acids. It was concluded that this potentiation was not the result of a deficiency of GTF activity in torula yeast, because a GTF fraction prepared from torula yeast had similar insulin potentiating activity. Differences in response among diets were not owing to differences in levels of amino acids or owing to concentrations of 22 (Al, As, B, Ca, Cd, Co, Cr, Cu, Fe, K, Mg, Mo, Na, Ni, P, Pb S, Se, Si, Sn, Sr, Zn) of the 23 trace elements investigated. The level of Mn was low in all diets, but particularly low in the torula yeast diet. Mn deficiencies have previously been implicated in perturbations of glucose metabolism, so that it is possible that this deficiency may be responsible for the effects attributed to the torula yeast diet.

Insulin potentiating factor and chromium content of selected foods and spices

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.

Synthesis of a new protected lactam-bridged dipeptide

A method has been developed for the synthesis of a new protected γ-lactam-bridged dipeptide. This R,S lactam has been prepared in good yield and incorporated into a peptide which is analogous to hGH (7–13) using standard solid phase peptide synthesis methodolgy. The peptide showed insulin-potentiating activity of the same order as those containing an imide in place of the lactam.

Insulin-like activity of chromium-binding fractions from brewer's yeast

51CrCl 3 was added to the incubation medium of Saccharomyces cerevisiae for up to 48 hr. After repeated freezing and thawing, lysing in 9 M urea with 1% NP-40 detergent, and dialysis against water, the lower molecular weight (Mr < 3500) dialysate was retained on a SE53 cationic exchange column, eluted with 0.25 M NH 4OH and fractionated on a Bio-gel P-2 column. The insulinlike biological activity of the fractions was measured by the 14C-glucose oxidation in isolated rat adipocytes. The biological activity that was found in two of nine fractions did not correspond to their chromium content. Moreover, identical findings were obtained when chromium was added not to the live yeast but to the yeast extract, which showed that its binding was a chemical process not requiring cellular activity. No fraction demonstrated insulin-potentiating activity on rat adipocytes.

Insulin-potentiating action of human growth hormone. Synthesis and activity of N-terminal fragments.

Four peptides from the N-terminal region of human growth hormone have been synthesized by the solid-phase method: hGH(6-13), hGH(7-13), hGH(8-13) and hGH(9-13). Although these peptides contain the sensitive -Asp-Asn-sequence, apparently homogeneous products were obtained by synthesis on polystyrene resin, cleavage by hydrogen fluoride and purification by ion-exchange chromatography. The insulin-potentiating activity of these peptides is reported. The data indicates that extension of hGH(9-13) at its N-terminus is required for in vitro activity.

An improved assay for biologically active chromium.

Biologically active forms of chromium were measured by determining their insulin potentiation on glucose oxidation by isolated fat cells. Adipocytes were isolated from the epididymal fat tissue of rats maintained on a Cr deficient diet. All natural and synthetic Cr compounds tested that yield real biological activity in previous assay systems were active in the assay. Biologically active organic Cr complexes potentiated the action of insulin more than 300% in this bioassay but inorganic Cr complexes yielded little insulin potentiating activity. Nicotinic acid, which interferes in the assay with fat tissue (Roginski, 1974) gave only a slight positive response in the fat cell assay. Cells isolated from two rats can be used for approximately 150 assays and large numbers of control samples are not needed because individual animal variation within an assay is virtually eliminated. This assay is more sensitive and more reproducible and can be used routinely for more samples than any of the previous assay techniques for biologically active chromium. 19 references, 2 figures.