Small molecule glucokinase activators as novel anti-diabetic agents

2005 ◽  
Vol 33 (2) ◽  
pp. 371-374 ◽  
Author(s):  
B. Leighton ◽  
A. Atkinson ◽  
M.P. Coghlan
Keyword(s):  
Diabetes Mellitus ◽  
Insulin Secretion ◽  
Blood Glucose ◽  
Type Ii Diabetes Mellitus ◽  
Glucose Sensing ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Glucokinase Activators

The monomeric enzyme GK (glucokinase) has a low affinity for glucose and, quantitatively, is largely expressed in the liver and pancreatic β-cells, playing a key ‘glucose sensing’ role to regulate hepatic glucose balance and insulin secretion. Mutations of GK in man can be inactivating, to cause a form of diabetes mellitus, or activating, to lower blood glucose levels. Recently, models of GK protein structure have helped to elucidate the role of inactivating and activating mutations, with the latter revealing an allosteric binding site, possibly for an unknown physiological activator. However, this discovery was pre-dated by Drug Discovery projects that have identified small organic molecules that activate pancreatic and liver GK enzyme activity. These compounds stimulate insulin secretion in islets and glucose metabolism in hepatocytes. The profile of these GK activators, both in vitro and in vivo and the potential role that GK activators play in lowering blood glucose levels in Type II diabetes mellitus will be discussed.

scholarly journals Oral DhHP-6 for the Treatment of Type 2 Diabetes Mellitus

2019 ◽  
Vol 20 (6) ◽  
pp. 1517 ◽  
Author(s):  
Kai Wang ◽  
Yu Su ◽  
Yuting Liang ◽  
Yanhui Song ◽  
Liping Wang
Keyword(s):  
Diabetes Mellitus ◽  
Type 2 Diabetes ◽  
Type 2 Diabetes Mellitus ◽  
Blood Glucose ◽  
Enzymatic Activity ◽  
Glucose Levels ◽  
Blood Glucose Levels

Type 2 diabetes mellitus (T2DM) is associated with pancreatic β-cell dysfunction which can be induced by oxidative stress. Deuterohemin-βAla-His-Thr-Val-Glu-Lys (DhHP-6) is a microperoxidase mimetic that can scavenge reactive oxygen species (ROS) in vivo. In our previous studies, we demonstrated an increased stability of linear peptides upon their covalent attachment to porphyrins. In this study, we assessed the utility of DhHP-6 as an oral anti-diabetic drug in vitro and in vivo. DhHP-6 showed high resistance to proteolytic degradation in vitro and in vivo. The degraded DhHP-6 product in gastrointestinal (GI) fluid retained the enzymatic activity of DhHP-6, but displayed a higher permeability coefficient. DhHP-6 protected against the cell damage induced by H2O2 and promoted insulin secretion in INS-1 cells. In the T2DM model, DhHP-6 reduced blood glucose levels and facilitated the recovery of blood lipid disorders. DhHP-6 also mitigated both insulin resistance and glucose tolerance. Most importantly, DhHP-6 promoted the recovery of damaged pancreas islets. These findings suggest that DhHP-6 in physiological environments has high stability against enzymatic degradation and maintains enzymatic activity. As DhHP-6 lowered the fasting blood glucose levels of T2DM mice, it thus represents a promising candidate for oral administration and clinical therapy.

scholarly journals Inhibitory effect of somatostatin on insulin secretion is not mediated via the CNS

2015 ◽  
Vol 225 (1) ◽  
pp. 19-26 ◽  
Author(s):  
Astrid C Hauge-Evans ◽  
James Bowe ◽  
Zara J Franklin ◽  
Zoheb Hassan ◽  
Peter M Jones
Keyword(s):  
Insulin Secretion ◽  
Blood Glucose ◽  
Pancreatic Beta Cells ◽  
Plasma Insulin ◽  
Inhibitory Effect ◽  
Isolated Islets ◽  
Glucose Levels ◽  
Blood Glucose Levels

The inhibitory effect of somatostatin (SST) on insulin secretionin vivois attributed to a direct effect on pancreatic beta cells, but this is inconsistent with somein vitroresults in which exogenous SST is ineffective in inhibiting secretion from isolated islets. We therefore investigated whether insulin secretion from the pancreatic islets may partly be regulated by an indirect effect of SST mediated via the CNS. Islet hormone secretion was assessedin vitroby perifusion and static incubations of isolated islets andin vivoby i.v. or i.c.v. administration of the SST analogue BIM23014C with an i.v. glucose challenge to conscious, chronically catheterised rats. Hormone content of samples was assessed by ELISA or RIA and blood glucose levels using a glucose meter. Exogenous SST14/SST28 or BIM23014C did not inhibit the release of insulin from isolated rodent isletsin vitro, whereas peripheral i.v. administration of BIM23014C (7.5 μg) with glucose (1 g/kg) led to decreased plasma insulin content (2.3±0.5 ng insulin/ml versus 4.5±0.5 ng/ml att=5 min,P<0.001) and elevated blood glucose levels compared with those of the controls (29.19±1.3 mmol/l versus 23.5±1.7 mmol/l,P<0.05). In contrast, central i.c.v. injection of BIM23014C (0.75 μg) had no significant effect on either plasma insulin (3.3±0.4 ng/ml,P>0.05) or blood glucose levels (23.5±1.7 mmol/l,P>0.05) although i.v. administration of this dose increased blood glucose concentrations (32.3±0.7 mmol/l,P<0.01). BIM23014C did not measurably alter plasma glucagon, SST, GLP1 or catecholamine levels whether injected i.v. or i.c.v. These results indicate that SST does not suppress insulin secretion by a centrally mediated effect but acts peripherally on islet cells.

scholarly journals Glycemic Variability in Diabetes Increases the Severity of Influenza

mBio ◽  
2020 ◽  
Vol 11 (2) ◽  
Author(s):  
Rebecca J. Marshall ◽  
Pornthida Armart ◽  
Katina D. Hulme ◽  
Keng Yih Chew ◽  
Alexandra C. Brown ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Glycemic Variability ◽  
Endothelial Barrier ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Severe Influenza ◽  
Increased Risk ◽  
History Of

ABSTRACT People with diabetes are two times more likely to die from influenza than people with no underlying medical condition. The mechanisms underlying this susceptibility are poorly understood. In healthy individuals, small and short-lived postprandial peaks in blood glucose levels occur. In diabetes mellitus, these fluctuations become greater and more frequent. This glycemic variability is associated with oxidative stress and hyperinflammation. However, the contribution of glycemic variability to the pathogenesis of influenza A virus (IAV) has not been explored. Here, we used an in vitro model of the pulmonary epithelial-endothelial barrier and novel murine models to investigate the role of glycemic variability in influenza severity. In vitro, a history of glycemic variability significantly increased influenza-driven cell death and destruction of the epithelial-endothelial barrier. In vivo, influenza virus-infected mice with a history of glycemic variability lost significantly more body weight than mice with constant blood glucose levels. This increased disease severity was associated with markers of oxidative stress and hyperinflammation both in vitro and in vivo. Together, these results provide the first indication that glycemic variability may help drive the increased risk of severe influenza in people with diabetes mellitus. IMPORTANCE Every winter, people with diabetes are at increased risk of severe influenza. At present, the mechanisms that cause this increased susceptibility are unclear. Here, we show that the fluctuations in blood glucose levels common in people with diabetes are associated with severe influenza. These data suggest that glycemic stability could become a greater clinical priority for patients with diabetes during outbreaks of influenza.

In vitro and in vivo anti-diabetic activity of Citrullus colocynthis pulpy flesh with seeds hydro-ethanolic extract

2020 ◽  
Vol 17 (2) ◽  
Author(s):  
Aymen Owais Ghauri ◽  
Saeed Ahmad ◽  
Tayyeba Rehman
Keyword(s):  
Blood Glucose ◽  
Normal Control ◽  
Ethanolic Extract ◽  
Negative Control ◽  
Antioxidant Potential ◽  
Blood Glucose Monitoring ◽  
Glucose Levels ◽  
Blood Glucose Levels

AbstractBackgroundDiabetes is the one of the leading cause of morbidity and mortality. Traditionally phytotherapy is widely being used for diabetes treatment and highly valued. Citrus colocynthis has known anti-diabetic potential. However, anti-diabetic potential of hydro-ethanolic extract of C. colocynthis pulpy flesh with seeds is not reported yet.MethodsThe extract of C. colocynthis pulpy flesh with seeds was done by maceration method using 70% ethanol. To evaluate anti-diabetic and antioxidant potential of the seeded fruit in vitro, α-glucosidase and DPPH inhibition assays was done, respectively. In vivo study used streptozotocin (STZ) induced diabetes model of rats. Rats were randomized in five groups i. e. normal control, negative control, standard control, C. colocynthis 150 and 300 mg/kg. STZ was administered to all groups except normal control. After wards, plant extract and glibenclamide is continued for 14 days. Blood samples were collected from rat tail vein daily and from Cardiac puncture at the end of study. The blood glucose levels were monitored daily by using one-touch blood glucose monitoring system. The blood glucose level was monitored on 0, 1st, 5th, 8th, 11th, and 14th day of induction.ResultsHydro-ethanolic extract of C. colocynthis pulpy flesh with seeds was able to decolorize DPPH and therefore possess antioxidant potential, continuous administration for 14 days showed a marked decrease in serum glucose levels (p 0.01) it is found to be somewhat less effective as glibenclamide (standard control) (p 0.001). A time-dependent decrease in blood glucose levels was observed (351.3 ± 4 to 258 m/kg).ConclusionHydro-ethanolic extract of C. colocynthis pulpy flesh with seeds lowered the serum triglyceride and cholesterol levels in diabetic rats significantly as compared to negative control. The hypoglycemic effect of hydro-ethanolic extract of C. colocynthis pulpy flesh with seeds is may be due to α-glucosidase inhibition potential.

Determination the limit of postprandial blood glucose increase and the metabolism of acetylated wheat starch on healthy mice

2019 ◽  
pp. 15-22
Author(s):  
Khoa Bao Chau Thai ◽  
Huu Tien Nguyen ◽  
Huu Dung Tran
Keyword(s):  
Blood Glucose ◽  
Wheat Starch ◽  
Postprandial Blood Glucose ◽  
Control Group ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Treatment Of Diabetes ◽  
Resistant Starches

Introduction: Nowadays, resistant starches are interested as a supplement food by effecting on the limit of postprandial blood glucose increase and supporting for the diabetes treatment. Recently, we have semisynthesized the acetylated wheat starch (AWS) oriented for supporting the treatment of diabetes mellitus, which is the RS4 formed by chemical structure modification. AWS has been proved itself to show strong resistance to amylase activity in-vitro as well as to be safety in-vivo. Materials and Methods: In this study, we continued to evaluate AWS’s ability to limit postprandial blood glucose increase and determined shortchain fatty acids (SCFAs) metabolized from AWS in the gastrointestinal tract of healthy mice by HPLC. Results: the mice fed AWS exhibited a very limited increase in blood glucose levels and remained stable for 2 hours after meals comparing with the control group (mice fed natural wheat starch) (NWS). Simultaneously, the content of SCFAs produced in the caecum of the mice fed AWS was significantly higher than mice fed NWS, especially with acetic and propionic acids by 28% and 26%, respectively. Conclusion: AWS has been shown to limit postprandial hyperglycemia in mice effectively through the resistance to amylase hydrolysis in the small intestine. When going into the caecum, it is fermented to form SCFAs that provide a part of the energy for the body’s activities and to avoid rotten fermentation causing digestive disorders, which are inherent restrictions of normal high cellulose and fiber food. Key words: acetylated wheat starch, natural wheat starch, SCFA, blood glucose

Comparative effects of phlorizin and phloretin on glucose transport in the cat kidney

1962 ◽  
Vol 203 (6) ◽  
pp. 975-979 ◽  
Author(s):  
Stephen S. Chan ◽  
William D. Lotspeich
Keyword(s):  
Blood Glucose ◽  
Glucose Transport ◽  
Renal Tubule ◽  
Tubular Reabsorption ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Dog Kidney ◽  
Glucose Carrier

The net tubular reabsorption of glucose (TG) was measured simultaneously in both kidneys of the cat before, during, and after the infusion of small amounts of phlorizin and phloretin at constant rates into one renal artery. Experiments were performed at endogenous and elevated blood glucose levels. The results show that phlorizin blocks glucose transport across the renal tubule at concentrations in renal blood and tissue in the range of 10–5 to 10–7 m. These estimates agree with those for dog kidney in vivo and hamster small intestine in vitro. In addition to this high affinity of phlorizin for the tubular glucose carrier, the experiments also reveal the easily dissociable nature of the phlorizin carrier complex. When blood glucose is elevated the TG is even more sensitive to small concentrations of phlorizin. At all blood glucose levels the aglucone, phloretin, is at least ten times less effective in inhibiting TG than phlorizin itself. These findings are discussed in relation to critical groupings in the phlorizin molecule.

scholarly journals Eurotium Cristatum Fermented Okara as a Potential Food Ingredient to Combat Diabetes

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Li Yan Chan ◽  
Masaki Takahashi ◽  
Pei Jean Lim ◽  
Shinya Aoyama ◽  
Saneyuki Makino ◽  
...  
Keyword(s):  
Blood Glucose ◽  
Postprandial Blood Glucose ◽  
Food Ingredient ◽  
Glucose Levels ◽  
Blood Glucose Levels ◽  
Reduce Blood Glucose ◽  
Good Nutrition ◽  
Physical Attributes

AbstractType 2 diabetes mellitus (T2DM) is a chronic disease, and dietary modification is a crucial part of disease management. Okara is a sustainable source of fibre-rich food. Most of the valorization research on okara focused more on the physical attributes instead of the possible health attributes. The fermentation of okara using microbes originated from food source, such as tea, sake, sufu and yoghurt, were explored here. The aim of this study is to investigate fermented okara as a functional food ingredient to reduce blood glucose levels. Fermented and non-fermented okara extracts were analyzed using the metabolomic approach with UHPLC-QTof-MSE. Statistical analysis demonstrated that the anthraquinones, emodin and physcion, served as potential markers and differentiated Eurotium cristatum fermented okara (ECO) over other choices of microbes. The in-vitro α-glucosidase activity assays and in-vivo mice studies showed that ECO can reduce postprandial blood glucose levels. A 20% ECO loading crispy snack prototype revealed a good nutrition composition and could serve as a fundamental formulation for future antidiabetes recipe development, strengthening the hypothesis that ECO can be used as a novel food ingredient for diabetic management.

scholarly journals Hypoglycemic Effects of Plant Flavonoids: A Review

2021 ◽  
Vol 2021 ◽  
pp. 1-12
Author(s):  
Foo Sok Yen ◽  
Chan Shu Qin ◽  
Sharryl Tan Shi Xuan ◽  
Puah Jia Ying ◽  
Hong Yi Le ◽  
...  
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Antioxidant Activities ◽  
Diabetic Rats ◽  
The Body ◽  
High Blood Glucose ◽  
Glucose Levels ◽  
Multiple Organs

Diabetes mellitus is a metabolic disorder with chronic high blood glucose levels, and it is associated with defects in insulin secretion, insulin resistance, or both. It is also a major public issue, affecting the world's population. This disease contributes to long-term health complications such as dysfunction and failure of multiple organs, including nerves, heart, blood vessels, kidneys, and eyes. Flavonoids are phenolic compounds found in nature and usually present as secondary metabolites in plants, vegetables, and fungi. Flavonoids possess many health benefits such as anti-inflammatory and antioxidant activities, and naturally occurring flavonoids contribute to antidiabetic effects.Many studies conducted in vivo and in vitro have proven the hypoglycemic effect of plant flavonoids. A large number of studies showed that flavonoids hold positive results in controlling the blood glucose level in streptozotocin (STZ)-induced diabetic rats and further prevent the complications of diabetes. The future development of flavonoid-based drugs is believed to provide significant effects on diabetes mellitus and diabetes complication diseases. This review aims at summarizing the various types of flavonoids that function as hyperglycemia regulators such as inhibitors of α-glucosidase and glucose cotransporters in the body. This review article discusses the hypoglycemic effects of selected plant flavonoids namely quercetin, kaempferol, rutin, naringenin, fisetin, and morin. Four search engines, PubMed, Google Scholar, Scopus, and SciFinder, are used to collect the data.

scholarly journals Controlled Type -II Diabetes Mellitus - No More Contra-Indication for Delayed Loading of Two Piece Dental Implants - A Case Report

2019 ◽  
Vol 7 (1) ◽  
pp. 1-4
Author(s):  
Alekhya Ayalapuram
Keyword(s):  
Diabetes Mellitus ◽  
Blood Glucose ◽  
Type Ii Diabetes ◽  
Survival Rates ◽  
Type Ii Diabetes Mellitus ◽  
Diabetic Patients ◽  
Type Ii ◽  
Obesity Prevalence ◽  
Glucose Levels ◽  
Blood Glucose Levels

With changing lifestyle and increasing obesity, prevalence of type -II Diabetes Mellitus is increasing in geriatric individuals, who are generally prone to tooth loss. As a result the demand for implants in these patients is also increasing and planning implants has been a challenge to present day dentists. Diabetes Mellitus causes impaired metabolism in general, especially bone metabolism resulting in impaired Osseointegration and poor wound healing. Growing demand of implants in Type II DM patients has initiated research towards implants survival rates. Extensive research till now states - poorly controlled diabetic patients have higher implant failure rates, where as Diabetic patients with controlled blood glucose levels respond to implants in similar way as healthy patients. The present article is one such trail to confirm that type II Diabetes Mellitus is no more contra-indication for Implants till Blood glucose levels are controlled to normal levels. Key words: Type-II Diabetes Mellitus; Two-piece implant; Delayed loading;

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