Evaluation of the Vasoprotective Effects of Metformin versus Glibenclamide in Type 2 Diabetic Patients

Adiponectin (APN) is an adipokine with anti-inflammatory and anti-atherogenic properties decreased in type 2 diabetes mellitus (T2DM) that may influence endothelial function by regulating serum nitric oxide (NO) levels. The current study aimed to investigate the effect of two oral hypoglycemic drugs, Metformin and Glibenclamide (GLC), on circulating APN and NO levels and to find a correlation between APN and NO levels in type 2 diabetic patients. Fifty males and females previously diagnosed with T2DM were conducted in this trial and classified into groups: Group A involved 18 untreated patients with T2DM, group B involved 16 patients receiving Metformin monotherapy (1000 mg/day) for up to 1 year and group C involved 16 patients receiving GLC (5 mg/day) for up to 1 year. Circulating APN and NO were measured. Compared to GLC, Metformin therapy showed a significant increase in APN and NO levels in type 2 diabetic patients. Our findings established that Metformin has a protective effect on endothelial function, including increased APN and NO bioavailability, beyond its glucose-lowering effect.

Investigation of possible underlying mechanisms behind water-induced glucose reduction in adults with high copeptin

Elevated copeptin, a surrogate marker of vasopressin, is linked to low water intake and increased diabetes risk. Water supplementation in habitual low-drinkers with high copeptin significantly lowers both fasting plasma (fp) copeptin and glucose. This study aims at investigating possible underlying mechanisms. Thirty-one healthy adults with high copeptin (> 10.7 pmol·L−1 (men), > 6.1 pmol−1 (women)) and 24-h urine volume of < 1.5L and osmolality of > 600 mOsm·kg−1 were included. The intervention consisted of addition of 1.5 L water daily for 6 weeks. Fp-adrenocorticotropic hormone (ACTH), fp-cortisol, 24-h urine cortisol, fasting and 2 h (post oral glucose) insulin and glucagon were not significantly affected by the water intervention. However, decreased (Δ baseline-6 weeks) fp-copeptin was significantly associated with Δfp-ACTH (r = 0.76, p < 0.001) and Δfp-glucagon (r = 0.39, p = 0.03), respectively. When dividing our participants according to baseline copeptin, median fp-ACTH was reduced from 13.0 (interquartile range 9.2–34.5) to 7.7 (5.3–9.9) pmol L−1, p = 0.007 in the top tertile of copeptin, while no reduction was observed in the other tertiles. The glucose lowering effect from water may partly be attributable to decreased activity in the hypothalamic–pituitary–adrenal axis.ClinicalTrials.gov: NCT03574688.

Therapeutic Efficacy of Ficus Glomerata Leaves in Alloxan Monohydrate Induced Type-1 Diabetes in Albino Rats

Present study was aimed to evaluate the anti-diabetic efficacy of Ficus glomerata in Alloxan monohydrate induced albino rats. Oral administration of fresh Ficus glomerataleaves (2 - 4 g/day) for 60 days shows significant blood glucose lowering effect in experimental alloxan induced diabetic rats. These diabetic rats blood glucose level became normal when fed with Ficus glomerata leaves. It is amply revealed that fresh Ficus glomerata indica leaves possessed anti-diabetic properties. The results suggest that statistically significant anti-diabetic potential in alloxan monohydrate induced diabetic rats. The Ficus glomerata leaves to be almost similar effect like insulin treatment in alloxan monohydrate administered animal model. From the present investigation it appeared that Ficus glomerata leaves might have some ingredients to increase the output of insulin by binding to the receptors of the Beta cells of the Langerhans located in the pancreas. Once they bind to the Sulphonyl urea receptors, the K+ -ATP channels are probably closed and therefore the membrane is depolarized and insulin production is stimulated.

In vivo antihyperglycaemic activity of crude and partitioned fractions of selected medicinal plants

The incidence of diabetes mellitus is skyrocketing in sub-Saharan Africa and the world at large, with about 8.8% of the adult population currently affected and projected to rise to 9.9% by the year 2045. The currently used drugs are beset with serious side effects, reduced efficacy due to prolonged use and high cost. This study therefore aimed at exploring the use of medicinal plants for the development of cheaper and more effective herbal remedies/plant-derived anti-diabetic drugs. Ethanol extracts of the leaves of three (3) medicinal plants – Bauhinia reticulata (BR), Cassytha filiformis (CF) and Daniella olieveri (DO) were subjected to in vivo anti-hyperglycaemic screening. The BR and CF crude extracts were partitioned because of their promising antihyperglycaemic potentials, using solvents of varying polarities. The partitioned fractions were thereafter evaluated for anti-hyperglycaemic activity. 100 and 200 mg/dL b.w. were the doses of extracts and fractions administered to the experimental animals. Crude ethanol extract of BR had the highest antihyperglycemic activity, as it lowered blood glucose level of experimental mice from 219.80±22.94 mg/dL to 105.40±10.87 mg/dL with percentage blood glucose lowering effect of 52.05±0.53 %, which was higher than that recorded by the standard drug-Metformin (50.88±0.86 %) at dose of 200 mg/kg b.w. There was no significant difference (p>0.05) in the percentage glucose lowering effect of the ethyl acetate and n-hexane partitioned fractions of BR (55.91±0.20 and 55.80±0.68 % respectively), although, the standard drug had a higher percentage glucose lowering effect (65.92±0.87 %) at dose of 200 mg/kg b.w. Further purification of the fractions could yield active compound(s) which could serve as leads in the development of novel anti-diabetic drugs

Metformin Targets Foxo1 to Control Glucose Homeostasis

Metformin is the first-line pharmacotherapy for type 2 diabetes mellitus (T2D). Metformin exerts its glucose-lowering effect primarily through decreasing hepatic glucose production (HGP). However, the precise molecular mechanisms of metformin remain unclear due to supra-pharmacological concentration of metformin used in the study. Here, we investigated the role of Foxo1 in metformin action in control of glucose homeostasis and its mechanism via the transcription factor Foxo1 in mice, as well as the clinical relevance with co-treatment of aspirin. We showed that metformin inhibits HGP and blood glucose in a Foxo1-dependent manner. Furthermore, we identified that metformin suppresses glucagon-induced HGP through inhibiting the PKA→Foxo1 signaling pathway. In both cells and mice, Foxo1-S273D or A mutation abolished the suppressive effect of metformin on glucagon or fasting-induced HGP. We further showed that metformin attenuates PKA activity, decreases Foxo1-S273 phosphorylation, and improves glucose homeostasis in diet-induced obese mice. We also provided evidence that salicylate suppresses HGP and blood glucose through the PKA→Foxo1 signaling pathway, but it has no further additive improvement with metformin in control of glucose homeostasis. Our study demonstrates that metformin inhibits HGP through PKA-regulated transcription factor Foxo1 and its S273 phosphorylation.

GP73 is a glucogenic hormone that contributes to SARS-CoV-2-induced hyperglycemia

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection induces new-onset diabetes and severe metabolic complications of pre-existing diabetes. The pathogenic mechanism underlying this is incompletely understood. Here, we provided evidence linking circulating GP73 with the exaggerated gluconeogenesis triggered by SARS-CoV-2 infection. We found that SARS-CoV-2 infection or glucotoxic conditions increased GP73 production and secretion. Secreted GP73 then trafficked to the liver and kidney to stimulate gluconeogenesis through the cAMP/PKA pathway. By using global phosphoproteomics, we found a drastic remodeling of the PKA kinase hub exerted by GP73. Notably, plasma GP73 levels were elevated and positively correlated with blood glucose in patients with COVID19 and diabetes. Neutralization of circulating GP73 in serum of individuals infected with SARS-CoV-2 or with diabetes reduced excessive gluconeogenesis in cultured hepatocytes, and lowered blood glucose levels in animal models of diabetes. Ablation of GP73 from whole animals has a profound glucose-lowering effect secondary to reduced gluconeogenesis. Thus, GP73 is a key glucogenic hormone contributing to SARS-CoV-2-induced glucose abnormality.