Comparative assessment of metal-specific adipogenic activity in zinc and vanadium-citrates through associated gene expression.

Diabetes mellitus comprises a group of metabolic abnormalities due to insulin deficiency and/or resistance. Obesity contributes to diabetes, with a strong causal relationship existing between diabetes and insulin resistance, especially in patients with Diabetes mellitus II. Adipocytes emerge as key constituents of adipose tissue physiology. In their pre-mature form to mature state transformation, adipocytes fully exemplify one of the key adipogenic actions of insulin. Poised to a) gain insight into adipogenesis leading to antidiabetic factors, and b) investigate adipogenesis through careful examination of insulin contributions to interwoven mechanistic pathways, a systematic comparative study was launched involving well-defined metal-citrates (zinc and vanadium), the chemical reactivity of which was in line with their chemistry under physiological conditions. Selection of the specific compounds was based on their common aqueous coordination chemistry involving the physiological chelator citric acid. Cellular maturation of pre-adipocytes to their mature form was pursued in the presence-absence of insulin and employment of closely linked genetic targets, key to adipocyte maturation (Peroxisome proliferator-activated receptor gamma (PPAR-γ), Glucose transporter 1,3,4 (GLUT 1,3,4), Adiponectin (ADIPOQ), Glucokinase (GCK), and Insulin receptor (INS-R)). The results show a) distinct adipogenic biological profiles for the metalloforms involved in a dose-, time- and nature-dependent manner, and b) metal ion-specific adipogenic response-signals at the same or higher level than insulin toward all selected targets. Collectively, the foundations have been established for future exploitation of the distinct metal-specific adipogenic factors contributing to the functional maturation of adipose tissue and their use toward hyperglycemic control in Diabetes mellitus.

Synthetic investigation of binary-ternary Cr(III)-hydroxycarboxylic acid-aromatic chelator systems. Structure-specific influence on adipogenic biomarkers linked to insulin mimesis.

In an attempt to understand the aqueous interactions of Cr(III) with low-molecular mass physiological ligands and examine its role as an adipogenic metallodrug agent in Diabetes mellitus II, the pH-specific synthesis in the binary-ternary Cr(III)-(HA = hydroxycarboxylic acid)-(N,N)-aromatic chelator (AC) (HA = 2-hydroxyethyl iminodiacetic acid/heidaH2, quinic acid; AC = 1,10-phenanthroline/phen) systems was pursued, leading to four new crystalline compounds. All materials were characterized by elemental analysis, UV-Visible, FT-IR, and ESI-MS spectroscopy, cyclic voltammetry, and X-Ray crystallography. Concurrently, the aqueous speciation of the binary Cr(III)-(2-hydroxyethyl iminodiacetic acid) system, complemented by ESI-MS, provided key-details of the species in solution correlating with the solid-state species. The structurally distinct Cr(III) soluble species were subsequently used in an in vitro investigation of their cytotoxic activity in 3T3-L1 fibroblast cultures. Compound 1 exhibited solubility, bioavailability, and atoxicity over a wide concentration range (0.1-100 µΜ) in contrast to 3, which was toxic. The adipogenic potential of 1 was subsequently investigated toward transformation of pre-adipocytes into mature adipocytes. Confirmation of that capacity relied on molecular biological techniques a) involving genes (glucose transporter type 4, peroxisome proliferator-activated receptor gamma, glucokinase, and adiponectin) serving as sensors of the transformation process, b) comparing the Cr(III)-adipogenicity potential to that of insulin, and c) exemplifying the ultimate maturity of adipocytes poised to catabolize glucose. The collective effort points out salient structural features in the coordination sphere of Cr(III) inducing adipogenic transformation relevant to combating hyperglycemia. The multiply targeted mechanistic insight into such a process exemplifies the role of well-defined Cr(III) complex forms as potential insulin-mimetic adipogenic agents in Diabetes mellitus II.

The adipogenic potential of Cr(III). A molecular approach exemplifying metal-induced enhancement of insulin mimesis in diabetes mellitus II.

Insulin resistance is identified through numerous pathophysiological conditions, such as Diabetes mellitus II, obesity, hypertension and other metabolic syndromes. Enhancement of insulin action and\or its complete replacement by insulin-enhancing or insulin-mimetic agents seems to improve treatment of metabolic diseases. Over the last decades, intensive research has targeted the investigation of such agents, with chromium emerging as an important inorganic cofactor involved in the requisite metabolic chemistry. Chromium in its trivalent state has been shown to play a central role in carbohydrate metabolism by enhancing insulin signaling, action, and thus the sensitivity of insulin-sensitive tissues. A very likely link between diabetes and obesity is the adipose tissue, which stores energy in the form of triglycerides and releases free fatty acids. To date, there is paucity of information on the exact mechanism of the chromium effect concerning insulin-activated molecular paths, such as adipogenesis. The aim of the present study is to delve into such an effect by employing a well-defined form of chromium (Cr(III)-citrate) on the a) survival of pre- and mature adipocytes (3T3-L1), b) endogenous cell motility, and c) insulin-enhancing adipogenic capacity. The emerging results suggest that Cr(III)-citrate a) is (a)toxic in a concentration- and time-dependent manner, b) has no influence on cell motility, c) can induce 3T3-L1 pre-adipocyte differentiation into mature adipocytes through elevation of tissue specific biomarker levels (PPAR-γ, GLUT 4 and GCK), and d) exemplifies structurally-based metal-induced adipogenesis as a key process contributing to the development of future antidiabetic metallodrugs.