Summary of recent progress in the field of diabetes research (01.31)

Summary of recent progress in the field of diabetes research (01.31)

January 31, 2018 Source: WuXi PharmaTech

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1. Researchers discover new potential therapeutic targets for diabetes

Hepatic glucose uptake (HGU) accounts for one-third of food-source glucose intake. An increase in postprandial blood glucose levels caused by damaged HGU is called postprandial hyperglycemia. Postprandial hyperglycemia is often observed in obese and type 2 diabetic patients, which is closely associated with higher cardiovascular complications and risk of death in these patients. Although the exact mechanism of HGU injury is unclear, there is evidence that it is associated with hepatic glucokinase and glucokinase regulatory protein (GKRP) dysfunction. Recently, a research team led by Professor Hiroshi Inoue of Kanazawa University and a collaborator of the National Centre for Global Health and Medicine in Tokyo found that sirtuin enzyme (Sirt2) is the key. It regulates hepatic glucokinase by modifying GKRP. The paper was published in Nature, a subsidiary of Nature Communications.

Previous studies have shown that nicotinamide adenine dinucleotide (NAD+), a coenzyme, regulates glucose metabolism. In this study, the researchers used an in vitro knockdown assay to identify Sirt2, an enzyme that is dependent on NAD+ and mediates HGU damage. However, Sirt2 does not affect the gene expression levels of glucokinase and glucose-6-phosphatase, suggesting that Sirt2 affects HGU through a mechanism of post-translational modification.

In normal cells, glucokinase binds to GKRP under low glucose conditions and dissociates after elevated glucose levels. However, in cells of diabetic mice, dissociation does not occur even at high glucose concentrations. The researchers found that overexpression of Sirt2 reverses this phenomenon, and Sirt2 binds directly to GKRP and deacetylates it in a NAD+-dependent manner to regulate the dissociation process. In a mouse experiment, the researchers found that GKRP, which is not acetylated, interferes with HGU, suggesting that acetylation of GKRP has a role in HGU and maintaining normal glucose levels. In addition, the researchers found that a decrease in NAD+-dependent Sirt2 activity, as well as a dysregulation of the GKRP deacetylation process by Sirt2, contributed at least in part to the HGU deficiency observed in obese diabetic mice.

These results indicate that NAD+ and Sirt2 regulate HGU, and Sirt2 regulates the deacetylation of GKRP. This regulatory process has the potential to become a new therapeutic target for type 2 diabetes and obesity.

2. Clinical trials of new insulin preparations released top line results

Adocia Biopharmaceuticals has announced a top-of-the-line trial of Phase 1b clinical trials to evaluate the dose of BioChaperone® Combo 75/25 (hereafter referred to as BioChaperone) when administered in 3 patients with type 2 diabetes. The relationship with the drug response.

BioChaperone is a proprietary formulation of a blend of basic insulin glargine (active ingredient is Santofi's Lantus® and Lilly's Basaglar®) and dietary insulin lispro (the active ingredient is Eli Lilly's Humalog® and Sanofi's Admelog®) . BioChaperone technology dissolves insulin glargine at neutral pH, making it compatible with fast-acting insulin analogs.

This study was designed to document the exposure dose relationship of BioChaperone in patients with type 2 diabetes. In a double-blind, randomized, four-stage crossover trial, 32 patients with type 2 diabetes were randomly assigned to receive either BioCaterone (0.6 U/kg, 0.8 U/kg, or 1.0 U/kg) in three doses, or The second dose of Humalog® Mix25TM (0.8 U/kg). The primary endpoint of the trial was the assessment of the ratio of total insulin exposure to the highest total plasma insulin concentration observed in the three doses of the BioChaperone group. The trial achieved two primary endpoints, and all pharmacokinetic parameters confirmed the dose proportional relationship at the early, intermediate, and baseline stages. Secondary endpoints included a dose-response relationship for total metabolic effects (glucose infusion rate: GIR) and a comparison of pharmacodynamics and pharmacokinetic profiles of BioChaperone (0.8 U/kg) with Humalog Mix 25TM (0.8 U/kg). All treatments were well tolerated, no new or unexpected safety results were reported, and no local reactions requiring treatment occurred at the site of application.

▲ Dr. Gérard Soula, CEO and Chairman of Adocia (Source: Adocia's official website)

“These strong clinical results validate the potential of BioChaperone® Combo75/25 for premixed insulin and the ability to compete with Ryzodeg®, the only approved insulin combination currently available,” Adocia Chief Executive Officer Dr. Gérard Soula, Chairman and Chairman of the Board of Directors, commented: “Premixed insulin is the main insulin treatment in many high-growth diabetes markets. For example, in China, premixed insulin accounts for about 65% of total insulin. We are exploring BioChaperone® Combo 75/25 has the opportunity to work with pharmaceutical companies to work together to provide the market with simple but first-rate, affordable drugs."

3. No blood collection! New biosensor monitors trace glucose in body fluids

In order to provide continuous blood glucose monitoring to diabetic patients, monitoring blood glucose levels through tears or sweat may be preferable to existing methods of blood glucose measurement. Recently, researchers reported in the journal ACS Nano a flexible ultra-thin sensor that can be attached to a contact lens or on the back of a watch to provide real-time blood glucose tracking monitoring.

Wearable sensors are part of an increasingly digital world, but commercially available sensors typically measure only basic parameters such as daily steps or heart rate, and measuring molecular levels of health markers can be challenging. For diabetic patients, measuring blood glucose is usually done by analyzing blood samples. However, the pain of blood drawn or blood drawn by the hand pointer can prevent people from continuously monitoring diabetes. The wearable glucose sensor was born to address this medical need, but its development has been hampered by a number of factors: some devices cannot detect low levels of glucose in sweat or tears, and some devices do not work properly when bent. These problems were solved by researchers such as Dr. Moh Amer and Professor Chongwu Zhou in Los Angeles, California: researchers used indium oxide nanoribbons, enzyme glucose oxidase, and chitosan. Film) and single-walled carbon nanotubes construct a biosensor. When glucose is present in the test sample, glucose interacts with the enzyme, initiating a cascade reaction that ultimately produces an electrical signal. Tests have shown that the device can detect glucose in the range of 10 nanomolar to 1 millimolar with a sensitivity sufficient to cover the range of glucose levels typical of sweat, saliva and tears in diabetic patients. In addition, the researchers have bent this sensor hundreds of times, and this treatment has not significantly affected the performance of the sensor, showing the great potential that can be applied to wearable devices. In addition to continuous glucose monitoring, the researchers also recommend that the sensor be used for monitoring in the food and environmental sectors.

4. “Smart” contact lenses monitor glucose levels in tears

The use of wearable sensors to provide patients with real-time monitoring of biological indicators has been a field of interest in recent years. Recently, Korean researchers published a paper in Science Advances, which reported a flexible contact lens that can monitor glucose levels in a patient's tears. The contact lens can also provide a test result using a lens display when the glucose level is too high. Remind users by turning off tiny embedded LED lights.

The authors say their contact lenses are the first devices that can display pixels on soft contact lenses to provide glucose information. This strategy may be used in the future to monitor pre-diabetes indicators and daily blood glucose. Importantly, this strategy differs from many current "smart" lenses in that it does not require the use of expensive materials or brittle components that may hinder the user's field of vision or even hurt the eye. Also, that system typically requires a large amount of equipment to measure the signal from the contact lens sensor.

In order to create a smart contact lens that can monitor glucose levels and is softer, easier to use, and also has wireless transmission capabilities, the first author of the paper, Jihun Park, and colleagues developed a method that allows the lens to be included. Flexible and transparent nanostructured glucose sensor, wireless charging loop, and LED pixel display technology for real-time reporting of measured data without the need for additional measurement equipment. This wireless display assembly in a system containing antennas, rectifiers, and LED pixels can utilize graphene sensors to sense changes in glucose levels while displaying glucose information through LED pixels. When a glucose level above the threshold is detected in the tears, the pixel will turn off, alerting the wearer to a change in blood glucose.

The researchers tested the device in the eyes of experimental rabbits and found that the sensor successfully monitored the increase in glucose concentration in the tears under wireless conditions. In addition to glucose monitoring, the hybrid system can be applied to other areas, such as smart devices for drug delivery, augmented reality, and even APPs that monitor various biomarkers through smartphones, the researchers said.

Reference materials:

[1] Potential enzyme as therapeutic target for diabetes

[2] Adocia Announces Positive Topline Data From a Dose-Proportionality Study of BioChaperone Combo in People With Type 2 Diabetes

[3] New biosensor could monitor glucose levels in tears and sweat

[4] 'Smart' contact lenses monitor glucose levels in tears

Original Title: Summary of Recent Progress in Diabetes Research (No. 49)

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