Let's all be honest here, in most cases when we need to find something instantly we whip out our cell phones for browsing the web. The web is something that we can carry around in our pockets.
The global adoption of mobile as a platform for ecommerce is no longer something you can neglect. According to a Statcounter report, in 2016 mobile web usage outperformed desktop usage. Currently, the usage of desktop and mobile are nearly the same 48% and 47% respectively.
With such large numbers of people using mobile phones to navigate the web, the trend is obvious: mobile is evolving fast and soon it'll be the dominant platform.
To continue succeeding in the digital era, and to appear in top search results, you need to design websites that provide a great mobile experience for users. Thus, building a website with a mobile-first approach has become a must. Your visitors expect your website to be optimized for mobile. Customers are looking forward to a high level of functionality and a beautiful design to be incorporated at the core of their online experience. Putting it differently, users demand functionality and design that is exclusively tailored for mobile. This is especially important for an ecommerce website where a poor shopping experience can lead to potential purchasers bouncing over to your competitors' websites.
Designing a mobile site for ecommerce is vital for turning website visitors into buyers. Perfectly, the layout of your website has to make the buying process as fast, facile, and relaxing as possible. No matter how good your products and services are, you are likely to lose many customers if your website is not optimized for mobile. To make sure your next step is made with the mobile consumer in mind there are few tips on how to optimize a website for mobile devices recommended by our team.
Mobile web browsing is already quite large and it's still rapidly developing. One of the reasons why you should design mobile site for ecommerce is that it's where your users are. Globally, the rate of online activity across devices is 49% mobile, 47% desktop, and 4 % tablet. People use mobile to interact with a brand, read the news, check emails, communicate on social networks, and buy products. Usually, people check the products on mobile and then, they finish the purchase on their desktops.
The importance of mobile optimized website is in that it will dramatically increase your sales. Recent researches show that 84% of companies that invested in a mobile presence indicated growth in new customers and showed immediate and long-term advantages. For instance, in recent years Facebook went to great lengths to please their mobile users. They made their website mobile friendly to improve user experience. Here are the results: Facebook reported $11.97 billion in revenue and $4.98 billion in profit, with 91% of its advertising revenue coming from mobile!
If you operate an ecommerce website, you are aware of the fact that ranking higher than your competitors on Google is pivotal for gross profit. Google officially reported that mobile searches overpassed desktop in 2015. Moreover, one of the main drivers for the increase of mobile first web design was that in October 2017, Google started counting its mobile-first index. This change means that Google provides users with different results on mobile than it does on a desktop for the exact same search. This means when a user browses from a mobile device, websites that are optimized for mobile viewing will rank higher than websites that aren't.
What is a mobile optimized design?
Mobile visitors navigate and search information differently comparing to the visitors exploring the desktop version of your website. For any retail company to get ahead in today's online market, it's crucial to have a website that responds smoothly on mobile devices and provides an easy user experience. So why wouldn't you offer your users a new and better version of the site?
When it comes to accomplishing that goal, you'll have a variety of options on how to develop the best mobile ecommerce website using "responsive," "mobile-friendly," or "mobile optimized" design. Let's look at each of them in detail.
The term responsive web design refers to a method where a website's design is automatically adopted based on the size of the visitors' screens. Because of that, website visitors can easily browse a website no matter what device they use.
Responsive websites have dynamic content that alters, texts and images change from a three-column layout to one that fits your device's screen perfectly.
Mobile-friendly design refers to a website designed to show content on mobile devices. The website content displays smaller on a mobile phone and may not work so effectively on a tablet or desktop. The website functionality remains the same regardless of the device.
Mobile-friendly is a minimum mobile design strategy you should hold to satisfy the demands of your mobile users. A smaller version of your desktop website may fit in a mobile screen and can be operational, but it's not developed for optimal user experience, it doesn't improve Google rankings, nor it converts mobile traffic into leads or purchases effectively.
For the most part, these sites will appear on mobile as they do on a personal computer, making it more difficult for visitors to navigate. Your internet shopping site is the face of your company and if visitors can't navigate your website effortlessly, they won't remain loyal users and can switch to your competitor. This is where mobile-optimized design beats out the competition.
A mobile-optimized website is designed and developed applying a mobile-first strategy and will reformat itself for mobile users. Mobile-first is a solution for present and future. This approach is becoming more in demand as the technology continues expanding extremely quickly.
Mobile-first means that we begin to design the website from sketching mobile's layout which has more limitations and expand its characteristics to make a desktop version. Mobile-first design is a strategy of creating a website or app, starting from designing the smallest screen first and adapting the changes to larger screens. Basically, it's about providing an excellent mobile user-experience to the appropriate device. It's designed to be viewed effectively on different devices without too many modifications.
Mobile-first design is not just a trend, it's a necessity, a basis of designing things for a multi-screen world. It changes the user experience in a better way regardless of what device they are using. The mobile-first strategy is an approach that's more content-focused, and thus — user-focused.
What's the difference between web and mobile ecommerce design?
It's a pervasive fallacy that web design and mobile design are equivalents. The difference between the two designs is more prominent than you may think.
First of all, the biggest distinction between web and mobile design is that you have far more freedom when it comes to designing desktop website since mobile design is linked to the interface elements of the OS. A smaller screen means that the visitor can see a lot less information on the website. The majority of modern mobile websites compensate for this by giving the user the opportunity to zoom in and out in a simple way, as well as adjusting font sizes to make the text easy to read. Usually, though, the visitor of the mobile website will have to zoom in if he/she wants to read the text in a larger size.
A mobile website is like any other website that includes browser-based HTML pages connected together and accessed over the Internet. The distinct characteristic that differentiates a mobile website from a desktop website is the fact that it has touch-based input. Similar to any website, mobile websites can demonstrate information, images, videos, and data. Rather than using a mouse or keyboard, most mobile users interact with their devices using their fingers. Moreover, users of a mobile website version can also have access to mobile-specific characteristics such as click-to-call (to call up) or location-based mapping (google map).
Another significant point that should be mentioned is that when someone is sitting behind their desktop they are likely to be at work, while if they are using their smartphone it's more probable that they are most of the time doing stuff in-between moments of work or other tasks (travel, shopping, games). In terms of UX, the key difference is contextual. Mobile users tend to do specific things and they're likely to do it swiftly, for instance, search and purchase products, look for locations, read the news, check their social media, buy tickets, etc.
Every retail company should optimize the website for mobile devices to be competitive on the market. That's not optional, it really is a must due to the steady growth of mobile users. So how to optimize your site for mobile users? Here're some ecommerce website design tips for mobile devices.
Like it or not, we live in a digital era where users not only anticipate but require lightning-fast websites. Speed is crucial. Actually, 47% of consumers demand websites to download in two seconds or less. In addition, around 40% of users leave a website that takes longer than three or more seconds to download.
Websites that load fast increase the lead generation for e-commerce businesses. What is more, quicker mobile sites have higher search ranks. You won't get the chance to be in the top search results if your page is loading very slowly. There's a direct connection between page loading speed and conversion rates. It's obvious that users won't go back to a website with poor performance. If you decrease page load time, there's a greater probability that a visitor will purchase the product on your website.
One of best tools available on market is Google's PageSpeed Insights (PSI). It can diagnose your mobile and desktop versions and give you the instructions with clear indications about what you need to rectify.
Think With Google is among other useful tools you can employ. The procedure is very simple. You just need to write your website URL and program will check it for you. The results will show whether your website is fast enough and what percentage of consumers you may be losing.
GTmetrix is also a handy tool that provides you with information on how fast your website loads and gives recommendations on how to improve it.
After you've checked your website speed, how do you make your website lightning-fast? First of all, try to compress the code. Minifying the code helps to diminish any code from its original size to the smallest probable size, without changing the code's operations. Essentially, it makes alterations by eliminating needless characters from your code such as white space and new lines. This procedure can compress the size of your code by up to 95%.
One more advice that we recommend is to keep your images small, but don't forget to maintain quality. Compressor.io is one of the best tools when it comes to reducing the size of your images. It helps you optimize your image size for faster page load maintaining high quality.
Your checkout page is one of your site's most significant pages. It should be sketched specifically for mobile, with a user-friendly look and functionality. To decrease cart abandonment and increase customer's conversion, you have to make the checkout process as easy as possible. It should be done in just a few clicks. Here's how to make checkout tailored to specific mobile visitors needs.
Consumers tend to have trust issues when they're making payments online. Worries about security of their data are one of the main causes of cart abandonment. The more evident it is that your internet shop is safe, the better chance you get for your users to complete the purchasing process. Holding an SSL ( Secure Sockets Layer) certificate with HTTPS ( HyperText Transfer Protocol Secure) is a good way to show the customers that they can trust the website. However, many customers don't always pay attention to that, particularly if they're browsing on a mobile device. In this case, an extended Validation SSL Certificate is a better option.
Asking customers to sign up on your site is definitely beneficial. It can help you find out their preferences and send them emails with new offers. Anyway, forcing visitors to create an account before they've purchased anything undoubtedly slows down the buying process and can cause irritation, especially on a mobile device. We recommend you to give your users some options: either sign up or checkout as a guest. In such a way, if people are purchasing the items while on the go, they can finish shopping with fewer difficulties. In addition, you can always suggest customers to create an account after they've checked out.
As you're trying to make the purchasing process as quick as possible, it's better to restrict the number of input fields needed for checkout. Only ask for the information that is necessary to fulfil an order. Autofill information can be a solution, saving the time. Even if it's a first-time visitor, you can still facilitate the procedure by filling in some of the information. For instance, you can automatically fill out the postcode information.
Users, especially those who are in hurry, want to know how long the checkout takes. A progress indicator guides shoppers through the checkout process, showing how many steps there are to take. It's difficult to carry on any task if you can't see an end goal. There are few ways to do this. On some sites, you can see a progress bar at the top of the page. If visitors see that, they are less likely to give up as it's shown how much they need to fill in before the payment process. They can also see the percentages or the approximate time they have.
When we were designing Turcom online shop for our US-based clients we tried to make checkout process as easy as possible. Our developers limited the number of input fields needed for checkout. They included only questions that were necessary to fulfil an order. We didn't ask visitors to create an account before purchasing process. Instead, we gave the customers some options to chose: either sign up or checkout as a guest.
Site search is a crucial element of a good mobile-first site. An efficient site search function on an e-commerce site has lots of benefits. Customers are used to finding search results in a fast way and expect a similar experience on e-commerce sites.
A position of search boxes. Navigation, including site search boxes, should be apparent across the entire site so that users can browse around in a walk. It's better to place the site search box in a visible position on the page near the top of the page in the left corner.
Size of the site search box. This is an aspect that depends on the various type of products marketed on the site and customer search preferences. If users are typing in phrases of two or more words then the box should be large enough so that visitors can see the whole phrase they are typing. This way users can rectify any errors if they need to, as they can fully view the search term. Short text can cause confusion. That's why people tend to cut their queries because they don't have a possibility to see the full search, nor can they change it. We would recommend applying expandable search-box. This is particularly significant for retailer companies with a wide product range.
Use auto-complete. Autocomplete function gives the possibility to guide customers to the most relevant and popular products. More than ever, retailer companies introduce an auto-complete tool which is aimed to suggest products when users have entered a few letters into the search box. It has various benefits. Firstly, it makes the search process faster. Secondly, it helps the users avoid mistakes. Thirdly, it also guarantees that customers' queries will give a product result. If submitted searches don't have a precise match, at least the autocomplete tool can show potential matches.
For example, on the jewellery website Foundrae designed by our developers on-search is improved for the better user experience. Search-box is placed near the top of the page in the left corner. The visitor of this online shop can also type long queries, as the company has a wide product range. The autocomplete function makes the search process that much faster.
Product position. While product descriptions play a key role in the desktop purchasing experience, it doesn't have as much influence on a mobile device. Considering that online customers base their purchasing decisions on the visual display of a product, product photography should be placed in the center of all pages of a mobile website.When we were designing Marimekko website for our US-based clients we placed all the product photographies in the center of all pages for better visual display. Marimekko is a design house.
Zoom-in Function. Another useful aspect that facilitates user experience and optimizes your product page is the zoom-in capability. The screen on a mobile phone is much smaller, but the quality of images is still quite important. In order to compensate for the smaller screen, give your customers the ability to zoom in on pictures. The best solution is to introduce flexible zoom, with the help of which a visitor can make the picture full screen by double-tapping it and making it even bigger by using two-finger pinch zoom.
Less text. On the mobile website, you have less space for product display. So, it's more difficult to convince your users to make a positive purchasing decision. To reassure that this decision-making process isn't too difficult for your users, try to reduce the amount of text on your product pages to the absolute minimum. This includes the reduction of unnecessary information. We recommend just leaving product name, price, short description, and a call-to-action button. If you have any additional information that is indispensable to include, hide it from permanent view with the help of collapsible menus. For example, on the internet shopping website Foundrae, designed by our developers, in "shipping and returns," the description is hidden. However, it can be easily accessed via clicking. We used a collapsible menu to hide the information that wasn't necessary. It saved space for product display.
Color Optimization. Colors are more important than you might think. They not only make the page beautiful, but are also used for directional cues. Colors turn our attention to the elements that should be highlighted.
Once you're done designing the mobile website, don't forget to test it. One way to do this is by checking your website on various devices. You can check the loading time, whether navigation is simple in usage, if the information is readable, and how well the product page works on a smaller screen. Testing your site on mobile devices can be time-consuming and expensive because of many different mobile devices. Fortunately, here are three tools for testing your website intended for mobile devices.
W3C mobileOK Checker. The W3C mobileOK Checker is among the top best tools available to test the compatibility of your site on mobile devices. The tool performs several tests that identify the user-friendliness of the mobile website.
Google Mobilizer. Google Mobilizer is a simple web tool to test your website on the mobile browser. You just have to enter your webpage address into the box provided on the tool. This is an excellent tool to check where you can make performance optimizations on your site.
The Gomez. Gomez mobile readiness tool tests your website on the basis of over 30 well-established techniques. It gives you a score between 1 and 5. The results are shown in a given document that suggests advice on how to improve your website. Be ready to fill in some personal information including your email address, phone number etc.
As we live in a mobile-centered world, more than ever before, people use their mobile phones to purchase products in the Internet. To remain competitive on the market and reach a wide-ranging audience, you need to have the best mobile ecommerce website design. Optimizing the design of your mobile website can give the opportunity to all your visitors get the chance to enjoy your amazing online shopping site, regardless of the device they're viewing it on.
Creating an effective mobile platform can be time-consuming. However, it's ultimately worth the effort. If you follow the tips mentioned in this article, you'll see that the number of your website visitors will increase significantly. Give it a go and you'll quickly see it for yourself.


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SIGNING TRACKER
Mark Masters
Kristen Shilton
MORE From TSN'S Hockey COLUMNISTS
Rick Westhead
NHL doctor slams 'situational ethics' on concussions in unsealed lawsuit documents
Documents unsealed Tuesday are the latest set of emails and records that have been opened to public scrutiny since the NHL concussion litigation began during the autumn of 2013.
By Rick Westhead
Niklas Kronwall hits Martin Havlat , Getty Images
TSN Senior Correspondent
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The National Hockey League team doctor had seen enough.
Hours earlier, he watched Chicago Blackhawks forward Martin Havlat return to the ice for Game 4 of the 2009 NHL Western Conference final, just two days after Havlat had been knocked unconscious during Game 3 by a ferocious bodycheck. In Game 4, Havlat was hit again and was forced to leave the game early.
The team doctor – one of at least 30 physicians charged with safeguarding the health of the NHL's players – couldn't understand why Havlat had been allowed back into the Blackhawks lineup for Game 4.
"I am once again disappointed in my colleagues in the [National Hockey League Team Physicians Society]," the doctor wrote in an email to Dr. Willem Meeuwisse, a Calgary-based member of the NHL's Concussion Working Group. "We all sit around and talk and talk about concussion management. Then it's the playoffs, someone suffers an obvious loss of consciousness and is back playing in less than 48 hours.
"This same Chicago player was hit hard again today and was unable to continue in the game. Another example of situational ethics. Our only job is to protect the players from harm including when the player is 'clearing' himself to play. We must be their advocate regardless of what the coach or general manager thinks."
A week later, Dr. Meeuwisse forwarded the doctor's email – after removing his identity – to Dr. Ruben Echemendia, a neuropsychologist in Pennsylvania and the co-chair of the NHL Concussion Working Group, NHL lawyer Julie Grand and Ottawa Senators doctor Mark Aubry.
"I chose to remove his name, and have not circulated to everyone on the concussion committee because it could be taken as quite inflammatory," Dr. Meeuwisse wrote in his May 31, 2009, email. "However, I think he is verbalizing what many people think, so I thought I should pass along the sentiment."
Grand forwarded the email the same day to NHL deputy commissioner Bill Daly. There is no record of a response from Daly in the documents.
The NHL has fought in court for months to prevent the emails from Dr. Meeuwisse and the NHL team doctor from being made public, but the league lost that battle on Tuesday when a U.S. federal court judge unsealed more than two dozen court exhibits that included that email string.
In a judgment released Tuesday, Judge Susan Richard Nelson wrote that while the NHL objected to the unsealing of the emails about Havlat, "citing a chilling effect on deliberations regarding medical issues," the league failed "to present compelling reasons to overcome the presumption of public access to [the emails about Havlat's injury and return to play.]"
Lawyers for a group of former players suing the NHL in a high-stakes concussion lawsuit say the doctor's candid comments are evidence that even some physicians within the NHL's own medical community feel conflicted about the pressure that players and their doctors face about returning to action after head injuries.
The documents unsealed Tuesday are the latest set of emails and records that have been opened to public scrutiny since the NHL concussion litigation began during the autumn of 2013.
The NHL has argued in the proposed class action lawsuit in U.S. federal court in Minneapolis that NHL players can educate themselves and "put two and two together" about the dangers of repeated head trauma. The league had asked the court to keep the 27 court exhibits sealed, arguing their release would hurt the league's competitive interests and chill future internal debates about player safety.
But lawyers for the group of former players say the NHL has marketed and profited from violence and has abdicated its responsibility to inform players about the long-term risks of concussions. Those lawyers say the new public documents are evidence that some NHL executives have held in contempt at least some doctors who work on concussion-related issues.
The court filings also highlight the NHL's lack of interest in helping researchers learn whether NHL players are more likely than the general public to develop cognitive problems such as Alzheimer's disease, the plaintiffs' lawyers say.
"Are we still paying him anything?"
The unsealed court exhibits include an email string following an incident during the 2010-11 season.
The NHL fined but did not suspend New York Rangers player Derek Stepan for elbowing Mike Green, then of the Washington Capitals, during a game. Days later, former NHL referee Kerry Fraser appeared on TSN and criticized the league's discipline.
Fraser sent an email to a group of 39 medical researchers on March 1, 2011, including Dr. Echemendia. Fraser included a link to a video of the incident on TSN's website.
"You will see the hit and then you can judge as to whether a 'fine' was warranted? You make the call," Fraser wrote.
Dr. Echemendia forwarded Fraser's email to Grand and Daly.
"FYI see below the kinds of emails that Kerry Fraser is circulating," Dr. Echemendia wrote.
Daly forwarded the email string to commissioner Gary Bettman.
"I'm not sure there is anything we can or should be doing, but I wanted you to be aware," Daly wrote.
"Are we still paying him anything?" Bettman asked in reply.
"Yes, his severance," Daly answered. "But I'm not sure we can stop paying him for expressing views critical of the League."
"It wouldn't be nice but maybe he should understand it's not nice to bite the hand that feeds you," Bettman wrote. "Please have someone check to see if there are any grounds to withhold. Don't want to hurt him – maybe just get his attention. This campaign, his book – somewhat delusional."
Repeated requests from researchers for NHL support
Many of the emails and records unsealed by the court go back a decade and detail repeated requests for NHL support from medical researchers.
In 2008, Dr. Echemendia forwarded an ESPN story about concussions in sports to Grand.
"Given the press on concussions in NHL (see story link below) would it make sense to issue a joint NHL/NHLPA press release on the many things that we are doing?" Echemendia wrote in a Feb. 8, 2008, email. "Given the cooperative spirit (NHL/NHLPA) on this issue, as well as the importance and visibility, does it make sense to begin discussions regarding a joint NHL/NHLPA retired players study? I just provided independent consultation [to] the NFL on the study they are planning and I know where they are headed."
Grand forwarded Dr. Echemendia's email to Daly.
"I am not sure we want to start focusing on a retired players' study at this point," Grand wrote in a Feb. 11, 2008, email. "Your thoughts? Ruben seems to be pushing this b/c he keeps bringing it up."
That wasn't the only time the NHL was asked to pursue a study on concussions.
Other email strings unsealed by the court show that an Ottawa-based company called Biokinetics asked the NHL to pursue similar research in 2002 that might help to make player helmets more effective. Grand dismissed the suggestion, saying the study "seemed expensive and unlikely to give us practical results that would be useful in reducing injuries."
In 2010, Baycrest Medical Centre asked Toronto Maple Leafs part owner Larry Tanenbaum to help begin a study of retired NHL players. Two years later, in 2012, Columbia University researchers also asked for similar help from the NHL.
The NHL has reportedly refused to fund any head trauma research. In January, USA Today reported the NHL has not given money to any of the four centres leading research into neurodegenerative diseases and earlier this year, the NHL retained a medical expert in its concussion litigation who argues chronic traumatic encephalopathy, or CTE, does not exist as a disease.
"...tree huggin, never played sport, leftist doctors..."
Some of the released emails disclosed describe the behind-the-scenes debate at the NHL following the death in January 2009 of Don Sanderson, a player in an Ontario men's senior league who died after his helmet came off and he hit his head on the ice during a fight.
Weeks after Sanderson's death, Stephen Walkom, the NHL's director of officiating, discussed with colleagues possible rule changes to prevent other serious injuries.
Johanna Kytola, who worked in the NHL's officiating department, emailed Walkom on Feb. 10, 2009, to ask whether a consensus had been reached on new rules regarding fighting.
"Ya love it, much to the dismay of the tree huggin, never played sport, leftist doctors… that soon won't let us climb stairs for fear of concussion..." Walkom responded.
"Well ultimately you can never get rid of fighting... No matter what the injury risk ;)" Kytola wrote.
Kytola wrote that she thought fighting would decrease in future seasons and asked whether other NHL executives supported the notion of ejecting players from games after two fights rather than three.
"Not a big change but we must demonstrate that we care about safety and want to minimize fighting in the game… at a minimum keep helmets on and secured during fights..." Walkom replied.
Over the following weeks, more emails and records showed some players and staff had worries about the NHL's handling of injuries.
Records from the NHL general manager meetings in March 2009 describe former NHLPA official Glenn Healy telling NHL executives that players who asked their teams for second medical opinions following injuries "often received grief from clubs."
Media at a "hysterical period"
One court exhibit featured notes from a general managers' meeting during the 2013-14 season. The date of the meeting is unclear although it occurred sometime before the Sochi Olympics in February 2014.
GMs and NHL officials again discussed rules for fighting, particularly after high-profile incidents involving Montreal Canadiens forward George Parros and Chicago goalie Ray Emery.
Parros was knocked out during a fight in Montreal's season-opening game on home ice. Emery weeks later skated down the ice during a game against Washington and picked a fight with Capitals goalie Braden Holtby.
"The media is at a hysterical period on this subject," Bettman is quoted as saying. "It's a combination of concussions, the NFL news, the Parros situation and the Emery situation. We need to push back a bit on what is being written on it. We should not have this debate publicly whether you support it or not. You can do what you want but it is being made more important than it is. Ken Dryden's book and Bobby Orr's books come out with conflicting views. Having this public debate is not good. Please don't speak to the media about it. Helping the media with the controversy of the issue doesn't help things."
Later in the meeting, San Jose Sharks GM Doug Wilson asks for guidance if media ask about fighting.
"The consensus right now is status quo," Bettman is quoted as answering. "If media asks about this, deflect the question. Tell them we are having a great season and we will continue to look into issues that come up in the future."

redpajama_set_name: RedPajamaCommonCrawl


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text:
Journal of Diabetes Research
Journal of Diabetes Research/
AbstractIntroductionMethodsResultsDiscussionData AvailabilityConflicts of InterestReferencesCopyrightRelated Articles
Volume 2020 | Article ID 4861681 | https://doi.org/10.1155/2020/4861681
Effect of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy in Japanese Subjects with Type 2 Diabetes Mellitus: A Retrospective Study
Yoshiro Fushimi,1Atsushi Obata,1Junpei Sanada,1Yuichiro Iwamoto,1Akiko Mashiko,1Megumi Horiya,1Akiko Mizoguchi-Tomita,1Momoyo Nishioka,1Yuki Kan,1Tomoe Kinoshita,1Seizo Okauchi,1and Hidenori Hirukawa1 et al.
Academic Editor: Ulrike Rothe
Received28 Oct 2019
Revised10 Feb 2020
Accepted20 Mar 2020
Recently, dipeptidyl peptidase-4 (DPP-4) inhibitors and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been very often used in subjects with type 2 diabetes mellitus (T2DM). In addition, combination drugs of both inhibitors have attracted much attention in aspects of its cost-effectiveness and improvement of patients' adherence. However, it is still poorly understood which factors are related to the efficacy of SGLT2 inhibitors as add-on therapy to DPP-4 inhibitors. Therefore, we aimed to elucidate in which type of individuals and/or under which conditions canagliflozin as add-on therapy to teneligliptin could exert more beneficial effects on glycemic control and/or renal protection. We retrospectively analyzed 56 Japanese subjects with T2DM in the real-world clinical practice. Three months after starting the combination therapy, the change of HbA1c (ΔHbA1c) was strongly related to HbA1c levels at baseline. As expected, serum glucagon level was increased after starting the combination therapy. Interestingly, however, the change of glucagon levels (Δglucagon) was not related to HbA1c levels at baseline, ΔHbA1c, and other parameters, which indicated that the increase of glucagon did not clinically affect the effectiveness of combination therapy. In addition, the change of urinary albumin excretion (ΔUAE) was negatively correlated with systolic blood pressure and HbA1c levels at baseline and positively correlated with the change of systolic blood pressure (ΔsBP) in univariate analysis. Furthermore, in multivariate analysis, only ΔsBP was the independent factor associated with ΔUAE. Taken together, canagliflozin as add-on therapy to teneligliptin improves glycemic control in a Δglucagon-independent manner and reduces UAE in a ΔsBP-dependent manner in Japanese subjects with T2DM.
Recently, DPP-4 inhibitors are commonly used in various individuals with type 2 diabetes mellitus (T2DM) from the young to the elderly because of their good glucose-lowering effect and safety including low risk of hypoglycaemia. DPP-4 inhibitors promote insulin secretion and suppress glucagon secretion by inhibiting the degradation of glucagon-like peptide-1 [1]. SGLT2 inhibitors, which emerged in clinical practice after DPP-4 inhibitors, improve glycemic control by reducing filtered renal glucose reabsorption from the proximal tubule and promoting excretion of excess glucose, which is a totally different mechanism compared with DPP-4 inhibitors [2]. SGLT2 inhibitors are promising drugs in view of reduction of glucose toxicity, body weight, and insulin resistance [3, 4]. In addition, large clinical trials have shown that SGLT2 inhibitors improved 3-point major adverse cardiovascular events (MACE) and renal outcomes [5–7], which were not observed with DPP-4 inhibitors. Since DPP-4 inhibitors and SGLT2 inhibitors have such different mechanisms of action and the risk of hypoglycaemia with both medications is pretty low, it seems that the combination therapy of both inhibitors is very promising. In fact, large clinical trials have shown the efficacy and safety of combination therapy in Japanese individuals with type 2 diabetes [8, 9]. In addition, very recently, combination drugs of both inhibitors became available in clinical practice and have drawn much attention in aspects of its cost-effectiveness and enhancement of patients' adherence. However, it is still poorly understood which factors and/or features of individuals mainly contribute to the glucose-lowering and/or renal protection effects of such combination therapy in real-world clinical practice. Therefore, we aimed to address the answer of these questions in this study.
2.1. Study Design
The present study was retrospectively carried out with outpatients in the Division of Diabetes, Endocrinology and Metabolism in Kawasaki Medical School from February to December in 2018. The subjects who had been taking teneligliptin (20 mg/day) for longer than 6 months without any other medication changes were included.
The participants were those who fulfilled the following criteria: (i) without severe renal dysfunction (); (ii) without any insulin and/or GLP-1RA usage; (iii) without infectious disease, malignancy, or diabetic coma; and (iv) not using steroid and/or immunosuppressant medications. A total of 91 participants (48 males, 43 females) were enrolled in the present study, and canagliflozin (100 mg/day) was added on to the subjects by each doctor's judgement. As a result, 56 out of 91 participants received canagliflozin (100 mg/day) and the remaining 35 participants continued teneligliptin. After starting canagliflozin add-on therapy for 3 months, blood and urinary samples after overnight fasting were obtained from all patients for measuring the multiple metabolic parameters. Serum glucagon levels were measured by SRL (Glucagon ELISA, Cosmic, Mercodia AB, Sylveniusgatan 8A, 75450 Uppsala, Sweden). The study protocol was approved by the institutional review board of Kawasaki Medical School (No. 3236), and the study was carried out in accordance with the Declaration of Helsinki, and we provided public information on the study via the Internet, instead of obtaining informed consent from each patient. We carried out data collection for variables such as type of medication as well as biochemical data.
2.2. Evaluation of Body Composition Parameters
Body composition variables were measured by a bioelectrical impedance body composition analyzer InBody 770 (InBody Japan Inc., Japan). Measurements were performed with the participants barefoot and in minimal clothing without any metallic materials. Body weight, total body water, intracellular and extracellular water, body fat mass, percent body of fat, soft lean mass, and skeletal muscle mass were measured before and after canagliflozin add-on therapy.
2.3. Statistical Analysis
All data were analyzed using JMP version 11.0 and are presented as (SD) or number (percentage). Changes in parameters from the baseline values in the same patient were evaluated using Wilcoxon singed-rank test. Baseline parameters and changes of various parameters of the teneligliptin continued group and canagliflozin add-on group were analyzed using Wilcoxon rank sum test. To examine which factors are associated with change (Δ) in HbA1c, glucagon, and UAE, we carried out Spearman's rank correlation coefficient test. Furthermore, to examine which factors independently determine ΔUAE after 12 weeks of canagliflozin add-on therapy, we carried out multiple regression analysis. value < 0.05 was considered to be statistically significant.
3.1. Clinical Characteristics of the Study Subjects
As shown in Table 1, clinical characteristics of the study subjects were as follows: in the teneligliptin continued group: age, years old; number (male/female), 35 (21/14); duration of diabetes, years; body weight, ; BMI, kg/m2; HbA1c, %; systolic blood pressure, ; diastolic blood pressure, ; triglyceride, ; LDL cholesterol, ; HDL cholesterol, ; and uric acid, . The prevalence rates of subjects with diabetic microangiopathy were as follows: peripheral neuropathy 40%, retinopathy 26%, and nephropathy stage 1 60%, stage 2 20%, and stage 3 20%, respectively. The prevalence of subjects with history of myocardial infarction and/or stroke was 34%. The prevalence of concomitant medication was as follows: DPP-4 inhibitor 100% (teneligliptin 20 mg/day), biguanide 46%, sulfonylurea or glinide 37%, thiazolidine 34%, and α-glucosidase inhibitor 29%. Insulin and/or GLP-1 receptor agonist users were not included in this study.
Efficacy of canagliflozin add-on therapy on various metabolic parameters.
On the other hand, in the canagliflozin add-on group, the clinical characteristics of the study subjects were as follows: age, years old; number (male/female), 56 (27/29); duration of diabetes, years; body weight, ; BMI, ; HbA1c, %; systolic blood pressure, ; diastolic blood pressure, ; triglyceride, ; LDL cholesterol, ; HDL cholesterol, ; and uric acid, . The prevalence rates of subjects with diabetic microangiopathy were as follows: peripheral neuropathy 14%, retinopathy 12%, and nephropathy stage 1 73%, stage 2 18%, and stage 3 9%, respectively. The prevalence of subjects with history of myocardial infarction and/or stroke was 9%. The prevalence of concomitant medication was as follows: DPP-4 inhibitor 100% (teneligliptin 20 mg/day), biguanide 46%, sulfonylurea or glinide 19%, thiazolidine 20%, and α-glucosidase inhibitor 2%. As you can see in Table 1, the teneligliptin continued group presented significantly older age, longer duration of diabetes, and lower body weight, FPG, HbA1c, blood pressure, ALT, γGTP, and eGFR at baseline compared with the canagliflozin add-on group. No severe adverse events were observed in this study.
3.2. Effects of Combination Therapy of Canagliflozin Added to Teneligliptin Monotherapy on Various Metabolic Parameters
Three months after starting canagliflozin as add-on therapy to teneligliptin, body weight, BMI, HbA1c, fasting blood glucose levels, both systolic and diastolic blood pressures, urinary albumin excretion (UAE), urinary acid, and transaminase were all significantly reduced compared to those before such combination therapy (Table 1). Body weight was decreased by approximately ( to , ), and HbA1c levels were decreased by approximately 0.7% (% to %, ). In body composition, fat mass was significantly decreased ( to , , respectively) accompanied with slight skeletal muscle mass reduction (decrease by approximately ), which was quite little compared to the reduction of fat mass (decrease by approximately ). Both systolic and diastolic blood pressures were decreased after starting canagliflozin as add-on therapy to teneligliptin ( to () and to (), respectively). Urinary albumin excretion was also significantly reduced after such combination therapy (. Cre to . Cre, ). In contrast, ketone body level was significantly increased ( to , ). Furthermore, interestingly, the serum glucagon level was significantly increased after starting the combination therapy ( to , ).
On the other hand, no variable changes were observed in the teneligliptin continued group between baseline and after three months. We next compared the changes of various parameters between baseline and 3 months later. As shown in Table 2, the decreased changes of body weight, BMI, FPG, and HbA1c were all significantly larger in the canagliflozin add-on group compared with the teneligliptin continued group. In addition, the decreased changes of γGTP, eGFR, and uric acid were also significantly larger accompanied with the significant increased change of Cre in the canagliflozin add-on group.
Changes of various parameters between baseline and 3 months later.
3.3. Search for Possible Factors Which Are Strongly Associated with Glucose-Lowering Effect and the Increase of Serum Glucagon Levels after Combination Therapy
We next investigated which factors were strongly associated with the glucose-lowering effect of canagliflozin as add-on therapy to teneligliptin. First, since HbA1c levels were significantly reduced after starting the combination therapy (Table 1), we evaluated which factors were closely associated with ΔHbA1c in univariate analysis. However, only HbA1c levels at baseline were strongly associated with ΔHbA1c (data not shown). Next, since serum glucagon levels were significantly elevated after the combination therapy (Table 1), we analyzed which factor levels at baseline were strongly associated with Δglucagon. As shown in Table 3, however, Δglucagon was not significantly related to HbA1c, IRI, and FPG at baseline in the univariate analysis. In addition, we examined the possible association of Δglucagon with the change of various parameters such as ΔHbA1c, ΔIRI, and ΔFPG. However, there were no factors which were strongly associated with Δglucagon, indicating that the elevation of glucagon levels did not affect the glucose-lowering effect in such combination therapy.
Various parameters associated with Δglucagon in univariate analyses.
3.4. Search for Possible Factors Which Are Strongly Associated with the Reduction of Urinary Albumin Excretion (UAE) after Combination Therapy
Since UAE was significantly reduced after starting canagliflozin as add-on therapy to teneligliptin (Table 1), we next investigated which factors were closely associated with the reduction of UAE (ΔUAE). First, in the univariate analysis, ΔUAE was significantly related to sBP, HbA1c levels at baseline, and ΔsBP (Table 4). Next, to elucidate the independent factors determining the efficacy of combination therapy, we performed multivariate analysis. To avoid the possible influence of age or gender, we included age and gender as independent variables as well and thus, we performed multivariate analysis using age, gender, sBP, and HbA1c levels at baseline and ΔsBP as explanatory variables and ΔUAE as an objective variable. As shown in Table 5, even after adjustment with age and gender, ΔsBP was an independent factor contributing to the reduction of UAE after combination therapy.
Various parameters associated with Δurinary albumin excretion (ΔUAE) in univariate analyses.
Determinant factors associated with Δurinary albumin excretion (ΔUAE) in multivariate analyses.
In this study, we showed that canagliflozin as add-on therapy to teneligliptin exerted beneficial effects on metabolic parameters such as body weight, HbA1c, and uric acid without any severe adverse events (Table 1), which were compatible with the previous reports about the effectiveness of SGLT2 inhibitors [10–12]. In addition, in the univariate analysis, HbA1c levels at baseline were strongly associated with ΔHbA1c (data not shown). Unexpectedly, lipid profile showed no significant improvement in this study (Table 1). As the lipid profile at baseline was relatively good in this study, it might have been hard to observe further improvement. It is also possible that as this study was retrospective, we could not educate exercise and/or diet adequately.
In this study, it is hard to directly compare the teneligliptin continued group and canagliflozin add-on group as participants' baseline characteristics were totally different. As canagliflozin was added on by each doctor's judgement, teneligliptin might be continued for patients whose HbA1c was relatively good and body weight was relatively low. It is true that there are some data defects such as fat mass, skeletal muscle mass, IRI, glucagon, IRI/glucagon ratio, ketone body, and urinary albumin excretion as this is a retrospective study. However, there were no other parameter changes after 3 months; we assume that there would be no change in parameters which were not measured in this study. On the contrary, we also explored the changes of various parameters between baseline and 3 months later (Table 2). As expected, the difference of changes such as body weight, BMI, FPG, and HbA1c was significantly larger in the canagliflozin add-on group. In addition, the difference of changes of Cre and eGFR became significant, which was not significantly different in each group comparison (Table 1). It is known that an initial eGFR drop is observed when SGLT2 inhibitors are used. This might partially explain the significant changes of Cre and eGFR in our study. However, unexpectedly, no significant difference in the changes of systolic and diastolic blood pressure was observed in our study. This might derive from some difference of the patients' background of each group or limited small sample size.
In general, it is said that SGLT2 inhibitors decrease serum insulin levels and increase serum glucagon levels, which lead to decrease of the insulin/glucagon ratio. However, in this study, IRI was not reduced after 3 months of combination therapy and there was no change in the IRI/glucagon ratio. There are some possible hypotheses that IRI was not decreased in this study. First, there were some patients who were recovering from glucose toxicity after adding canagliflozin. In these subjects, IRI levels were increased drastically. As sample size was rather small in this study, these subjects might have influenced the total IRI average. Second, as this study is retrospective, the difference of fasting time of each patient might have led to this result.
On the contrary, the serum glucagon level was significantly elevated after starting canagliflozin as add-on therapy to teneligliptin. Furthermore, the univariate analysis revealed Δglucagon was not significantly associated with HbA1c, IRI, and FPG at baseline and ΔHbA1c, ΔIRI, and ΔFPG. These results suggested that the increase of glucagon had no or little impact on glycemic control. Several previous studies reported that treatment with an SGLT2 inhibitor for 1–12 weeks significantly increased fasting or postprandial plasma glucagon levels in type 2 diabetes patients [13–15]. On the contrary, there are some reports which suggest that canagliflozin does not increase the serum glucagon level during meal tolerance test [8, 16]. In addition, it is also presented that SGLT1 but not SGLT2 is expressed in the murine αTC1 cell line and human and murine pancreatic islets and that canagliflozin reduced glucagon secretion from αTC1 cells in an SGLT1-dependent manner [17]. On the other hand, it is also reported that SGLT2 but not SGLT1 is expressed in glucagon-secreting alpha cells of human and murine pancreatic islets and dapagliflozin triggers glucagon secretion [18]. From the results of these reports, it is possible that some drug effects exist due to the difference of each drug affinity to SGLT1 and SGLT2. It will need further investigation to elucidate whether there are some drug effects on the changes of glucose metabolism and glucagon secretion. Although it is still controversial, we think it is important that our study showed that serum glucagon change did not affect overall metabolic changes in an adverse manner.
Noda et al. reported that teneligliptin and teneligliptin/canagliflozin combination therapy improved blood glucose levels after meal tolerance test (MTT) in 12 participants in a hospitalized setting for 14 days [16]. Interestingly, absolute values of glucagon and active GLP-1 were elevated after starting canagliflozin combination therapy, while Δglucagon was significantly reduced and Δactive GLP-1 was increased during MTT compared to teneligliptin monotherapy. This study presented that canagliflozin actually increased glucagon levels, which was similar to our study. However, Δglucagon during MTT was significantly reduced, which could not be confirmed in our study as we did not conduct MTT.
Okahata et al. reported that canagliflozin and canagliflozin/teneligliptin combination therapy improved blood glucose levels after MTT in 26 participants in a hospitalized setting for 6 days [19]. This study presented that canagliflozin increased that serum glucagon level during MTT and addition of teneligliptin reversed this increase. They also evaluated the change of the IRI/glucagon ratio during MTT, which resulted in no difference between canagliflozin treatment and canagliflozin/teneligliptin treatment.
These two studies suggest that addition of canagliflozin actually increases the serum glucagon level. Furthermore, the latter study presented no IRI/glucagon ratio difference during MTT between canagliflozin therapy and canagliflozin/teneligliptin combination therapy. On the contrary, these studies are in an inpatient setting, and the intervention term was quite short, and patients' backgrounds such as age and disease duration are totally different from our study.
Kadowaki et al. reported two large randomized control studies regarding the canagliflozin/teneligliptin combination vs. the monotherapy [8, 9]. One was canagliflozin added on to teneligliptin. The other was vice versa. Canagliflozin added on to teneligliptin improved glucose levels during MTT. However, the serum glucagon level was not increased in this study. This result might have derived from the method of glucagon measurements. In their study, glucagon was measured by radioimmunoassay (RIA). It is reported that there is crossreactivity against several proglucagon-derived fragments in RIA for glucagon determination. Some reports have elucidated a large difference in glucagon results in the same sample between RIA and sandwich ELISA [20, 21]. This might partially explain the difference of the glucagon result from our study. Anyway, all studies including our study presented that canagliflozin add-on therapy to teneligliptin improved various metabolic parameters.
Next, in this study, we presented that ΔUAE was significantly related to sBP and HbA1c levels at baseline and ΔsBP. Furthermore, multivariate analysis showed that ΔsBP was an independent factor contributing to the reduction of UAE after combination therapy. Several large clinical trials reported that SGLT2 inhibitors such as empagliflozin, canagliflozin, and dapagliflozin reduced the incidence of end-stage kidney disease, doubling of the serum creatinine levels from baseline, or death from renal or cardiovascular disease [5–7]. Although there was no change in eGFR after starting combination therapy in this study, such ΔsBP-dependent reduction of UAE might lead to a renal protective effect of canagliflozin add-on therapy in the long term.
Needless to say, there are limitations in this study. First, since this study was retrospective and our sample size was small, a large-scale and randomized prospective study would be necessary to achieve higher levels of evidence. Second, since most of the subjects in this study had mild to moderate renal dysfunction, the data obtained in this study is not necessarily true for subjects with severe renal dysfunction. Third, since these study subjects were middle aged and relatively obese, the data obtained in this study is not necessarily true for relatively aged and lean subjects. In addition, it is known that dual-energy X-ray absorptiometry is a gold standard method for the evaluation of body composition, but in this study, we used bioelectric impedance assessments to evaluate body composition because of their simplicity and portability.
Taken together, treatment with canagliflozin in addition to teneligliptin showed beneficial effects on various metabolic parameters and significantly reduced urinary albumin excretion. Furthermore, multivariate analyses showed that the reduction of urinary albumin excretion was mainly determined by the decrease of blood pressure. In addition, the change of serum glucagon levels was not related to any metabolic parameters, suggesting that the increase of glucagon levels after adding canagliflozin did not mainly, if any, contribute to the aggravation of overall metabolism. In conclusion, treatment with canagliflozin in addition to teneligliptin decreases urinary albumin excretion, at least in part, through the reduction of blood pressure and improves a variety of metabolic parameters in a glucagon-independent manner in Japanese subjects with type 2 diabetes mellitus.
The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.
Hideaki Kaneto has received honoraria for lectures and received scholarship grants from Sanofi, Novo Nordisk, Lilly, Boehringer Ingelheim, MSD, Takeda, Ono Pharma, Daiichi Sankyo, Sumitomo Dainippon Pharma, Mitsubishi Tanabe Pharma, Pfizer, Kissei Pharma, AstraZeneca, Astellas, Novartis, Kowa, Chugai Pharmaceutical, and Taisho Pharmaceutical. Kohei Kaku has been an advisor to, received honoraria for lectures from, and received scholarship grants from Novo Nordisk, Sanwa Kagaku Kenkyusho, Takeda, Taisho Pharmaceutical, MSD, Kowa, Sumitomo Dainippon Pharma, Novartis, Mitsubishi Tanabe Pharma, AstraZeneca, Nippon Boehringer Ingelheim, Chugai Pharmaceutical, Daiichi Sankyo, and Sanofi. All other authors declare that they have no conflicts of interest.
D. J. Drucker and M. A. Nauck, "The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes," The Lancet, vol. 368, no. 9548, pp. 1696–1705, 2006.
A. A. Tahrani, A. H. Barnett, and C. J. Bailey, "SGLT inhibitors in management of diabetes," The Lancet Diabetes and Endocrinology, vol. 1, no. 2, pp. 140–151, 2013.
H. Kaneto, A. Obata, M. Shimoda et al., "Promising diabetes therapy based on the molecular mechanism for glucose toxicity: usefulness of SGLT2 inhibitors as well as incretin-related drugs," Current Medicinal Chemistry, vol. 23, no. 27, pp. 3044–3051, 2016.
H. Kaneto, A. Obata, T. Kimura et al., "Beneficial effects of sodium-glucose cotransporter 2 inhibitors for preservation of pancreatic β-cell function and reduction of insulin resistance," Journal of Diabetes, vol. 9, no. 3, pp. 219–225, 2017.
B. Zinman, C. Wanner, J. M. Lachin et al., "Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes," The New England Journal of Medicine, vol. 373, no. 22, pp. 2117–2128, 2015.
B. Neal, V. Perkovic, K. W. Mahaffey et al., "Canagliflozin and cardiovascular and renal events in type 2 diabetes," The New England Journal of Medicine, vol. 377, no. 7, pp. 644–657, 2017.
S. D. Wiviott, I. Raz, M. P. Bonaca et al., "Dapagliflozin and cardiovascular outcomes in type 2 diabetes," The New England Journal of Medicine, vol. 380, no. 4, pp. 347–357, 2019.
T. Kadowaki, N. Inagaki, K. Kondo et al., "Long-term safety and efficacy of Canagliflozin as add-on therapy to teneligliptin in Japanese patients with type 2 diabetes," Diabetes, Obesity & Metabolism, vol. 20, no. 1, pp. 77–84, 2018.
T. Kadowaki, N. Inagaki, K. Kondo et al., "Efficacy and safety of teneligliptin added to canagliflozin monotherapy in Japanese patients with type 2 diabetes mellitus: a multicentre, randomized, double-blind, placebo-controlled, parallel-group comparative study," Diabetes, Obesity & Metabolism, vol. 20, no. 2, pp. 453–457, 2018.
T. Kinoshita, M. Shimoda, J. Sanada et al., "There is a close association between the recovery of liver injury and glycemic control after SGLT2 inhibitor treatment in Japanese subjects with type 2 diabetes: a retrospective clinical study," Diabetes Therapy, vol. 9, no. 4, pp. 1569–1580, 2018.
S. Kamei, M. Iwamoto, M. Kameyama et al., "Effect of tofogliflozin on body composition and glycemic control in Japanese subjects with type 2 diabetes mellitus," Journal Diabetes Research, vol. 2018, article 6470137, pp. 1–6, 2018.
T. Kimura, J. Sanada, M. Shimoda et al., "Switching from low-dose thiazide diuretics to sodium-glucose cotransporter 2 inhibitor improves various metabolic parameters without affecting blood pressure in patients with type 2 diabetes and hypertension," Journal of Diabetes Investigation, vol. 9, no. 4, pp. 875–881, 2018.
E. Ferrannini, E. Muscelli, S. Frascerra et al., "Metabolic response to sodium-glucose cotransporter 2 inhibition in type 2 diabetic patients," The Journal of Clinical Investigation, vol. 124, no. 2, pp. 499–508, 2014.
W. Alsalim, M. Persson, and B. Ahrén, "Different glucagon effects during DPP-4 inhibition versus SGLT-2 inhibition in metformin-treated type 2 diabetes patients," Diabetes, Obesity & Metabolism, vol. 20, no. 7, pp. 1652–1658, 2018.
R. Martinez, H. al-Jobori, A. M. Ali et al., "Endogenous glucose production and hormonal changes in response to canagliflozin and liraglutide combination therapy," Diabetes, vol. 67, no. 6, pp. 1182–1189, 2018.
T. Noda, E. Ebihara, H. Ueno et al., "Concurrent use of teneligliptin and canagliflozin improves glycemic control with beneficial effects on plasma glucagon and glucagon-like peptide-1: a single-arm study," Diabetes Therapy, vol. 10, no. 5, pp. 1835–1846, 2019.
T. Suga, O. Kikuchi, M. Kobayashi et al., "SGLT1 in pancreatic α cells regulates glucagon secretion in mice, possibly explaining the distinct effects of SGLT2 inhibitors on plasma glucagon levels," Molecular Metabolism, vol. 19, pp. 1–12, 2019.
C. Bonner, J. Kerr-Conte, V. Gmyr et al., "Inhibition of the glucose transporter SGLT2 with dapagliflozin in pancreatic alpha cells triggers glucagon secretion," Nature Medicine, vol. 21, no. 5, pp. 512–517, 2015.
S. Okahata, K. Sakamoto, T. Mitsumatsu, Y. Kondo, S. Tanaka, and T. Shiba, "Mechanistic insights from sequential combination therapy with a sodium glucose co-transporter-2 inhibitor and a dipeptidyl peptidase-4 inhibitor: results from the CANARIS trial using canagliflozin and teneligliptin," Diabetes, Obesity & Metabolism, vol. 21, no. 2, pp. 388–392, 2019.
T. Matsuo, J. Miyagawa, Y. Kusunoki et al., "Postabsorptive hyperglucagonemia in patients with type 2 diabetes mellitus analyzed with a novel enzyme-linked immunosorbent assay," Journal of Diabetes Investigation, vol. 7, no. 3, pp. 324–331, 2016.
A. Miyachi, M. Kobayashi, E. Mieno et al., "Accurate analytical method for human plasma glucagon levels using liquid chromatography-high resolution mass spectrometry: comparison with commercially available immunoassays," Analytical and Bioanalytical Chemistry, vol. 409, no. 25, pp. 5911–5918, 2017.
Copyright © 2020 Yoshiro Fushimi et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.


Reimagining the Dinosaur exhibition at the Queensland Museum was an exciting project we undertook with exhibition designers Thylacine.
As well as detailed interactive screens that allowed visitors to explore 3D models of dinosaurs, videos, and images from the Museums large collection, Mental Media produced animated life sized visualisations of the dinosaurs and megafauna for projection.
A final touch was the projection mapping of animated dinosaur shadows onto a replica section of the Trackway, fossilised dinosaur footprints found in outback Queensland and now mounted on the wall of the gallery.


Until now, Alvin Youngblood Hart has been best-known as an acoustic folk-blues performer. His first two albums—1996's Big Mama's Door and 1998's Territory—showed him carrying a traditional torch similar to that of blues revivalists Taj Mahal and Guy Davis. So it comes as quite a surprise that the Oakland-born musician is rocking out with an electric guitar on his new CD, Start With the Soul. The transformation is no big deal to him, though.
Start With the Soul is partially dedicated to former Thin Lizzy leader Phil Lynott, and includes a cover of a tune by '70s southern-rockers Black Oak Arkansas. Does anybody out there remember "Jim Dandy to the Rescue"? Well, Hart does. But he recorded BOA's "Cryin' Shame" instead.
Hart is in Berkeley "rounding up the troops", getting his new rhythm section of bassist Bill MacBeath and drummer Ed Michaels together for a tour that brings them to the Yale Hotel next Thursday (June 1). Although his new album also includes smart covers of Chuck Berry's go-go–era "Back to Memphis" and the early-'70s R&B chestnut "Treat Her Like a Lady", it's the curious Black Oak selection that keeps me intrigued. Considering the Confederate flag–waving theatrics and redneck stance of southern-rock bands like Lynyrd Skynyrd, I find it a little strange that Hart, an African American, is a devotee of the genre. But it turns out he didn't have that much say in the matter.
Gov't Mule is a three-piece band, heavy on the slide guitar, that pushes the boundaries of blues-oriented rock. Now that Hart's gone electric, his group is doing that too. But he's still not quite ready to assume the "power trio" stance.


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Lauren Mansfield sparks Flames to WNBL win
Published: Saturday, 14 November 2020 5:40 PM GMT+11
Lauren Mansfield top-scored with 24 points as the Sydney Uni Flames beat the Bendigo Spirit. Credit: AAP
Lauren Mansfield has put in a star turn to guide the Sydney Uni Flames to a comfortable 37-point win over the Bendigo Spirit in the WNBL.
The Opals point guard was a thorn in the Spirit's side throughout at the Townsville Stadium, helping herself to 24 points and laying up five assists as the Flames sparked into life in the second half to win 100-63.
She was ably assisted by the impressive Funda Nakkasoglu, who scored 14 points and tormented the tiring Spirit with her direct approach.
In the final quarter, the Flames piled on 16 points without reply against demoralised opponents who were never able to match their promising showing in the opening period.
The result gives Sydney their first win of the condensed eight-team, six-week WNBL campaign, which is taking place in a North Queensland hub as a result of the COVID-19 pandemic.
They lost their opener 85-70 to the Melbourne Boomers on Thursday.
Mansfield was delighted with her performance, but said the Flames' attention will turn immediately to Sunday's clash with the Liz Cambage-led Southside Flyers.
"We'll review the game," she said. "We're looking to build, we know it's a process and we want to get better each time we get on the court.
"It's always nice when you make your shots. I was feeling very confident ... it's a lot of fun when you can play that way.
"We've got a big game tomorrow and we've really got to concentrate on our recovery so we're ready to go."
Opal Tessa Lavey did her best to inspire Bendigo, notching up 15 points and 10 assists, but following on from their 42-point humbling by Southside in Thursday's opening match, it has been a tough start for Tracy York's side.
They next face UC Capitals on Monday evening in Mackay.
3:27 AM Senegal, Guinea through, but Keita banned


Mission's Tortilla Route for sale in the Goose Creek, South Carolina region for $120,900! Currently generating $398,476 in yearly sales and nets $82,566. Distributorship and territory are purchased through seller and contracted through Mission Foods. Mission Foods currently distributes its well-known brand of tortillas, chips, and more. This route currently has 19 accounts delivering to popular grocery stores and a military base. Located in a rapidly developing area, this route has huge growth potential.


The TrueNorth Community Services Resource Search is a tool to help you locate which TrueNorth programs and services are available in your county.
TrueNorth strives to provide up-to-date, accurate, and comprehensive information. However, information for any listings is always subject to change. Thank you for visiting us.
To get help from the emPower Heat and Energy Assistance Program for 2018-2019, visit http://helpforheat.com.
Para obtener ayuda del programa de asistencia de energía y calor de emPower para 2018-2019, visite http://helpforheat.com.
Please note not all TrueNorth programs are available in each of the 83 Michigan counties that we serve. To find out if a specific program is available in your county, please use the Research Search tool.
To find other possible assistance resources in your area, please call 2-1-1 or (844) 875-9211; visit www.mi211.org; contact your local Michigan Department of Health & Human Services (DHHS) office; or visit www.heatingmyhome.org.


The world is full of insecurities, but when one kid changes the way people see things, it breaks barriers and sets in new norms for everyone around us, seeing how people that love us the most would do anything for us to fit into the society and that we should spread the thing the world needs these days, Kindness.
"Wonder" tells the inspiring and heartwarming story of August Pullman (Jacob Tremblay). Born with facial differences that, up until now, have prevented him from going to a mainstream school, Auggie becomes the most unlikely of heroes when he enters mainstream school on his fifth grade.
As his family, his new classmates, and the larger community all struggle to find their compassion and acceptance, Auggie's extraordinary journey will unite them all and prove you can't blend in when you were born to stand out.
During her appearance in The Late Show with James Corden, Julia Roberts who plays Auggie's mom Isabel Pullman, had nothing but praises as she sums up what "Wonder" is all about.
"We can always use more kindness in our lives, but I think right now is really a good time to be reminded of maybe sharpening our kindness skills."


One cannot fully comprehend the meaning of liturgy in the Church, whether in East or West, without an understanding and appreciation of the musical forms by which the Word itself is conveyed. Studies in Eastern Chantis an ongoing series which provides scholars in music with the opportunity to publish the results of their latest research. Articles in the present volume of this important journal include: "A Medieval Slavonic Theoretical Treatise on Music," by Stefan Lazorov, "Notes on Cyprian the Hymnographer," by Mariangela Arata, "A New Approach to the Work of Chrysanthos of Madytos," by K. Romanou, "The Relationship of Music to Text in the Akathistos Hymn," by Antonia Filonov Gove, "Constantine A. Psachos: A Contribution to the Study of His Life and Work," by M. Ph. Dragoumis, "Performance of the Kanon in Thessaloniki in the Fourteenth Century," by Christian Hannick, and "Byzantine and Modern Greek Para-hymnography," by K. Misakis.


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Q: OCaml syntax error in functor I'm trying to create a functor that makes a polynomial ring out of a ring.  My underlying type, Ring_elt, has the following signature:
module type Ring_elt = sig
  type t
  val add : t -> t -> t
  val mul : t -> t -> t
  val zer : t
  val one : t
  val neg : t -> t
end;;

My polynomial functor looks like:
module Make_Poly2(Underlying:Ring_elt) = struct
  type t = Poly of Underlying.t list
  let rec create lst =
    match List.rev lst with
    | Underlying.zer :: tl -> create List.rev tl
    | _                    -> Poly of lst
end;;

(so the 'create' function should take a list, remove the leading zeros, and then return the polynomial of the result).  However, I get a syntax error and utop underlines the "zer" after "Underlying."
By comparison, the following code (for making integer polynomials) works:
module Make_int_poly = struct
  type t = Poly of int list
  let rec create lst =
    match List.rev lst with
    | 0 :: tl -> create (List.rev tl)
    | _       -> Poly lst
end;;

Any idea what's going on?

A: An OCaml pattern is built from constants, data constructors, and new names bound by the pattern match. Underlying.zer isn't any of those things. But 0 is one of them.
Seems like you can just use an if to compare against Underlying.zer.

A: Jeffrey's answer is good but instead of correcting it with an if construction, what you should do is the following : use algebraic data types
Instead of writing
val zer : t
val one : t

You could write
module type Ring_elt = sig
  type t = Zer | One | Num of t
  val add : t -> t -> t
  val mul : t -> t -> t
  val neg : t -> t
end

module Make_int_poly = struct
  type t = Poly of int list
  let rec create lst =
    match List.rev lst with
     | Underlying.Zer :: tl -> create (List.rev tl)
     | _                    -> Poly lst
end

It's a much better way of doing it since you can easily pattern match on it and even add some constants to your type t without problems.

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text:
Phillips: Recovery an everyday feat
In a candid, unscripted speech, Phillips shared stories of her long battle with addiction.
Phillips: Recovery an everyday feat In a candid, unscripted speech, Phillips shared stories of her long battle with addiction. Check out this story on desertsun.com: https://www.desertsun.com/story/news/health/2014/10/05/mackenzie-phillips-addiction-speech-palm-springs/16789705/
Tatiana Sanchez, The Desert Sun Published 7:32 p.m. PT Oct. 5, 2014 | Updated 8:31 p.m. PT Oct. 5, 2014
Mackenzie Phillips speaks about addiction on Sunday, October 5, 2014 at the Palm Springs Library during a dedication for the library's new addiction and recovery resource center.(Photo: Crystal Chatham/The Desert Sun)Buy Photo
In a candid, unscripted speech — peppered with endearing moments of humor — Mackenzie Phillips shared stories of her long battle with addiction with about 50 residents at the Palm Springs Library on Sunday.
Best known for playing the rebellious teenager Julie on the 1970s sitcom "One Day at a Time" and as the oldest daughter of the late Palm Springs resident John Phillips of the Mamas and the Papas, Phillips left no stone unturned, recounting a troubled childhood, 11 relapses and a long but fateful journey to recovery.
"What I have found in my struggle to achieve sobriety … is that time doesn't necessarily heal, nor does it treat our disease," she said, adding that recovery is an everyday feat. "I always have to self-intervene."
Phillips was a guest speaker for a dedication ceremony celebrating the library's new addiction and recovery resource section.
Mackenzie Phillips talks about addiction at Palm Springs Library
Mackenzie Phillips speaks about addiction on Sunday, October 5, 2014 at the Palm Springs Library during a dedication for the library's new addiction and recovery resource center. Crystal Chatham/The Desert Sun
Audience members listen as Mackenzie Phillips speaks about addiction on Sunday, October 5, 2014 at the Palm Springs Library during a dedication for the library's new addiction and recovery resource center. Crystal Chatham/The Desert Sun
City of Palm Springs Library Director Jeannie Kays gives opening remarks on Sunday, October 5, 2014 during a dedication for the library's new addiction and recovery resource center. Crystal Chatham/The Desert Sun
A dedication ceremony is held for Palm Springs Library's new addiction and recovery resource center on Sunday, October 5, 2014. New additions to the library include books and DVDs covering various aspects of addiction. At left is Michael's House alumni and event coordinator Renee Baribeau and at right is City of Palm Springs Library Director Jeannie Kays. Library board members are among the people between them. Crystal Chatham/The Desert Sun
Michael's House alumni and event coordinator Renee Baribeau speaks during a dedication ceremony for Palm Springs Library's new addiction and recovery resource center on Sunday, October 5, 2014. Crystal Chatham/The Desert Sun
Mackenzie Phillips' book "High on Arrival" is displayed before the actress speaks about addiction on Sunday, October 5, 2014 at the Palm Springs Library at a dedication for the library's new addiction and recovery resource center. Crystal Chatham/The Desert Sun
The resource center — with books and DVDs covering various aspects of addiction — was funded collaboratively by Michael's House, a Palm Springs-based addiction treatment center, and Heroes in Recovery, a grassroots, nationwide program that recognizes those seeking help for addiction and mental health issues.
Michael's House alumni and event coordinator Renee Baribeau speaks during a dedication ceremony for Palm Springs Library's new addiction and recovery resource center on Sunday. (Photo: Crystal Chatham/The Desert Sun)
"Addiction is a spiritual plague," said Renee Baribeau, Michael's House alumni and event coordinator, who said she's been sober for 27 years.
An estimated 25 million Americans struggle with addiction, Baribeau said.
She also stressed that addiction is not just physical but is caused in part by mental health deficiencies.
Despite the seriousness of the topic, Phillips found genuine ways to make the audience laugh throughout her speech as she shared very personal stories.
Her description of a 2008 arrest by the Los Angeles Airport Police for cocaine and heroin possession, which she said marked a turning point in her addiction, also included many laugh lines.
"There I was in handcuffs," Phillips said several times.
She said a buckle on a pants pocket containing a bag of drugs and syringes set off a metal detector, drawing security officers' attention and prompting her to hide the bag in her underwear. The crowd laughed as Phillips described the moment the bag fell to her feet during the ensuing screening.
Sunday's dedication ceremony brought together Michael's House staff and alumni, patrons of the library and local residents.
Michael's House alumni and event coordinator Renee Baribeau, left, and Palm Springs Library Director Jeannie Kays, right, are joined by library board members at a dedication ceremony for Palm Springs Library's new addiction and recovery resource center on Sunday. (Photo: Crystal Chatham/The Desert Sun )
"Mackenzie was fabulous, absolutely fabulous," said Indio resident Darby Young, who brought along her friend Pippin Gill.
Young said she most liked "her authenticity, her hope for the future and her obvious love for her family and those who care for her."
Phillips, now an addiction recovery advocate at Pasadena Recovery Center, also recounted memories of her father, with whom she had a complex relationship until he died in Palm Springs in 2001.
Phillips has accused her father of introducing her to drugs and engaging in an incestuous relationship with her for a decade.
"I am a survivor of incest and sexual abuse," she said Sunday. "But I am not a victim."
Phillips said she views her sobriety as the one thing that her father couldn't take from her.
Read or Share this story: https://www.desertsun.com/story/news/health/2014/10/05/mackenzie-phillips-addiction-speech-palm-springs/16789705/
Flight from coronavirus epicenter lands in county; news conference expected


ACADEMIC Staff Union of Universities (ASUU)has suspended the three month old strike after signing all agreements with the Federal Government.
The agreement was reached through at the end of the conciliatory meeting held at the instance of the Minister of Labour and Employment, Senator Chris Ngige and his Education counterpart, Malam Adamu Adamu.
Ngige, who read the agreement signed by both parties, expressed optimism that the strike would be suspended.
According to him, the parties unanimously resolved the eight contentious issues that had prolonged the strike. He noted that the issue of the NUMPENCO has been resolved as ASUU collected the licence on the 28th January, 2019.
Besides, the Minister said that the Visitation panel has also been instituted and will commence work on 2nd March with the view to sanitizing the tertiary institutions, adding that it was in tandem with anti-corruption campaign. On Earned Allowances, he said that the Federal Government has released the sum of N20 billion to all categories of staff but with ASUU having a bigger chunk of the money.
He however noted that Government has approved additional N5 billion for payment of Earned Academic Allowances and others. He further stated that the sum of N25 billion will be released as Revitalisation Fund between April and May 2019 and resume full implementation of the MoU signed since 2009.