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The following snippet shows the top part of an application with several icons. The user agent might show both the two friends mentioned earlier, as well as the "astrophy" and "astronomy" values given in the datalist element. In the future, you can display this message by double-clicking the warning icon displayed in the status bar. If the given value is the empty string, set url 's fragment to null.

: The Picture element - HTML: HyperText Markup Language | MDN

Cross-Browser and manipulation, event handling, animation, and Ajax much simpler with an easy-to-use API that works across a multitude of browsers. With a​. html,body,div,span,applet,object,iframe,h1,h2,h3,h4,h5,h6,p,blockquote,pre,a,​abbr,acronym,address,big,cite,code,del,dfn,em,img,ins,kbd,q,s,samp,small,strike​. Sign in. Use your Google Account. Email or phone. Forgot email? Type the text you hear or see. Not your computer? Use a private browsing window to sign in. To force a browser to download the contents of a link rather than display it, you can use dl=1 as a Some browsers aren't configured to correctly preview files. The Document object; The DocumentOrShadowRoot interface The object element; The param element; The video element These are guaranteed to never be touched by browsers, and allow scripts to Errors where the error-handling behavior is not compatible with streaming user agents.

Si object browsersi object browser er 8 ダウンロード. The attribute can furthermore be given a value, to specify the filename that user agents are to use when storing the resource in a file system.

量産中. MySTに保存. Sensor and motion algorithm software expansion for STM32Cube. ソフトウェア入手 ソフトウェア入手 データブリーフのダウンロード. hasOwnProperty(a)&&seoauditing.ru(i,e[a],a,e);else if(li(e)||n(e)){var s="object"! getAttribute(r))}),i){if(!mi)return void seoauditing.ru("Angular: disabling ),gi=/[​A-Z]/g,_i=!1,bi=1,yi=2,$i=3,ki=8,wi=9,Ci=11,Si={full:"",major:1,minor:6,dot:0 only in HTML5 mode and only in browsers supporting HTML5 History API");​return this. SafeFrame , specified objects and functions are used to manipulate and interact with created. SafeFrame containers, allowing for rich-interactions. To force the browser to download a file it would otherwise be capable of starts or even inform the user in a friendly manner that an error has occurred. This is not supported on all browsers: seoauditing.ru​asp Chrome, Firefox, Opera and IE (>= ) – Kunal Kakkad Jan 13 '16 at 8:​ The browser will consider each child element and choose the best match among them. 8. ​. footer { font-size.8rem; position: absolute; bottom: 10px; right: This lets browsers opt for lower-density versions in data-saving positioning of the image within the element's frame, and the object-fit.

Mocha - the fun, simple, flexible JavaScript test framework

Some browsers attempt to aid the user by automatically filling form color, Color, An sRGB color with 8-bit red, green, and blue components, A color well in an error, then return an error; otherwise, return a new Date object. The iframe element; The embed element; The object element; An introduction to error handling and strange cases in the parser MIME type, then it will be processed as an HTML document by Web browsers. at the 0° longitude), not UTC (the approximation of UT1 that ticks in SI seconds).Si object browsersi object browser er 8 ダウンロード Is your Android phone or tablet full of junk and running slowly? Clean, optimize and boost the performance of your device with CCleaner for Android! Brought to. Over 10 million users' choice! FAST, SAFE, LIGHT & PRIVATE! APUS Browser is one of the best web browser apps for android, one of the best private browser. @param obj the object which will raise the event @param evType the event I'​ve tested version on all browsers I have and can confirm that it works with: answered Sep 5 '16 at function onVisibilityChange(callback) { var visible = true; if (!callback) { throw new Error('no callback given'); } function focused() { if. the computer stack, attacks on browsers can cause more damage because a storage objects, and the basic object store includes op- tional parameters, such. 7. Letter to the Shareholders. 8. Financial Highlights. Introduction for purchases: three mobile browsers out of four Adesso Si, the stories of homosexual couples source and object of study for the whole are free from material misstatement, whether due to fraud or error, and to issue an auditors'.

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Table of contents A script error occurs in Internet Explorer, the webpage cannot be displayed correctly and you receive an error message. Configuring Web Browsers to Use Virtual Console. RACADM — The RACADM command or the object that you must use is provided the browser's certificate error warning may display a second time after you si::sysinit:/etc/rc.d/seoauditing.rut.

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Objects and methods available to JavaScript modules. Step 8. Select the '​Finish' button. CKAN creates the dataset and To fix this error, install frontend dependencies. a higher value might cause time-outs, or unresponsive browsers for outputs a span with the number in SI unit eg -> k. MetaMask is an extension for accessing Ethereum enabled distributed applications, or "Dapps" in your browser! The extension injects the Ethereum web3 API.  Si object browsersi object browser er 8 ダウンロード browser support; simple async support, including promises; run seoauditing.ru tests in a new Mocha instance for the single test file, and: The worker repeats step 8 from If you use callback-based async tests, Mocha will throw an error if done() is (​6ms) 1 failing 1) double done: Error: done() called multiple times at Object. In lean subjects with normal glucose tolerance (NGT), the mean plasma glucose and insulin concentrations during the OGTT were mg/dl and 62 μU/ml, while​.

Script errors in Internet Explorer - Browsers | Microsoft Docs

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The value sanitization algorithm is as follows : If the value of the element is not a valid week string , then set it to the empty string instead. The min attribute, if specified, must have a value that is a valid week string.

The max attribute, if specified, must have a value that is a valid week string. The step attribute is expressed in weeks. The step scale factor is ,, which converts the weeks to milliseconds, which is the base unit of comparison for the conversion algorithms below.

The default step is 1 week. The default step base is ,, the start of week W01 which is the Monday 3 days before The algorithm to convert a string to a number , given a string input , is as follows : If parsing a week string from input results in an error, then return an error; otherwise, return the number of milliseconds elapsed from midnight UTC on the morning of the time represented by the value " T The algorithm to convert a number to a string , given a number input , is as follows : Return a valid week string that represents the week that, in UTC, is current input milliseconds after midnight UTC on the morning of the time represented by the value " T The algorithm to convert a string to a Date object , given a string input , is as follows : If parsing a week from input results in an error, then return an error; otherwise, return a new Date object representing midnight UTC on the morning of the Monday of the parsed week.

The algorithm to convert a Date object to a string , given a Date object input , is as follows : Return a valid week string that represents the week current at the time represented by input in the UTC time zone. If the element is mutable , the user agent should allow the user to change the time represented by its value , as obtained by parsing a time from it.

User agents must not allow the user to set the value to a non-empty string that is not a valid time string. Constraint validation : While the user interface describes input that the user agent cannot convert to a valid time string , the control is suffering from bad input.

The value attribute, if specified and not empty, must have a value that is a valid time string. The value sanitization algorithm is as follows : If the value of the element is not a valid time string , then set it to the empty string instead.

The form control has a periodic domain. The min attribute, if specified, must have a value that is a valid time string. The max attribute, if specified, must have a value that is a valid time string. The step attribute is expressed in seconds. The step scale factor is which converts the seconds to milliseconds, which is the base unit of comparison for the conversion algorithms below.

The default step is 60 seconds. The algorithm to convert a string to a number , given a string input , is as follows : If parsing a time from input results in an error, then return an error; otherwise, return the number of milliseconds elapsed from midnight to the parsed time on a day with no time changes.

The algorithm to convert a number to a string , given a number input , is as follows : Return a valid time string that represents the time that is input milliseconds after midnight on a day with no time changes. The algorithm to convert a string to a Date object , given a string input , is as follows : If parsing a time from input results in an error, then return an error; otherwise, return a new Date object representing the parsed time in UTC on The algorithm to convert a Date object to a string , given a Date object input , is as follows : Return a valid time string that represents the UTC time component that is represented by input.

If the element is mutable , the user agent should allow the user to change the date and time represented by its value , as obtained by parsing a date and time from it. User agents must not allow the user to set the value to a non-empty string that is not a valid normalized global date and time string. Constraint validation : While the user interface describes input that the user agent cannot convert to a valid normalized global date and time string , the control is suffering from bad input.

The Local Date and Time state and other date-related states are not useful for vague values, and are only useful for dates ranging from recent history through a few thousand years. For example, "one millisecond after the big bang", "the Ides of March, 44BC", "the early part of the Jurassic period", or "a winter around BCE", and many other expressions of time cannot be sensibly expressed in HTML form states.

For the input of dates before the introduction of the Gregorian calendar, authors are encouraged to not use the Local Date and Time state and the other date- and time-related states described in subsequent sections , as user agents are not required to support converting dates and times from earlier periods to the Gregorian calendar, and asking users to do so manually puts an undue burden on users.

This is complicated by the manner in which the Gregorian calendar was phased in, which occurred at different times in different countries, ranging from partway through the 16th century all the way to early in the 20th. Instead, authors are encouraged to provide fine-grained input controls using the select element and input elements with the Number state. Applications need to use care when working with datetime-local values, since most date time objects in languages such as JavaScript or server-side languages such as Java use incremental time values tied to the UTC time zone.

Implicit conversion of a floating time value to an incremental time can cause the actual value used to be different from user expectations. The value attribute, if specified and not empty, must have a value that is a valid floating date and time string. The value sanitization algorithm is as follows : If the value of the element is a valid floating date and time string , then set it to a valid normalized floating date and time string representing the same date and time; otherwise, set it to the empty string instead.

The min attribute, if specified, must have a value that is a valid floating date and time string. The max attribute, if specified, must have a value that is a valid floating date and time string. The algorithm to convert a string to a number , given a string input , is as follows : If parsing a date and time from input results in an error, then return an error; otherwise, return the number of milliseconds elapsed from midnight on the morning of the time represented by the value " T The algorithm to convert a number to a string , given a number input , is as follows : Return a valid normalized floating date and time string that represents the date and time that is input milliseconds after midnight on the morning of the time represented by the value " T The following common input element content attributes, IDL attributes, and methods apply to the element: autocomplete , list , max , min , readonly , required , and step content attributes; list , value , and valueAsNumber IDL attributes; select , stepDown , and stepUp methods.

If the element is mutable , the user agent should allow the user to change the number represented by its value , as obtained from applying the rules for parsing floating-point number values to it.

User agents must not allow the user to set the value to a non-empty string that is not a valid floating-point number. Constraint validation : While the user interface describes input that the user agent cannot convert to a valid floating-point number , the control is suffering from bad input. The value attribute, if specified and not empty, must have a value that is a valid floating-point number.

The value sanitization algorithm is as follows : If the value of the element is not a valid floating-point number , then set it to the empty string instead. The min attribute, if specified, must have a value that is a valid floating-point number. The max attribute, if specified, must have a value that is a valid floating-point number. The step scale factor is 1. The default step is 1 allowing only integers to be selected by the user, unless the step base has a non-integer value.

If there are two such numbers, user agents are encouraged to pick the one nearest positive infinity. The algorithm to convert a string to a number , given a string input , is as follows : If applying the rules for parsing floating-point number values to input results in an error, then return an error; otherwise, return the resulting number.

The algorithm to convert a number to a string , given a number input , is as follows : Return a valid floating-point number that represents input. The following common input element content attributes, IDL attributes, and methods apply to the element: autocomplete , list , max , min , placeholder , readonly , required , and step content attributes; list , value , and valueAsNumber IDL attributes; select , stepDown , and stepUp methods.

The following content attributes must not be specified and do not apply to the element: accept , alt , checked , dirname , formaction , formenctype , formmethod , formnovalidate , formtarget , height , maxlength , minlength , multiple , pattern , size , src , and width. This might include handling grouping separators as in ",,," and various decimal separators such as "3,99" vs "3.

For example, it would be inappropriate for credit card numbers or US postal codes. So it would not make sense for the user to select a credit card number using "up" and "down" buttons. User agents must not allow the user to set the value to a string that is not a valid floating-point number. User agents must not allow the user to set the value to the empty string. The value attribute, if specified, must have a value that is a valid floating-point number.

The value sanitization algorithm is as follows : If the value of the element is not a valid floating-point number , then set it to the best representation, as a floating-point number , of the default value. The default value is the minimum plus half the difference between the minimum and the maximum , unless the maximum is less than the minimum , in which case the default value is the minimum.

If two numbers match these constraints, then user agents must use the one nearest to positive infinity. Note how the user agent determined the orientation of the control from the ratio of the style-sheet-specified height and width properties. The colors were similarly derived from the style sheet. The tick marks, however, were derived from the markup.

In particular, the step attribute has not affected the placement of tick marks, the user agent deciding to only use the author-specified completion values and then adding longer tick marks at the extremes. The user agent could pick which one to display based on the dimensions given in the style sheet. This would allow it to maintain the same resolution for the tick marks, despite the differences in width.

In this state, the range and step constraints are enforced even during user input, and there is no way to set the value to the empty string. The default minimum is 0. The default maximum is The default step is 1 allowing only integers, unless the min attribute has a non-integer value. The algorithm to convert a number to a string , given a number input , is as follows : Return the best representation, as a floating-point number , of input.

The following content attributes must not be specified and do not apply to the element: accept , alt , checked , dirname , formaction , formenctype , formmethod , formnovalidate , formtarget , height , maxlength , minlength , pattern , placeholder , readonly , required , size , src , and width.

In this state, there is always a color picked, and there is no way to set the value to the empty string. If the element is mutable , the user agent should allow the user to change the color represented by its value , as obtained from applying the rules for parsing simple color values to it. User agents must not allow the user to set the value to a string that is not a valid lowercase simple color. Constraint validation : While the user interface describes input that the user agent cannot convert to a valid lowercase simple color , the control is suffering from bad input.

The value attribute, if specified and not empty, must have a value that is a valid simple color. The value sanitization algorithm is as follows : If the value of the element is a valid simple color , then set it to the value of the element in ASCII lowercase ; otherwise, set it to the string " ".

The following common input element content attributes and IDL attributes apply to the element: autocomplete and list content attributes; list and value IDL attributes; select method. The following content attributes must not be specified and do not apply to the element: accept , alt , checked , dirname , formaction , formenctype , formmethod , formnovalidate , formtarget , height , max , maxlength , min , minlength , multiple , pattern , placeholder , readonly , required , size , src , step , and width.

The indeterminate IDL attribute only gives the appearance of a third state. The activation behavior is to fire a simple event that bubbles named input at the element and then fire a simple event that bubbles named change at the element. If the element is not mutable , it has no activation behavior. Constraint validation : If the element is required and its checkedness is false, then the element is suffering from being missing.

When set, overrides the rendering of checkbox controls so that the current value is not visible. The following common input element content attributes and IDL attributes apply to the element: checked , and required content attributes; checked and value IDL attributes.

The following content attributes must not be specified and do not apply to the element: accept , alt , autocomplete , dirname , formaction , formenctype , formmethod , formnovalidate , formtarget , height , list , max , maxlength , min , minlength , multiple , pattern , placeholder , readonly , size , src , step , and width.

The input element represents a control that, when used in conjunction with other input elements, forms a radio button group in which only one control can have its checkedness state set to true. The radio button group that contains an input element a also contains all the other input elements b that fulfill all of the following conditions:. A document must not contain an input element whose radio button group contains only that element.

The activation behavior for R is to fire a simple event that bubbles named input at R and then fire a simple event that bubbles named change at R. Constraint validation : If an element in the radio button group is required , and all of the input elements in the radio button group have a checkedness that is false, then the element is suffering from being missing.

If none of the radio buttons in a radio button group are checked when they are inserted into the document , then they will all be initially unchecked in the interface, until such time as one of them is checked either by the user or by script.

The following common input element content attributes and IDL attributes apply to the element: checked and required content attributes; checked and value IDL attributes. The input element represents a list of selected files , each file consisting of a file name, a file type, and a file body the contents of the file.

File names must not contain path components , even in the case that a user has selected an entire directory hierarchy or multiple files with the same name from different directories. Unless the multiple attribute is set, there must be no more than one file in the list of selected files. If the element is mutable , the user agent should allow the user to change the files on the list in other ways also, e. Constraint validation : If the element is required and the list of selected files is empty, then the element is suffering from being missing.

The accept attribute may be specified to provide user agents with a hint of what file types will be accepted. If specified, the attribute must consist of a set of comma-separated tokens , each of which must be an ASCII case-insensitive match for one of the following:.

To obtain the list of tokens from the attribute, the user agent must split the attribute value on commas. User agents may use the value of this attribute to display a more appropriate user interface than a generic file picker. User agents should prevent the user from selecting files that are not accepted by one or more of these tokens. Authors are encouraged to specify both any MIME types and any corresponding extensions when looking for data in a specific format.

Similarly, on a system that does not have file names or extensions but labels documents with MIME types internally, the MIME types can be used to pick the allowed files, while the extensions can be used if the system has an extension registration table that maps known extensions to MIME types used by the system.

Extensions tend to be ambiguous e. The value IDL attribute is in mode filename. The following content attributes must not be specified and do not apply to the element: alt , autocomplete , checked , dirname , formaction , formenctype , formmethod , formnovalidate , formtarget , height , list , max , maxlength , min , minlength , pattern , placeholder , readonly , size , src , step , and width.

The input element represents a button that, when activated, submits the form. The element is a button , specifically a submit button. The formaction , formenctype , formmethod , formnovalidate , and formtarget attributes are attributes for form submission.

The formnovalidate attribute can be used to make submit buttons that do not trigger the constraint validation. The following common input element content attributes and IDL attributes apply to the element: formaction , formenctype , formmethod , formnovalidate , and formtarget content attributes; value IDL attribute.

The value IDL attribute is in mode default. The following content attributes must not be specified and do not apply to the element: accept , alt , autocomplete , checked , dirname , height , list , max , maxlength , min , minlength , multiple , pattern , placeholder , readonly , required , size , src , step , and width.

The input element represents either an image from which a user can select a coordinate and submit the form, or alternatively a button from which the user can submit the form. The element is a button , specifically a Submit Button. The coordinate is sent to the server during form submission by sending two entries for the element, derived from the name of the control but with ". The image is given by the src attribute. The src attribute must be present, and must contain a valid non-empty URL potentially surrounded by spaces referencing a non-interactive, optionally animated, image resource that is neither paged nor scripted.

If this is true before the image is completely downloaded, each task that is queued by the networking task source while the image is being fetched must update the presentation of the image appropriately. User agents must not support non-image resources with the input element. User agents must not run executable code embedded in the image resource.

User agents must only display the first page of a multipage resource. User agents must not allow the resource to act in an interactive fashion, but should honor any animation in the resource.

The task that is queued by the networking task source once the resource has been fetched, must, if the download was successful and the image is available , queue a task to fire a simple event named load at the input element; and otherwise, if the fetching process fails without a response from the remote server, or completes but the image is not a valid or supported image, queue a task to fire a simple event named error on the input element.

The alt attribute provides the textual label for the button for users and user agents who cannot use the image. The alt attribute must be present, and must contain a non-empty string giving the label that would be appropriate for an equivalent button if the image was unavailable.

The input element supports dimension attributes. If the user activates the control without explicitly selecting a coordinate, then the coordinate 0,0 must be assumed. The selected coordinate must consist of an x -component and a y -component. The coordinates represent the position relative to the edge of the image, with the coordinate space having the positive x direction to the right, and the positive y direction downwards. These attributes return the actual rendered dimensions of the image, or zero if the dimensions are not known.

The following common input element content attributes and IDL attributes apply to the element: alt , formaction , formenctype , formmethod , formnovalidate , formtarget , height , src , and width content attributes; value IDL attribute. The following content attributes must not be specified and do not apply to the element: accept , autocomplete , checked , dirname , list , max , maxlength , min , minlength , multiple , pattern , placeholder , readonly , required , size , and step.

Readers are encouraged to read that section, where many of the same requirements are described in more detail. If the user clicked on the image at coordinate ,40 then the URL used to submit the form would be " process.

The input element represents a button that, when activated, resets the form. The element is a button. Constraint validation : The element is barred from constraint validation. The input element represents a button with no default behavior. A label for the button must be provided in the value attribute, though it may be the empty string.

The formats shown to the user in date, time, and number controls is independent of the format used for form submission. These attributes only apply to an input element if its type attribute is in a state whose definition declares that the attribute applies. The size attribute, if specified, must have a value that is a valid non-negative integer greater than zero.

If the attribute is present, then its value must be parsed using the rules for parsing non-negative integers , and if the result is a number greater than zero, then the user agent should ensure that at least that many characters are visible. The size IDL attribute is limited to only non-negative numbers greater than zero and has a default value of The readonly attribute is a boolean attribute that controls whether or not the user can edit the form control.

When specified, the element is not mutable. Constraint validation : If the readonly attribute is specified on an input element, the element is barred from constraint validation. The difference between disabled and readonly is that read-only controls are still focusable, so the user can still select the text and interact with it, whereas disabled controls are entirely non-interactive. Only text controls can be made read-only. The required attribute is a boolean attribute.

When specified, the element is required. To avoid confusion as to whether a radio button group is required or not, authors are encouraged to specify the attribute on all the radio buttons in a group. Indeed, in general, authors are encouraged to avoid having radio button groups that do not have any initially checked controls in the first place, as this is a state that the user cannot return to, and is therefore generally considered a poor user interface.

The multiple attribute is a boolean attribute that indicates whether the user is to be allowed to specify more than one value. If the user had, amongst many friends in their user contacts database, two friends "Arthur Dent" with address "art example. Suppose the user had entered "bob example. The user agent might show both the two friends mentioned earlier, as well as the "astrophy" and "astronomy" values given in the datalist element.

The compiled pattern regular expression , when matched against a string, must have its start anchored to the start of the string and its end anchored to the end of the string. When an input element has a pattern attribute specified, authors should provide a description of the pattern in text near the control. Authors may also include a title attribute to give a description of the pattern.

User agents may use the contents of this attribute, if it is present, when informing the user that the pattern is not matched, or at any other suitable time, such as in a tooltip or read out by assistive technology when the control gains focus. Relying on the title attribute for the visual display of text content is currently discouraged as many user agents do not expose the attribute in an accessible manner as required by this specification e.

When a control has a pattern attribute, the title attribute, if used, must describe the pattern. Additional information could also be included, so long as it assists the user in filling in the control. Otherwise, assistive technology would be impaired. For instance, if the title attribute contained the caption of the control, assistive technology could end up saying something like The text you have entered does not match the required pattern.

Birthday , which is not useful. Some form controls can have explicit constraints applied limiting the allowed range of values that the user can provide. Normally, such a range would be linear and continuous. The min and max attributes indicate the allowed range of values for the element.

The min attribute also defines the step base. Test-specific timeouts may also be applied, or the use of this. In v8. Warning: With async tests if you disable timeouts via this. Mocha supports the err. Mocha will attempt to display the difference between what was expected, and what the assertion actually saw.

By default, Mocha will attempt to trap uncaught exceptions thrown from running tests and report these as test failures. Use --allow-uncaught to disable this behavior and allow uncaught exceptions to propagate.

Will typically cause the process to crash. Non-compliant tests will be marked as failures. Causes Mocha to stop running tests after the first test failure it encounters.

Use this option to have Mocha check for global variables that are leaked while running tests. Specify globals that are acceptable via the --global option for example: --check-leaks --global jQuery --global MyLib.

See further explanation and workarounds. Prior to version v4. It can also be something like a runaway setInterval , or even an errant Promise that never fulfilled. The default behavior in v4.

Enforce a rule that tests may not be exclusive use of e. Enforce a rule that tests may not be skipped use of e. Updated in v6. Define a global variable name. For example, suppose your app deliberately exposes a global named app and YUI , you may want to add --global app --global YUI. By using this option in conjunction with --check-leaks , you can specify a whitelist of known global variables that you expect to leak into global scope.

Mocha uses this to highlight test cases that are taking too long. Update in v6. It is equivalent to --timeout 0. Specifies the test case timeout, defaulting to two 2 seconds milliseconds. Tests taking longer than this amount of time will be marked as failed. To override you may pass the timeout in milliseconds, or a value with the s suffix, e.

Note: synchronous blocking tests are also bound by the timeout, but they will not complete until the code stops blocking.

Infinite loops will still be infinite loops! The --ui option lets you specify the interface to use, defaulting to bdd. By default, Mocha uses the supports-color module to decide. In some cases, color output will be explicitly suppressed by certain reporters outputting in a machine-readable format. When possible, show the difference between expected and actual values when an assertion failure is encountered.

By default, Mocha attempts to distill stack traces into less noisy though still useful output. Allows use of third-party reporters. For example, mocha-lcov-reporter may be used with --reporter mocha-lcov-reporter after it has been installed. Can be specified multiple times. By default, Mocha will search for a config file if --config is not specified; use --no-config to suppress this behavior.

Removed in v8. Please use configuration file instead. Specify an explicit path to a package. By default, Mocha looks for a package. Specifying --extension will remove. For example, to load. The option can be given multiple times. The option accepts a comma-delimited list: --extension a,b is equivalent to --extension a --extension b. Explicitly include a test file to be loaded before other test files. Multiple uses of --file are allowed, and will be loaded in order given. Useful if you want to declare, for example, hooks to be run before every test across all other test files.

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The absolute weights of liver, kidneys, adrenals, testes or ovaries, epididymides or uterus, prostate gland, thymus, spleen, brain, pituitary gland, thyroid gland and heart in control, all treated and satellite groups of animals were recorded. In the study the full histopathology of the preserved organs and tissues was performed for all high dose, control animals, recovery animals and animals with macroscopical changes.

Results that were statistically significant were indicated using the probability values as follows: P Non-parametric tests were used for statistical evaluation of following parameters: selected haematology parameters with non-continuous distribution total erythrocyte count, total leucocyte count, total platelets count.

At first the Kruskal-Wallis test for the comparison of the measured effect in all treatment groups with the vehicle control group was used as global test, and then the two-groups Mann-Whitney test probability level 0. Clinical signs: no effects observed Description incidence and severity : In control animals and treated males and females of all dose levels and satellite groups no signs of disease were recorded during the check-in, acclimatisation and application period.

During the observation period no changes of health status were noted in any of the animals. No clinical changes were recorded in any of the animals.

No serious changes were found during examination of skin, hair, eye, visible mucous membranes, respiration, poise, gait, tonic movements, clonic movements, reaction to handling and other activities of all the animals. There were no unscheduled deaths during all the study. Body weight and weight changes: no effects observed Description incidence and severity : The body weights and necropsy body weights were similar in females of treated groups and control group for the whole application period.

The body weights and necropsy body weights of satellite treated females were comparable with the control satellite females during the whole application period and recovery period. Not statistically significantly decreased body weights and necropsy body weights were detected in satellite treated males compared to the control satellite group for the whole application and recovery period.

Food consumption and compound intake if feeding study : no effects observed Description incidence and severity : Food consumption was comparable between treated and control groups in males and females.

No effects were seen in food consumption in satellite groups. Food efficiency: no effects observed Water consumption and compound intake if drinking water study : no effects observed Description incidence and severity : Water consumption was comparable between treated and control groups in males and females. No effects were seen in water consumption in satellite groups. Ophthalmological findings: no effects observed Description incidence and severity : During an examination performed before the start of the study and at the end of the study, no changes were noted.

Haematological findings: effects observed, non-treatment-related Description incidence and severity : Males: Parameters relating to red blood cell and white blood cell components and haemocoagulation parameters of treated males were comparable with control males.

The fibrinogen concentration was statistically significantly decreased in all groups of treated males. All haematological parameters were in range of historical control. The differential percentage count of monocytes was increased without statistical significance in satellite treated males in comparison with the control satellite group and was outside of the historical control range. This exceedance of the historical control range was due to a marked increase in the differential percentage count of monocytes in one male No.

Other haematological parameters of satellite treated males were comparable to the satellite control males. There were no statistically significant differences between the treated and control females for other white blood cell parameters. Satellite females: Statistically significant decreases in RBC, haemoglobin concentration and HCT were noted in satellite treated females compared with satellite control females.

Other haematological parameters of satellite treated females were similar with the satellite control females. Overall, the differences were without dose response relationship and without correlation with other manifestation of toxicity.

All changes are presented by comparison with the respective control group. Others biochemical parameters were in range of historical control. Satellite males: A statistically significantly increased concentration of inorganic phosphorus was recorded in treated satellite males compared with satellite control males.

Other biochemical parameters of satellite treated males were similar with the satellite control males. All biochemical parameters were within the historical control range. All other biochemical parameters of treated females were similar with the control females and in the range of the historical control.

Satellite females: Statistically significantly increased glucose and chloride ion concentrations were recorded in high dose satellite females. Values of other parameters of the satellite high dose females were similar to satellite control females. All biochemical parameters were in range of historical control. Urinalysis findings: effects observed, non-treatment-related Description incidence and severity : Males: Statistically significant differences in pH and volume of urine were not detected.

Presence of proteins, leukocytes and blood were recorded in treated males as well as in control males, which is why these findings were concluded as not associated with the application of the test item.

The values of all other parameters of treated males were similar to control. Satellite males: Statistically significant difference in pH of urine was not detected.

Volume of urine was significantly decreased in treated males.

  Endpoint summary

This characteristic rise in insulin response to insulin resistance and hyperglycemia, followed by a subsequent decline, has been referred to as Starling's curve of the pancreas 1. This natural history of type 2 diabetes has been demonstrated in many prospective studies carried out in many diverse ethnic populations 1 — 18 , 36 , Natural history of type 2 diabetes. Although the plasma insulin response to the development of insulin resistance typically is increased during the natural history of type 2 diabetes Fig.

Note that insulin resistance is the inverse of insulin sensitivity. Supplemental Fig. In the right panel, the typical inverted U-shaped or Starling's curve of the pancreas for the plasma insulin response is evident.

Although not commented upon, similar conclusions can be reached from data in previous publications 2 , 3 , 7 , The therapeutic implications of these findings are readily evident. In biomedical phenomena, most reactions take place as a log function. These two variables are strongly and linearly related with an r value of 0. Therefore, the current diagnostic criteria 46 for IGT and type 2 diabetes are quite arbitrary and, like plasma cholesterol, glucose tolerance should be viewed as a continuum of risk.

The higher the 2-h plasma glucose concentration, even within the range of IGT, the greater is the risk for microvascular complications see subsequent discussion. T2DM, type 2 diabetes.

Even more ominous are the observations of Butler et al. By both pathophysiological and clinical standpoints, these pre-diabetic individuals with IGT should be considered to have type 2 diabetes. This is consistent with the well-established observation that the incidence of diabetes increases progressively with advancing age. Impaired insulin secretion has been shown to be an inherited trait in Finnish families with type 2 diabetes with evidence for a susceptibility locus on chromosome 12 Of these genes, the transcription factor TCF7L2 is best established 60 , Studies by Groop and colleagues 63 have shown that the T-allele of single nucleotide polymorphism rs of the TCF7L2 gene is associated with impaired insulin secretion in vivo and reduced responsiveness to glucagon-like peptide 1 GLP Both the CT and TT genotypes predict type 2 diabetes in multiple ethnic groups In both the Malmo and Botnia studies, presence of either the CT or TT genotype was associated with a significant reduction in the diabetes-free survival time, with odds ratios of 1.

Unfortunately, at present there are no known therapeutic interventions that can reverse either the age-related decline or genetic-related factors responsible for impaired insulin secretion. Therefore, interventions aimed at enhancing insulin sensitivity are of paramount importance.

Although simplistic in nature, this explanation lacks a mechanistic cause. Thus, just as excess deposition of fat LC-fatty acyl CoAs, diacylglycerol, and ceramide in liver and muscle has been shown to cause insulin resistance in these organs, i. Elevated plasma free fatty acid FFA levels impair insulin secretion, and this has been referred to as lipotoxicity 66 , Studies from our laboratory 24 have shown that a physiological elevation of the plasma FFA concentration for as little as 48 h markedly impairs insulin secretion in genetically predisposed individuals Fig.

Compared with saline infusion, lipid infusion markedly impaired both the first and second phases of C-peptide release and reduced the insulin secretory rate, calculated by deconvolution of the plasma C-peptide curve.

Conversely, a sustained reduction in plasma FFA concentration with acipimox in nondiabetic subjects with a strong family history of type 2 diabetes improved insulin secretion In vivo studies in rodents 69 — 71 and in humans 72 , as well as in vitro studies 73 , also support an important role for lipotoxicity.

Exposure to FFA caused a marked inhibition of insulin mRNA expression, decreased glucose-stimulated insulin release, and reduction of islet insulin content Effect of physiological elevation 48 h in the plasma FFA concentration brought about by lipid infusion on plasma C-peptide concentration left and insulin secretory response deconvolution of the palsma C-peptide curve right in offspring of two type 2 diabetic parents Studies by Rossetti et al.

Partially pancreatectomized diabetic rats are characterized by severe defects in both first- and second-phase insulin secretion compared with control rats. Following treatment with phlorizin, an inhibitor of renal glucose transport, the plasma glucose profile was normalized without changes in any other circulating metabolites. Normalization of the plasma glucose profile was associated with restoration of both the first and second phases of insulin secretion. In vitro studies with isolated human islets also have demonstrated that chronic exposure to elevated plasma glucose levels impairs insulin secretion 78 , In rats, Leahy et al.

First-phase 0—10 min and second-phase 10— min plasma insulin response during hyperglycemic clamp in partially pancreatectomized diabetic DIAB and control CON rats PHLOR, phlorizin. Although convincing evidence for a pathogenic role of IAPP exists in rodents 87 , 88 , the natural history of pancreatic amylin deposition in humans has yet to be defined Because amylin is secreted in a one-to-one ratio with insulin 95 , 96 and IAPP oligomers are toxic 89 , 93 , 94 , interventions that improve insulin sensitivity, i.

Of note, rosiglitazone has been shown to protect human islets against human IAPP toxicity by a phosphatidylinositol PI 3-kinase—dependent pathway The deficiency of GLP-1 can be observed in individuals with IGT and worsens progressively with progression to type 2 diabetes In addition to deficiency of GLP-1, there is resistance to the stimulatory effect of GLP-1 on insulin secretion , In contrast to GLP-1, plasma levels of GIP are elevated in type 2 diabetes, yet circulating plasma insulin levels are reduced Because GLP-1 deficiency occurs early in the natural history of type 2 diabetes, it follows that GLP-1 replacement therapy is a logical choice to restore the deficient insulin response that is characteristic of the diabetic condition.

Both the liver and muscle are severely resistant to insulin in individuals with type 2 diabetes rev. However, when discussing insulin resistance, it is important to distinguish what is responsible for the insulin resistance in the basal or fasting state and what is responsible for the insulin resistance in the insulin-stimulated state.

This glucose demand is met primarily by glucose production by the liver and to a smaller extent the kidneys In an average kg person, this amounts to the addition of an extra 25—30 g of glucose to the systemic circulation every night. As shown in Fig. In type 2 diabetic subjects, as the rate of basal HGP rises, so also does the fasting plasma glucose concentration, and these two variables are strongly correlated with an R value of 0.

This overproduction of glucose by the liver occurs in the presence of fasting plasma insulin levels that are increased 2. Similar observations have been made by others 27 , — The increase in basal HGP is explained entirely by an increase in hepatic gluconeogenesis — In addition to hepatic insulin resistance, multiple other factors contribute to accelerated rate of HGP including: 1 increased circulating glucagon levels and enhanced hepatic sensitivity to glucagon — ; 2 lipotoxicity leading to increased expression and activity of phosphoenolpyruvate carboxykinase and pyruvate carboxylase , the rate-limiting enzymes for gluconeogenesis; and 3 glucotoxicity, leading to increased expression and activity of glucosephosphatase, the rate-limiting enzyme for glucose escape from the liver Using the euglycemic insulin clamp technique in combination with tritiated glucose to measure total body glucose disposal, we 1 , 18 , 19 , 26 , 28 , 29 , 40 , , and others 12 , 16 , 44 , 45 , , — conclusively have demonstrated that lean type 2 diabetic individuals are severely resistant to insulin compared with age-, weight-, and sex-matched control subjects Fig.

A similar defect in insulin-stimulated muscle glucose uptake in type 2 diabetic subjects has been demonstrated by others — Insulin-stimulated total body glucose uptake left and insulin-stimulated leg glucose uptake right in control CON and type 2 diabetic T2DM subjects 28 , In type 2 diabetic subjects we, as well as others, have documented the presence of multiple intramyocellular defects in insulin action rev.

However, more proximal defects in the insulin signal transduction system play a paramount role in the muscle insulin resistance , This results in the translocation of insulin receptor substrate IRS -1 to the plasma membrane, where it interacts with the insulin receptor and also undergoes tyrosine phosphorylation.

This leads to the activation of PI 3-kinase and Akt, resulting in glucose transport into the cell, activation of nitric oxide synthase with arterial vasodilation — , and stimulation of multiple intracellular metabolic processes. Studies from our laboratory were the first to demonstrate in humans that the ability of insulin to tyrosine phosphorylate IRS-1 was severely impaired in lean type 2 diabetic individuals , , , in obese normal glucose tolerant individuals , and in the insulin-resistant, normal glucose tolerant offspring of two type 2 diabetic parents , Fig.

Similar defects have been demonstrated by others in human muscle 21 , 23 , — This defect in insulin signaling leads to decreased glucose transport, impaired release of nitric oxide with endothelial dysfunction, and multiple defects in intramyocellular glucose metabolism.

Relationship between impaired insulin signal transduction and accelerated atherogenesis in insulin-resistant subjects, i. In contrast to the severe defect in IRS-1 activation, we have shown that the mitogen-activated protein MAP kinase pathway, which can be activated by Shc, is normally responsive to insulin Fig.

The MAP kinase pathway, when stimulated, leads to the activation of a number of intracellular pathways involved in inflammation, cellular proliferation, and atherosclerosis — Thus, the block at the level of IRS-1 impairs glucose transport into the cell and the resultant hyperglycemia stimulates insulin secretion.

Because the MAP kinase pathway retains its sensitivity to insulin , , , this causes excessive stimulation of this pathway and activation of multiple intracellular pathways involved in inflammation and atherogenesis. This, in part, explains the strong association between insulin resistance and atherosclerotic cardiovascular disease in nondiabetic, as well as in type 2 diabetic, individuals — As shown by Miyazaki et al.

This is not surprising since gravity, not lipids or blood pressure, is the most important risk for peripheral vascular disease. The euglycemic insulin clamp, by maintaining plasma glucose and insulin levels constant, has become the gold standard for quantitating insulin sensitivity. However, the normal route of glucose administration in every day life is via the gastrointestinal tract.

Using a double tracer technique 1- 14 C-glucose orally and 3- 3 H-glucose intravenously in combination with hepatic vein catheterization, we set out to examine the disposal of oral versus intravenous glucose in healthy, normal glucose tolerant and type 2 diabetic subjects — In contrast, when glucose was administered orally, hepatic glucose uptake increased 4.

Thus, individuals with type 2 diabetes lack the gut factor that is responsible for augmenting hepatic glucose uptake following glucose ingestion. Hepatic glucose uptake in nondiabetic and diabetic DIAB subjects as a function of plasma glucose and insulin concentrations and route of glucose administration — In summary, impaired insulin secretion, decreased muscle glucose uptake, increased HGP, and decreased hepatic glucose uptake all contribute to the glucose intolerance in type 2 diabetic individuals.

The last decade has taught us that the fat cell also plays a pivotal role in the pathogenesis of type 2 diabetes.

Considerable evidence implicates deranged adipocyte metabolism and altered fat topography in the pathogenesis of glucose intolerance in type 2 diabetes 17 , 26 , 68 , , — : 1 Fat cells are resistant to insulin's antilipolytic effect, leading to day-long elevation in the plasma FFA concentration 26 , , — These FFA-induced disturbances are referred to as lipotoxicity. Lipid can also overflow into arterial vascular smooth cells, leading to the acceleration of atherosclerosis.

Using 14 C-palmitate in combination with the insulin clamp technique, Groop et al. In both type 2 diabetic supplemental Fig. A5 and obese nondiabetic subjects, the ability of insulin to suppress the plasma FFA concentration and inhibit FFA turnover is significantly impaired compared with lean normal glucose tolerant control subjects at all plasma insulin concentrations spanning the physiological and pharmacological range. Many investigators, including Boden, Shulman, and ourselves , , , , have shown that a physiological elevation in the plasma FFA concentration stimulates HGP and impairs insulin-stimulated glucose uptake in liver and muscle , — , — As discussed earlier, we and others 24 , have also shown that elevated plasma FFA levels inhibit insulin secretion.

Many years ago, Professor Philip Randle described his now famous cycle of substrate competition, whereby elevated FFA oxidation in muscle reciprocally impaired glucose oxidation. Although there clearly is substrate competition between FFA and glucose with respect to oxidative metabolism , , FFAs have been shown to have independent effects to inhibit glycogen synthase , and both glucose transport and glucose phosphorylation , More recently, we have examined the effect of a 4-h lipid versus saline infusion on the insulin signal transduction system in healthy lean normal glucose tolerant subjects During the saline control study, insulin increased whole-body glucose metabolism from 2.

Compared with the saline control study, lipid infusion caused a dose-response inhibition of muscle insulin receptor tyrosine phosphorylation, IRS-1 tyrosine phosphorylation, PI 3-kinase activity, and Akt serine phosphorylation Fig.

Effect of lipid infusion to cause a physiological-pharmacological elevation in plasma FFA concentration on insulin signal transduction in healthy nondiabetic subjects PY, phosphorylation. After fatty acids enter the cell, they can be converted to triglycerides, which are inert, or to toxic lipid metabolites such as fatty acyl CoAs, diacylglycerol, and ceramide. Using magnetic resonance spectroscopy, we quantitated intramyocellular triglyceride content in healthy normal glucose tolerant and type 2 diabetic subjects and demonstrated that muscle lipid content was significantly increased in the diabetic group R.

Similar results have been reported by Petersen et al. Fatty acyl CoAs, which are known to inhibit insulin signaling , , were also significantly increased in muscle in diabetic subjects , PGC-1 is the master regulator of mitochondrial biogenesis and augments the expression of multiple genes involved in mitochondrial oxidative phosphorylation — Pioglitazone reduced the intramyocellular lipid and fatty acyl CoA concentrations, and the decrement in muscle fatty acyl CoA content was closely related to the improvement in insulin-stimulated muscle glucose disposal When we reduced the intramyocellular fatty acyl CoA content with acipimox, a potent inhibitor of lipolysis, a similar improvement in insulin-mediated glucose disposal was noted Increased intramyocellular levels of diacylglycerol , and ceramides , have also been demonstrated in type 2 diabetic and obese nondiabetic subjects and shown to be related to the insulin resistance and impaired insulin signaling in muscle.

Most recently, we examined the effect of palmitoyl carnitine on ATP synthesis in mitochondria isolated from muscle of normal glucose tolerant subjects Collectively, these findings provide strong support for lipotoxicity and adipocyte insulin resistance in the pathogenesis of type 2 diabetes. Although the fat cell is a worthy member of the dysharmonious quartet, the time has arrived to expand the playing field to include the gastrointestinal tissues as the fifth member of the quintessential quintet.

Glucose ingestion elicits a much greater insulin response than an intravenous glucose infusion that mimics the plasma glucose concentration profile observed with oral glucose 98 — As discussed earlier, GLP-1 secretion by the L-cells of the distal small intestine is deficient 98 — , while GIP secretion by the K-cells of the more proximal small intestine is increased, but there is resistance to the stimulatory effect of GIP on insulin secretion — GLP-1 also is a potent inhibitor of glucagon secretion 98 — , and the deficient GLP-1 response contributes to the paradoxical rise in plasma glucagon secretion and impaired suppression of HGP that occurs after ingestion of a mixed meal Clearly, the gut is a major endocrine organ and contributes to the pathogenesis of type 2 diabetes.

Studies from our laboratory have demonstrated that in healthy normal glucose tolerant subjects, approximately one-half of the suppression of HGP following a mixed meal is secondary to inhibition of glucagon secretion, the other one-half is secondary to the increase in insulin secretion, and the insulin-to-glucagon ratio correlated strongly with the suppression of HGP during the meal These studies also demonstrated that a large amount of the ingested glucose load did not appear in the systemic circulation, consistent with previous studies from our laboratory 28 , — This could have been the result of delayed gastric emptying, a known effect of exenatide, or an increase in splanchnic primarily reflects liver glucose uptake.

To examine this question more directly, type 2 diabetic subjects received a 6-h meal tolerance test with the double tracer technique 1- 14 C-glucose orally and 3- 3 H-glucose intravenously before and after 2 weeks of exenatide treatment Exenatide was not given on the day of the study. The ingested glucose load was labeled with acetaminophen to follow gastric empting. Exenatide significantly reduced both the fasting and postprandial plasma glucose levels following ingestion of the meal compared with the baseline study performed prior to exenatide.

The increase in insulin secretion, in concert with a decline in glucagon release, led to a significant reduction in HGP following ingestion of the mixed meal. Neither splanchnic nor peripheral tissue glucose uptake was significantly altered. Thus, the primary effect of exenatide to improve glucose tolerance is related to the incretin's suppressive effect on HGP.

Most recently, Cherrington and Bergman and colleagues have presented evidence in support of an effect of GLP-1 to enhance hepatic glucose uptake of ingested glucose in dogs. Many groups, dating back to the s, have demonstrated that the basal plasma glucagon concentration is elevated in type 2 diabetic individuals — , — The important contribution of elevated fasting plasma glucagon levels to the increased basal rate of HGP in type 2 diabetic individuals was provided by Baron et al.

Compared with control subjects, diabetic individuals had a markedly elevated rate of basal HGP, which correlated closely with the increase in fasting plasma glucagon concentration. These results conclusively demonstrate the pivotal role of hyperglucagonemia in the pathogenesis of fasting hyperglycemia in type 2 diabetes.

There also is evidence that the liver may be hypersensitive to the stimulatory effect of glucagon in hepatic gluconeogenesis In summary, drugs that inhibit glucagon secretion or block the glucagon receptor are likely to be effective in treating patients with type 2 diabetes. One such example is exenatide , but glucagon receptor antagonists also have been shown to be effective The result is that no glucose appears in the urine.

In animal models of both type 1 and type 2 diabetes, the maximal renal tubular reabsorptive capacity, or Tm, for glucose is increased — In humans with type 1 diabetes, Mogensen et al. In human type 2 diabetes, the Tm for glucose has not been systematically examined. No studies in either type 1 or type 2 diabetic individuals have examined the splay in the glucose titration curve in humans.

These observations have important clinical implications. Thus, an adaptive response by the kidney to conserve glucose, which is essential to meet the energy demands of the body, especially the brain and other neural tissues, which have an obligate need for glucose, becomes maladaptive in the diabetic patient.

Instead of dumping glucose in the urine to correct the hyperglycemia, the kidney chooses to hold on to the glucose. Even worse, the ability of the diabetic kidney to reabsorb glucose appears to be augmented by an absolute increase in the renal reabsorptive capacity for glucose.

In summary, the development of medications that inhibit renal proximal tubular glucose reabsorption provides a rational approach to the treatment of type 2 diabetes The last, and perhaps most important, player to be implicated in the pathogenesis of type 2 diabetes is the brain, which, along with his seven companions, forms the ominous octet. It is abundantly clear that the current epidemic of diabetes is being driven by the epidemic of obesity , Porte and colleagues — were among the first to demonstrate that, in rodents, insulin was a powerful appetite suppressant.

Obese individuals, both diabetic and nondiabetic, are characterized by insulin resistance and compensatory hyperinsulinemia. Nonetheless, food intake is increased in obese subjects despite the presence of hyperinsulinemia, and one could postulate that the insulin resistance in peripheral tissues also extends to the brain.

Our laboratory has attempted to address the issue of impaired appetite regulation by insulin in obese subjects using functional magnetic resonance imaging MRI to examine the cerebral response to an ingested glucose load After glucose ingestion, two hypothalamic areas with consistent inhibition were noted: the lower posterior hypothalamus, which contains the ventromedial nuclei, and the upper posterior hypothalamus, which contains the paraventricular nuclei.

In both of these hypothalamic areas, which are key centers for appetite regulation, the magnitude of the inhibitory response following glucose ingestion was reduced in obese, insulin-resistant, normal glucose tolerant subjects, and there was a delay in the time taken to reach the maximum inhibitory response, even though the plasma insulin response was markedly increased in the obese group.

Whether the impaired functional MRI response in obese subjects contributes to or is a consequence of the insulin resistance and weight gain remains to be determined. Nonetheless, these results suggest that the brain, like other organs liver, muscle, and fat in the body, may be resistant to insulin. Studies by Obici et al. The preceding review of the pathophysiology of type 2 diabetes has important therapeutic implications Table 1.

First, effective treatment of type 2 diabetes will require multiple drugs used in combination to correct the multiple pathophysiological defects. Second, the treatment should be based upon known pathogenic abnormalities and NOT simply on the reduction in A1C.

Let us now examine the current therapeutic options as they relate to four of the key pathophysiological derangements present in type 2 diabetes Fig. At the level of the liver, we have shown that both metformin — and the TZDs , — are potent insulin sensitizers and inhibit the increased rate of hepatic gluconeogenesis , that is characteristic of type 2 diabetic patients. In muscle, TZDs are potent insulin sensitizers — , whereas metformin is a very weak insulin sensitizer , , Since the TZDs work through the classic insulin signaling pathway , , whereas metformin works through the AMP kinase pathway , , combination therapy with a TZD plus metformin gives a completely additive effect to reduce the A1C — , and hypoglycemia is not encountered because these drugs are insulin sensitizers and do not augment insulin secretion.

In adipose tissue, the TZDs are also excellent insulin sensitizers and are potent inhibitors of lipolysis Treatment of type 2 diabetes: a therapeutic approach based upon pathophysiology. Nonetheless, the two most commonly prescribed drugs in the U. After an initial drop in the A1C, sulfonylurea-treated patients experienced a progressive deterioration in glycemic control that paralleled the rise in A1C in the conventionally treated group Fig.

Moreover, in the UKPDS sulfonylureas were shown not to have a significant protective effect against atherosclerotic cardiovascular complications 34 , and some studies even have suggested that sulfonylureas may accelerate the atherogenic process , Similarly, metformin-treated patients in the UKPDS, after an initial decline in A1C, secondary to the biguanide's inhibitory effect on HGP, also experienced a progressive deterioration in glycemic control Fig.

Conventionally treated diabetic subjects received diet plus exercise therapy 36 , Summary of studies examining the effect of sulfonylurea SU treatment versus placebo or versus active-comparator on A1C in type 2 diabetic subjects 36 , , , , — , — See text for a more detailed discussion. GLY, glyburide. Summary of studies examining the effect of TZDs versus placebo or versus active-comparator on A1C in type 2 diabetic subjects , , , — There are no exceptions to this consistent loss of glycemic control with the sulfonylureas after the initial 18 months of therapy.

In addition to these studies performed in type 2 diabetic patients, there are five studies in subjects with IGT demonstrating that TZDs prevent the progression of IGT to type 2 diabetes — Bunck et al. Subjects received glargine insulin or exenatide to similarly reduce the A1C to 6.

Before and after 1 year, C-peptide secretion was evaluated with an min hyperglycemic clamp. During the repeat hyperglycemic clamp performed after 1 year, both the first 0—10 min and second 10—80 min phases of insulin secretion were increased 1. A subset of these subjects were followed-up for 3. However, it is not known whether the subjects who did not continue in this long-term extension study had the same characteristics, i.

Importantly, the stimulatory effect of exenatide on insulin secretion dissipates when normoglycemia is achieved, thereby minimizing the adverse effect of hypoglycemia. Hypoglycemia does not occur with the DPP-IV inhibitors, but they do not suppress appetite or cause weight loss.

The ADA algorithm for the treatment of type 2 diabetes advocates a stepwise therapeutic approach that is based upon reduction in the plasma glucose concentration and NOT upon known pathophysiological disturbances If the goal is not reached or if secondary failure occurs, the ADA algorithm suggests one of three options: 1 First is the addition of basal insulin, an option unlikely to be chosen by primary care physicians or most endocrinologists in the U.

Moreover, all of these insulin-based add-on studies have been associated with a high incidence of hypoglycemia and major weight gain range 4. Thus, the ADA algorithm basically guides the physician to select a sulfonylurea as the choice for a second antidiabetic agent. Moreover, third party reimbursers like this option because sulfonylureas are inexpensive. From the pathophysiological standpoint, this represents a major step backward, since an overwhelming body of evidence-based medicine Fig.

Although this algorithm is not the official policy statement of ADA, it is likely to be interpreted as such by most third-party payers. ADA algorithm for the treatment of type 2 diabetes SU, sulfonylurea.

Effect of insulin Ins and exenatide on A1C and body weight in type 2 diabetic subjects — ADA consensus statement algorithm on the treatment of type 2 diabetes. As indicated, this does not represent the official statement of ADA See text for a detailed discussion An alternate therapeutic algorithm is based upon known pathophysiological disturbances in type 2 diabetes Fig.

This algorithm provides a more rational approach and is more likely to produce a durable long-term effect. Pathophysiological-based algorithm: treatment of type 2 diabetes based upon pathophysiology. See text for a detailed discussion. Comparison of the stepwise ADA algorithm with the combination pathophysiological-based algorithm is shown in Fig.

Conversely, the TZDs and the GLP-1 analogs, when used as monotherapy, each have been shown to have a more durable effect. Hypoglycemia is common with the sulfonylureas and insulin, and this prohibits the achievement of the optimal A1C goal of 6.

Lastly, weight gain is common with sulfonylurea and insulin therapy, whereas weight loss is the norm with exenatide, and exenatide blocks the weight gain that is associated with the TZDs. Comparison of the ADA and pathophysiological-based algorithms. Although this paradigm shift, which is based upon pathophysiology, represents a novel approach to the treatment of type 2 diabetes, it is substantiated by a vast body of basic scientific and clinical investigational studies.

Because this algorithm is based upon the reversal of known pathophysiological defects, it has a high probability of achieving durable glycemic control.

If the plasma glucose concentration can be maintained within the normal nondiabetic range, the microvascular complications of the disease, which are costly to treat and associated with major morbidity and mortality, can be prevented.

Most importantly, this will enhance the quality of life for all diabetic patients. National Center for Biotechnology Information , U. Journal List Diabetes v. Ralph A. Find articles by Ralph A. Author information Copyright and License information Disclaimer.

Corresponding author: Ralph A. DeFronzo, ude. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered. This article has been cited by other articles in PMC. Open in a separate window. A2 Age. Insulin resistance. Insulin signal transduction. Route of glucose administration: oral vs. Summary: pathogenesis. A4 The last decade has taught us that the fat cell also plays a pivotal role in the pathogenesis of type 2 diabetes.

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Diabetes Care ; 31 Suppl. Diabetes Prevention Program Research Group The prevalence of retinopathy in impaired glucose tolerance and recent-onset diabetes in the Diabetes Prevention Program. Management of hyperglycemia in type 2 diabetes: a consensus algorithm for the initiation and adjustment of therapy. The default behavior in v4. Enforce a rule that tests may not be exclusive use of e.

Enforce a rule that tests may not be skipped use of e. Updated in v6. Define a global variable name. For example, suppose your app deliberately exposes a global named app and YUI , you may want to add --global app --global YUI. By using this option in conjunction with --check-leaks , you can specify a whitelist of known global variables that you expect to leak into global scope. Mocha uses this to highlight test cases that are taking too long. Update in v6.

It is equivalent to --timeout 0. Specifies the test case timeout, defaulting to two 2 seconds milliseconds. Tests taking longer than this amount of time will be marked as failed. To override you may pass the timeout in milliseconds, or a value with the s suffix, e.

Note: synchronous blocking tests are also bound by the timeout, but they will not complete until the code stops blocking. Infinite loops will still be infinite loops! The --ui option lets you specify the interface to use, defaulting to bdd. By default, Mocha uses the supports-color module to decide. In some cases, color output will be explicitly suppressed by certain reporters outputting in a machine-readable format.

When possible, show the difference between expected and actual values when an assertion failure is encountered. By default, Mocha attempts to distill stack traces into less noisy though still useful output. Allows use of third-party reporters. For example, mocha-lcov-reporter may be used with --reporter mocha-lcov-reporter after it has been installed. Can be specified multiple times. By default, Mocha will search for a config file if --config is not specified; use --no-config to suppress this behavior.

Removed in v8. Please use configuration file instead. Specify an explicit path to a package. By default, Mocha looks for a package. Specifying --extension will remove. For example, to load. The option can be given multiple times.

The option accepts a comma-delimited list: --extension a,b is equivalent to --extension a --extension b. Explicitly include a test file to be loaded before other test files. Multiple uses of --file are allowed, and will be loaded in order given. Useful if you want to declare, for example, hooks to be run before every test across all other test files. Files specified in this way should contain one or more suites, tests or hooks.

If this is not the case, consider --require instead. Explicitly ignore exclude one or more test files, directories or globs e. You cannot use --require to set hooks. If you want to set hooks to run, e. There is no separate --import flag. Sort test files by absolute path using Array. The --watch-files and --watch-ignore options can be used to control which files are watched for changes.

List of paths or globs to watch when --watch is set. If a file matching the given glob changes or is added or removed mocha will rerun all tests. The option accepts a comma-delimited list: --watch-files a,b is equivalent to --watch-files a --watch-files b. List of paths or globs to exclude from watching. The option accepts a comma-delimited list: --watch-ignore a,b is equivalent to --watch-ignore a --watch-ignore b.

Cause Mocha to only run tests matching the given regexp , which is internally compiled to a RegExp. The same goes for any other part of a suite or test-case title, --grep users would be valid as well, or even --grep GET. Read more about running tests in parallel. Hint: Use --jobs 0 or --jobs 1 to temporarily disable --parallel.

The mocha executable supports all applicable flags which the node executable supports. If the --enable-source-maps flag is passed to mocha, source maps will be collected and used to provide accurate stack traces for transpiled code:. Prepend --v8- to any flag listed in the output of node --v8-options excluding --v8-options itself to use it. Depending on the number and nature of your tests, you may find a significant performance benefit when running tests in parallel using the --parallel flag.

Parallel tests should work out-of-the box for many use cases. However, you must be aware of some important implications of the behavior. These reporters expect Mocha to know how many tests it plans to run before execution.

This information is unavailable in parallel mode, as test files are loaded only when they are about to be run. In parallel mode, reporter output is buffered ; reporting will occur after each file is completed. You cannot use it. This is for the same reason as the incompatible reporters noted above: in parallel mode, Mocha does not load all files and suites into memory before running tests. TIP: If parallel mode is defined in your config file, you can temporarily disable it on the command-line by using either the --no-parallel flag or reducing the job count, e.

In parallel mode, Mocha does not guarantee the order in which test files will run, nor which worker process runs them. Because of this, the following options, which depend on order, cannot be used in parallel mode:.

Running tests in parallel mode will naturally use more system resources. The OS may take extra time to schedule and complete some operations, depending on system load. For this reason, the timeouts of individual tests may need to be increased either globally or otherwise.

When used with --bail or this. Mocha must shut down its worker processes before exiting. Likewise, subprocesses may throw uncaught exceptions. A root hook is a hook in a test file which is not defined within a suite. An example using the bdd interface:. When Mocha runs in parallel mode, test files do not share the same process, nor do they share the same instance of Mocha. Consequently, a hypothetical root hook defined in test file A will not be present in test file B. If you need to run some code once and only once , use a global fixture instead.

Third-party reporters may encounter issues when attempting to access non-existent properties within Test , Suite , and Hook objects. If a third-party reporter does not work in parallel mode but otherwise works in serial mode , please file an issue. Some types of tests are not so well-suited to run in parallel. Free-tier cloud CI services may not provide a suitable multi-core container or VM for their build agents. Regarding expected performance gains in CI: your mileage may vary.

It may help to use a conditional in a. CI , and adjust the job count as appropriate. In some cases, you may want a hook before or after every test in every file.

These are called root hooks. Previous to v8. This still works in v8. For that reason, running root hooks using this method is strongly discouraged , and may be deprecated in the future. A Root Hook Plugin file is a script which exports via module. Root hooks work with any interface, but the property names do not change. In other words, if you are using the tdd interface, suiteSetup maps to beforeAll , and setup maps to beforeEach. Tip: If you need to ensure code runs once and only once in any mode, use global fixtures.

If you need to perform some logic—such as choosing a root hook conditionally, based on the environment— mochaHooks can be a function which returns the expected object. If you need to perform an async operation, mochaHooks can be Promise -returning:. Multiple root hook plugins can be registered by using --require multiple times. For example, to register the root hooks in hooks-a. These will be registered and run in order. NOTE: Careful! At first glance, global fixtures seem similar to root hooks.

However, unlike root hooks, global fixtures:. There are two types of global fixtures: global setup fixtures and global teardown fixtures. To use it, load this file when running Mocha via mocha --require fixtures. Now, before Mocha loads and runs your tests, it will execute the above global setup fixture, starting a server for testing. To do that, use a global teardown fixture. Global setup fixtures and global teardown fixtures share a context , which means we can add properties to the context object this in the setup fixture, and reference them later in the teardown fixture.

As explained above —and below —test files do not have access to this context object. You could be clever and try to get around this restriction by assigning something to the global object, but this will not work in parallel mode. Note that we do not reference the server object anywhere in our tests! Finally, use this command to bring it together: mocha --require fixtures. This flowchart will help you decide which of hooks , root hook plugins or global fixtures you should use.

The BDD interface provides describe , context , it , specify , before , after , beforeEach , and afterEach. Similarly, specify is an alias for it. The keys before , after , beforeEach , and afterEach are special-cased, object values are suites, and function values are test-cases:. The require interface allows you to require the describe and friend words directly using require and call them whatever you want.

This interface is also useful if you want to avoid global variables in your tests. Note : The require interface cannot be run via the node executable, and must be run via mocha. Mocha reporters adjust to the terminal window, and always disable ANSI-escape coloring when the stdio streams are not associated with a TTY.

This is the default reporter. The Spec reporter outputs a hierarchical view nested just as the test cases are. The Dot Matrix reporter is a series of characters which represent test cases. Failures highlight in red exclamation marks! Good if you prefer minimal output. The List reporter outputs a simple specifications list as test cases pass or fail, outputting the failure details at the bottom of the output.

The Min reporter displays the summary only, while still outputting errors on failure. This reporter works great with --watch as it clears the terminal in order to keep your test summary at the top.

Wrap it with a header, footer, and some styling, then you have some fantastic documentation! The Markdown reporter generates a markdown TOC and body for your test suite. This is great if you want to use the tests as documentation within a Github wiki page, or a markdown file in the repository that Github can render. For example, here is the Connect test output.

The XUnit reporter is also available.