text:
Allison Point Campground
Valdez, Alaska
Phone: (907) 835-2530
Visit Campground Website
Sites: 61
Recent Rate: $15 8/2014
Latitude: 61.0862770042762
Longitude: -146.341540576935
These reviews are the opinion of an RVParkReviews' member and not the views of RVParkReviews.com
Date of Stay: August, 2014 - $15.00
Beware of the access road! It dead ends without warning, and with no space to turn around. There are 2 poorly-maintained pit toilets for the entire campground. The view is beautiful, so this could be a great site if it received some TLC. We camped at Allison Point Campground in a Fifth Wheel.Undo
Date of Stay: July, 2006 - $10.00
Sites are tight, but everyone is friendly, lots of RV's that have been coming for years, canning and smoking salmon. Great place to stay if staying long term in Valdez.. We camped at Allison Point Campground in a Motorhome.Undo
Date of Stay: July, 2005 - $10.00
This campground is right on the water. The only problem was the salmon were running and there were dead fish all over the place. We camped at Allison Point Campground in a Motorhome.Undo
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Not much to really tell about myself. Simple teenage girl, who loves rock/metal music, and video games. I also enjoy to write stories. Short ones. With blood. Tons of it. Anyway, Ciao darlings Steam: CrY40t!c 4nGe|
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John Sibley Butler says creativity is a necessary asset in business and shares the source of his inspiration. Butler is the director of the Herb Kelleher Center for Entrepreneurship and the Institute for Innovation and Creativity (IC2).
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Wednesday, April 1, 2015
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Winnipeg Free Press - ONLINE EDITION
A sexist blow to 'hot' women
Just when women think that equality between the sexes is nigh, along comes something outlandish to snap us into place.
The latest reminder was delivered by the Iowa Supreme Court. In a 7-0 decision, it ruled that a dentist could fire his assistant merely because he found her presence in the office to be too titillating — an "irresistible attraction" are the words chosen by Justice Edward Mansfield in his opinion.
That's right, ladies. If the boss finds you too hot, you can be fired. This is not a joke, although portions of the December decision read like the satirical news site The Onion. Male immaturity just got a big thumbs up from the all-male Iowa Supreme Court.
Melissa Nelson, 32, had been a valued employee for more than 10 years. Dentist James H. Knight, 53, admitted in court records she was "the best dental assistant he ever had."
Both are married with children and insist they did not have a sexual relationship. However, Knight is a man you wouldn't want as a boss and probably not as a husband. He clearly crossed the line of civility, judging by examples in the court records.
He told Nelson "that if she saw his pants bulging, she would know her clothing was too revealing," according to court documents.
The dentist admitted telling Nelson that her lack of a sex life was akin to "having a Lamborghini in the garage and never driving it." He also texted her asking how often she had orgasms.
Finally, Knight's wife (who also worked in the office) grew concerned. At her insistence, Nelson was fired, given one month's severance.
The dentist argued that he was within his rights to fire Nelson, as she was a threat to his marriage. He feared he wouldn't be able to resist an affair.
This man needed a marriage counselor, not a free pass from the state supreme court.
And just what were the justices thinking? Surely, they know that Knight's lame justification has long been used to keep women out of particular jobs. The idea is that with females around, men wont be able to control themselves. And we can't have that, now can we?
Law enforcement, the military, firefighting, construction — any number of fields have used this argument to exclude women.
Nelson's case was undercut by the fact that other women, presumably more resistible ones, were also employed in the office. The case also did not meet guidelines for "a hostile work environment" or "abusive atmosphere." Nelson didn't sue for that. Her complaint was based on the firing. She argued that she was let go due to her gender.
Men, too, have reason to find the ruling a little bit insulting. It treats them like little boys. It implies that they are incapable of controlling their sexual urges. Women must bear the burden of maintaining chaste relations between the sexes.
The sad reality is that there are no legal protections against much of the demeaning, ridiculously immature behavior that still occurs far too often in workplaces.
And, yes, women can be offensive too, although there is no clear evidence Nelson behaved in a questionable manner. Knight complained of her tight clothing. In interviews, she says she wore scrubs.
In the course of their deliberations about what to do about Knight's impure thoughts toward Nelson, the dentist and his wife sought the advice of their pastor. The pastor endorsed their idea of firing the other woman, even though he knew nothing had transpired between her and the dentist.
If this is what passes for defending traditional marriage, that institution is in trouble.
It's going to take a few more generations to breed that sort of short-sided foolishness away. And don't expect the courts to help.
Mary Sanchez is an opinion-page columnist for The Kansas City Star.
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Hydrangea has lots of flower buds but they do not bloom
I have a hydrangea that has a lot of flower buds but only 1 or 2 of them will actually bloom. The blooms are a lightblue/pale yellow color. The plant gets morning sun and afternoon shade. Any suggestions as to why the buds won't bloom?
Sorry I took so long to reply. The buds are not getting eaten, right now there has got to bee at least 50 large flower buds, some of them have a couple of petal open around the edges. I will take a picture when it stops raining. I have had this plant for about 4-5 years, at first I was cutting it down in the fall, then discovered that is why I had no buds, now I don't prune and get lots of buds that won't bloom!!!
photos of hydrangea that won't bloom
Here is a link that might be useful: photobucket
It looks like you are growing a lacecap hydrangea, and it looks normal to me--although I've never grown a lacecap. One reason I've avoided them is because they do not get those big "mophead" blooms that many gardeners want from their hydrangeas. Were you expecting a mophead bloom? If so, you will have to plant a mophead instead of a lacecap.
I hope I haven't misunderstood your problem, but for a lacecap, your hydrangea is looking pretty good.
Kate is correct, you have a lacecap hydrangea. What you see is all you will get from this hydrangea. Although I think it looks pretty good because I like lacecaps.. I bought some aluminum sulfate at my garden center and added it to my lacecap. The flowers are now very deep dark blue and much more striking than they were before.


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Starbucks to Offer Wireless Charging Pads
Starbucks (SBUX) and Duracell say they are rolling out Powermat wireless charging devices in stores in San Francisco. The charging spots will expand into other major markets in 2015, and the companies plan to put the devices in all Starbucks and Teavana locations over time.
The companies say stores will have "Powermat Spots," designated areas on tables and counters where customers can put their smartphones and charge them wirelessly.
Some Starbucks locations in Boston and San Jose already have Powermat devices.
Powermat makes the equipment. It formed a joint venture with Duracell in 2011. Duracell is a unit of Procter & Gamble (PG).
More from The Associated Press
•Federal Agents Charged With Stealing Digital Currency
•McDonald's to Test All-Day Breakfast Menu in San Diego
•Former Fed Chairman Starting 'Ben Bernanke's Blog'


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Hiking Deer Creek Trail in Grand Canyon
Most Inner Canyon river trips stop to enjoy Deer Creek Falls and hike the Deer Creek Trail. Get information about this popular trail and a map to the trailhead.
Most Inner Canyon river trips stop to enjoy Deer Creek Falls and hike the Deer Creek Trail. Get information about this popular trail and a map to the trailhead.
To see Grand Canyon by helicopter or plane, you need to start outside the park. Kathleen Bryant tells you how much flightseeing costs and offers tour company recommendations.
Grand Canyon National Park sprawls over more than 1,900 square miles, but it's the 40-mile stretch along the South Rim that draws the most visitors.
What does the South Rim have to offer vs the Inner Canyon? Plan your trip with an overview and travel maps of the different regions within Grand Canyon.
Arizona's Grand Canyon is a place of grand drama and serene vistas, so vast and varied that each visitor will experience it from a different perspective.
This full-color guide to the Grand Canyon includes vibrant photos and helpful planning maps. Local Arizonan Kathleen Bryant shares the many ways to experience the wonders of the Grand Canyon, from river rafting in the inner canyon to "walking on air" on the Grand Canyon Skywalk. Bryant includes a range of diverting trip strategies, including […]
You'll find merchants with Mexican imports, folk arts, Western Americana, and Indian jewelry; boutiques with clothes you'll find nowhere else; and galleries featuring the work of artists from Tucson and the rest of the world.
Near Tucson are three casinos owned and operated by Native American tribes that offer a variety of gaming along with fine accommodations and restaurants.
Gas up the car, grab some road food and sodas, make that perfect highway mix for the stereo (pick songs that go well with long, empty views), and hit the road on one of these scenic drives around Arizona.
Whether you're shopping in the streets or hiking in the hills, Arizona's incessant sun can quickly become dangerous for the unprepared. Learn to recognize the symptoms of heatstroke and other travel safety tips.


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Posted| Updated
The early-hours lockout for patrons of hotels and clubs hurts the right of venues to trade, the Full Court of the South Australian Supreme Court has heard.
Barrister Dick Whitington has argued in court on behalf of the owner of The Palace nightclub in Hindley Street in Adelaide.
He has told the hearing the Liquor Licensing Act infers a "right to trade" which has been "radically altered" by the SA Government's Late Night Trading Code of Practice, introduced last month.
Mr Whitington has suggested the right to serve alcohol could be made so difficult that there really is no right at all.
Topics: courts-and-trials, law-crime-and-justice, hospitality, industry, business-economics-and-finance, alcohol, adelaide-5000, sa
Posted| Updated
New research has found the stress of working in busy commercial kitchens is driving apprentice chefs to drink.
Topics: education, alcohol-education, drug-use, health, alcohol, business-economics-and-finance, industry, hospitality, bullying, australia, qld, brisbane-4000
Gaming group Echo Entertainment has outlined its expansion plans at its annual general meeting.
Topics: gambling, hospitality, tourism, activism-and-lobbying, programs-and-initiatives, brisbane-4000, southport-4215, sydney-2000
Coffs Harbour restaurateur is supporting a push for penalty rate cuts
Topics: work, hospitality, regional, coffs-harbour-2450, port-macquarie-2444
Plans for a $24 million hotel and conference centre in Newcastle are now on public display.
Topics: urban-development-and-planning, hospitality, newcastle-2300
Posted| Updated
Pub owners and hospitality staff fear changes to liquor licensing under Queensland's new anti-bikie legislation could make it harder for them to do their jobs.
Topics: law-crime-and-justice, crime, crime-prevention, laws, alcohol, hospitality, qld, australia
Topics: reptiles, animal-science, travel-and-tourism, hospitality, animals, animals-and-nature
In Tibooburra in far west New South Wales, German backpacker Kerstin Meyer was looking for a real outback adventure but didn't anticipate finding a strange animal in her room late one night. Thinking it was a crocodile, Ms Meyer ran for help but soon discovered it was something less dangerous but rather a small goanna.
Topics: reptiles, travel-and-tourism, lifestyle-and-leisure, animals-and-nature, hospitality
Posted| Updated
It value adds and costs nothing, yet it is something some Perth businesses struggle to provide.
Topics: hospitality, perth-6000
Topics: history, hospitality, mining-rural, ravenswood-4816
Posted| Updated
James Packer confirms Crown is in talks with the Sri Lankan Government to build a $US400m casino in Colombo.
Topics: business-economics-and-finance, industry, hospitality, australia, sri-lanka
The Byron Mayor says if a liquor licence is transferred to a new topless bar in Byron Bay, it will be able to stay open until seven o'clock in the morning.
Topics: hospitality, local-government, byron-bay-2481, lismore-2480
Requirements will need to be satisfied before topless bar can satisfy further customers
Topics: hospitality, byron-bay-2481
The Byron Mayor wants to shut down a new topless bar in Byron Bay.
Simon Richardson says the council is not in favour of the operation, but could do nothing to stop it because the bar is operating under an existing liquor and restaurant licence.
Topics: local-government, hospitality, byron-bay-2481, lismore-2480
Posted| Updated
The Byron Shire Mayor says the council could do nothing to stop a topless bar opening in Byron Bay's CBD.
Topics: women, hospitality, tourism, byron-bay-2481, lismore-2480
The Railwaytown area of Broken Hill is without a pub for the first time in 125 years with the closure of the South Australian Hotel.
Topics: hospitality, industry, history, broken-hill-2880
Topics: hospitality, industry, history, broken-hill-2880
Posted| Updated
A legal challenge will be heard in the Supreme Court against regulations to prevent people entering licensed venues in Adelaide after 3:00am.
Topics: law-crime-and-justice, crime-prevention, states-and-territories, government-and-politics, hospitality, adelaide-5000, sa, australia
Skills shortages in tourism and hospitality under scrutiny in Coffs Harbour
Topics: work, tourism, hospitality, government-and-politics, coffs-harbour-2450, port-macquarie-2444
James Packer's company has reported a drop in earnings after selling its stake in Echo Entertainment.
Topics: business-economics-and-finance, company-news, industry, hospitality, australia
Newcastle Trades Hall Council is welcoming a crackdown on dodgy hospitality businesses in the Hunter.
Topics: hospitality, newcastle-2300
Posted| Updated
The Federal Government has defended a slow take-up in the number of visas granted for low-paid seasonal workers.
Topics: industrial-relations, business-economics-and-finance, immigration, hospitality, agricultural-crops, australia, solomon-islands, vanuatu, papua-new-guinea, east-timor, pacific
Posted| Updated
The Fair Work Ombudsman has announced a crackdown on the work rates paid by Australian cafes, restaurants and catering companies.
Topics: hospitality, business-economics-and-finance, australia, nt
Posted| Updated
The workplace watchdog is warning hospitality business owners in Newcastle to make sure they have their books in order.
Topics: hospitality, regulation, small-business, newcastle-2300
The founding owner of Bacchus says if the restaurant closes permanently it will be a major loss to Newcastle's fine dining culture.
Topics: hospitality, newcastle-2300


text:
home | issues | standard version
spiked issue: Iraq
-- Mon 9 March --
ISIS's very modern war on the past
It is not just the museum-destroying Islamic State that yearns for a Year Zero.
by Frank Furedi
-- Thu 26 February --
Is ISIS going to invade Europe from Libya?
In a nutshell, no. So stop the scaremongering.
by Henry Williams
-- Mon 23 February --
An ominous pilgrimage to Syria: what made them go?
Blaming jihadist 'groomers' for warping young Brits' minds is a moral copout.
by Frank Furedi
-- Tue 10 February --
'Hey, who are we to judge the Islamic State?'
Why many in the West are so cagey about condemning IS.
by Brendan O'Neill
-- Thu 5 February --
The Western press is now the PR wing of the Islamic State
In poring over its murder-stunt videos, we give IS exactly what it wants.
by Brendan O'Neill
-- Thu 22 January --
Waiting for Chilcot
Why politicians and pundits are so desperate to see the Iraq War report.
by Tim Black
-- Thu 20 November --
From the London riots to the Islamic State
Jihadi John's alleged involvement in the riots makes perfect sense.
by Tim Black
-- Wed 8 October --
In praise of Arin Mirkan
The Kurdish 'suicide bomber' dealt a psychological blow to IS – and the West.
by Brendan O'Neill
-- Wed 8 October --
Why are young Brits joining IS?
by WORLDbytes
-- Wed 8 October --
Intervention is making things worse – again
The airstrikes in Iraq will help nobody – except maybe IS.
by Tim Black
-- Wed 8 October --
Cameron is doing the Islamic State's work for it
Our government would rather crack down on its citizens' liberty than enter into a battle of ideas with IS.
by Luke Gittos
-- Mon 15 September --
The West's sad semi-war against ISIS is worse than useless
Our leaders say the Islamic State threatens civilisation – why won't they fight it?
by Brendan O'Neill
-- Tue 9 September --
ISIS defectors should be allowed to return
Standing by its principles is Britain's best weapon against ISIS.
by Luke Gittos
-- Tue 26 August --
Caliph Cameron brings ISIS-style intolerance to Britain
Our rulers' authoritarian response to ISIS is trashing freedom and tolerance.
by Brendan O'Neill
-- Wed 20 August --
This gruesome video contains a message to Britain, too
What that barbaric beheading tells us about a crisis of Britishness.
by Frank Furedi
-- Tue 12 August --
ISIS: a monster made by the moralists of the West
The West weeps over the Yazidi people, yet is responsible for their suffering.
by Brendan O'Neill
-- Fri 4 July --
ISIS, intervention and the unravelling of the Middle East
Podcast: Karl Sharro, Brendan O'Neill and Bill Durodié debate the crisis in Iraq.
by spiked podcast
-- Tue 1 July --
'Jihad cool': an Islamist version of Occupy
The Brits who become jihadists have some very familiar-sounding prejudices.
by Frank Furedi
-- Mon 16 June --
Iraq: there is no Western solution, and never was one
Western intervention has destroyed Iraq, as spiked predicted it would.
by Brendan O'Neill
-- Tue 3 June --
We don't need a judge to tell us Iraq was wrong
It's moral cowardice to beg Chilcot to condemn Bush and Blair.
by Tim Black
Next >>
home | issues | standard version


text:
Cost per serving: 42¢
This recipe is so easy you'll never want to buy prepared pudding again. It uses mint tea bags steeped in warm milk to infuse the flavor. If you don't like mint, leave it out and use an additional ounce of semisweet chocolate instead.
See recipe: Chocolate Mint Pudding


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Marimekko Joonas Wallpaper
Marimekko Joonas Wallpaper
Weights & Dimensions
|Product Type: Roll
|Style: Scandinavian
|Pattern: Abstract
|Finish Type: Matte
|Primary Material: Vinyl
|Number of Items Included: 1
|Water Resistant: Yes
|Stain Resistant: No
|Application Type: Non-pasted
|Match Type: Drop
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|Eco-Friendly: Yes
|Country of Manufacture: Italy
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Marimekko Joonas Wallpaper
About the Designer
Maija Isola & Kristina Isola Finland (1927 - 2001)
Maija Isola (1927–2001) designed her first printed textiles in 1949 for Printex Oy, Marimekko's predecessor. She worked as head designer of Marimekko's interior fabrics until 1987. She also had an illustrious career as a visual artist. Textile designer Kristina Isola has followed in the footsteps of her mother Maija Isola. She made her first sketches for fabrics at the age of sixteen as an assistant to her mother. Between 1978 and 1987 mother and daughter designed for Marimekko under the joint name of Maija Isola/Kristina Isola. At present, Kristina Isola designs her own fabric prints and is also responsible for the new colorways of Maija Isola's designs and the adaptation of their patterns to suit different product
About the ManufacturerMarimekko has been breaking boundaries since 1951. It has created an international reputation and cult-like following based on a series of happy contradictions: bold colours against graphic black and white, free associations opposed to perfect geometry, form versus function as well as art and design combined as one. This Finnish brand has achieved global success by highlighting colourful print design and championing being brave, being equal and being full of joie de vivre.
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Jan 5, 2013; Green Bay, WI, USA; Minnesota Vikings quarterback Joe Webb (14) is hit by Green Bay Packers outside linebacker Clay Matthews (52) in the backfield in the third quarter of the NFC Wild Card playoff game at Lambeau Field. Mandatory Credit: Andrew Weber-USA TODAY Sports
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TMPA Restarted with October 2014
reported on Mar 04, 2015
TRMM DSC (Deep Space Calibration) Feb. 26-27, 2014 and TMI Data
reported on Mar 02, 2015
PPS Updating GPM Radiometer Products due to Sun Angle Corrections
reported on Dec 05, 2014
Data input issues for 3B4XRT
reported on Oct 24, 2014
IMPORTANT: TRMM PR Data Unavailable After Oct. 07, 2014 Due to Satellite Descent
reported on Oct 09, 2014
Effective October 8th, 2014 all PR data will not be available.
reported on Oct 08, 2014
The following images depict the Diurnal variation of annual precipitation from 3 TRMM algorithms.
The are two types of images represented:
1. Seasonal -image composites based on a 3-month period (i.e., DJF -Dec, Jan, Feb)
2. All Season -image composites combined together from January 1998 - December 2007.
Based on 10 years (January 1998 - December 2007) of 1x1 degree gridded TRMM subset 3G68.
Each image indicates the time of 1-hourly composite.
View TRMM 3G68 1-hourly time series graphs (January 1998 - December 2007)
(Courtesy Roongroj Chokngamwong and L. S. Chiu)
Click on an image to see a page containing all seasonal animations for that algorithm.
All Season Diurnal variation of all season precipitation from TRMM Combined Instrument Algorithm (2B31)
All Season Diurnal variation of all season precipitation from TRMM Microwave Imager Algorithm (2A12)
All Season Diurnal variation of all season precipitation from TRMM Precipitation Radar Algorithm (2A25)


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Mr. clean mop
chiathomasDecember 11, 2012
Anyone used this mop? Is it safe on vinyl floors?
Chemocurl zn5b/6a Indiana
There are a lot of Mr. Clean Mops found out there via a Google search.
What one were you referring to?
Here is a link that might be useful: Mr. clean mop Google search results


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Make a Wish - Feb 26th - Deanna (faintheart)
Just starting a thread for everyone to post when they send their blocks to Deanna and for Deanna to reply when she receives them.
Kristene (tinyteena)
Kitty, your blocks arrived Saturday. Thank you so much for the wonderful blocks!
Jayne, your block arrived yesterday. Another beautiful block and I appreciate the extra blue fabric as well!
I have been in a quilting cloud finishing the bargello started a few weeks ago (done as of last night) and am looking forward to working with these great b-day blocks next. I love the diversity of pattern choices and fabrics. Thank you all!
Two more squishies today! I am really liking this birthday month despite -19* temps on the way to work this morning.
Kristine, your pretty block arrived today. Thank you for the extra fabric as well! Your predicted arrival date was right on target. :)
Eileen, your lovely block arrived today as well. Thank you too for the extra tuck-in!
So far the tally for received blocks is:
This is going to be a wonderful sampler quilt for sure! I'd best start planning the layout.
Hi, I'm going to try and mail your block on Friday. Another snow day tomorrow and I don't go to town unless I have to. Hopefully Friday things will be better. I know we don't have it very bad here in Oklahoma but we aren't use to this either. When we have snow it is usaully gone the next day. all the snow hadn't melted from last week and we got more. But I will mail your block as soon as I can. tara
Tara, no problem. I certainly understand about the unusual weather you've been experiencing too. It takes even those of us who are used to getting some snow a while to get back in the swing of winter driving. The cold has been horrible here the last few weeks and I can imagine how unbearable it must be for those not used to such extremes this winter! Spring is on the way!!!
Thanks for letting me know, Jackie. Sure hope there aren't any more huge snows as they will likely come through here first!
Tara and Paula, your beautiful blocks arrived yesterday. Thank you both for your addition to this sampler! This is so much fun and I am admiring everyone's wonderful work.
Here is the count as of this morning:
Have a great day all!
off to work.......
Melissa, your block arrived yesterday. Another great addition to what is going to be a wonderful sampler quilt. Thank you!
All are on the design wall and I will wait until I've got them all for picture. :)
I'm sorry your block will be late. It's been finished for a week, but I didn't get to the PO because of too many little ones. Now we're having a wonderful (?) snow storm. I sure hope this is our last before spring arrives!! I will get it to the PO later today if we can get out, if not it will definitely go tomorrow --- even if I have to drive it to you myself!
[How's YOUR weather?? Maybe I WANT to drive your way! LOL]
Thank you all! I am having a great day! This old lady is about birthday'd out now. lol
Jackie, your block arrived the other day. Thank you so much for it and the extra HSTs! Couldn't have come on a better day as I had to endure some unexpected medical tests. To come home and find your envie was a wonderful surprise! The block is beautiful!!! I've put together the HSTs and it helped take my mind off waiting for test results.
The cake Kristene made looks delicious! ;) Thank you! I've got extra pink champagne cake that DD made left also. By all means, grab a piece of cake before I eat both of them by myself!!!
Vasu and Marie, your blocks arrived yesterday and Cindy's came today. They are beautiful!
I am so excited to put together this quilt! It will go in the master bedroom when finished. Now I need to get busy and plan the layout. I think all blocks have been received and accounted for. Thank you all!!!!!
Aren't they beautiful?
Thank you for making this birthday a great one! 54 isn't so bad after all. ;)


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Surgical Specialist
Tioga - Nicetown
3500 S Broad St
Philadelphia, PA 19145 Phone number & directions
3500 S Broad St
Philadelphia, PA 19145 Phone number & directions
License & Identifications
A medical license is required for a doctor to practice medicine in a particular state. Requirements vary by state but most require, at a minimum, post-graduate training in the doctor's specific specialty. An NPI number is a national identifier unique to an individual health care provider and is managed by the Center for Medicare & Medicaid Services (CMS).
Learn more about Dr. Eric Maiorino:
View the full profile to get information on:
- Qualifications
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Patient Reviews
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Home > Find a Surgeon > PA > Philadelphia Surgeons > Dr. Eric Maiorino, MD
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- Additional Information
- Dr. Eric Maiorino MD is a male Surgeon and practices in Surgery.
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- Dr. Eric Maiorino has 1 office location.
Dr. Eric Maiorino practices Surgery near Philadelphia, PA.
See Philadelphia Surgeons.


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Visit create.airbnb.com »
Thanks for taking the time to report this user.
Your participation helps keep Airbnb a safe and trusted
community, and it doesn't go unnoticed!
Hallo! Mein Name ist Louis und ich würde mich freuen viele freundliche und offene Gäste aus aller Welt begrüßen und unterbringen zu können!
Louis has completed online and offline ID verification.
Learn more »
Luis and Dimitri - thank you for hosting us and for the help with the early / late check in / out.
Highly recommendable. The apartment was really clean and accurate to the description. Beds are comfortable and Internet connection was working perfectly as well. No big luxury but the location is perfect, 5 minutes walking to the UBahn. Lots of restaurants, supermarkets, etc.
Moreover Louis is a great host, he answers fast and with all the information you need.
The apartment was simple and comfortable. Some of the amenities needed a bit of tuning up, but it fit our expectations and was perfect for three young guys looking for a place to stay. The location was incredible. This was most important in my opinion.
Very nice place, perfect for a week end. Clean and not so far from the U-bahn.
Nous n'avons pas rencontré l'hôte car ce n'est pas un appartement privé qui et loué mais un hôtel "(Come 2 friends"). L'appartement est extrêmement basique, sans aucun charme et contient le minimum (par exemple que 2 petites cuillères, 4 grandes assiettes, 3 verres et même pas une machine à café ou des lampes de chevet). Par contre après avoir demandé au gérant, nous avons obtenu ce qui manquait. La propreté est correcte, hormis une vielle moquette.
Le wifi est extrêmement lent, donc pratiquement pas utilisable. L'appartement se trouve à 10 mn à pied des stations de S- et U-Bahn qui vous mènent dans le centre ville de Berlin.
It is a fine nice apartment, close to the City. Definently recommendable.
Nice large and clean place. Loved the fact they have 2 bathrooms! Kitchen is small but fine if you go out for dinner.
We were disappointed by this stay. We were put in a different room, one which did not look (or smell - the place smelled of smoke) nearly as nice as the pictures here. The room was all the way up many flights of stairs (difficult with luggage, which he did not know we had a lot of, as well as after a long day out sightseeing!) and then was small and minimalistic (not in a modern way). There were issues with the bathroom and shower. Additionally, even though I had checked about the WiFi working ahead of time (after reading about past issues), the WiFi did not work - however, we did not ask him to fix it as a) we did not know if there was still anyone in the office, b) we did not want to walk down and back up the stairs again, and c) WiFi was not crucial for us at that point.
Overall, we were disappointed with the stay. I have had great luck in the past with airbnbs, but this was the first time for my family and they became nervous about others we had booked for our trip. I would not stay here again, but I think that for someone who just needs a place to sleep and does not mind stairs, the place is fine - and the people are nice and helpful! They suggested where to get food, provided maps, and called a taxi for us.
War alles bestens, nur einen Parkplatz zu finden in der Naehe war auf Grund der spaeten Stunde, zu der wir ankamen etwas schwierig. Gerne aber wieder!
Louis und sein Sohn waren tolle Gäste! :) Sehr freundlich, höflich, sauber und ordentlich und super sympathisch! :) Sie sind jederzeit willkommen! :)
Louis and his friends are great! I met with one of them wich arrived early and I stayed chating for a time, while I showed her the flat; I found the 6 of them pretty easy going people, with positive vibes and a great communication, I didn't have a problem at all, nor something close to be called a problem/missunderstood, everything went great.
Louis war mit seinem Sohn nur für zwei Nächte hier. Es war nett, ihn kennenzulernen, ein angenehmer Gast, mit dem man sich gut unterhalten kann. Alles war sauber und ordentlich. Ich freue mich, wenn er mal wieder hier einkehrt und kann ihn uneingeschränkt weiterempfehlen.


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The vineyard and winery are located on 35 acres of rolling hills, dotted with three ponds and glimpses of Lake Huron. We are currently open by appointment only.
Brew Tours are offered. We have an amazing lineup of hand-crafted beers, wines and meads, all made in-house. Along with this diverse group of drink selections. We will offer unique food pairings to complement these libations and provide...
The concept of opening an establishment that would both compliment and support the Greenville community was a dream of Greenville natives and entrepreneurs Bob and Dottie Olsen. Through careful consideration and hard work, they began...
Since its inception in 1902, the A.E. Seaman Mineral Museum has housed one of the premiere crystal collections in North America and has showcased the world's finest display of minerals from Michigan's famous Lake Superior Copper...
Astronomy and Space Science Education Center. Building includes small gift counter, exhibit hall, gallery, sky theater. Shows presented in sky theater. Call for schedule of viewing.
Talent reaches from New York to Hollywood and brings a new dimension to entertainment and the arts in Harbor Country, traditional to the avant garde.
Activities to do in warm weather.More
Join 500,000 other
people who receive the free Pure Michigan e-newsletter. View the Current Issue
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300 N. Washington Sq., Lansing, MI 48913


text:
Tribble FAQ - Tribble Breeding for Fun and, well, Loss
View Single Post
Archived Post
Lt. Commander
Join Date: Dec 2007
Posts: 120
# 842
I hope Cryptic will improve tribble breeding and bring in more effects.
As it is now you can forget anything about breeding if you have a Mattson and a Howe because you need only those two and a handful rare food for breeding the existing 4 rare tribbles.
Daxter DPS x2 <-- Ricossa + Cardassian Taspar Egg
Griffis Resi x2 <-- Ricossa + Jumbo Romulan Mollusk
Ricossa DPS+Resi <-- Howe + Klingon Gladst / Klingon Octopus / Jumbo Romulan Mollusk
Highison HP-Regen x2 <--Mattson + Romulan Ale
That's the whole essence of tribble breeding, nothing more


text:
StartUpHire is the place to find Fashion News Editor - StyleBistro jobs. Review the list of Fashion News Editor - StyleBistro career opportunities to the left. These Fashion News Editor - StyleBistro jobs represent some of the most rewarding careers available.
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Who We Are HowAboutWe is the offline dating site. We help people go on great dates -- in an easeful, natural, and effective manner. HowAboutWe was founded in 2010 and was acquired by Match Group in 2014. Today, the HowAboutWe Team consists of dedicated engineers, designers and3/4/2015 Brooklyn, NY Save This Job
SheKnows Media is a top women?s digital lifestyle media company. Its acquisition of BlogHer in October 2014 gives the company 75.3 million unduplicated unique visitors per month, which is more than the current number-one women?s lifestyle media brand (comScore, Multiplatform2/12/2015 New York, NY Save This Job


text:
Personal Assistant - Email/Support/Inventory Tasks
Closed - This job posting has been filled and work has been completed.
Job Description
Hello, I'm looking for long term assistant for helping with small tasks such as:
- sending daily follow-up message emails to customers
- checking email daily
- checking inventory levels daily
- being in constant communication with me on new tasks
- other administrative tasks.
Eventually you will be helping more with ordering products and helping with daily business activities with e-commerce accounts.
You must be dedicated, trust-worth and hard working with attention to detail.
We will start with just a couple hours each day Monday-Friday
Then we can progress to a more full time schedule over the next 4-6 weeks.
Please let me know your availability, experience and why we should work together.
Also include the word 'sunhine in your reply so I know you read my post.
Thank you and have a great day!
Julie & Brandon


text:
Date: 2 years ago
Runtime: 3:07
Views: 10,824
Fucking a old friend (Part 3)
black, fucking, interracial, anal, pounding
Categories: Interracial, Anal
All Comments
nice nut
good nutt
Hot man.
i would pay you to fuck my ass raw
You fuck him as a pornstar!
I'd like to be an old friend of yours!
Real Hot Fuckin...Love Verbal BTM & TOP Is So SEXY & HOT
Loved it when you came. Let the vid go a little longer. Keep in in and really milk that dick.


text:
Beef on Twitter with some random dude
Vertex of Saints and IcecreAM,
New Products
The products you buy makes the products you buy.
Now you can find new products and developments and actually contribute to the final outcomes of products for rewards.
To fill out surveys for rewards and to find new products coming out that you can review and actually have a say in the final design of the product, go here:
See and Shape New and Interesting Products
mm ed vis art
Spiraling into the Spiral… continual #spirals #spiraling
–is lost in the depths of the spiral with Jenny McCarthey
— is spiralling into a sprial with other spirals all grouped , groups of spirals some going in some, outwards, all deep and intertwined with the spiral flux clinging onto the gold thread so I can leave the inner depths of the vacuum of the spiral and other interconnected spirals…messed up in the spiral, from the spiral with love
this is my picket fence the one below is a spiral, yo
all the way from the depths of the vacuum of the lost silence of the interior underbelly of the spiral flux comes this rippin piano solo by the chairman of the boards.
and here is castles made of sand: they fall into the sea, eventually…
Only Time
I'm blowing smoke into the air and handing my life over to the winds of fate…. What will be, will be; all in it's own time… My future depends on the whims of creativity in terms of the ever-dying present tense which is so closely entwined with what vague glimpse of reality I Imagine to lie ahead. And yes, I do believe that each day should be better than the next…Only time will tell.
My #currentwork #currentproject #zen
My current project:
scribbling abstract and weird words into a journal with tons of spirals and weird doodles continuously until the entire book is finished
burn the notebook on the grill outside…
you have to build things up
just to tear them down
and sometimes all of the work you do
is for nothing
I consider it
an experiment in zen in response to the environment
(I am sitting ten feet away from the street in my house and the street is busy)
a continually shifting environment intended to clear negativty
eventually I would like to have
a lot of cactus plants and some gargoyles hung ouside facing the street, I dunno
maybe the gargoyles will replace the scribbling
either way I've been working fervently on this notebook
which is an endless aim,
it's the journey that's the most fun
not the destination


text:
The Saratoga blog
What's happening around Saratoga.
Posts filtered on Category
Big title, tiny mandate for next Saratoga County leader
Contacted recently after squeaking out the narrowest of election wins, Supervisor Paul Sausville said he was "happy to make it out the other side of the wormhole." It was vintage Sausville. The Malta Republican had survived a September primary contest and a bitter general election dispute that went to the courts, yet he still managed […] [Read More]
Malta race goes to Appellate Division Monday
Cynthia Young, Democratic candidate for supervisor of Malta, takes her appeal of a judge's election ruling to the state Appellate Division of Supreme Court at 3 p.m. Monday. Young lost last month's election to incumbent Republican Paul Sausville by one vote, 1,582 to 1,581, after state Supreme Court Justice Robert Chauvin disqualified two votes cast […] [Read More]
Young to appeal election result
A candidate who lost the Malta supervisor election by one vote has filed a notice appealing a judge's decision to toss two absentee ballots cast for her, which cost her the election. Democrat Cynthia Young filed paperwork with the state Appellate Division of Supreme Court Monday, preserving her right to challenge state Supreme Court Justice […] [Read More]
Judge: Sausville wins by a vote
Republican Paul Sausville won re-election as Malta town supervisor by one vote Thursday after a judge in Saratoga County threw out two votes for his opponent because they contained written words on the rear of the ballots. State Supreme Court Justice Robert Chauvin, a Republican, ruled two ballots cast for Democrat Cynthia Young, contained written […] [Read More]
As close as it gets in Malta
Literally every vote counted in Malta. In a Saratoga County political nail-biter, Republican town Supervisor Paul Sausville pulled ahead of Democrat Cynthia Young by a single vote Wednesday, 1,582 to 1,581, with two remaining votes cast for Young not counted due to objections by Sausville's attorney. State Supreme Court Justice Robert Chauvin will decide whether […] [Read More]
Malta race goes to court
A state Supreme Court judge will hear arguments Wednesday over what absentee ballots should count in the tight race for Malta supervisor. Malta Democrat Cynthia Young leads Supervisor Paul Sausville by four votes with 23 disputed ballots to be contested at 11 a.m. Wednesday in Saratoga County State Supreme Court. Lawyers for both camps will appear […] [Read More]
That Malta race
The razor-thin race to lead Malta will come down to disputed ballots and possibly military votes. Absentee and affidavit ballots counted in the town supervisor race Wednesday left Democratic challenger Cynthia Young leading incumbent Supervisor Paul Sausville by four votes with more than 3,560 total votes cast. Sausville is a Republican seeking his fifth two-year […] [Read More]
Rematch in Malta
Supervisor Paul Sausville over the last eight years has guided the town through unprecedented growth powered mostly by the GlobalFoundries manufacturing plant. On Nov. 5, voters will decide if he's the right person to lead Malta through what's expected to be a new round of change. Sausville, a Republican, won his party's nomination in the […] [Read More]
Candidate forums
Good morning. Political forums start this week. The League of Women Voters of Saratoga County will sponsor candidate forums Tuesday in Malta; Wednesday in Clifton Park; Oct. 22 (commissioners) and Oct. 24 (mayor and city supervisors) in Saratoga Springs; and Oct. 30 in Halfmoon. The league's online voter guide guide is here. The Chamber of […] [Read More]
Primary night results
Primary night in Saratoga County went late into the night, with polls closing at 9 p.m., and tallies not reported until around midnight, well after other counties in the region. Here's a recap of the primary races and results. Any thoughts? The big race in the county on Tuesday was for sheriff, and Michael Zurlo […] [Read More]
Show More


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500 m
2000 ft
Walking directions are in beta.
Use caution – This route may be missing sidewalks or pedestrian paths.
Use caution – This route may be missing sidewalks or pedestrian paths.
Suggested routes
- 1.5 mi, 31 minsN Woodside Rd
- 1.5 mi, 31 minsPark Rd and N Woodside Rd
- 1.7 mi, 35 minsSauchiehall St and Maryhill Rd
- 30 minsOr take Public Transport (Bus, one transfer)
Walking directions to Glasgow G20 7AL, UK
These directions are for planning purposes only. You may find that construction projects, traffic, weather, or other events may cause conditions to differ from the map results, and you should plan your route accordingly. You must obey all signs or notices regarding your route.
Map data ©2015 Google


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does anyone know if the Hungry Owl is open on sundays, it doesn't say on the website and i can't find out anywhere, apart from calling which is a hassle from the UK!
According to UrbanSpoon they are closed on Sundays. I'll try to call them today and ask.
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text:
Take a look at Trulia's listings here: http://www.trulia.com/for_rent/Hudson,WI/
Ali, Community manager
Take a look at some of the listings here on Trulia: http://www.trulia.com/for_rent/Hudson,WI/SINGLE-FAMILY_HOME_type/
Hope this helps,
Ali, Community manager
M ... more
Here is a report that covers water quality in Hudson. I am not sure if you are looking for well water or City Water. Please call me to d ... more
http://www.cit ... more


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Baumgarten: Chill on the ice bucket challenge
There's another challenge making its rounds on social media, but its chilling effect is beginning to become more about the person doing it rather than helping people.
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From Wikipedia, the free encyclopedia - View original article
Swap.com, formerly SwapTree, is a consumer trading service for pre-owned items operated by Netcycler Inc., a company based in Bolingbrook, Illinois.[1]
Users list items they have and they'd like to receive. A trade, or swap, is initiated when at least two users agree to swap items they have. Swap.com charges a service fee for processing and listing items that are sent to its logistics center, as well as a sales commission. Three-way trades are created when at least one user has something to trade, but wants something other than what their trade partner has to give.[2][3]
The Swap.com Valet Service was introduced in October 2012. The Valet Service lets users trade (buy, sell or swap) kids' items like sports equipment, clothing, toys, and kids' accessories.


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www.drsarma.in Glucose Homeostasis Counter Regulation Dr.Sarma.R.V.S.N M.D., (Med) M.Sc., (Canada) Consultant Physician and Chest Specialist BioEd Online Glucose Equilibrium – A Wonder !! Normal Blood Glucose Fasting state : 60 to 100 mg% Postprandial : 100 to 140 mg % What keeps the blood glucose in such a narrow range? Why are we not becoming hypoglycemic when we fast? Why is our blood sugar not shooting up to very high levels after a rich meal ? What are the regulatory and counter regulatory hormones ? 2 Glucose Equilibrium – A Wonder !! Normal Blood Glucose Fasting state : 60 to 100 mg% Postprandial : 100 to 140 mg % Let us grasp some of the fascinating What keeps the blood glucose in such a narrow range? answers !! Why are we not becoming hypoglycemic when we fast? Why is our blood sugar not shooting up to very high levels after a rich meal ? What are the regulatory and counter regulatory hormones ? 3 Glucose Homeostasis Research Timeline 1552BC 1st Century AD 1776 18th Century 1869 1889 1921-23 1983 2001 1552 BC: Ebers Papyrus in ancient Egypt. First known written description of diabetes. 1st Century AD: Arateus — ―Melting down of flesh and limbs into urine.‖ 1776: Matthew Dobson conducts experiments showing sugar in blood and urine of diabetics. Mid 1800s: Claude Bernard studies the function of the pancreas and liver, and their roles in homeostasis. 1869: Paul Langerhans identifies cells of unknown function in the pancreas. These cells later are named ―Islets of Langerhans.‖ 1889: Pancreatectomized dog develops fatal diabetes. 1921: Insulin ―discovered‖ — effectively treated pancreatectomized dog. 1922: First human treated with insulin. Eli Lilly begins mass production. 1923: Banting and Macleod win Nobel Prize for work with insulin. 1983: Biosynthetic insulin produced. 2001: Human genome sequence completed. 4 Cell growth and energy metabolism Carbohydrates Glucose Pyruvate Fatty acids Fats Amino acids TCA Cycle Kreb's Cycle Proteins ATP 5 Intermediary Metabolism of Fuels 6 Intermediary Metabolism of Fuels Clinical Pearl 1. All the fuels are inter changeable in the body 2. It is the total calorie restriction that is important in Obesity and T2D 7 Glucose-6-Phosphate – The Central Molecule 8 Glucose-6-Phosphate – The Central Molecule Clinical Pearl G-6-Phosphate is the Center Stage for CHO Metabolism Glucose-6-Phosphate dehydrogenase (G6PD) is the crucial enzyme 9 Homeostasis of Glucose Counter Regulation Mechanisms A steady maintenance of blood glucose with in a narrow range Fasting state and fed states – their effects on BG Rate of glucose appearance Ra Rate of disappearance Rd must be in balance Blood Glucose (BG) = Ra - Rd Control systems Glucose Receptors, GLUT 1-14 Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc., Insulin Signaling sequences, Glucagon signaling Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue Feedback loops Negative feedback Positive feedback 10 Homeostasis of Glucose Counter Regulation Mechanisms A steady maintenance of blood glucose with in a narrow range Fasting state and fed states – their effects on BG Rate of glucose appearance Ra Clinical Pearl Rate of disappearance Rd must be in balance INSULIN R - R Blood Glucose (BG) = v/s GLUCAGON a d and Rd V/s Ra Control systems Glucose Receptors, GLUT 1-14 Controlling Hormones, Insulin, Glucagon, Cortisol, Epinephrine etc., Insulin Signaling sequences, Glucagon signaling Effector Cells – Muscles, Liver, Brain, Heart and Adipose tissue Feedback loops Negative feedback Positive feedback 11 Normal, Hyper and Hypoglycemic states Ra Ra is the rate of appearance of Glucose 100 mg Rd is rate of disappearance of Rd Glucose When Ra = Rd; It is Ra Ra Ra Euglycemic state Ra 200 200 50 50 mg mg m m Rd Rd g Rd g Rd Ra > Rd; Ra ↑or Rd↓ Ra < Rd; Ra ↓or Rd ↑ HYPERGLYCEMIA HYPOGLYCEMIA 12 Effect of CHO intake on Glucose Metabolism Gluconeogen Glycogenoly Exogenous esis sis CHO Lipolysis Ra GLUCAG ON INSULIN Rd 13 Glucose Homeostasis Lower Blood Between meals Glucose -cells release -cells release Glucagon insulin stimulate glycogen stimulate glucose breakdown and uptake by gluconeogenesis peripheral tissues Higher Blood Food Glucose 14 High blood glucose affects the size of beta cells 15 Pancreatic Hormones Pancreas Exocrine Pancreas – P Lipase, P amylase etc Endocrine Pancreas – Islets of Langerhans Hormones secreted are – Alpha cells – Glucagon Beta cells – Insulin C cells - Somatostatin D cells - Somatostatin E cells - ?? Function F cells - Pancreatic polypeptide (PPP) 16 Regulation of Blood Glucose levels Glucose is the major source of energy for cells Blood Glucose (BG) regulated by Insulin & Glucagon 17 Regulation of beta-cell size by the level of Glucagon Glucose Homeostasis – Insulin and blood glucose 18 Glucose Homeostasis Chart High Blood Sugar Low Blood Sugar Condition Toxic to the cells - AGP Energy needs unmet Receptor Glucose transporter Glucose transporter Control Center -cell of the pancreas -cell of the pancreas Effector Insulin Glucagon Glucose uptake by Liver breaks down Result muscle/fat tissue glycogen to glucose Lowers blood glucose Raises blood glucose 19 The Six Mechanisms of Transport - CM 2 1 3 6 5 4 20 Membrane Transport Proteins 21 Channel Proteins 22 Cell Membrane - Transporters 23 ATP Powered Receptors 24 Glucose Transport FIRST STEP GLUCOSE ABSORPTION IN THE GI TRACT 25 Intestinal Cell Transport 26 Intestinal Cell Transport Clinical Pearl New approach in T2D, MS and Obesity - GLUT-2 Blockers 27 The First Messengers from GI tract THE MESSERGERS INCRETINS – GLP1 and GIP_ 28 Entero-Insular Axis of Secretion Insulin secretion is also increased By intestinal polypeptide hormones GLP-1 (glucagon like peptide) [exendin-4] Glucose-dependent insulinotropic peptide(GIP) GLP-1 and GIP are called Incretins Cholecystokinin and by pancreatic Glucagon. Insulin secretion is decreased by pancreatic somatostatin. 29 Entero-Insular Axis of Secretion Insulin secretion is also increased By intestinal polypeptide hormones GLP-1 (glucagon like peptide) [exendin-4] Clinical Pearl New Glucose-dependent insulinotropic peptide(GIP) Drugs for T2D- Incretin (GLP-1 and GIP) Function Enhancers GLP-1 and GIP are called Incretins Cholecystokinin and by pancreatic Glucagon. Insulin secretion is decreased by pancreatic somatostatin. 30 Response to Elevated Blood Glucose In the post prandial state (after a meal) Remember there are two separate signaling events First signal is from the ↑ Blood Glucose to pancreas To stimulates insulin secretion in to the blood stream The second signal from insulin to the target cells Insulin signals to the muscle, adipose tissue and liver to permit to glucose in and to utilize glucose This effectively lowers Blood Glucose 31 Response to Elevated Blood Glucose In the post prandial state (after a meal) Remember there are Clinical Pearl signaling events two separate Insulin secretion must be triggered – First Signal 1.First signal is from the ↑ Blood Glucose to pancreas 2.To stimulates insulin secretion in to the blood stream– Secreted Insulin must trigger Glucose uptake Second signal The second signal from insulin to the target cells 3. T2D may result from failure of either or both Insulin signals to the muscle, adipose tissue and liver to permit to glucose in and to utilize glucose This effectively lowers Blood Glucose 32 Glucose induced Insulin secretion Glucose enters the beta cells through uniporter GLUT 2 Oxidative phosphorylation ATP closes the ATP gated K+ channel and depolarizes the cell membrane Depolarization opens the voltage gated Ca+ channels Ca+ enters the beta cells This leads to exocytosis of Insulin and secretion 33 Glucose induced Insulin secretion Glucose enters the beta cells through uniporter GLUT 2 Clinical Pearl Oxidative phosphorylation Closure of KATP Channels by Glucose is + ATP closes the ATP gated K fundamental channel and depolarizes the Glucose is necessary to cell membrane stimulate Insulin Depolarization opens the Insulin is necessary let in glucose tovoltage gated Ca+ channels Ca+ enters the beta cells This leads to exocytosis of Insulin and secretion 34 K+ATP Channel Closed by ↑ BG and SU 35 K+ATP Channel Closed by ↑ BG and SU Clinical Pearl 1. SU Group close KATP Channels – Secrete Insulin 2. Differences in action of SU are because of the differences in their action on KATP Channels 3. Gliclazide and Glimiperide just hit the SUR closure and stop 36 Intricacies in the Beta Cell 37 K+ ATP – Sulfonylurea Receptor K+ ATP channel has two sub units – Kir6.2 and regulatory sulfonylurea receptor(SUR) ATP gated K+ channel is coupled to SUR K+ channel can be closed independently of glucose This leads to increased insulin secretion SUR1 are ATP binding transporters superfamily 38 K+ ATP – Sulfonylurea Receptor K+ ATP channel has two sub Clinical Pearl – Kir6.2 and regulatory units sulfonylurea receptor(SUR) 1. Glibenclamide, Tolbutamide cause prolonged closer of the SUR + ATP gated K channel is coupled to SUR 2. This causes prolonged and intense pressure on + K channel can be closed Beta cells independently of glucose 3. This is the cause of late hypoglycemia with these This leads to increased SUs insulin secretion in fast after a few years of 4. Beta cell apoptosis sets SUR1 are ATP binding use transporters superfamily 39 (F)PHHI (Familial) Persistent Hyperinsulinemic Hypoglycemia of Infancy Unregulated insulin secretion Profound hypoglycemia and brain damage Manifests at birth or at first year of life Under diagnosed Probably the cause of undiagnosed postnatal deaths Defect is KATP Channels mutation – Persistent closure with continuous trigger for Insulin release Treatment is pancreatectomy – (95% of pancreas) 40 K+ATP Channel Opening is Cardio-protective 41 K+ATP Channel Opening is Cardio-protective Clinical Pearl 1. Glibenclamide, Tolbutamide close the SUR in myocardium 2. This effect is deleterious to heart in ischemia 42 Tyrosine Kinase Pathway - Insulin 43 Tyrosine Kinase Pathway - Insulin Clinical Pearl 1. Tyrosine Kinase (TK) phosphorylation is the fundamental step 2. Its failure stops further cascade of intracellular signals 3. This is one of the possible mechanisms of Insulin Resistance 4. PPAR- Gamma (Pioglitazone) enhances TK signaling pathway 44 Insulin Receptor (IR) Insulin Receptor is a tyrosine kinase. Consists of 2 units -dimerize when bound with insulin. Inside cell - auto phosphorylation occurs, Increasing tyrosine kinase activity. Insulin Receptor phosphorylates intracellular signaling molecules. Stimulates insertion of GLUT-4 proteins which let in glucose Stimulate glycogen, fat and protein synthesis. 45 + HN NH3+ 3 S S Insulin -subunits S S -S-S- EXTRACELLULAR -OOC S S COO- + HN S S 3 NH3+ Plasma membrane CYTOPLASM Transmembrane Tyrosine domain kinase domain -OOC COO- -subunits Figure 2. The insulin receptor. Insulin binding to the -chains transmits a signal through the transmembrane domain of the -chains to activate46 the tyrosine kinase activity Extracellular 1 2 IRTK (R) 3 insulin IRTK (L) phosphorylated/ binds activated activated OP OP L R P P Cytoplasm P P P ATPs ADPs Phosphorylation catalyzed by IRTK (L) Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by 47 insulin binding, followed by interchain autophosphorylation Extracellular 1 2 IRTK (R) 3 4 insulin IRTK (L) phosphorylated/ IRTK (L) binds activated activated phosphorylated OP PO OP OP PO P OP L R ATPs P P P P P Cytoplasm ADPs ATPs ADPs Phosphorylation catalyzed by IRTK (L) Figure 3. Activation of the tyrosine kinase domains of the insulin receptor by 48 insulin binding, followed by interchain autophosphorylation Insulin Signaling – TK Receptor phosphorylation Binding of insulin to the TK Receptor causes Transphosphorylation of tyrosines on the receptor Phosphotyrosine residues bind to IRS-1 (insulin receptor substrate – adopter protein) 49 Insulin Receptor (IR) A key regulator of growth signaling IR is hetero-tetramer Insulin binding induces conformation change and stimulation of receptor Tyrosine kinase activity IR auto-phosphorylates and phosphorylates downstream second messengers, like IRS (Insulin Receptor Substrate) Obesity down regulation of IR Diabetes up regulation of IR 50 Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity) Receptor tyrosine kinases The interaction of the external domain of a receptor tyrosine kinase with the ligand, often a growth factor, up- regulates the enzymatic activity of the intra cellular catalytic domain, which causes tyrosine phosphorylation of cytoplasmic signaling molecules. 51 Epidermal Growth Factor (EGF) Receptor Auto-phosphorylation of TK (Obesity) Receptor tyrosine kinases The interaction of the external domain of a receptor tyrosine kinase Clinical Pearl with the ligand, often a growth factor, up- 1. Up regulation of TK receptor regulates the enzymatic (autophosphorylation) in obesityactivity of the intra cellular catalytic 2. Leads to Glucose entry into cells with out insulin domain, which causes signal tyrosine phosphorylation of cytoplasmic signaling molecules. 52 Insulin Signaling – PKB and MAPK pathways Ras independent signaling – The PKB Signaling and Ras dependent – The MAPK Signaling Ras independent through activation of Protein Kinase B Responsible for immediate non-genomic effects Ras dependent – Activation of Mitogen Activated Protein Kinase (MAPK) pathway Responsible for genomic effects 53 Insulin Signaling – PKB and MAPK pathways 54 Insulin Signaling – PKB and MAPK pathways Clinical Pearl 1. Ras independent signaling cascade – PI3P – PKB 2. Ras dependent signaling cascade – MAP Kinase 55 Glucose Uniporter - GLUTs 56 Glucose Uniporter - GLUTs Clinical Pearl 1. Translocation of GLUT-4 to cell surface is crucial for Glu. uptake 2. Insulin resistance is usually due to failure of this step 57 Ras Independent – PI3K - PKB Signaling IRS1 binds PI3 kinase through SH2 domain This phosphorylates PIP2 to PIP3 Increased concentration of PIP3 recruits PKB to the plasma membrane PKB is phosphorylated by two membrane associated kinases PKC λ and ξ Active PKB is released into the cytosol Where it translocates glucose transporter (GLUT-4) GLUT-4 (uniporter) moves on to the membrane GLUT-4 lets Glucose in and increases glucose uptake 58 PIP Signaling Pathway 59 Ras - Independent Insulin Signaling 60 Insulin and PI3K Signaling 61 Ras Independent Extracellular Space = GLUT-4 Cytoplasm Active IRTK PO OP IRS PO OP tyr-OH ATP [1] IRTK ADP catalyzed IRS p85 [2] activated IRS by docking PI- active IRS IRS tyr-OP 3K IRS IRSactive tyr-OP IRS PIP2 Figure 5. Mechanism for insulin to PIP3 mobilize GLUT-4 transporter to the tyr-OPtyr-OP tyr-OP plasma membrane in muscle & adipose + [4] signals Golgi to tissue. PDK PKB traffic GLUT-4 to IRS, insulin-receptor substrate; membrane IRTK, insulin receptor tyrosine kinase; PI-3K, phosphatidyl-inositol kinase; GOLGI PDK; phospholipid-dependent kinase PKB, protein kinase B 62 Ras Dependent – MAPK Signaling At the same time… Phosphorylated insulin receptor binds to adapter protein SHC through GRB2 GRB2 also has SH3 domains that bind and activates Sos Binding of Sos to inactive Ras causes a conformational change that permits release of GDP and binding of GTP (activation of Ras) Sos is a GEF for monomeric G protein Ras Sos dissociates from activated Ras Linking insulin receptor to Ras 63 Ras - Dependent Insulin Signaling 64 Ras Dependent – MAPK Signaling Activated Ras passes the signal to raf kinase Raf activates a cascade of kinases (MAP Kinase cascade) Mitogen Activated Protein Kinases (MAP Kinases) Highly conserved kinase cascades Last kinase in the cascade has to be double phosphorylated It has high specificity (since it is double phosphorylation) 65 Ras Dependent Glucose Extracellular GLUT-4 PO OP Cytoplasm Glucose transport PO OP (muscle/adipose) Activated IRTK metabolic responses Signal transduction (e.g., phosphorylation of IRS, SHC, PLC) Activation of protein phosphatase Dephosphorylation of: KINASE CASCADE glycogen synthase (protein phosphorylation) glycogen phosphorylase mitogenic phosphorylase kinase Cell growth response acetyl CoA carboxylase and replication hormone-sensitive lipase phosphofructokinase-2 NUCLEUS pyruvate kinase HMG CoA reductase DNA synthesis regulatory kinases mRNA synthesis Protein synthesis 66 Ras Dependent – MAPK Signaling MAPK regulates the activity of transcription factors Active MAPK translocates to the nucleus It phosphorylates several transcription factors And production of more GLUT4 67 Glucose Entry in to the Cell Insulin/GLUT4 is not the only pathway Insulin-dependent, GLUT 4 - mediated Cellular uptake of glucose into muscle and adipose tissue (40%) Insulin-independent glucose disposal (60%) GLUT 1 – 3 in the Brain, Placenta, Kidney SGLT 1 and 2 (sodium glucose symporter) Intestinal epithelium, Kidney 68 Fatty Acid Dysregulation impairs Insulin action 69 Fatty Acid Dysregulation impairs Insulin action Clinical Pearl 1.Excess FFA – cause dysregulation of IR 2.GLUT-4 function is impaired – Insulin Resistance 70 Cyclic AMP Pathway - Glucagon Off switch PDE inactivates cAMP PDE stops signal transduction. Caffeine inhibits PDE! 71 Glucose controls Insulin and Glucagon release 72 Liver and Kidney Major source of net endogenous glucose production Accomplished by gluconeogenesis and glycogenolysis when glucose is low And of glycogen synthesis when glucose is high. Can oxidize glucose for energy and convert it to fat which can be incorporated into VLDL for transport. 73 Metabolic Effects of Insulin - in the Liver 74 Muscle Can convert glucose to glycogen. Can convert glucose to pyruvate through glycolysis - further metabolized to lactate or transaminated to alanine or channeled into the TCA cycle. In the fasting state, can utilize FA for fuel and mobilize amino acids by proteolysis for transport to the liver for gluconeogenesis. Can break down glycogen But cannot liberate free glucose into the circulation. 75 Metabolic Effects of Insulin - in the Muscle 76 Adipose Tissue (AKA fat) Can store glucose by conversion to fatty acids and combine these with VLDL to make triglycerides. In the fasting state can use fatty acids for fuel by beta oxidation. 77 Effects of Insulin - in the Adipose tissue 78 Metabolic Effects of Glucagon 79 Insulin – Anabolic and Glucagon - Catabolic Metabolic Action Insulin Glucagon Glycogen synthesis ↑ ↓ Glycolysis (energy release) ↑ ↓ Lipogenesis ↑ ↓ Protein synthesis ↑ ↓ Glycogenolysis ↓ ↑ Gluconeogenesis ↓ ↑ Lipolysis ↓ ↑ Ketogenesis ↓ ↑ 80 Glucose Uniporters - GLUTs Transport can work in both directions 81 The GLUT – Glucose Transporters 14 transporters of Glucose are identified Their genes are located and cloned The function of some is yet under evaluation Some genetic defects produce specific diseases like GLUT-1-DS In breast and prostate cancer GLUT- 11 is hyper expressed and supplies the high needs of glucose to the cancer cells. – Anti GLUT – 11 drugs might be a therapeutic approach for these cancers. 82 The GLUT – Glucose Transporters 14 transporters of Glucose are identified Their genes are located and cloned Clinical Pearl The function of some is yet under evaluation 1. GLUT -1 DS – a genetic disorder of Glucose Some genetic defects produce specific diseases like metabolism GLUT-1-DS 2. Anti GLUT -11 drugs in breast & prostate Ca are In breast and prostate cancer GLUT- 11 is hyper underway expressed and supplies the high needs of glucose to the cancer cells. – Anti GLUT – 11 drugs might be a therapeutic approach for these cancers. 83 Glucose Transporter Proteins - GLUTs GLUT - 1 - Responsible for feeding muscle during exercise (that is how exercise lowers blood glucose) Placenta, BB, RBC, Kidney and many tissues. Low in liver. Mainly ―house keeping‖ GLUT – 2 – Uniporter of glucose into the beta cells and stimulates insulin secretion. Beta cells of pancreas. Liver, small intestinal epithelium, Kidney. Has high Km (60 mM). Never saturates. GLUT - 3 – Insulin independent glucose disposal in to the tissues. Abundant in neuronal tissue, placenta and kidney. It feeds the high glucose requirement with out insulin. 84 Glucose Transporter Proteins - GLUTs GLUT - 1 - Responsible for feeding muscle during Clinical lowers exercise (that is how exercisePearl blood glucose) Placenta, BB, RBC, Kidney and many tissues. Low in 1. The GLUT-3 Receptors liver. Mainly ―house keeping‖ are Insulin independent GLUT – 2 – Uniporter of glucose into the beta cells and stimulates insulin secretion. Beta cells of pancreas. 2. In brain GLUT-3 mediate glucose uptake Liver, small intestinal epithelium, Kidney. Has high 3. In mM). Never saturates. Km (60 placenta also GLUT-3 mediate Glucose uptake GLUT - 3 – Insulin independent glucose disposal in to 4. Foetal growth in not affected very much the tissues. Abundant is neuronal tissue, placenta andin kidney. It feeds the high glucose requirement with out IR insulin. 85 Glucose Transporter Proteins – GLUTs contd.. GLUT – 4 – Insulin dependent – It is the main channel for glucose entry into cells. Muscle, Heart and adipose tissues depend on GLUT –4 for glucose entry in to cells GLUT – 5 – Rich in small intestine and conduct absorption of dietary glucose and fructose transport. Mediate glucose for spermatogenesis GLUT – 6 – Pseudo gene – Mediates none so far GLUT – 7 – Only in liver endoplasmic reticulum and it conducts glucose back out – G6P transporter in ER SGLT 1 and 2 - Sodium - Glucose symporter in the intestinal epithelium and renal tubular epithelium 86 Glucose Transporter Proteins – GLUTs contd.. GLUT – 4 – Insulin dependent – It is the main channel for glucose entry into cells. Muscle, Heart and adipose tissues depend on GLUT –4 for glucose entry in to cells Clinical Pearl GLUT – 5 – Rich in small intestine and conduct 1. GLUT-4 is main Glucose transporter in absorption of dietary glucose and fructose transport. all tissues Mediate glucose for spermatogenesis 2. It cannot function without TK so far GLUT – 6 – Pseudo gene – Mediates none signaling of GLUT – 7 – Only in liver endoplasmic reticulum and it Insulin conducts glucose back out – G6P transporter in ER SGLT 1 and 2 - Sodium - Glucose symporter in the intestinal epithelium and renal tubular epithelium 87 Brain Converts glucose to CO2 and H2O. Can use ketones during starvation. Is not capable of gluconeogenesis. Has no glycogen stores. 88 Know Our Brain !! Brain is the major glucose consumer Consumes 120 to 150 g of glucose per day Glucose is virtually the sole fuel for brain Brain does not have any fuel stores like glycogen Can't metabolize fatty acids as fuel Requires oxygen always to burn its glucose Can not live on anaerobic pathways One of most fastidious and voracious of all organs Oxygen and glucose supply can not be interrupted 89 Know Our Brain !! Brain is the major glucose consumer Consumes 120 to 150 g of glucose per day Clinical Pearl Glucose is virtually the sole fuel for brain 1. Brain does not need Insulin for glucose does not Brainuptake have any fuel stores like glycogen 2. metabolize fatty acids as mediate it without Can'tThe GLUT-3 Receptorsfuel Requires oxygen always to burn its glucose Insulin 3. In live on anaerobic pathways Can not hypoglycemia we need to give Glucose One of most fastidious and voracious of all organs only Oxygen and glucose supply can not be interrupted 90 Second Signaling Now Insulin that is secreted in to the blood starts the second signaling event Insulin binds to the Insulin Receptors (IR) on the muscle and fat cells Muscle and fat cells increase glucose uptake This leads to lowering of blood glucose 91 Insulin – C peptide Insulin is dimer of two peptides Each peptide consists of A and B chains A has 21 amino acids B has 30 amino acids 2 chains are linked by pair of S – S bonds C peptide has 35 amino acids and is cleaved 92 Insulin – C peptide Insulin is dimer of two peptides Clinical Pearl Each peptide consists of 1. Insulin Analogs are substitutions of AA in α and ß A and B chains chains A has 21 amino acids Insulin lispro etc., 2. Insulin Glargine, Insulin aspart, has 30 amino acids B RAIA, LAIA 2 chains are linked by pair of S – S bonds C peptide has 35 amino acids and is cleaved 93 Preproinsulin – Proinsulin – Insulin 94 Preproinsulin – Proinsulin – Insulin Clinical Pearl 1. C – Peptide assay is simpler, less costly than Insulin assay 2. It is the surrogate for endogenous Insulin secretion 3. It is not affected by exogenously administered Insulin 4. It is not largely influenced by food intake 95 PPAR Family of Nuclear Receptors Peroxisome Proliferator Activated Receptors 96 PPAR Family of Nuclear Receptors Peroxisome Proliferator Activated Receptors Clinical Pearl 1. PPAR alpha are essential regulators of serum lipids 2. PPAR gamma are essential for Insulin Sensitivity 3. In Insulin Resistance the PPAR Gamma are inactivated 4. Glitazones enhance the PPAR Gamma activity 97 The Role of Pancreas Insulin Hypoglycemic hormone Beta cells of pancreas Two chain polypeptide – Anabolic in nature Receptor interactions Intracellular interactions Transporters Clinical correlation 98 Insulin - Mechanism of action Insulin binds to its trans-membrane receptor. β subunits of the receptor become phosphorylated Receptor has intrinsic tyrosine kinase activity. Intracellular proteins are activated/inactivated— IRS-1, IRS-2 and seven PI-3-kinases GLUT-4, Transferrin, LDL-R, IGF-2-R move to the cell surface. Cell membrane permeability increases: Glucose, K+, amino acids, PO4 enter 99 Insulin Insulin Release In a 24 hour period, 50% of the insulin secreted is basal and 50% is stimulated. The main stimulator for secretion is glucose. Amino acids also stimulate insulin release, especially lysine, arginine and leucine. This effect is augmented by glucose. 100 Control of Insulin Secretion Glucose interacts with the GLUT-2 transporter on the pancreatic beta cell. Glucose enters the cell releases - hexokinase→ G-6-P Increased metabolism of glucose → ATP → Excess of ATP- blocks ATP dependent K channels → Membrane depolarization → ↑ Cytosolic Ca++ → This stimulates degranulation and Releases ↑ insulin secretion. 101 Control of Insulin Secretion Insulin secretion is also increased by Growth hormone (acromegaly) Glucocorticoids (Cushings') Prolactin (lactation) Placental lactogen (pregnancy) Sex steroids 102 Regulation of Insulin Secretion Summary of feedback mechanism for regulation ↑ blood glucose ↓ ↑ insulin ↓ ↑ transport of glucose into cells, ↓ gluconeogenesis, ↓ glycogenolysis ↓ ↓ blood glucose ↓ ↓ insulin 103 Role of Insulin Metabolic Effects of Insulin Main effect is to promote storage of nutrients Paracrine effects Decreases Glucagon secretion Carbohydrate metabolism Lipid metabolism Protein metabolism and growth 104 Role of Insulin Carbohydrate metabolism Increases uptake of glucose Promotes glycogen storage Stimulates glucokinase Inhibits gluconeogenesis Inhibits hepatic glycogenolysis Inactivates liver phophorylase 105 Sources of Glucose in to blood Glucose is derived from 3 sources Intestinal absorption of dietary carbohydrates Glycogen breakdown in liver and in the kidney. Only liver and kidney have glucose-6-phosphatase. Liver stores 25-138 grams of glycogen, a 3 to 8 hour supply. Gluconeogenesis, the formation of glucose from precursors These include lactate and pyruvate, amino acids (alanine and glutamine), and to a lesser degree, from glycerol 106 Fasting State Short fast Utilizes free glucose (15-20%) Break down of glycogen (75%) Overnight fast Glycogen breakdown (75%) Gluconeogenesis (25%) Prolonged fast Only 10 grams or less of liver glycogen remains. Gluconeogenesis becomes sole source of glucose Muscle protein is degraded for amino acids. Lipolysis generates ketones for additional fuel. 107 Role of Insulin Lipid Metabolism Insulin promotes fatty acid synthesis Stimulates formation of α-glycerol phosphate α-glycerol phosphate + FA CoA = TG TG are incorporated into VLDL and transported to adipose tissues for storage. Insulin inhibits hormone-sensitive lipase, Thus decreasing fat utilization. 108 Role of Insulin Protein Metabolism and Growth Increases transport of amino acids increases mRNA translation and new Proteins, A direct effect on ribosomes Increases transcription of selected genes, Especially enzymes for nutrient storage Inhibits protein catabolism Acts synergistically with growth hormone 109 Role of the Pancreas Lack of insulin Occurs between meals, and in diabetes. Transport of glucose and amino acids into the cells decreases, leading to hyperglycemia. Hormone sensitive lipase is activated, Causing TG hydrolysis and FFA release. ↑ FFA conversion in liver → Phospholipids and cholesterol → Lipoproteinemia, FFA breakdown leads to ketosis and acidosis. 110 Insulin Resistance Associated with obesity Underlying metabolic defect in Type 2 diabetes Polycystic ovarian disease Associated with Hypertension, gout, high triglyceride 30% of general population 111 What causes insulin resistance? Decreases in receptor concentration Decreases in tyrosine kinase activity, Changes in concentration and phosphorylation of IRS-1 and IRS-2, Decreases in PI3-kinase activity, Decreases in glucose transporter translocation, Changes in the activity of intracellular enzymes. 112 What causes insulin resistance? Decreases in receptor concentration Clinical Pearl Decreases in tyrosine kinase activity, 1. T2D in concentration and phosphorylation Changesis mostly a question of Insulin of Resistance IRS-1 and IRS-2, Decreases in PI3-kinase activity, 2. Drugs which improve Insulin resistance are crucial Decreases in glucose transporter translocation, Changes in the activity of intracellular enzymes. 3. Quantitative deficiency is only a late feature in T2D 113 The Role of Pancreas Other pancreatic hormones Somatostatin 14 amino acid paracrine factor Potent inhibitor of glucagon release Stimili: glucose, arginine, GI hormones It is anti GH (somatotrophin) in its actions Pancreatic polypeptide 36 amino acids, secreted in response to food Glucagon 114 Counter Regulatory Hormones Early response Glucagon Epinephrine Delayed response Cortisol Growth hormone 115 Counter Regulatory Hormones Glucagon Acts to increase blood glucose Secreted by alpha cells of the pancreas Chemical structure 29 amino acids Derived from 160 aminoacid proglucagon precursor GLP-1 (Glucagon Like Peptide -1) The most potent known insulin Secretagogue It is made in the intestine by alternative processing of the same precursor Intracellular actions 116 Role of Glucagon Metabolic Effects of Glucagon Increases hepatic glycogenolysis Increases gluconeogenesis Increases amino acid transport Increases fatty acid metabolism (ketogenesis) 117 Role of Glucagon Metabolic Effects of Glucagon Clinical Pearl Increases hepatic glycogenolysis 1. Glucagon is the treatment for hypoglycemia Increases gluconeogenesis 2. Glucagon Kit – 1 mg s/c or IM or IV injection Increases amino acid transport – Increases fatty acid metabolism (ketogenesis) 3. In 2 to 3 minutes recovery 4. Costs Rs. 400 per dose 118 Glucagon Secretion Stimulation of Glucagon secretion Blood glucose < 70 mg/dL High levels of circulating amino acids Especially arginine and alanine Sympathetic and parasympathetic stimulation Catecholamines Cholecystokinin, Gastrin and GIP Glucocorticoids 119 Responses to decreasing Glucose levels Response Glycemic Physiological Role in counter theshhold effects regulation ↓ Insulin 80 - 85 mg% ↑ Ra (↓ Rd) Primary First Defense ↑ Glucagon 65 - 70 mg% ↑ Ra Primary Second Defense ↑ Epinephrine 65 - 70 mg% ↑ Ra ↓ Rd Critical Third Defense ↑ Cortisol, GH 65 - 70 mg% ↑ R a ↓ Rd Not Critical ↑ Food ingestion 50 - 55 mg% ↑ Exogenous < 50mg% no Glucose cognitive change 120 Role of Epinephrine Epinephrine The second early response hyperglycemic hormone. This effect is mediated through the hypothalamus in response to low blood glucose Stimulation of sympathetic neurons causes release of epinephrine from adrenal medulla . Epinephrine causes glycogen breakdown, gluconeogenesis, and glucose release from the liver. It also stimulates glycolysis in muscle Lipolysis in adipose tissue, Decreases insulin secretion and Increases glucagon secretion. 121 Role of Cortisol and GH These are long term hyperglycemic hormones Activation takes hours to days. Cortisol and GH act to decrease glucose utilization in most cells of the body Effects of these hormones are mediated through the CNS. 122 Cortisol Cortisol is a steroid hormone It is synthesized in the adrenal cortex. Synthesis is regulated via the hypothalamus (CRF) and anterior pituitary (ACTH). Clinical correlation: Cushing's Disease 123 Growth Hormone (GH) GH is a single chain polypeptide hormone. Source is the anterior pituitary somatotrophs. It is regulated by the hypothalamus. GHRH has a stimulatory effect. Somatostatin (GHIF) has an inhibitory effect. Clinical correlation: Gigantism and Acromegaly cause insulin resistance. Glucose intolerance—50% Hyperinsulinemia—70% 124 What is T2D or T1D ? 125 Normal, T2D and T1D Normal Subject Type 2 Diabetes (T2D) Type 1 Diabetes (T1D) High blood glucose High blood glucose High blood glucose -cells destroyed by autoimmune reaction Blood glucose remains high Blood glucose remains high Detected by -cells Poor function of -cells No -cells to detect & respond -cells release insulin -cells release of insulin is Insulin secretion is nil inadequate or inefficient Peripheral cells respond to Peripheral cells poorly Peripheral cells have no insulin & take up glucose respond to insulin and insulin to respond and glucose up take is poor take up glucose Lower blood glucose Blood glucose remains high Blood glucose remains very high 126 Type 2 Diabetes Mellitus Peripheral Tissue Insulin -cell Insulin Disease Resistance v. Time Production v. Time Progression Relative Insulin Resistance -cell Insulin Production Diabetic Pre-Diabetic Age Normal Glucose Homeostasis Time in years Time in years Birth 127 T2D – It is Question of Balance ! Non-Diabetic State PERIPHERAL INSULIN ß-CELL MASS RESISTANCE & FUNCTION Diabetic State 128 Pathology of Type 2 Diabetes 129 Time Sequence of Events in T2D 130 Insulin Kinetic Defect in T2D 131 Natural History of T2D Obesity IGT* Diabetes Uncontrolled Hyperglycemia Post-meal Plasma Glucose Glucose Fasting Glucose 120 (mg/dL) Relative -Cell Insulin Resistance Function 100 (%) Insulin Level -20 -10 0 10 20 30 *IGT = impaired glucose tolerance Years of T2D 132 Net Beta Cell Mass Replication Neoformation Apoptosis Neoformation Apoptosis -cell mass 133 Net Beta Cell Mass Replication Clinical Pearl 1. Crucial determinant of the course of T2D patient 2. Beta cell apoptosis is the cause of Neoformation Apoptosis Neoformation secondary OHA failure Apoptosis -cell mass 134 Net Beta Cell Mass THE FORMULA FOR ß-CELL MASS - (Mitogenesis + Size + Neogenesis) - Apoptosis = Growth Increased ß-mass (i.e. compensation for insulin resistance): (Mitogenesis + Size + Neogenesis) > Apoptosis Decreased ß-mass (i.e. Type-2 diabetes): Apoptosis > (Mitogenesis + Size + Neogenesis) 135 Approaches to lower Blood Glucose 136 Approaches to lower Blood Glucose Clinical Pearl 1. Various approaches to treat T2D and T1D 2. To restore normoglycemia is the goal 3. These approaches have additive effect 137 Evolution of the Modern Cardio-metabolic Man Grotesque not in physical appearance alone !! 138 Fatty Acid Oxidation - What is the Switch ? Glucose Stearoyl CoA Desaturase (SCD) Thrifty Gene Hypothesis 139 Fatty Acid Oxidation - What is the Switch ? Glucose Clinical Pearl SCD SWITCH MANIPULATION might be the answer Stearoyl CoA Desaturase (SCD) Thrifty Gene Hypothesis 140 The Web of Cardio-metabolic pathogenesis 141 Leptin Produced almost exclusively by adipose tissues Regulates appetite via ‗satiety signal' to Hypothalamus Has beneficial effects on muscle fat oxidation and insulin resistance These are compromised by Leptin insensitivity Has a suggested role in the development of various cardiac risk factors – including high blood pressure 142 Adipsin (ASP) ASP – Acylation Stimulation Protein Role in the uptake and esterification of Fatty Acids Facilitates fatty acid storage through Triacylglycerols Stimulates Triacylglycerol synthesis via Diacylglycerol Acyl Transferase (DGAT) Stimulates translocation of GLUT to cell surface ASP release is induced by HDLc 143 Adiponectin Significant homology to complement factor C1q Accumulates in vessel walls in response to ET injury Reduced in obesity Weight loss causes increase in its levels Reduced in patients with CAD Beneficial effects on CAD may be through Inhibition of mature macrophage function Modulation of endothelial inflammatory response Inhibition of TNFα induced release of adhesion molecules 144 WISH YOU ALL A HAPPY NEW YEAR 145
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Featured Episode: Automated Capitalism – ¥€$
Acting on a tip, Section 9 breaks up a cabal of thieves hell-bent on wrecking a Japanese financial institution. Shortly after the raid a Chinese intelligence official contacts Section 9 and informs them of suspicious activity that he believes may indicate an assassination attempt by Chinese Socialists on a prominent, yet reclusive, Japanese multi-millionaire. Section 9 is therefore tasked with protecting the millionaire, a 56-year-old ex-mathematician who has amassed a fortune by playing the stock market. Section 9 and the assassin arrive within minutes of each other, but after reaching the millionaire's bedroom both sides make an unexpected discovery. The millionare has actually been long dead, with the only reason why people believed that he was alive being his advanced financial program that automatically managed his investements.
Read More at Automated Capitalism – ¥€$
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