text:
Comment Re:Alternative Approach (Score 1) 127
Instead, companies could set reasonable standards for productivity and discipline those who don't meet them. It doesn't matter if an unproductive employee is unproductive because they are on their phone, or because they spend too much time at the watercooler, or because they are just pretty bad at their jobs.
I think part of it is a (work) cultural problem.
At one employer, working in a sort of repair/assembly atmosphere, my boss text messaged while I was working. In fact, he sent several text messages.
Hours later he asked me, "Hey, I wanted to talk to you, didn't you get my text messages?"
I told him that I usually don't check my messages while I'm working, and that I could do that if it was what he wanted.
I didn't get the feeling he was testing me; I genuinely think he expected me to stop what I was doing, pick up my phone, and read my messages as I received them. I don't think he realizes that it means every time I get a text message, I have to stop what I'm doing and take out my phone to verify if it is from him. That from that point forward, every text I get is money out of my employers pocket.


text:
Select Local Merchants
Cort Furniture Rental District OfficeRead MoreKeep your home looking modern and fresh with a brand new furniture set from CORT District Office in Austin. Splurge on a new bedroom set from here, such as bedroom furniture, and enjoy the benefits of a beautifully designed and well-furnished bedroom. Don't let your office get outdated. Shop for some new office furniture at this store and impress your clients in style. Perfect for the warmer months, the outdoor furniture here is just what you need to make your patio complete. Making over your bathroom is super simple with the cute and affordable furniture selection. Liven up your home's interior with beautiful furniture sets from here, such as living room furniture. If you're in the market for a bold piece of art, check out the beautiful works featured here. Say bye to bare walls and empty space. Just a few of the pieces here that will work well in almost any room include rugs, throw pillows, and vases. Wall decorations such as curtains and mirrors are sure to catch your eye, so stop in and see what else is on hand. No matter what type of vehicle you drive, you can find safe parking options nearby. Stick with the classics, go modern, or even blend your styles. Furnish your home any way you want when you shop the shelves at CORT District Office.200 Parker DrAustin, TX US
Michael AngeloRead MoreAn Italian eatery in Austin's Corridor Park area, Michael Angelo is a prime spot for a delicious plate of pasta. Endless parking options are readily available close to Michael Angelo. Dining at Michael Angelo will set you back about $30 per person on average. When in Rome, you do as the Romans do. When at Michael Angelo, you eat as deliciously as the Italians do.200 Michael Angelo WayAustin, TX US
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Commvault SystemsRead MoreA new computer can make your work and personal life easier. Check out laptops, computer parts, computer monitors, printer_copier_scanner_string, and desktop computers at store and pick out your most suitable option. The area holds many available spaces for customers to park.1930 Rawhide DrRound Rock, TX US
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subset: commoncrawl


text:
Alexis Conran wins Celebrity Master Chef 2016
After six weeks of cooking, Conran saw off competition from 19 other celebrities to be named champion by judges Gregg Wallace & John Torode.
Herman Miller opens new facility in Bengaluru
Herman Miller today inaugurated its production facility at Bidadi and said it plans to double s...
Greek debt deal would 'end six years of darkness': Greek Prime Minister Alexis Tsipras
Tsipras also welcomed signs that the EU and the Intern...
Greece cannot carry migrant burden on its own: PM Alexis Tsipras
"Greece will demand that all countries respect the European treaty and that there will be sanctions for those that do not," Tsipras said.
Greek parliament approves Prime Minister Alexis Tsipras' social justice bill
The plan affects mainly self-employed professionals and farmers, who have been blockading roads and border crossings in protest for weeks.
Greece's Alexis Tsipras vows to implement pension reform at anniversary rally
Tsipras, at a rally Sunday to mark a year in power, stood by a vow to overhaul the country's pension system despite fierce opposition.
IMF behaviour in Greek crisis not constructive: Alexis Tsipras
"This is a stance that cannot be called constructive in this process," the leftist leader said in a television interview.
Greece's Alexis Tsipras facing the music after rollercoaster year in power
A day earlier, Tsipras will address his party in a celebratory speech, promising that the upturn is just around the corner.
Arsenal's frequent flyer Alexis Sánchez
Somebody might one day explain to Alexis Sánchez the meaning of fatigue and burnout. Right now, he just doesn't get it.
Greeks strike against austerity in test for Alexis Tsipras
Tsipras was re-elected two months ago on a mandate to implement that agreement, vowing to work hard to buffer its impact, particularly on vulnerable Greeks.
Alexis Tspiras: 'Vindicated' by election victory
Tspiras said he "felt vindicated" after quitting in August to start on a clean slate with voters after a revolt in his party against a multi-billion-euro bailout with international lenders.
Greek PM Alexis Tsipras says differences between lenders delaying bailout review: Report
Reforming Greece's ailing pension system is a prerequisite for the conclusion of the review, which is expected to open the way for debt relief talks.
Greek yields highest since elections as Alexis Tsipras hits out at IMF
Tsipras was re-elected in September's snap poll with a mandate to implement the tough terms of a third IMF/EU aid package.
Greeks strike again over pensions in test for Alexis Tsipras reforms
Striking Greek workers marched through Athens on Thursday and disrupted public transport, schools and shipping in the second big protest in three weeks against planned pension reforms, but turnout was lower amid a mood of resignation.
Avoiding further pension cuts under bailout: Alexis Tsipras
Greek Prime Minister Alexis Tsipras told his leftist Syriza party's lawmakers the government would do everything it could to ensure there were no further cuts in pensions.


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Orlanda s Place Bolhão - Dit hjem
Størrelse45 m²
- Familie/børnevenlig
- Internet/WIFI
- Køkken
- Rygning tilladt
- Balkon/terrasse
- Håndklæder
|Rua Fernandes Tomás, 4000-212 Porto, Portugal
|Inden for få timer
|Kalenderen er opdateret
|I går
Let at nå med bus, metro - Bolhão Metrostationen er et par meter væk - eller simpelthen ved at gå, er dette område godt tjent i lokale købmandsforretninger, det marked, hvor du kan købe frisk mad og grøntsager, caféer, hæveautomater, indkøbscentre , taxier og nogle af de mest interessante og ikoniske steder i Porto, ligesom Majestic Café, Capelas das Almas, Aliados Avenue og rådhuset, Clerigos Tower, Galerias de Paris, São Bento Station, osv. Alt i gå rækkevidde.
Det har et fuldt udstyret moderne køkken med spiseplads, et komplet badeværelse - håndklæder leveres - og en behagelig værelse med to enkeltsenge, tv og wi-fi.
Det er en rolig og hyggelig lejlighed, i stand til at give dig med sindsro og samtidig være i centrum af Porto liv og aktivitet, og så oplever det mest, som du måtte ønske.
Casa da Musica er en 10min rejse med metro, samme som Campanhã Railway Station eller Estádio do Dragão. Ribeirinha er 7min væk ved mund.
Tager metroen fra lufthavnen vil kun tage omkring 25 min, og samtidig få slukket den station, du har ingen problemer med at finde lejligheden, som det er lige foran det.
|Check-in efter
|Check-in før
|Efter aftale
|Check ud før
Maria was waiting for us when we arrived at the appartment and she gave us very useful information for our visit. The location is perfect, within walking distance to the city center and the river, and the appartment has everything one could need during a few days in Porto. Very recommendable!
Really nice place and better landlord. The apartment is confortable and is in a central location (10 minutes walking from Sao Bento Station). I recommend it if you want to pass some days in the city.
The apartment is very cute and perfect for a few days in porto .
Good location, metro station in front of the door or 15 minutes to the douro by feet. Maria is very friendly and helpful.
Very nice family that helped us in everything they could. The apartment is exactly the same than in the photos. Very confortable but noisy because of a bus parking
we had a perfect stay with everything we needed. the rooms were very clean and the bed really comfortable. a fast wifi helped us to find everything real quick. the house is located in a very good area. not long to walk (at least 10minutes) and you're in the center! although maria could not receive us personally, she was really hospitable and helpful. we definitely can recommend this place!
Nice appartment at Bolhao Market, excellent location in the historical centre. Subway on the doorstep. The host Maria is very friendly, Good price.
We enjoyed it very much!
Rien and Marianne
Big, clean and comfortable appartment in good location. Nice host.
Absolutely recommendable !
From the very first moment Maria was really warm and hospitable. There was no trouble whatsoever in finding the apartment, and she showed us around and gave us some useful info for Porto. The apartment is very well located opposite of the Bolhao market, and the bed is very comfortable :)
Maria is really nice, and her son as well. Kind and friendly.
The apartment is very cute, perfect for a short stay. It only needs thicker courtains to dark the bedroom properly for us who are used to shutters. The rest is perfect.
Very nice renovated appartment in a well renovated building. Very clean, good beds, all necessary things for our stay.Easy to park car in the street, and really near from down town to go walking. We were very well received, and very happy from our stay by Maria. We recommand it!
- Kvalitetssikrede boliger
- Alle værter verificeres via telefon
- Sikker betaling med SSL-kryptering


text:
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Network Engineer Atlanta, GA, United States Network Engineering is a position that is strategic to Vertafore?s SaaS Operations in a number of ways. As a Senior Network Engineer in Hosting Services, you will design and implement highly available network architectures to meet8/26/2016 Atlanta, GA Save This Job
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Work Location: Kansas City, MO The Datacenter / Facilities Technician with LightEdge Solutions will be responsible for managing and maintaining all aspects of our datacenters, and other critical facilities. This will include working directly with other engineers, support staff,8/13/2016 Kansas City, MO Save This Job
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Description Do you have experience working in the Financial Services, Banking or Mortgage industries as a statistician, modeler or analyst? Acurian is looking for a Statistical Analyst who has the ability to dissect and analyze large healthcare-related datasets while producing8/10/2016 Horsham, PA Save This Job
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Peak 10 provides IT infrastructure solutions that ensure the 24/7/365 availability and security of our customers? critical data and applications. Customer-centric and cost-competitive, Peak 10 IT infrastructure solutions are designed to scale and adapt to customers? changing8/9/2016 Nashville, TN Save This Job
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text:
Relevant offers
A 60-year-old woman who went missing in Kapiti yesterday has still not been found this morning.
Police have concerns for the welfare of Robyn Wilson, who has a medical condition.
Just after 4pm yesterday, Wilson left her Rifleman Lane, Paraparaumu home to go on a casual walk.
She had not returned or made contact with her family.
Searches were carried out by police and Search and Rescue volunteers overnight and were planned to continue this morning.
Police are asking people in the area to check their properties, sheds, crawl spaces and waterways for her.
Wilson is caucasian, 170cm tall, of slim build and has short dark red hair. She was not believed to be carrying anything.
She may have become confused about her whereabouts, police said.
- The Dominion Post
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Ex-Miss Universe Alicia Machado becomes US citizen to vote against Donald Trump
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text:
Millenium Fever Lyrics by 1140 Mississippi
Millenium Fever by 1140 Mississippi
Hush now my baby
Hush now my love
The angels are watching
From heaven above
They know that I love you
They know that it´s true
I´ll stay here beside you
Whatever you do
When I wake beside you
I feel like I shine
I wish you forever
And ever be mine
A new day tomorrow
When you open your eyes
You let in the sunshine
And all darkness dies
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text:
Readyville Used Car Dealers
Right Price Auto Sales, Inc.
Low Priced Used Cars
Come See Our Selection Today.
Used Car Dealers Since 1993.
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1. Vance Auto Sales
600 W Main StWoodbury, TN 37190
From Business: Randy Vance, the company founder, had been in the auto business for several years before establishing his own auto dealership. After deciding to venture out to beco…
2. All BMW Parts -- Bavarian Auto Recycling Inc.
Serving the Readyville Area.
From Business: As one of the largest BMW parts recyclers in the US, we specialize in rebuilt, new, and used BMW parts for all BMW car models. Our recycled BMW parts inventory incl…
3. We Buy Junk Cars & Used Cars
Serving the Readyville Area.
From Business: Cash For Junk Cars Inc is ready to get you top dollar for your junk car. Here is how it works: Step 1. Call and receive an immediate quote for your car right over t…
4. All European Engines & Transmissions - Bavarian Engine Exchange, Inc
Serving the Readyville Area.
From Business: Thank you for choosing Bavarian Engine Exchange to help with your used and rebuilt European Engine & Transmission needs. We are committed to providing you with cons…
5. QuoteWizard
Serving the Readyville Area.
From Business: We are an insurance comparison shopping site. We allow consumers to easily compare what all the largest insurers would charge them in their area. We've been in busi…
6. Vance Brothers Motor Company, Inc.
405 McMinnville HwyWoodbury, TN 37190
From Business: VVance Brothers Motor Company, Inc., in Woodbury, TN, is the area's premier dealer of used vehicles. We are a member of the Woodbury Lions Club serving Murfreesboro…
7. Precision Auto Sports
175 Alexander DrWoodbury, TN 37190
8. Bill Trail Motor Co
228 McMinnville HwyWoodbury, TN 37190
9. Howse Auto Credit
1520 Middleborough CtMurfreesboro, TN 37130
10. Star One Motors
1702A Bradyville PikeMurfreesboro, TN 37130
11. Riverside Motors
I saw a car on their website, called and was connected with Bill who was very pleasant to talk to. He was helpful and knowledgeable. Went in the sam…
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Purchased my recent vehicle from Broadway Motors and the vehicle is absolutely everything Steve said it would be. They are very honest about there c…
13. Jerry Lewis Autos
I bought a Mustang for Jerry Lewis in 2008. It was going to paid off in 2009 Well in Feb of 09 my husband had back surgery, Than in April and Augest…
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great,friendly people. never pressured me to buy anything and had low prices and were always willing to deal with outside financing.
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Great friendly service. Strait foward and fair business. Great prices on all vehicles and haven't had any problems with my vehicle purchase. I would…
16. E-1 Auto Exchange
1605 Memorial BlvdMurfreesboro, TN 37129
17. Premier Auto Sales
129 SE Broad StMurfreesboro, TN 37130
18. Supreme Auto Sales-Repair Inc
610 S Church StMurfreesboro, TN 37130
19. Jim Kirby AutomotiveProducts
Great vehicles, Great Family, Pleasure doing business with them. Highly recommended!
20. Double E Motors
Bought a Truck there a month ago found out that Tape was put over the overdrive light to keep us from seeing it, now we are putting money into a tra…
21. Auto EZ
1540 S Church StMurfreesboro, TN 37130
From Business: We sell used cars to the people for the people low down payments and easy weekly payments
22. Carbiz of Tennessee Inc
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23. Evans Automotive
2240 NW Broad StMurfreesboro, TN 37129
24. Master Auto Sales
363 SE Broad StMurfreesboro, TN 37130
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My daughter wrote a bad review concerning CarZone last month. She is only 15 and had no buisines writing about what she does not know. i am a loyal …
26. Big Tim's Auto Sales II
2269 NW Broad StMurfreesboro, TN 37129
27. Nashville Motor Cars Premier
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Slick advertising for grossly overpriced, high mileage vehicles. Take it or leave it price policy, these people will not negotiate. Avoid this pla…
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text:
Cooking macaroni-and-cheese without milk is easy and quite similar to cooking it with milk. The same process is followed, except the milk is substituted with replacement ingredient, such butter and water, or sour cream and yogurt for a thick and creamy consistency.Continue Reading
Macaroni-and-cheese is an extremely popular dish made up of macaroni pasta and cheese mixed in a creamy sauce that is either cooked on the stove top or baked in the oven. Traditionally the dish is made with cheddar cheese, but it is such a versatile dish that almost anything can be added to it. Some popular ingredients to add to the dish include bread crumbs, hot dogs, onions, tuna, ketchup, ground beef and vegetables. It can be made from scratch or prepared using a packaged mix which comes with macaroni and a packet of cheese mix. Many people choose to create a healthier version of this calorie-high meal by substituting the milk, butter or cheese with a low fat replacement such as cottage cheese and water.
Although it is known as being a quintessential American comfort food, its roots can be traced back to Italy and its popularity extends to all of North America, the UK, Europe and Australia.Learn more about Substitutions
To make homemade macaroni and cheese, cook the macaroni pasta and add to a sauce of butter, flour, eggs, milk, dry mustard, cheddar cheese, salt, ground black pepper and seasoned salt. For alternative flavors, add cayenne pepper, paprika or thyme to the sauce.Full Answer >
To make baked macaroni and cheese from a mix, prepare the boxed macaroni and cheese according to the instructions, then mix with shredded cheese, milk, bacon and seasonings and bake in the oven. Sprinkle with a breadcrumb topping before baking, if desired.Full Answer >
To cook lasagna with cottage cheese, first cook 12 ounces of ground beef and mix it with spaghetti sauce. Start with some spaghetti sauce on the bottom of a pan, then layer noodles, meat and cheese in the pan. Cover the pan in foil, bake, cut and serve.Full Answer >
Substitutes for kefalotiri cheese are other hard cheeses such as Romano or Parmesan, both of which have a similar sharp flavor and dry texture. When a recipe calls for the cheese to be sprinkled on top of the dish, nutritional yeast is a suitable vegan substitute. Nutritional yeast is high in protein, low in fat and not made from animal products.Full Answer >


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1857 10C PR64 Cameo PCGS....Click the image to load the highest resolution version.
Rare 1857 Ten Cent, PR64 Cameo1857 10C PR64 Cameo PCGS. The 1857 proof dime is a scarce issue overall, and extremely rare in Cameo format. The fields on this near-Gem piece are deeply reflective with a significant overlay of frost on the devices which gives the coin its two-toned, cameo effect. Just the slightest hint of golden color is seen on each side, but the coin basically presents as brilliant. The design elements are exquisitely brought up. The diagnostic repunching is visible just below the flag of the 1 in the date. Population: 2 in 64 Cameo, 0 finer (3/09).
From The Joseph C. Thomas Collection. (NGC ID# 23CB, PCGS# 84746)
View all of [The Joseph C. Thomas Collection, Part One ]
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ATLANTA (AP) — A coroner investigator says an up-and-coming rapper has been shot to death outside a popular recording studio in Atlanta.
Fulton County Medical Examiner senior investigator Tami Sedivy-Schorder says 28-year-old Trentavious White, also known as rapper Bankroll Fresh, was found shot outside Street Execs Studio around 11 p.m. Friday.
Atlanta police say White was pronounced dead at a hospital. Police told local news media they collected more than 50 shell casings inside and outside the recording studio.
White was signed to rapper 2 Chainz's Street Execs record label. White was known for his single "Hot Boy" and "Walked In" featuring Travis Porter, Boochie and Street Money.
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Several rappers from T.I. and 2 Chainz sent their condolences for White through social media.


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Obama Tells Epic Civil War Joke At National Academy Of Sciences
Without the science that helped the North win the civil war, "certainly I would not be here," Obama jokes. From the president's address to to the National Academy of Sciences Monday celebrating the group's 150th anniversary.
2. The transcript:
Since I did not do well enough in chemistry or physics to impress you much on those topics, let me instead tell a story.
One hundred and fifty years ago, the nation, as all of you know, was in the midst of the Civil War, and the Union had recently suffered a devastating defeat at Fredericksburg. The road ahead seemed long and uncertain. Confederate advances in weapons technology cast a dark shadow on the Union.
The previous spring, in the waters outside of Hampton Roads, the ironclad Confederate battleship Virginia had sunk two wooden Union ships and advanced on a third, and this endangered the Union blockade of Virginia and threatening Union forces along the Potomac River. And then, overnight, the USS Monitor, an ironclad herself, arrived and fought the Virginia to a draw in the world's first battle between iron-sided ships.
There was no victor, but the era of ironclad warfare had begun. And it brought unexpected challenges for President Lincoln and his Navy as they expanded this fleet in early 1863, because aboard their new iron-side battleships, sailors found that the iron siding made the ships' compasses unpredictable, so it skewed navigation, and they were bumping into things and going the wrong way. (laughter) So the basic physics of magnetism undermined the usefulness of the ironclad vessels, even as the Confederates were stocking up on them.
And that's where your predecessors came in. Because in March of 1983 —1863, rather — President Lincoln and Congress established the National Academy of Sciences as an independent and nonprofit institution charged with the mission to provide the government with the scientific advice that it needed. And this was advice that was particularly useful in the thick of battle.
The National Academy soon counted the nation's top scientists as members. They quickly got to work. By the next year, they were inspecting the Union's ironclads and installing an array of bar magnets around the compasses to correct their navigation. So right off the bat, you guys were really useful. (laughter) In fact, it's fair to say we might not be here had you not — (laughter) — certainly I would not be here. (laughter and applause)
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I tried the 'raw food diet' to get healthy - Holy Crap!
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My older brother did this many years ago in his mid twenties.
First off, he never put anything up his arse. No coffee enemas, nothing.
His diet consisted of nuts, pulses, fruit and veg. All raw. He drank only water. Never took a pill, vitamin, pain killer or otherwise.
At first the weight fell off him. My poor mother was worried sick. He insisted he was fine, he looked awful.
Within a couple of months the weight came back, the whites of his eyes shone and he had the whitest teeth you ever saw. He was, unbelievably, in perfect health.
He lived like that for a few years before deciding that it was 'extreme' and hard work to keep it up.
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27-year-old Convicted in 2009 Lower Manhattan Office Building Homicide
Joseph Pabon, a 27-year-old former handyman at a Rector Street skyscraper, was convicted on Monday, Apr. 2, of killing a 46-year-old co-worker in their office building and then allegedly stuffing her body in an air duct. According to a press release distributed by the city's DA's office, almost three years ago on the evening July 7, 2009, Pabon was working as a freight elevator operator one evening while the victim Eridania Rodriguqez was cleaning sections of the building. The DA ascertained Pabon followed Rodriguez to the eighth floor that night, where he allegedly attacked her and proceeded to suffocate her with industrial tape. The DA believes Pabon then used the freight elevator to transport her body to the 12th floor. Rodriguez was discovered four days after being killed.
"The defendant hunted down the victim in this case, a co-worker and mother of three, like a predator," said District Attorney Vance. "He senselessly and brutally murdered her, and discarded her body as if it were trash. Our hearts go out to the victim's family and hope this verdict provides some closure. I would also like to thank the skilled and experienced prosecutors in this Office for their work on this case, and the jury for its service."
Pabon was convicted of one count of murder in the second degree and one count of kidnapping in the first degree, both class A felonies.
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Moses Built New York's Coliseum
MoMA's Brief History of Time
Candle Caf� Remakes Ambiance
Letter: A Sad Farewell
Putting My Best Foot Forward
Moses Built New York's Coliseum
MoMA's Brief History of Time
Candle Caf� Remakes Ambiance
Letter: A Sad Farewell
Putting My Best Foot Forward


text:
|Publication number
|Publication type
|Application number
|Publication date
|Nov 28, 2006
|Filing date
|Jun 4, 2004
|Priority date
|Apr 9, 2003
|Fee status
|Also published as
|Publication number
|Thue Johansen, Kjell Malmlof
|Original Assignee
|Novo Nordisk A/S
|Export Citation
|BiBTeX, EndNote, RefMan
|Non-Patent Citations (25), Referenced by (3), Classifications (21), Legal Events (5)
|External Links: USPTO, USPTO Assignment, Espacenet
This application is a continuation of U.S. patent application Ser. No. 10/822,020, filed Apr. 9, 2004 now abandoned, and claims priority under 35 U.S.C. § 119 of Danish Patent Application No. PA 2003 00548, filed Apr. 9, 2003, and U.S. Provisional Patent Application No. 60/467,07, filed May 1, 2003, the contents of which are fully incorporated herein by reference.
Obesity is known to be associated with serious risk factors, and there is currently intense interest in identifying new principles for treatment of this condition. These efforts have hitherto resulted in identification of a substantial number of potential central and peripheral targets for treatment. It has also been shown that growth hormone (GH), more specifically human growth hormone (hGH) in human beings, acts as a potent regulator of body fat storage, and thus promotes breakdown of adipose tissue in obese humans while preserving lean tissues. Since a large proportion of glucose disposal and energy expenditure is thought to take place in lean tissues, preservation of such tissues combined with a selective loss of adiposity appears to be a highly desirable objective.
Although it is known that the protein anabolic aspect of the GH—insulin like growth factor-1 axis is influenced by diet composition, there does not appear to have been any focus on the question of whether this is also true for GH-stimulated loss of adipose tissue. The effect of GH during restriction of energy intake has also been unclear. There have been some reports indicating no additional effects of GH administration compared to the effect of energy restriction alone, whilst other reports have indicated the such effects.
A recently reported study by the present inventors and co-workers indicated GH-stimulated breakdown of adipose tissue in genetically intact old rats that had become obese while receiving a high-fat diet. However, despite normalisation of body fat stores following GH injection, basal insulin levels were significantly elevated.
It has been suggested that an excessive hyperinsulinemic response to GH injections would decrease the net effect of GH on adipose tissue. This would not be surprising since GH and insulin have been suggested to have opposing effects in adipose tissue. Moreover, sustained hyperinsulinemia would also increase the risk of development of overt Type 2 diabetes in susceptible obese individuals that already are at risk.
There is thus a clear need to identify factors determining the insulin response to administration of GH, both from a mechanistic and a safety point of view. The present inventors have now obtained clear indications that the macronutrient composition of the diet received by obese individuals constitutes one such factor, and that total energy intake constitutes another.
The present inventors have found that the insulin response in a subject to administration of GH can be modulated, for example, by varying diet composition and caloric intake, and/or by administering a drug which brings about a reduction in blood lipid levels (more precisely a reduction in the level of one or more blood lipid components), and that this influences adipose tissue loss and serum leptin levels. Among blood lipid components, free fatty acids (FFA) are of particular interest since high FFA levels often are associated with a decrease in insulin sensitivity leading to a compensatory hyper-secretion of insulin. A broad aspect of the invention thus relates to a method for substantially preventing hyperinsulinemia in an animal or human subject undergoing treatment with growth hormone (GH), the method comprising subjecting the subject, during the growth hormone treatment period, to one or more measures (such a diet regimen and/or a drug treatment) which cause a reduction in blood lipid levels (more precisely a reduction in the level of one or more blood lipid components). Further aspects of the invention include, inter alia:
Other aspects of the invention include medical kits suitable for use in methods according to the invention.
Further detailed aspects of the invention are described below.
The present invention provides methods and compositions for minimizing the risk of development of diabetes as a consequence of excessive overloading of insulin-producing beta-cells.
One aspect of the present invention relates to a method for substantially preventing hyperinsulinemia in an animal or human subject undergoing treatment with growth hormone (GH), the method comprising subjecting the subject, during the growth hormone treatment period, to one or more measures which cause a reduction in blood lipid levels. The method in question is believed to be of general applicability, irrespective of the underlying rationale for treatment of the subject with growth hormone. Thus, for example, the method of the invention may be used in the context of established GH treatments of immature humans (children or adolescents), such as for the purpose of stimulating growth to counteract development of short stature or dwarfism, as well as of mature (adult) humans.
A closely related further aspect of the invention relates to a method for achieving breakdown of adipose tissue in an animal or human subject—particularly an obese human subject—substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst subjecting the subject to one or more measures which cause a reduction in blood lipid levels.
Measures of the type referred to in relation to methods of the invention include, without limitation, diet regimens or drug treatments. In one embodiment, the subject is provided with restricted amounts of a high-fat (HF) diet as sole food source (nutrition source). Appropriate drug treatments include, without limitation, treatment with agents such as the antihyperlipoproteinemic Acipimox™ (Olbetam™), i.e. 5-methylpyrazinecarboxylic acid 4-oxide, and related compounds (see U.S. Pat. No. 4,002,750); statins, such as Fluvastatin™, Lovastatin™, Pravastatin™ or Simvastatin™; and fibrates, such as Bezafibrat™, Clofibrat™ or Gemfibrozil™, in amounts and dosage regimens that are effective in lowering blood lipid levels.
Another, related aspect of the present invention relates to a method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst providing the subject with restricted amounts of a high-fat (HF) diet as sole food source.
A still further aspect of the invention provides another method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst inhibiting lipolysis in the subject. In this connection, inhibition of lipolysis may be reflected in inhibition of the lipase known as Hormone-Sensitive Lipase (HSL), although inhibition of other families of lipases may also be of relevance in the context of the method in question according to the invention. Non-limiting examples of substances capable of inhibiting the lipolytic effect of HSL include those disclosed in U.S. Pat. No. 6,596,742 B1 (corresponding to WO 01/17981), WO 01/66531, WO 03/051841, WO 03/051842 and WO 03/105860.
Yet another aspect of the invention relates to a method for reducing blood lipid levels in an animal or human subject substantially without induction of hyperinsulinemia in the subject, the method comprising administering a growth hormone (GH) to the subject whilst stimulating lipid clearance from the circulation. In this connection, stimulation of clearance of lipid from the circulation may, for example, be achieved by administration of a substance which acts to stimulate, activate or potentiate a lipase such as Lipoprotein Lipase (LPL). Non-limiting examples of LPL-potentiating substances include those described in WO 01/27088.
With regard to what constitutes "restricted" amounts of a HF diet in the context of the invention, it is generally preferable that the energy content (caloric content) of the amount of HF diet with which the subject is provided does not exceed (i.e. is below or is equal to or at least approximately equal to) the theoretical maintenance level for the subject in question. In the case of human subjects, there is an extensive body of published data which enables the establishment of the theoretical maintenance level for an individual on the basis of parameters such as age, gender, weight, height, ethnicity and level of physical activity. Published sources of such data include: Ritz, P., Factors affecting energy and macronutrient requirements in elderly people, Public Health Nutrition 4 (2001) pp. 561–569; and Lin et al., Estimation of energy requirements in a controlled feeding trial, Am. J. Clin. Nutr. 77 (2003) pp. 639–645.
With regard to animal species, particularly "farm" animals (animals of importance in relation to production of meat products, dairy products, eggs and the like, such as cattle, pigs, goats and poultry), and other domestic animals, such as horses, data are available from sources such as the UK Agricultural Research Council (ARC), the Commonwealth Agricultural Bureau, and the US National Research Council (NRC; e.g. data from 1988 and 1998, published by National Academy Press, Washington D.C.).
In some embodiments, the present invention relates to the treatment of humans, in particular obese humans. In these embodiments, the growth hormone to be employed will preferably be human growth hormone (hGH).
In the light of the above methods of the invention, still further aspects of the present invention include the following:
Also encompassed by the invention is the use of a substance which acts as a growth hormone secretagogue (GHS; also known, inter alia, as a growth hormone releasing substance), i.e. a substance which, when administered to a subject by an appropriate route, is capable of stimulating the release of growth hormone from the pituitary of the subject, as an alternative to a GH per se in the various aspects of the invention (i.e. as an active ingredient in methods, pharmaceutical compositions, medical kits etc. as described above). Non-limiting examples include the synthetic hexapeptide His-D-Trp-Ala-Trp-D-Phe-Lys-NH2, also known as GHRP-6 (see, e.g., Bowers et al. in Endocrinology 114 (1984) pp. 1537–1545 and in Endocrinology 128 (1991) pp. 2027–2035) and the peptide derivatives described in WO 95/17423. Naturally occurring growth hormone releasing substances of potential relevance in the context in question include so-called "growth hormone releasing hormone" (often abbreviated GHRH or GHRH(1–44)NH2) and truncated forms thereof (see, e.g., Guillemin et al., Science 218 (1982) pp. 585–587 and Rivier et al., Nature 300 (1982) pp. 276–278).
Pharmaceutical Administration
The regimen for treatment of a given subject/patient with growth hormone and, where appropriate, with another drug, in the manner described herein, may be determined by one skilled in the art. The daily dose to be administered can be determined by a physician and will depend on the particular substance employed, on the route of administration and on the age and the condition of the subject or patient. A convenient daily dosage of GH is typically in the range of from about 0.001mg/kg body weight to about 2.0 mg/kg body weight, often from about 0.01 mg/kg body weight to about 1.0 mg/kg body weight. The therapeutic dose of the substance will depend upon the frequency and mode of administration, the sex, age, weight and general condition of the subject treated, the nature and severity of the condition treated and any concomitant diseases to be treated and other factors evident to those skilled in the art.
GH may be administered in a single dose or in repeated doses during the day. Administration in the manner described herein should continue until the treated individual is no longer in need of such treatment, for example, until an initially obese individual is no longer obese.
The route of GH administration may be any route that effectively transports the active compound to the appropriate or desired site of action, such as by infusion (continuous or pulsatile), injection, pulmonary inhalation, or by oral or nasal administration. Presently preferred routes include parenteral routes (e.g. via intramuscular, intraperitoneal, intravenous or subcutaneous injection, or by implant). The growth hormone can be formulated in dosage forms appropriate for each route of administration. The compositions or dosage forms may be in conventional forms, e.g. aerosols, solutions or suspensions.
A GH composition may be in a form suited for systemic injection or infusion, and may, as such, be formulated with a suitable liquid vehicle such as sterile water or an isotonic saline or glucose solution. The compositions may be sterilized by conventional sterilization techniques which are well known in the art. The resulting aqueous solutions may be packaged for use as such, or they may be filtered under aseptic conditions and lyophilized, the lyophilized preparation being combined with the appropriate sterile aqueous vehicle prior to administration. The composition may contain pharmaceutically acceptable auxiliary substances as required to approximate physiological conditions, such as buffering agents, tonicity-adjusting agents and the like. Non-limiting examples of buffering agents include citrate salts and histidine; non-limiting examples of tonicity adjusting agents include sugars, such as sucrose and mannitol, and salts, such as alkali metal and alkaline earth metal chlorides, e.g. sodium, potassium or calcium chloride, and the like. Examples of liquid carriers are syrup, peanut oil, olive oil, phospholipids, fatty acids, fatty acid amines, polyoxyethylene and water. Aqueous liquid formulations, in particular, may advantageously contain a non-ionic surfactant, e.g. a polysorbate [such as polysorbate 20 (e.g. Tween™ 20) or a poloxamer [such as poloxamer 188 (e.g. Pluronic™ F68) or poloxamer 407 (e.g. Lutrol™ F127)], and a preservative, such as benzyl alcohol, phenol or a cresol (e.g. m-cresol), will often be incorporated.
It may be advantageous to provide GH in the form of a sustained release formulation. As such, the composition may be formulated as microcapsules or microparticles containing the growth hormone encapsulated in, or dispersed in, a suitable pharmaceutically acceptable biodegradable polymer, such as polylactic acid, polyglycolic acid or a lactic acid/glycolic acid copolymer.
For nasal administration, the GH preparation may contain growth hormone dissolved or suspended in a liquid carrier, in particular an aqueous carrier, for aerosol application. The carrier may contain additives such as solubilizing agents (e.g. propylene glycol), surfactants, absorption-enhancers such as lecithin (phosphatidylcholine) or cyclodextrin, or preservatives such as parabenes.
Growth hormone may be formulated by any of the established methods of formulating pharmaceutical compositions, e.g. as described in Remington: The Science and Practice of Pharmacy (1995).
A liquid hGH formulation which is well suited, in particular, for administration by injection in the context of the present invention is Norditropin™ SimpleXx™ (Novo Nordisk).
High-fat (HF) diet: A high-fat diet for humans, includes, without limitation, that given by M. R. Freedman et al. in a review article in Obesity Research 9, Suppl. 1 (March 2001) pp. 1S–40S. With reference to humans, the following table provides appropriate definitions not only of high-fat (HF) diets in the context of the present invention, but also of moderate-fat (MF) and low-fat (LF) diets:
Caloric composition of diets*
Diet type
Fat (% kcals)
Carbohydrate (% kcals)
(% kcals)
High-fat (HF)
Moderate-fat (MF)
Low-fat (LF)
*M. R. Freedman, J. King and E. Kennedy, Popular diets: a scientific review, Obesity Research 9, Suppl. 1 (March 2001) pp. 1S-40S
Obesity: the terms "obesity" and "obese" when employed in the context of the present invention imply an excess of adipose tissue. In this context obesity is best viewed as any degree of excess adiposity that imparts a health risk. The distinction between normal and obese individuals can only be approximated, but the health risk imparted by obesity is probably a continuum with increasing adiposity. However, in the context of the present invention, human individuals with a body mass index (BMI=body weight in kilograms divided by the square of the height in meters) above 25 are to be regarded as obese.
Growth hormone (GH): Growth hormone is a hormone that stimulates growth of all tissues capable of growing. Growth hormone is released from the pituitary. The release is under tight control of a number of hormones and neurotransmitters, either directly or indirectly. Growth hormone release can be stimulated by growth hormone releasing hormone (GHRH; vide supra) and inhibited by somatostatin. In both cases, the hormones are released from the hypothalamus, but their action is mediated primarily via specific receptors located in the pituitary. In the present context "growth hormone" may be growth hormone of any origin, e.g. avian, bovine, equine, human, ovine, porcine, salmon, trout or tuna growth hormone. Human growth hormone (hGH) will normally be preferred for the treatment of humans. The growth hormone used in accordance with the invention may be native growth hormone isolated from a natural source, e.g. by extracting pituitary glands in a conventional manner, or a growth hormone produced by recombinant techniques, e.g. as described in E. B. Jensen and S. Carlsen in Biotech and Bioeng. 36 1990) pp. 1–11. The term growth hormone (GH) in the context of the invention also encompasses: truncated forms of GH, i.e. truncated forms of a growth hormone wherein one or more amino acid residues has/have been deleted; GH analogues, wherein one or more amino acid residues in the native molecule has/have been substituted with another amino acid residue, preferably a residue of a naturally occurring amino acid, as long as the substitution does not lead to any adverse effect such as antigenicity or reduced activity; and GH derivatives, e.g. deamidated or sulfoxidated forms of the growth hormone, or forms having an N- or C-terminal extension (such as Met-hGH, Met-Glu-Ala-Glu-hGH or Ala-Glu-hGH). Other GH derivatives of relevance include those in which a GH (or biologically active fragment thereof) is conjugated to a molecule such as an albumin, e.g. human serum albumin (see, e.g., WO 97/24445), or a water-soluble polymer such as a polyethyleneglycol (PEG) (see, e.g., WO 03/044056), in order to achieve, e.g., protracted duration of GH activity. As mentioned above, among growth hormones per se, the preferred growth hormone in relation to treatment of humans is normally hGH (i.e. natural human growth hormone, or recombinantly produced human growth hormone which is identical to the natural hormone). Methionylated human growth hormone may, however, often be employed.
Blood lipids: Lipids are generally defined as being a group of fats, fat-derived substances and fatlike substances that are of low solubility in water, are soluble in organic solvents such as benzene, chloroform and ether, and are utilizable by animal organisms. They are easily stored in the body, serve as a source of fuel (energy), are important constituents of cell structure, and serve other physiological functions. Lipids may be considered to include neutral fats, fatty acids, certain steroidal substances (e.g. sterols) and certain waxes.
Fats: Fats (neutral fats) are glyceryl esters of higher fatty acids (such as stearic and palmitic acid), and include, in particular, triglycerides (glyceryl esters in which each of the three hydroxy groups of glycerol is esterified with a fatty acid).
Fatty acids: Fatty acids are generally defined as being straight-chain, saturated and unsaturated monocarboxylic acids in which the carboxylic acid group is terminal, and which have a total (usually even-numbered) of from 4 to 22 (sometimes 24) carbon atoms.
Steroidal substances: These include, e.g., cholesterol (a sterol). In blood, cholesterol is transported primarily in the form of various lipoproteins, e.g. the so-called low-density lipoproteins (LDL) and high-density lipoproteins (HDL). In analyses of lipid levels, e.g. in blood, cholesterol is often determined as total cholesterol, i.e. the sum total level of all forms of cholesterol present in the blood.
In blood, lipids of major importance include triglycerides, fatty acids [i.e. free fatty acids (FFA)], and cholesterol.
Usage of the terms "lipid", "fat", "fatty acid", "triglyceride", "cholesterol" and "total cholesterol" in relation to blood lipids and levels thereof in the context of the present invention is in accordance with the definitions and explanation given above.
As used herein, hyperinsulinemia encompasses a fasting plasma level of insulin greater than the normal range, which may be, e.g., about 30 μIU (micro international units) per ml. Insulin may be measured by any conventional method, including, e.g., radioimmunoassay (Pharmacia, Medical Research Laboratories International).
Prevention of hyperinsulinemia encompasses the clinical observation that a patient receiving GH therapeutically does not exhibit a significant rise in fasting plasma insulin levels over that exhibited by the same patient prior to GH treatment. It also encompasses the clinical observation that a patient receiving GH therapy, who exhibits hyperinsulinemia consequent to the GH treatment, exhibits a detectable reduction in fasting plasma insulin levels once the measures of the invention (e.g., restricted high-fat diet and/or lipid-lowering drugs) have been added to the treatment regimen.
The following are intended as non-limiting examples of the present invention.
The following experiments were performed in order to evaluate the effect of varying diet on the effect of GH administration on insulin levels and other metabolic parameters.
Materials and Methods
Animals and Test Substances
Female Wistar rats weighing about 260 g were purchased 1 month before the start of experiments from Mřllegĺrd Breeding and Research Centre (Lille Skensved, Denmark). On arrival, rats were placed in conventional rat cages housing 2–3 animals. They were weighed weekly, and had free access to drinking water and a standard rat feed. All diets, including the experimental diets (see Table 1, below), were purchased from a local feed supplier (Brogaarden, Gentofte, Denmark). The experimental protocol was approved by the Danish national ethical committee for animal experiments (Dyreforsřgstilsynet, Copenhagen, Denmark). The growth hormone (GH) used in the present study was recombinantly produced human GH (hGH) from Novo Nordisk A/S (Bagsvćrd, Denmark).
Experimental Procedures
At an age of 12 months, rats were randomly assigned to receive either a high-fat (HF) diet [number of rats (n)=58] or a low-fat (LF) diet (n=23) (Table 1).
Composition of high-fat (HF) and low-fat (LF) diets with
theoretical energy content (percent) in parentheses.
Ingredients (g/kg)
Maize meal
Wheat bran
Animal fat
Vitamins and minerals
Chemical composition (g/kg)
Crude protein (energy %)
170 (18%)
170 (25%)
Crude fat (energy %)
320 (55%)
50 (12%)
Carbohydrates, total
344 (27%)
565 (63%)
Crude fibre
Metabolizable energy (Mcal/kg)
Fatty acids
Total (% of crude fat)
Saturated (% of total)
Mono-unsaturated (% of total)
Poly-unsaturated (% of total)
The diet in question was continued for 14 weeks, during which body weight development was recorded
Allocation of rats to high-fat (HF) and low-fat (LF) diets
during a 14-week period before dosing and during
a 3-week period of dosing with either saline or growth
hormone (GH). GH was administered in a total dose
of 4 mg/kg/day, divided into two injections.
Diet before dosing
Diet during dosing
Low Fat
Low Fat
High Fat
High Fat
Energy restricted*
Low Fat
Pair fed*
*Age- and weight-matched rats were fed the same amount of metabolizable energy consumed by HF/LF-GH-group. In the HF/HF-GHre group, this was achieved by restricting food intake (energy-restricted), whereas rats in the HF/LF-Salpf group were pair-fed with the HF/LF-GH group. Both these groups were run behind the others.
Injection of GH continued for 3 weeks, after which the rats were sacrificed by decapitation. After bleeding, serum and plasma were prepared and frozen at −80° C.
The large fat pad embedding the kidneys (denoted peri-renal fat), and fat pads around the uterus, ovaries and intestines (denoted body fat or adipose tissue ) were quickly dissected. After dissection the adipose tissue was weighed and frozen at −80° C. One thigh muscle, the quadriceps femoris, was also dissected and weighed.
With a view, inter alia, to supplementing measurements of changes in levels of blood lipids, glycerol and β-hydroxy-butyrate (BHBT) as a consequence of the administration of GH or saline in combination with the various diet regimens, a series of similar experiments of shorter duration (4 days) was conducted using 45 rats (n=15 in each group) that were all obese due to 10 weeks of feeding with high-fat (HF) diet. All the animals in question received a low-fat (LF) diet during the 4-day treatment period. They were divided into three groups receiving (a) saline alone, (b) GH and (c) saline in combination with pair-feeding with the GH group.
Chemical Analyses
The content of fat in muscle tissue was analysed by Bioteknologisk Institut (Kolding, Denmark) using gas chromatography and employing standardized methods. Plasma concentrations of metabolites were determined with a Synchron™ CX5 auto-analyzer system (Beckman Instruments, Fullerton, USA).
Blood Analyses
Concentrations of lipids, glycerol and β-hydroxybutyrate (BHBT) were likewise determined using a Synchron™ CX5 auto-analyzer system (Beckman Instruments, Fullerton, USA).
Hormone Assays
Total plasma IGF-I was measured after acid-ethanol extraction as previously described (19); the intra-assay and inter-assay coefficients of variation were 6% and 13%, respectively. Plasma insulin was determined using an assay described previously (20); the intra- and inter-assay coefficients of variation for this assay were 5.4% and 8.4% respectively. Plasma leptin was determined using a commercial kit from Linco research, Inc. (St Charles, USA); the intra- and inter-assay coefficients of variation were 4.6% and 5.7%, respectively.
Statistical Analyses
All experimental data were entered into the 6.11 version of the SAS statistical software program, whereby descriptive statistics were calculated using the univariate procedure (SAS Inc, Cary, USA). Before further analysis, data were checked for normal distribution. In some cases where deviations were found, data were logarithmically transformed to achieve such a distribution. Potential differences between treatment groups were tested with a one-way analysis of variance (GLM procedure of SAS) followed by Duncan's multiple-range test. In most cases these tests were performed with an α-value of 0.05, but where applicable an α-value of 0.01 was used. Data are presented as means ±standard error (SE).
Body Weight Gain and Feed Consumption in the Period Before GH Dosing
At the start of the 14-week "fattening" period, rats in the HF group and the LF group had body weights of 279±3 and 280±6 g, respectively. Rats in the HF group gained 111±5 g in body weight during the 14 week period. Rats receiving the LF diet gained 63±5 g, which was significantly (p<0.01) lower. This resulted in significant (p<0.01) differences in live weights, viz. 390±6.4 (HF diet group) vs. 343±8.6 g (LF diet group).
As can be seen from
Food Consumption During GH Dosing
As was the case during the "fattening" period, rats fed the LF diet during GH dosing consumed significantly (p<0.05) more food than did rats fed the HF diet (see Table 3, below), but due to the lower energy content of the LF diet the intakes of metabolizable energy were not significantly different between the two groups.
There was a general decrease in food intake in the first phase after commencement of GH injections (data not shown), thus confirming our previous observations (18). Measured over the three-week dosing period, this effect remained statistically significant for rats fed the LF diet (Table 3). GH-treated rats which were switched from the HF diet to the LF diet successively increased their consumption between the second and third week of treatment, ending up with about the same total amount of food ingested as the corresponding saline-control rats. During this phase the pair-fed group could not follow the GH-treated group, and small food refusals were occasionally observed, resulting in a slightly lower total consumption of food (Table 3).
Effects of growth hormone (GH) dosing on: consumption of high-fat (HF) and low-fat (LF) diets,
body weights, adipose tissue, skeletal muscle weight and muscle content of fat.
Food intake was registered per cage unit containing 2–3 animals (n = 6),
and fat in muscle was analysed on a randomly selected number (n = 5) of animals
from each group. In other cases, means ± SE are based on 11–12 observations.
Body weight
Tissue weights and composition
Change in
Fat in
Final weight
46a ± 2.0
149ab ± 6.5
7.8a ± 0.34
345bc ± 13
355e ± 11
9.7d ± 3.6
41bc ± 3.8
2.3b ± 0.10
4.4a ± 1.6
40b ± 1.9
129bc ± 6.1
6.8b ± 0.32
341c ± 12
419abc ± 11
78a ± 3.7
30de ± 2.3
3.0a ± 0.07
1.7c ± 0.2
33cd ± 1.7
158a ± 8.0
5.6cd ± 0.28
391ab ± 17
400bcd ± 16
9.0d ± 3.7
60a ± 4.7
2.3b ± 0.08
3.1abc ± 0.9
29d ± 1.5
142ab ± 7.2
5.0d ± 0.25
390ab ± 15
452a ± 13
62b ± 4.9
38cd ± 2.7
2.8a ± 0.11
1.9bc ± 0.4
22* ±
106* ± 0.12
3.7* ± 0.00
389ab ± 9
429ab ± 9
40c ± 7.6
26e ± 1.6
3.0a ± 0.16
1.8bc ± 0.1
37bc ± 2.4
119cd ± 7.9
6.2bc ± 0.42
388ab ± 17
381cde ± 16
−7e ± 3.6
50ab ± 4.5
2.2b ± 0.09
3.8ab ± 0.6
33cd ± 2.8
106d ± 9.0
5.6cd ± 0.47
389ab ± 16
431ab ± 10
41c ± 8.2
31cde ± 2.7
2.9a ± 0.07
1.6c ± 0.3
30* ±
97* ± 6.7
5.1* ± 0.35
393a ±
371de ± 15
−22e ± 5.4
49b ± 3.8
2.2b ± 0.05
2.8abc ± 0.4
*Groups that did not have free access to food were excluded from statistical analyses of food intake variables.
a,b,c,d,eDifferences between groups were tested with a one-way analysis of variance followed by Duncan's multiple range-test. Values within columns not sharing a common letter superscript differ significantly (p < 0.05).
TABLE 4 Effect of GH and diet on levels of blood lipids and related substances. Duration of Experiment Diet before dosing Diet during dosing Dosing FFA Glycerol BHBT Triglyceride Cholesterol 4 Days High-fat Low-fat Saline 0.56 ± 0.05 0.33 ± 0.01 0.60 ± 0.07 0.69 ± 0.09 1.17 ± 0.09 4 Days High-fat Low-fat GH 0.63 ± 0.07 0.34 ± 0.01 1.32 ± 0.244 0.48 ± 0.035 0.64 ± 0.057 4 Days High-fat Pair-fed Saline 0.68 ± 0.07 0.30 ± 0.01 1.17 ± 0.114 0.39 ± 0.03 1.03 ± 0.08 21 Days Low-fat Low-fat Saline 0.75 ± 0.08 0.39 ± 0.03 0.25 ± 0.04 1.41 ± 0.21 1.39 ± 0.10 21 Days Low-fat Low-fat GH 0.43 ± 0.041 0.33 ± 0.023 0.24 ± 0.02 1.40 ± 0.14 1.01 ± 0.087 21 Days High-fat High-fat Saline 0.49 ± 0.03 0.35 ± 0.03 0.51 ± 0.04 0.88 ± 0.09 1.27 ± 0.06 21 Days High-fat High-fat GH 0.36 ± 0.041 0.39 ± 0.02 0.30 ± 0.04 1.54 ± 0.126 0.90 ± 0.077 21 Days High-fat Energy-restricted GH 0.20 ± 0.012 0.20 ± 0.012 0.92 ± 0.092 0.53 ± 0.042 0.82 ± 0.03 21 Days High-fat Low-fat Saline 0.60 ± 0.06 0.38 ± 0.03 0.17 ± 0.03 1.58 ± 0.25 1.21 ± 0.10 21 Days High-fat Low-fat GH 0.38 ± 0.041 0.30 ± 0.013 0.22 ± 0.03 1.27 ± 0.13 0.92 ± 0.057 21 Days High-fat Pair-fed Saline 0.74 ± 0.07 0.41 ± 0.03 0.50 ± 0.074 1.00 ± 0.13 1.28 ± 0.06 FFA = free fatty acids; BHBT = β-hydroxybutyrate; Cholesterol = total cholesterol. All values in mM. Superscript numbers indicate significant effects as follows: 1GH lowered FFA level after 21 days compared to saline; 2FFA, glycerol and triglyceride levels in the high-fat/energy restricted group were lower, while BHBT level was elevated, compared to the other GH-treated groups initially fed high-fat diet; 3GH lowered glycerol levels in animals on low-fat diet compared to saline; 4BHBT level elevated compared to saline; 5Triglyceride decreased after 4 days of GH treatment compared to saline, but not with the pair-fed group; 6After 21 days, the combination of GH and high-fat diet caused elevated triglyceride levels compared to saline; 7GH decreased the cholesterol level after both 4 and 21 days compared to saline
lower, while BHBT level was elevated, compared to the other GH-treated groups initially fed high-fat diet; 3GH lowered glycerol levels in animals on low-fat diet compared to saline; 4BHBT level elevated compared to saline; 5Triglyceride decreased after 4 days of GH treatment compared to saline, but not with the pair-fed group; 6After 21 days, the combination of GH and high-fat diet caused elevated triglyceride levels compared to saline; 7GH decreased the cholesterol level after both 4 and 21 days compared to saline
Body Weight During Dosing
Irrespective of diet, three weeks of GH treatment generally increased body weight (Table 3). A change of diet from HF to LF, combined with saline alone, produced a significant (p<0.05) reduction of live weight. Rats with the same dietary record which were pair fed with GH-treated counterparts also lost weight (Table 3).
Effects of Diet and GH on Body Composition
GH treatment significantly (p<0.05) decreased the weight of adipose tissue excised from rats fed HF or LF diet, or rats that were switched from HF to LF, both in absolute numbers (Table 3) and in relation to their body weight (
Effects of Diet and GH on Blood Lipids
The blood concentrations (levels) of free fatty acids (FFA), glycerol, β-hydroxybutyrate (BHBT), triglyceride and cholesterol (total cholesterol) are shown in Table 4. Serum FFA levels and total cholesterol levels were lowered significantly after 21 days of GH treatment, as was plasma glycerol, except during HF diet feeding. Triglyceride levels were elevated at that time, but only when GH was combined with HF diet. In contrast, triglycerides were markedly lowered by feeding restricted amounts of HF diet in combination with GH treatment, whilst no changes were seen in the other groups. Cholesterol levels were already low after 4 days of GH injection. BHBT increased initially following GH injection and pair-feeding. Only the group which received GH and restricted access to HF diet, and the pair-fed group, exhibited elevated BHBT levels after 21 days.
Effects of GH on Plasma Variables
Injection with GH produced a significant (p<0.05) increase of plasma IGF-1 concentrations irrespective of dietary regimen (
Discussion of Results
At the conclusion of the experiments described above, rats that had received the HF diet throughout contained about 30% more adipose tissue than rats fed the LF diet. This difference is likely founded in the phase when rats first were introduced to a HF diet, since in that phase their daily intake of metabolizable energy was clearly elevated for several weeks. After about 6 weeks, their caloric intake had fallen to the same level as that of rats fed the LF diet, indicating that although this adaptation is not as fast as has been observed in young animals, the old rats employed in the present work still retain some ability to regulate their caloric intake.
Injections of GH produced an increase in skeletal muscle weight, loss of adipose tissue and a transient decrease in food intake in those groups of animals that had free access to food. These effects were observed irrespective of whether rats were maintained on their habitual diets or were shifted from the HF to the LF diet. Shift of diet without GH injection, but with essentially the same caloric intake (pair-fed), produced a fall in body weight, but only marginal effects on adipose tissue weight. In view of this, it can be concluded that treatment with GH produces a significant and specific loss of adipose tissue. It also appears that promotion of fat loss is a consistent effect of GH under a variety of dietary conditions, but that modulation of this effect by the amount of diet eaten occurs. Thus, if the HF diet is fed in restricted amounts, the fat loss after GH injections is greater than if there is free access to the same diet (and thereby is greater consumption of metabolizable energy). This observation shows that caloric intake either directly or indirectly modulates the effect of GH on fat loss.
Surpisingly low plasma insulin levels were found in blood from animals which had been fed restricted amounts of the HF diet during GH treatment, whereas hyperinsulinemia was especially marked in the case of animals which had had free access to the same diet. The degree of adipose tissue breakdown was significantly different between these groups. The present inventors thus believe that they have identified a dietary situation whereby the hyperinsulinemic response to GH administration may be avoided, thus presenting the possibility of increasing both the efficacy and safety aspects of GH treatment of obese humans. It can be seen from Table 4 that this dietary situation is associated with significant reductions in blood lipid levels, especially in the case of FFA levels. This can most probably explain the low insulin levels since it is widely established that high FFA levels are associated with a decrease in insulin sensitivity, leading to a compensatory hyper-secretion of insulin. There is little doubt that prolonged and uncontrolled hyperinsulinemia represents a real hazard to the patient and must be taken seriously. For this reason the present invention is believed to be of considerable importance.
To summarize, the results reported herein demonstrate not only that GH mediates breakdown of adipose tissue under a variety of dietary conditions, but—very importantly and surprisingly—that induction of hyperinsulinemia can be prevented if GH treatment is combined with restricted feeding of a diet which is relatively low in carbohydrates and rich in fat, and that same treatment regimen also promotes a fall in plasma leptin levels.
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|Citing Patent
|Filing date
|Publication date
|Sep 26, 2008
|Oct 4, 2011
|Abbott Diabetes Care Inc.
|Glucose measuring device integrated into a holster for a personal area network device
|Jun 10, 2003
|Jun 11, 2013
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|Deodorizing container that includes an anthraquinone ink
|U.S. Classification
|514/5.3, 530/399, 424/198.1, 514/7.4, 514/11.3, 514/4.8, 514/5.1
|International Classification
|Cooperative Classification
|European Classification
|Jan 7, 2009
Owner name: NOVO NORDISK HEALTHCARE AG, SWITZERLAND
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Effective date: 20081219
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