MK677 and Insulin Resistance.

[kitchenchemist]

Anyone notice a marked increase in insulin resistance when using MK677???
Any thoughts/suggestions would be greatly appreciated.
Heres the current regimen Ive been following for the last 12wks....below is just the items I feel relevant to the situation.
MK677 30mg prebed
300mcg HuperzineA Twice/day
6mg Melatonin prebed

PreTraining Meal is 1.5hrs before gym and consists of 70gP/60gC with 400mg Berberine.
IntraTraining is 40g BCAA/EAA with 80g HBCD. 15min before training I take my preworkout mix and 400mg RALA.
PostTraining is usually 30-40min after gym and is 75gP/75gC

My daily carb intake doesnt exceed 230-250g unless its a refeed day and the outlined carbs above are the only significant carbs I take in aside from the accidental ones in other meals.

Fasted glucose was always between 81-89 before MK677 regardless of my dieting phase. However, now, after 7-8wks using MK my fasted glucose is 104-109 every morning.

2wks ago I added an additional 400mg Berberine and 2g Cinnamon prebed with no change in fasted glucose. I also added 50mcg of IGF1-LR3 pretraining with no change in fasted glucose.
Ive removed the MK677 from this weeks regimen and will begin checking fasted levels again next week. Ive also switched Berberine brands to see of that plays a role.

 

[BigTex]

Anyone notice a marked increase in insulin resistance when using MK677???
Any thoughts/suggestions would be greatly appreciated.

Fasting blood glucose rose, while insulin sensitivity declined, which is common with GH injections.

Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008 Nov 4;149(9):601-11.

Abstract
BACKGROUND:
Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated.
OBJECTIVE:
To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults.
DESIGN:
2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.
SETTING:
General clinical research center study performed at a university hospital.
PARTICIPANTS:
65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.
INTERVENTION:
Oral administration of MK-677, 25 mg, or placebo once daily.
MEASUREMENTS:
Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months.
RESULTS:
Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.
LIMITATION:
Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.
CONCLUSION:
Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.​

 

[kitchenchemist]

Fasting blood glucose rose, while insulin sensitivity declined, which is common with GH injections.

Nass R, Pezzoli SS, Oliveri MC, Patrie JT, Harrell FE Jr, Clasey JL, Heymsfield SB, Bach MA, Vance ML, Thorner MO. Effects of an oral ghrelin mimetic on body composition and clinical outcomes in healthy older adults: a randomized trial. Ann Intern Med. 2008 Nov 4;149(9):601-11.



Abstract

BACKGROUND:

Growth hormone secretion and muscle mass decline from midpuberty throughout life, culminating in sarcopenia, frailty, decreased function, and loss of independence. The decline of growth hormone in the development of sarcopenia is one of many factors, and its etiologic role needs to be demonstrated.

OBJECTIVE:

To determine whether MK-677, an oral ghrelin mimetic, increases growth hormone secretion into the young-adult range without serious adverse effects, prevents the decline of fat-free mass, and decreases abdominal visceral fat in healthy older adults.

DESIGN:

2-year, double-blind, randomized, placebo-controlled, modified-crossover clinical trial.

SETTING:

General clinical research center study performed at a university hospital.

PARTICIPANTS:

65 healthy adults (men, women receiving hormone replacement therapy, and women not receiving hormone replacement therapy) ranging from 60 to 81 years of age.

INTERVENTION:

Oral administration of MK-677, 25 mg, or placebo once daily.

MEASUREMENTS:

Growth hormone and insulin-like growth factor I levels. Fat-free mass and abdominal visceral fat were the primary end points after 1 year of treatment. Other end points were body weight, fat mass, insulin sensitivity, lipid and cortisol levels, bone mineral density, limb lean and fat mass, isokinetic strength, function, and quality of life. All end points were assessed at baseline and every 6 months.

RESULTS:

Daily administration of MK-677 significantly increased growth hormone and insulin-like growth factor I levels to those of healthy young adults without serious adverse effects. Mean fat-free mass decreased in the placebo group but increased in the MK-677 group (change, -0.5 kg [95% CI, -1.1 to 0.2 kg] vs. 1.1 kg [CI, 0.7 to 1.5 kg], respectively; P < 0.001), as did body cell mass, as reflected by intracellular water (change, -1.0 kg [CI, -2.1 to 0.2 kg] vs. 0.8 kg [CI, -0.1 to 1.6 kg], respectively; P = 0.021). No significant differences were observed in abdominal visceral fat or total fat mass; however, the average increase in limb fat was greater in the MK-677 group than the placebo group (1.1 kg vs. 0.24 kg; P = 0.001). Body weight increased 0.8 kg (CI, -0.3 to 1.8 kg) in the placebo group and 2.7 kg (CI, 2.0 to 3.5 kg) in the MK-677 group (P = 0.003). Fasting blood glucose level increased an average of 0.3 mmol/L (5 mg/dL) in the MK-677 group (P = 0.015), and insulin sensitivity decreased. The most frequent side effects were an increase in appetite that subsided in a few months and transient, mild lower-extremity edema and muscle pain. Low-density lipoprotein cholesterol levels decreased in the MK-677 group relative to baseline values (change, -0.14 mmol/L [CI, -0.27 to -0.01 mmol/L]; -5.4 mg/dL [CI, -10.4 to -0.4 mg/dL]; P = 0.026); no differences between groups were observed in total or high-density lipoprotein cholesterol levels. Cortisol levels increased 47 nmol/L (CI, 28 to 71 nmol/L (1.7 microg/dL [CI, 1.0 to 2.6 microg/dL]) in MK-677 recipients (P = 0.020). Changes in bone mineral density consistent with increased bone remodeling occurred in MK-677 recipients. Increased fat-free mass did not result in changes in strength or function. Two-year exploratory analyses confirmed the 1-year results.

LIMITATION:

Study power (duration and participant number) was insufficient to evaluate functional end points in healthy elderly persons.

CONCLUSION:

Over 12 months, the ghrelin mimetic MK-677 enhanced pulsatile growth hormone secretion, significantly increased fat-free mass, and was generally well tolerated. Long-term functional and, ultimately, pharmacoeconomic, studies in elderly persons are indicated.​

Thanks for the response.
Sorry, I should have pointed out that Im aware that GH use can/will lead to insulin resistance.
Im just left a little confused and concerned about my numbers. Seems like most of the MK studies were done long term and as stated in the study above were generally well tolerated. Wouldnt a fasted glucose reading of 107 for a health male in his late 30s be concerning? Knowing GHs affect on the body, I was still a little shocked to see my fasted reading being so high after just 12wks of MK.
I have about 6-7wks remaining of the MK. Should I stay off until my fasted numbers are back to normal? Or should I not be so concerned with a number under 110?
To me it seems my carb intake is moderate and Im utilizing some GDAs to restore or atleast combat the insulin resistance. I just dont want the lack of sensitivity to lead to an excessive gain in fat tissue.

 

[BigTex]

Thanks for the response.
Sorry, I should have pointed out that Im aware that GH use can/will lead to insulin resistance.
Im just left a little confused and concerned about my numbers. Seems like most of the MK studies were done long term and as stated in the study above were generally well tolerated. Wouldnt a fasted glucose reading of 107 for a health male in his late 30s be concerning? Knowing GHs affect on the body, I was still a little shocked to see my fasted reading being so high after just 12wks of MK.
I have about 6-7wks remaining of the MK. Should I stay off until my fasted numbers are back to normal? Or should I not be so concerned with a number under 110?
To me it seems my carb intake is moderate and Im utilizing some GDAs to restore or atleast combat the insulin resistance. I just dont want the lack of sensitivity to lead to an excessive gain in fat tissue.

I am sure you are aware that normal blood glucose concentration is between 64.8-104.4mg/dl. So 107-110 is not something to be very concerned about. However, it you are you might consider taking Metformin. I will definitely bring those numbers down and reverse insulin resistance. Science has also determined that the SARM GW 501516 also does much the same. Both help release and burn fat.

EIther way, since you numbers are not that bad I would just keep using the ML fpr the remaining time you planned.

 

[kitchenchemist]

I am sure you are aware that normal blood glucose concentration is between 64.8-104.4mg/dl. So 107-110 is not something to be very concerned about. However, it you are you might consider taking Metformin. I will definitely bring those numbers down and reverse insulin resistance. Science has also determined that the SARM GW 501516 also does much the same. Both help release and burn fat.



EIther way, since you numbers are not that bad I would just keep using the ML fpr the remaining time you planned.

Thank you sir. I'll leave the MK in and continue monitoring my fasted levels. Ive run the GW501516 twice in the past and never noticed any assistance in fatloss, but did notice a considerable increase in cardio endurance......its ability to increase insulin sensitivity is interesting, I didnt know that so I'll keep that in mind for future protocols. I was hoping the Berberine would serve the same purpose as Glucophage (as per Mike Arnolds recommendations and others) since the GI side effects of Glucophage are definitely not appealing since my gut already hates most things!
Thanks again

 

[Thebigone]

I noticed that as little as 10mg only 3x per week increased my fasting glucose by around 10 pints but had no effect on glucose other times of the day. I have no idea why.

 

[BigTex]

Thank you sir. I'll leave the MK in and continue monitoring my fasted levels. Ive run the GW501516 twice in the past and never noticed any assistance in fatloss, but did notice a considerable increase in cardio endurance......its ability to increase insulin sensitivity is interesting, I didnt know that so I'll keep that in mind for future protocols. I was hoping the Berberine would serve the same purpose as Glucophage (as per Mike Arnolds recommendations and others) since the GI side effects of Glucophage are definitely not appealing since my gut already hates most things!
Thanks again

Mike is right as far as Metformin possibly causing gastric distress. If I don't take it with food I get heart burn. But I rarely have issues. Not sure what else Mike said about it but be aware that most everything that controls glucose levels and insulin resistance has the same working properties. Berberine is also known as an AMP-activated protein kinase (AMPK) activator. Its insulin-independent hypoglycemic effect is related to inhibition of mitochondrial function, stimulation of glycolysis and activation of AMPK pathway. Berberine, like Metformin is known as an AMP-activated protein kinase (AMPK) activator. Its insulin-independent hypoglycemic effect is related to inhibition of mitochondrial function, stimulation of glycolysis and activation of AMPK pathway. Some believe this has a direct effect in the reducion of mTOR, which effects hypertrophy in a negative way. However, I know a lot of very big guys who use Metformin and have no issue with growth while on it. GW-501516 works in much the same fashion as Berbarine and Metformin. So if you are happy with the Berberine and it is not causing any gastric issues then stick with it.

 

[BigTex]

I noticed that as little as 10mg only 3x per week increased my fasting glucose by around 10 pints but had no effect on glucose other times of the day. I have no idea why.

Are you talking about GW 501516? If so here is the scientific explanation of how it works to control insulin resistance:

In a study on mice they found that the combination of high fructose intake and PPARβ/δ deficiency increases CD36 protein levels via Nrf2, a process that promotes chronic inflammation and insulin resistance in adipose tissue. GW501616 is a peroxisome proliferator activator receptor delta (PPAR delta or PPARδ), so it help prevent PPARδ deficiency. This in turn was show to decrease glucose output by the liver and increases insulin sensitivity in mice. Science has identify liver as a major PPARδ-responsive tissue and reveal an unexpected glucose-burning pathway, which contributes to the ability of PPARδ agonists to alleviate hyperglycemia and improve insulin sensitivity. So PPARδ is a fatty acid receptor known to activate lipid oxidation and enhance glucose utilization.