Ignite Creation Date:
2024-05-05 @ 5:09 PM
Last Modification Date:
2024-10-26 @ 9:28 AM
Study NCT ID:
NCT00393770
Status:
COMPLETED
Last Update Posted:
2011-06-10
First Post:
2006-10-27
Brief Title:
Acetylcarnitine and Insulin Sensitivity
Sponsor:
Mario Negri Institute for Pharmacological Research
Organization:
Mario Negri Institute for Pharmacological Research
Study Overview
Official Title:
A Pilot Study to Evaluate the Short-term Effects of Acetyl-carnitine on Insulin Resistance and the Metabolic Syndrome in Patients at Increased Risk of Type 2 Diabetes Acetyl-carnitine in Insulin Resistance
Status:
COMPLETED
Status Verified Date:
2011-06
Last Known Status:
None
Delayed Posting:
No
If Stopped, Why?:
Not Stopped
Has Expanded Access:
False
If Expanded Access, NCT#:
N/A
Has Expanded Access, NCT# Status:
N/A
Acronym:
None
Brief Summary:
Decreased insulin sensitivity eg insulin resistance is a hallmark and a major pathogenic factor of type 2 diabetes It is the key factor of the metabolic syndrome - a cluster of arterial hypertension obesity impaired glucose tolerance dyslipidemia coagulation abnormalitiesalbuminuria and increased cardiovascular risk - that may precede or accompany type 2 diabetes
Insulin function and the abnormalities associated with insulin resistance may have a major role in preventing type 2 diabetes and in the long-term diabetes micro- and macrovascular complications Carnitine is involved in lipids and carbohydrates metabolism and acetyl-L-carnitineALC an intramitochondrial carrier of acylic group may modulate cell fuel substrate utilization Studies found that carnitine may improve insulin sensitivity and glucose disposal in healthy subjects and in patients with type 2 diabetes A recent study also found that a primed constant infusion of acetyl-L-carnitine ALC may increase glucose utilization in type 2 diabetic patients possibly restoring the glycogen synthase activity
Thus we designed the Acetylcarnitine in insulin resistance study a pilot sequentiallongitudinal study aimed to assess whether acetyl-carnitine may improve insulin function and lipid profile in patients at increased risk of type 2 diabetes
Insulin function and the abnormalities associated with insulin resistance may have a major role in preventing type 2 diabetes and in the long-term diabetes micro- and macrovascular complications Carnitine is involved in lipids and carbohydrates metabolism and acetyl-L-carnitineALC an intramitochondrial carrier of acylic group may modulate cell fuel substrate utilization Studies found that carnitine may improve insulin sensitivity and glucose disposal in healthy subjects and in patients with type 2 diabetes A recent study also found that a primed constant infusion of acetyl-L-carnitine ALC may increase glucose utilization in type 2 diabetic patients possibly restoring the glycogen synthase activity
Thus we designed the Acetylcarnitine in insulin resistance study a pilot sequentiallongitudinal study aimed to assess whether acetyl-carnitine may improve insulin function and lipid profile in patients at increased risk of type 2 diabetes
Detailed Description:
Decreased insulin sensitivity eg insulin resistance is a hallmark and a major pathogenic factor of type 2 diabetes Diabetes often is related to a cluster of arterial hypertension obesity impaired glucose tolerance dyslipidemia coagulation abnormalities albuminuria and increased cardiovascular risk which is called metabolic syndrome A reduction of insulin-resistance may improve metabolic syndrome decreasing in the long term the onset of clinical diabetes and the incidence of important cardiovascular and renal complications In the presence of insulin resistance it is altered the normal signal to the adipose tissue with a consequent reduction of absorption and use of glucose In subjects with increased fat mass mainly visceral it has been shown the influence of several factors as tumoral necrosis factor alfa TNF alfa and fatty free acids FFAs on the peripheral activity of the insulin TNF alfa a key modulator in fat metabolism has a direct role on insulin-mediated homeostasis of glucose and fatty acids regulating the action of lipoprotein lipases and fatty acid carriers influencing CoA synthesis and leptin production that finally inhibits insulin secretion by pancreatic beta cells Increasing of circulating concentration of fatty acids due to the absence of suppression of lipolysis due to insulin inactivity contributes to peripheral and hepatic insulin resistance It is also correlated with a condition of active inflammation which is linked to a higher incidence of atherosclerosis and cardiovascular risk typical of diabetes
Other factors such as adiponectin and resistin showed to have a role in glucose metabolism Adiponectin a protein produced by adipocytes has well-known anti-inflammatory and anti-atherogenic actions and it is postulated to improve insulin sensitivity through the improvement of carbohydrates and lipids metabolism In contrast resistin seems to induce insulin resistance and decreased glucose tolerance Thus the improvement of metabolic syndrome by means of an increase of insulin sensitivity and correction of correlated lipids and carbohydrates metabolism may play a primary role in the prevention of type 2 diabetes and in the long term may decrease micro- and macro-vascular complications Large prospective trials will help us to understand cellular mechanisms involved in metabolic syndrome and may be useful to identify new therapeutic targets aimed to reduce insulin resistance Carnitine is involved in lipids and carbohydrates metabolism and acetyl-L-carnitine ALC may increase glucose utilization in type 2 diabetic patients possibly restoring the glycogen synthase activity ALC is a mitochondrial carrier of acylic groups which directly and indirectly participates to carbohydrates metabolism acting on fatty acids and on glucose oxidation on pyruvate dehydrogenase PDH PDH is formed by an enzymatic complex PDC which catalyzes an irreversible reaction in carbohydrates oxidation and it is controlled by a phosphorylation-dephosphorylation cycle in which Pyruvate Dehydrogenase Kinase uses ATP to phosphorylate PDH causing its inactivation and Pyruvate Dehydrogenase Phosphatase dephosphorylates PDH inactivating it Kinase is activated by an increased ratio intramitochondrial acetylCoACoA as we can see in conditions of high fatty acid levels The consequent reduction of PDC activity dramatically decreases glucose oxidation Carnitine participates to trans-esterification forming acetylcarnitine By means of catching acylic groups it decreases ratio acetylCoACoA indirectly stimulating PDC activity and favouring pyruvate oxidation and of glucose Thus acetylcarnitine can be considered a modulator of substrates utilization in cells with consequences in the metabolism of both lipids and carbohydrates Several studies demonstrated that carnitine contributes to the improvement of insulin sensitivity and glucose utilization in both healthy subjects and type 2 diabetics Thus it is interesting to confirm the hypothesis that acetylcarnitine may improve insulin sensitivity in patients with a risk for type 2 diabetes and verify if this improvement is associated with other components of metabolic syndrome
Primary aim To evaluate insulin sensitivity eg Glucose disposal rate during an euglycemic hyperinsulinemic clamp in 40 patients with normal morning fasting glucose and increased risk of type 2 diabetes mellitus
Secondary aims
To evaluate drug effects on sitting systolicdiastolic blood pressure lipid profile morning fasting glucose and postprandial glucose
To assess the correlation between insulin sensitivity and serum inflammatory markers Erythrocyte Sedimentation Rate C-reactive protein and insulin leptin and adiponectin levels
To assess treatment tolerability
Design of the study This will be a sequential and longitudinal study
Potentially eligible patients will have a baseline evaluation of the following parameters
Clinical Systolicdiastolic blood pressure Heart rate Body weight BW BMI Total body water TBW Fat-free mass FFM Fat mass FM Metabolic Fasting morning blood glucose oral glucose tolerance test Insulin leptin adiponectin level Lipid profile Total VLDL and HDL cholesterol total triglycerides Apolipoprotein A and B Inflammatory markers Erythrocyte Sedimentation Rate C-reactive protein and plasma TNF alfa Patients satisfying the inclusionexclusion criteria will have their insulin sensitivity evaluated by an euglycemic hyperinsulinemic clamp and will enter a six month treatment period with Acetylcarnitine 2 gday At the end of the treatment period and 2 months after treatment withdrawal all baseline parameters including insulin sensitivity will then be evaluated No changes in diet and in concomitant treatments in particular with diuretics ACE inhibitors angiotensin II receptor antagonists dihydro and non-dihydro calcium channel blockers statins will be introduced throughout the whole study period
Calculated by the Hume and Weyers formula TBW in males 02968 x weight in kg 01948 x height in cm - 140129 TBW in females 01838 x weight in kg 03446 x height in cm - 352701
FFM TBW073
FM BW - FFM
Other factors such as adiponectin and resistin showed to have a role in glucose metabolism Adiponectin a protein produced by adipocytes has well-known anti-inflammatory and anti-atherogenic actions and it is postulated to improve insulin sensitivity through the improvement of carbohydrates and lipids metabolism In contrast resistin seems to induce insulin resistance and decreased glucose tolerance Thus the improvement of metabolic syndrome by means of an increase of insulin sensitivity and correction of correlated lipids and carbohydrates metabolism may play a primary role in the prevention of type 2 diabetes and in the long term may decrease micro- and macro-vascular complications Large prospective trials will help us to understand cellular mechanisms involved in metabolic syndrome and may be useful to identify new therapeutic targets aimed to reduce insulin resistance Carnitine is involved in lipids and carbohydrates metabolism and acetyl-L-carnitine ALC may increase glucose utilization in type 2 diabetic patients possibly restoring the glycogen synthase activity ALC is a mitochondrial carrier of acylic groups which directly and indirectly participates to carbohydrates metabolism acting on fatty acids and on glucose oxidation on pyruvate dehydrogenase PDH PDH is formed by an enzymatic complex PDC which catalyzes an irreversible reaction in carbohydrates oxidation and it is controlled by a phosphorylation-dephosphorylation cycle in which Pyruvate Dehydrogenase Kinase uses ATP to phosphorylate PDH causing its inactivation and Pyruvate Dehydrogenase Phosphatase dephosphorylates PDH inactivating it Kinase is activated by an increased ratio intramitochondrial acetylCoACoA as we can see in conditions of high fatty acid levels The consequent reduction of PDC activity dramatically decreases glucose oxidation Carnitine participates to trans-esterification forming acetylcarnitine By means of catching acylic groups it decreases ratio acetylCoACoA indirectly stimulating PDC activity and favouring pyruvate oxidation and of glucose Thus acetylcarnitine can be considered a modulator of substrates utilization in cells with consequences in the metabolism of both lipids and carbohydrates Several studies demonstrated that carnitine contributes to the improvement of insulin sensitivity and glucose utilization in both healthy subjects and type 2 diabetics Thus it is interesting to confirm the hypothesis that acetylcarnitine may improve insulin sensitivity in patients with a risk for type 2 diabetes and verify if this improvement is associated with other components of metabolic syndrome
Primary aim To evaluate insulin sensitivity eg Glucose disposal rate during an euglycemic hyperinsulinemic clamp in 40 patients with normal morning fasting glucose and increased risk of type 2 diabetes mellitus
Secondary aims
To evaluate drug effects on sitting systolicdiastolic blood pressure lipid profile morning fasting glucose and postprandial glucose
To assess the correlation between insulin sensitivity and serum inflammatory markers Erythrocyte Sedimentation Rate C-reactive protein and insulin leptin and adiponectin levels
To assess treatment tolerability
Design of the study This will be a sequential and longitudinal study
Potentially eligible patients will have a baseline evaluation of the following parameters
Clinical Systolicdiastolic blood pressure Heart rate Body weight BW BMI Total body water TBW Fat-free mass FFM Fat mass FM Metabolic Fasting morning blood glucose oral glucose tolerance test Insulin leptin adiponectin level Lipid profile Total VLDL and HDL cholesterol total triglycerides Apolipoprotein A and B Inflammatory markers Erythrocyte Sedimentation Rate C-reactive protein and plasma TNF alfa Patients satisfying the inclusionexclusion criteria will have their insulin sensitivity evaluated by an euglycemic hyperinsulinemic clamp and will enter a six month treatment period with Acetylcarnitine 2 gday At the end of the treatment period and 2 months after treatment withdrawal all baseline parameters including insulin sensitivity will then be evaluated No changes in diet and in concomitant treatments in particular with diuretics ACE inhibitors angiotensin II receptor antagonists dihydro and non-dihydro calcium channel blockers statins will be introduced throughout the whole study period
Calculated by the Hume and Weyers formula TBW in males 02968 x weight in kg 01948 x height in cm - 140129 TBW in females 01838 x weight in kg 03446 x height in cm - 352701
FFM TBW073
FM BW - FFM
Study Oversight
Has Oversight DMC:
None
Is a FDA Regulated Drug?:
None
Is a FDA Regulated Device?:
None
Is an Unapproved Device?:
None
Is a PPSD?:
None
Is a US Export?:
None
Is an FDA AA801 Violation?:
None