Acetylcarnitine and Insulin Sensitivity
Condition: Type 2 Diabetes Mellitus
MeSH terms: Diabetes Mellitus, Type 2
Study type: Interventional
Phase: Phase 2

Summary: 
      Decreased insulin sensitivity (e.g. 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
      abnormalities,albuminuria 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-carnitine(ALC), 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,
      sequential,longitudinal 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 (e.g. 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 acetylCoA/CoA, 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 acetylCoA/CoA, 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 (e.g. 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 systolic/diastolic 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 Systolic/diastolic blood pressure, Heart rate, Body weight (BW), B.M.I., 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 inclusion/exclusion criteria will have their insulin sensitivity evaluated by an
      euglycemic hyperinsulinemic clamp and will enter a six month treatment period with
      Acetylcarnitine 2 g/day. 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 = (0.2968 x weight in kg) + (0.1948
      x height in cm) - 14.0129 TBW in females = (0.1838 x weight in kg) + (0.3446 x height in cm)
      - 35.2701

      ** FFM = TBW/0.73

      *** FM = BW - FFM
    

Intervention name(s): L-acetylcarnitine
Intervention type(s): Drug
Intervention description(s): 250-500 mg/kg/die.
Intervention MeSH terms: Acetylcarnitine
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Risk of type 2 diabetes