NAC-N Acetyl cysteine as an insulin sensitizers ,and antioxidants : Role of NAC in PCOS , Diabetes and NASH

 NAC-N Acetyl cysteine  as an insulin sensitizers ,and antioxidants  : Role of NAC  in PCOS , Diabetes and NASH (Non Alcoholic Stato hepatitis N-Acetyl Cysteine is considered as one of the insulin sensitizers. Further NAC is believed  as antioxidant as well . As such NAC alone or more commonly with metformin is used in Ovulation induction but not routinely. So, it is felt that NAC is used occasionally in PCO women to potentiate the action of insulin.

Such NAC containg agents i.e. branded drugs as available in Indian  market are followings:  :-A) Chrominac-A (TTK) B) Met PCO Care (metformin 500, NAC 500 and C) Chirocyst Myoinositol  550 mg, DCI 13.8, NAC 600 mg

A)      NAC is used along with either CC and or letrozole to promote ovulation and improved oocyte quality NAC is also recognized as an antioxidants and researchers believe it prevents cellular injury in men and women with high blood sugar. High blood sugar causes glucose toxicity. However NAC and the antioxidant α[alpha ]-lipoid acid have  been in this way proposed and clinically used as an insulin sensitizer. 

 

B)         Can NAC be used along with  CC in unexplained subfertility ?? 

 

C)         Following are the comments in Fertility and Sterility

D)         Volume 86, Issue 3, September 2006, Pages 647-650

E)           

F)           Ovulation induction

G)         Clomiphene citrate plus N-acetyl cysteine versus clomiphene citrate for augmenting ovulation in the management of unexplained infertility: a randomized double-blind controlled trial

H)         Author links open overlay panel::  AhmedBadawyM.D.^aAbuBaker El NasharM.D.^bMohamedEl TotongyM.D.^a

I)             Show more

J)            https://doi.org/10.1016/j.fertnstert.2006.02.097Get rights and content

K)         Objective

L)          To compare clomiphene citrate with N-acetyl cysteine vs. clomiphene citrate alone for augmenting ovulation in management of unexplained infertility.

M)       Design

N)         Prospective randomized double-blind controlled trial.

O)         Setting

P)           Department of obstetrics and gynecology in a university medical faculty in Egypt.

Q)         Patient(s)

R)         Four hundred four patients as a study group (clomiphene citrate plus N-acetyl cysteine group) and 400 patients as a control group (clomiphene citrate–alone group). All women had unexplained infertility.

S)           Intervention(s)

T)          Patients in the study group were treated with clomiphene citrate (50-mg tablets) twice per day and with N-acetyl cysteine (1,200 mg/d orally) for 5 days starting on day 2 of the cycle. Patients in the control group were treated with clomiphene citrate with sugar powder.

Main Outcome Measure(s)

The primary outcomes were number and size of growing follicles, serum E₂, serum P, and endometrial thickness. The secondary outcome was the occurrence of pregnancy.

Result(s)

There were no statistically significant differences between the two groups in the number of follicles sized >18 mm, mean E₂ levels, serum P, or endometrial thickness. Pregnancy rate was comparable in both groups (22.2% vs. 27%). Miscarriage rate was comparable in both groups (6.7% in the study group vs. 7.4% in the control group).

Conclusion(s)

N-Acetyl cysteine is ineffective in inducing or augmenting ovulation in patients with unexplained infertility and cannot be recommended as an adjuvant to clomiphene citrate in such patients.

 

NAC is used in various indications and one of the uncommon indication is  NASH(non‐alcoholic steatohepatitis (NASH) which may appear in 4/5^th decades of life in PCO women . It has been observed that combination of N‐acetylcysteine and metformin improves histological steatosis and fibrosis in patients with non‐alcoholic steatohepatitis

There is no proven medical therapy for the treatment of non‐alcoholic steatohepatitis (NASH). Oxidative stress and insulin resistance are the mechanisms that seem to be mostly involved in its pathogenesis of liver injury in long standing PCO or Diabetes mellitus in either sex, . There have been studies  to evaluate the efficacy of  treatment. N ‐acetylcysteine (NAC) in combination with metformin (MTF) in improving the aminotransferase and histological parameters (steatosis, inflammation, hepatocellular ballooning, and fibrosis)

 

Methods: months. A low calorie diet was prescribed for all patients. months. All patients underwent evaluation of serum aminotransferase, fasting lipid profile and serum glucose, anthropometric parameters, and nutritional status at 0 and 12 mg/day) were given orally for 12 g/day) and MTF (850–1000 years [36–68] and body mass index [BMI] 29 [25–35]) with biopsy‐proven NASH were enrolled in the study. NAC (1.2 2 ± Twenty consecutive patients (mean age 53

Results: NAC along with Metformin may yield to  modest reduction of followings like serum alanine aminotransferase, high‐density lipoprotein, insulin, and glucose concentrations and the  homeostasis model assessment–insulin resistance (HOMA‐IR) index .The BMI  too declined, but without statistical significance. Where NAC are ineffective?? Aspartate aminotransferase, gamma‐Glutamyl Transferase, alkaline phosphatase, cholesterol, and triglycerides levels are  not altered with the treatment by combination of  NAC & metformin . Liver steatosis and fibrosis decreased ( P <0.05), but no improvement was noted in lobular inflammation or hepatocellular ballooning. The NASH activity score was significantly improved after treatment. 

Conclusion: Based on the biochemical and histological evidence of different studies  NAC in combination with MTF appears to ameliorate several aspects of NASH, including fibrosis.

What is glucose toxicity in DM & longstanding  PCO  and  role of antioxidants    α[alpha ]-lipoid acid & NAC ??  Long standing high glucose in blood leads to Oxidative stress. This oxidative stress (ROS)  has been implicated in glucose toxicity. It is presumable that  certain antioxidants may prevent insulin-resistant glucose transport that develops in adipocytes after sustained exposure to high glucose, provided insulin is present.

The antioxidant α[alpha ]-lipoid acid has been proposed as an insulin sensitizer. In research settings 3T3-L1 adipocytes were preincubated 18 hours in media containing insulin (0.6 nmol/L) with low (5 mmol/L) or high (25 mmol/L) glucose with or without [alpha ]-lipoate, dihydrolipoate (each 0.1 to 0.5 mmol/L), or N-acetylcysteine (1 to 5 mmol/L). After extensive re-equilibration in insulin and antioxidant-free media, basal and maximally insulin-stimulated (100 nmol/L) glucose transport was measured.

Insulin was quantified by radioimmunoassay. Preincubation with   α [alpha ]-lipoate and dihydrolipoate but not N-acetylcysteine increased subsequent basal glucose transport; the effect was much smaller than that of acute maximal insulin stimulation.

 

Preincubation in high glucose without antioxidants inhibited acutely insulin-stimulated glucose transport by 40% to 50% compared with low glucose. This down- regulation was partially or completely prevented by each antioxidant. In cell-free media, the 2 reluctant, dihydrolipoate and N-acetylcysteine, rapidly decreased immunoreactive insulin, but [alpha ]-lipoate was ineffective. However, during incubation with adipocytes, [alpha ]-lipoate, and dihydrolipoate promoted the decline in immunoreactive insulin nearly equally.

Because insulin and high glucose are synergistic in inducing insulin resistance in this model, the reduction in immunoreactive insulin probably contributed to the protective effect of the antioxidants. 3T3-L1 adipocytes efficiently metabolize [alpha ]-lipoate to dihydrolipoate, which may be released into the medium. The stimulation of glucose transport by [alpha ]-lipoid acid may represent redox effects in sub cellular compartments that are accessible to dihydrolipoate.

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