Pioglitazone improves glucose metabolism and modulates skeletal muscle TIMP-3–TACE dyad in type 2 diabetes mellitus: a randomised, double-blind, placebo-controlled, mechanistic study

Aims/hypothesis

Pioglitazone (PIO) is a peroxisome proliferator-activated receptor (PPAR)γ agonist insulin-sensitiser with anti-inflammatory and anti-atherosclerotic effects. Our objective was to evaluate the effect of low-dose PIO (15 mg/day) on glucose metabolism and inflammatory state in obese individuals with type 2 diabetes.

Methods

A randomised, double-blind, placebo-controlled, mechanistic trial was conducted on 29 patients with type 2 diabetes treated with metformin and/or sulfonylurea. They were randomised to receive PIO or placebo (PLC) for 6 months, in a 1:1 ratio. Participants were allocated to interventions by central office. All study participants, investigators and personnel performing measurements were blinded to group assignment. At baseline and after 6 months patients underwent: (1) OGTT; (2) muscle biopsy to evaluate expression of TNF-α, tissue inhibitor of metalloproteases 3 (TIMP-3) levels, TNF-α converting enzyme (TACE) expression and enzymatic activity; (3) euglycaemic–hyperinsulinaemic clamp; (4) measurement of plasma high-sensitivity C-reactive protein (hsCRP), plasminogen activator inhibitor type-1 (PAI-1), TNF-α, IL-6, monocyte chemotactic protein-1 (MCP-1), adiponectin and fractalkine (FRK). The interventions were PIO 15 mg/day vs placebo and the main outcomes measured were absolute changes in whole-body insulin sensitivity, insulin secretion and inflammatory state.

Results

Fifteen participants were randomized to receive PIO and 14 participants were randomized to receive PLC. Eleven participants completed the study in the PIO group and nine participants completed the study in the PLC group and were analysed. Fasting plasma glucose and HbA_1c decreased modestly (p?<?0.05) after PIO and did not change after PLC. M/I (insulin-stimulated whole-body glucose disposal), adipose tissue insulin resistance (IR) index, insulin secretion/IR (disposition) index and insulinogenic index improved significantly after PIO, but not after PLC. Circulating MCP-1, IL-6, FRK, hsCRP and PAI-1 levels decreased in PIO- as compared with PLC-treated patients, while TNF-α did not change. TNF-α protein expression and TACE enzymatic activity in muscle were significantly reduced by PIO but not PLC. Adiponectin levels increased significantly after PIO as compared with PLC treatment. Given that the mean TACE enzymatic activity level at baseline in the PIO group was 0.29?±?0.07 (fluorescence units [FU]), and at end of study decreased to 0.05 vs 0.14 in the PLC group, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.80. Given that M/I was 2.41?±?0.35 μmol kg^?1 min^?1 (pmol/l)^?1 at baseline and increased by 0.55 in the PIO and 0.17 in the PLC groups, the power to reject the null hypothesis that the population means of the PIO and PLC groups are equal after 6 months is greater than 0.85. The type I error probability associated with this test of this null hypothesis is 0.05. No serious adverse events occurred in either group.

Conclusions/interpretation

Low-dose PIO (15 mg/day) improves glycaemic control, beta cell function and inflammatory state in obese patients with type 2 diabetes.

Trial registration

Clinical.Trial.gov NCT01223196

Funding

This study was funded by TAKEDA.     

Acridine and Its Derivatives: Synthesis,Biological, and Anticorrosion Properties

The phenomenon of corrosion threatens metallic components, human safety, and the economy. Despite being eco-friendly and promising as a corrosion inhibitor, acridine has not been explored to its full potential. In this review, we have discussed multiple biological activities that acridines have been found to show in a bid to prove that they are environmentally benign and much less toxic than many inhibitors. Some synthetic routes to acridines and substituted acridines have also been discussed. Thereafter, a multitude of acridines and substituted acridines as corrosion inhibitors of different metals and alloys in various corrosive media have been highlighted. A short mechanistic insight into how acridine-based compounds function as corrosion inhibitors have also been included. We believe this review will generate an impression that there is still much to learn about previously reported acridines. In the wake of recent surges to find efficient and non-toxic corrosion inhibitors, acridines and their analogs could be an appropriate answer.     

Malabsorption syndrome in ascariasis

This group of researchers recently reported findings on the overall effect of Ascaris lumbricoides infection on human nutrition. On the basis of available data, it was suggested that intestinal malabsorption is a potential cause of nutritional impairment in children infected with Ascaris lumbricoides. The purpose of this discussion is to present additional data on the effect of Ascaris infection on small bowel function and structure in children. 5 children with heavy Ascaris infection without any evidence of clinical malnutrition were admitted to a metabolic unit. On admission, each child was placed on a constant diet consisting of 82-95 kcal and approximately 1 g protein/kg body weight/day. The amount of dietary fat varied from 55-60 g; the levels of vitamins and minerals in the diet were adjusted to meet the recommended dietary allowances. After an adjustment period of 4-6 days, fecal samples were collected during 2 periods of 4 days each for nitrogen and fat analysis. Peroral jejunal biopsies were obtained using an 8 mm Crosby-Kugler biopsy capsule. The samples were processed and stained according to standard techniques. The children then received deworming treatment consisting of 75 mg piperazine/kg body weight daily for 5 consecutive days. In 4 of 5 children there was reduced fecal nitrogen excretion; the mean reduction represented 6.5% of dietary nitrogen. Steatorrhea was present in 4 children; deworming resulted in a reduction of fecal fat from 9.9-2.3% of dietary fat. 3 children demonstrated an impairment in D-xylose excretion. It returned to normal following deworming in only 1 child. The jejunal morphology was found to be abnormal in all children. In each case a significant improvement was noted soon after deworming. The study results strongly suggest that there is a cause and effect relationship between Ascaris infection and intestinal lesions in children.     

Efficiency of address cards, experienced health visitors and motivated registry clerks in obtaining the home address of urban patients in South India

The address card, a card on which the patient's home address is asked to be recorded by the local postman, or by a knowledgeable and literate neighbour, relative or friend, was investigated for acceptability and efficiency in 4 tuberculosis out-patient clinics, in an urban community with substantial levels of illiteracy in Madras City. In the 4 clinics combined, 96% of the patients who reattended returned the completed card. Letters posted to the address on the cared were received by 85% of 419 patients, while 5% were returned by the post office as undelivered and a further 4% were, in all probability, not delivered; no information was available about the remaining 6%. A formal comparison in 392 of the above patients demonstrated the address card method to be significantly more efficient than interrogation by experienced health visitors. A retrospective comparison suggested that the efficiency of experienced health visitors was slightly better than that of highly motivated registry clerks, the proportions of letters received being 72% and 65% respectively.     

Bilateral stress fractures of femoral neck in non-athletes: a report of four cases

Femoral neck stress fractures (FNSFs) are rare,constituting only 5％ of all stress fractures in young adults.These fractures are usually seen in athletes,military recruits and patients with underlying m...     

Live Music Is Beneficial to Preterm Infants in the Neonatal Intensive Care Unit Environment

Abstract: Background: Music stimulation has been shown to provide significant benefits to preterm infants. We hypothesized that live music therapy was more beneficial than recorded music and might improve physiological and behavioral parameters of stable preterm infants in the neonatal intensive care unit. Methods: Thirty‐one stable infants randomly received live music, recorded music, and no music therapy over 3 consecutive days. A control of the environment noise level was imposed. Each therapy was delivered for 30 minutes. Inclusion criteria were postconceptional age ≥ 32 weeks, weight ≥ 1,500 g, hearing confirmed by distortion product otoacoustic emissions (DPOAEs), and no active illness or documentation of hyperresponsiveness to the music. Heart rate, respiratory rate, oxygen saturation, and a behavioral assessment were recorded, every 5 minutes, before, during, and after therapy, allowing 30 minutes for each interval. The infant's state was given a numerical score as follows: 1, deep sleep; 2, light sleep; 3, drowsy; 4, quiet awake or alert; 5, actively awake and aroused; 6, highly aroused, upset, or crying; and 7, prolonged respiratory pause > 8 seconds. The volume range of both music therapies was from 55 to 70 dB. Parents and medical personnel completed a brief questionnaire indicating the effect of the three therapies. Results: Live music therapy had no significant effect on physiological and behavioral parameters during the 30‐minute therapy; however, at the 30‐minute interval after the therapy ended, it significantly reduced heart rate (150 ± 3.3 beats/min before therapy vs 127 ± 6.5 beats/min after therapy) and improved the behavioral score (3.1 ± 0.8 before therapy vs 1.3 ± 0.6 after therapy, p < 0.001). Recorded music and no music therapies had no significant effect on any of the tested parameters during all intervals. Both medical personnel and parents preferred live music therapy to recorded music and no music therapies; however, parents considered live music therapy significantly more effective than the other therapies. Conclusions: Compared with recorded music or no music therapy, live music therapy is associated with a reduced heart rate and a deeper sleep at 30 minutes after therapy in stable preterm infants. Both recorded and no music therapies had no significant effect on the tested physiological and behavioral parameters. (BIRTH 33:2 June 2006)