Dapagliflozin improves muscle insulin sensitivity but enhances endogenous glucose production

Chronic hyperglycemia impairs insulin action, resulting in glucotoxicity, which can be ameliorated in animal models by inducing glucosuria with renal glucose transport inhibitors. Here, we examined whether reduction of plasma glucose with a sodium-glucose cotransporter 2 (SGLT2) inhibitor could improve insulin-mediated tissue glucose disposal in patients with type 2 diabetes. Eighteen diabetic men were randomized to receive either dapagliflozin (n = 12) or placebo (n = 6) for 2 weeks. We measured insulin-mediated whole body glucose uptake and endogenous glucose production (EGP) at baseline and 2 weeks after treatment using the euglycemic hyperinsulinemic clamp technique. Dapagliflozin treatment induced glucosuria and markedly lowered fasting plasma glucose. Insulin-mediated tissue glucose disposal increased by approximately 18% after 2 weeks of dapagliflozin treatment, while placebo-treated subjects had no change in insulin sensitivity. Surprisingly, following dapagliflozin treatment, EGP increased substantially and was accompanied by an increase in fasting plasma glucagon concentration. Together, our data indicate that reduction of plasma glucose with an agent that works specifically on the kidney to induce glucosuria improves muscle insulin sensitivity. However, glucosuria induction following SGLT2 inhibition is associated with a paradoxical increase in EGP. These results provide support for the glucotoxicity hypothesis, which suggests that chronic hyperglycemia impairs insulin action in individuals with type 2 diabetes.     

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.     

Vectorial capacity and genetic diversity of Anopheles annularis (Diptera: Culicidae) mosquitoes in Odisha,India from 2009 to 2011

Anopheles annularis is one of the major vectors of malaria in Odisha, India. The present study was undertaken to determine the vectorial capacity and assess the genetic diversity of An. annularis collected from different endemic regions of Odisha. Mosquitoes were collected from thirteen endemic districts using standard entomological collection methods from 2009 to 2011. Sibling species of An. annularis were identified by PCR-RFLP and sequencing of D3 region of 28S ribosomal DNA (rDNA) region. Plasmodium falciparum (Pf) sporozoite rate and human blood fed percentage (HBF) were estimated by multiplex PCR using Pf and human specific primers. Genetic diversity of An. annularis was estimated by ISSR markers. Out of 1647 An. annularis collected, 1353 (82.15%) were collected by mechanical aspirators and 294 (17.85%) by light trap. 49 (2.97%) were positive for human blood and 18 (1.09%) were positive for Pf sporozoite. PCR-RFLP and sequencing analyses detected only An annularis A in the study areas. Overall genetic differentiation among An. annularis populations was moderate (F_ST = 0.048) and showed significant correlation between genetic distance and geographic distance (r = 0.882; P < 0.05). Angul population proved to be genetically unique and was highly divergent F_ST > 0.110) from other populations, suggesting low gene flow between them. The study indicated that only An. annularis A was found in Odisha with potential vectorial capacity that can play a major role in malaria transmission. ISSR markers proved to be useful molecular tools to evaluate genetic variability in An. annularis populations.     

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...