Combined Intranasal Insulin/Saxagliptin/Metformin Therapies Ameliorate the Effect of Combined Oral Contraceptive- (COC-) Induced Metabolic Syndrome (MetS) with a Major Target on Glucose Metabolism in Adult Female Wistar Rats

Objective. To evaluate the effect of the chronic use of combined oral contraceptives (COCs: ethinyl estradiol and levonorgestrel) on the indices of metabolic syndrome in adult female Wistar rats and possible therapeutic management. Materials and Methods. 64 female Wistar rats received either distilled water, norethindrone (NOR), COC, intranasal insulin (INI), metformin (MET), saxagliptin (SAX), INI+MET, and INI+SAX. After 8 weeks of exposure to COC, the animals were sorted into the therapeutic groups. Several parameters were assayed for, such as body weight changes, fasting blood glucose (FBG) level, insulin levels, inflammatory cytokines, and glycated hemoglobin (Hb1Ac). Results. The levels of FBG, insulin, and Hb1Ac were increased consequent upon COC treatment. Treatment with INI+SAX and INI+MET reduced significantly the levels of FBG and Hb1Ac; in addition, the level of insulin was significantly increased in the INI+MET groups ( p ≤ 0.05 ). Serum lipid profile analysis showed a statistical reduction in high-density lipoprotein (HDL) level; this reduction was also significantly reversed in the INI+SAX group. Reduced catalase activity observed in the COC group was reversed in the INI+MET group ( p ≤ 0.05 ). A nonsignificant increase in the level of TNF-α as a result of COC treatment was reversed by INI and INI+MET treatment. Liver GLUT4 and G-6-phosphate levels were significantly increased by COC treatment, and this effect was reversed by INI+SAX in both assays, respectively ( p ≤ 0.01 ). Conclusions. The use of MET and SAX in combination with INI has been shown to reverse some indices of MetS. This study proposes a clinical phase to backup and ascertain these preclinical findings.

Intranasal insulin for treatment of delirium in older hospitalised patients: study protocol for a randomised controlled trial

IntroductionDelirium is one of the most common conditions diagnosed in hospitalised older people and is associated with numerous adverse outcomes, yet there are no proven pharmacological treatments. Recent research has identified cerebral glucose hypometabolism as a pathophysiological mechanism offering a therapeutic target in delirium. Insulin, delivered via the intranasal route, acts directly on the central nervous system and has been shown to enhance cerebral metabolism and improve cognition in patients with mild cognitive impairment and dementia. This trial will determine whether intranasal insulin can reduce the duration of delirium in older hospitalised patients.Methods and analysisThis is a prospective randomised, placebo-controlled, double-blind study with 6 months follow-up. One hundred patients aged 65 years or older presenting to hospital with delirium admitted under geriatric medicine will be recruited. Participants will be randomised to intranasal insulin detemir or placebo administered twice daily until delirium resolves, defined as Confusion Assessment Method (CAM) negative for 2 days, or discharge from hospital. The primary outcome measure will be duration of delirium using the CAM. Secondary outcome measures will include length of hospital stay, severity of delirium, adherence to treatment, hospital complications, new admission to nursing home, mortality, use of antipsychotic medications during hospital stay and cognitive and physical function at 6 months postdischarge.Ethics and disseminationThis trial has been approved by the South Eastern Sydney Human Research and Ethics Committee. Dissemination plans include submission to a peer-reviewed journal for publication and presentation at scientific conferences.Trial registration numberACTRN12618000318280.

Genetic Findings as the Potential Basis of Personalized Pharmacotherapy in Phelan-McDermid Syndrome

Phelan-McDermid syndrome (PMS) is a genetic disorder often characterized by autism or autistic-like behavior. Most cases are associated with haploinsufficiency of the SHANK3 gene resulting from deletion of the gene at 22q13.3 or from a pathogenic variant in the gene. Treatment of PMS often targets SHANK3, yet deletion size varies from < 50kb to > 9Mb, potentially encompassing dozens of genes and disrupting regulatory elements altering gene expression, inferring the potential for multiple therapeutic targets. Repurposed drugs have been used in clinical trials investigating therapies for PMS: insulin-like growth factor 1 (IGF-1) for its effect on social and aberrant behaviors, intranasal insulin for improvements in cognitive and social ability, and lithium for reversing regression and stabilizing behavior. The pharmacogenomics of PMS is complicated by the CYP2D6 enzyme which metabolizes antidepressants and antipsychotics often used for treatment. The gene coding for CYP2D6 maps to 22q13.2 and is lost in individuals with deletions larger than 8Mb. Because PMS has diverse neurological and medical symptoms, many concurrent medications may be prescribed, increasing the risk for adverse drug reactions. At present, there is no single best treatment for PMS. Approaches to therapy are necessarily complex and must target variable behavioral and physical symptoms of PMS.

Intranasal insulin rescues repeated anesthesia-induced deficits in synaptic plasticity and memory and prevents apoptosis in neonatal mice via mTORC1

Long-lasting cognitive impairment in juveniles undergoing repeated general anesthesia has been observed in numerous preclinical and clinical studies, yet, the underlying mechanisms remain unknown and no preventive treatment is available. We found that daily intranasal insulin administration to juvenile mice for 7 days prior to repeated isoflurane anesthesia rescues deficits in hippocampus-dependent memory and synaptic plasticity in adulthood. Moreover, intranasal insulin prevented anesthesia-induced apoptosis of hippocampal cells, which is thought to underlie cognitive impairment. Inhibition of the mechanistic target of rapamycin complex 1 (mTORC1), a major intracellular effector of insulin receptor, blocked the beneficial effects of intranasal insulin on anesthesia-induced apoptosis. Consistent with this finding, mice lacking mTORC1 downstream translational repressor 4E-BP2 showed no induction of repeated anesthesia-induced apoptosis. Our study demonstrates that intranasal insulin prevents general anesthesia-induced apoptosis of hippocampal cells, and deficits in synaptic plasticity and memory, and suggests that the rescue effect is mediated via mTORC1/4E-BP2 signaling.

Central insulin modulates dopamine signaling in the human striatum

Objective Activity in the dopaminergic pathways of the brain is highly sensitive to body weight and metabolic states. Animal studies show that dopamine neurons are important targets for the metabolic hormone insulin with abolished effects in the insulin resistant state, leading to increases in body weight and food intake. In humans, the influence of central acting insulin on dopamine and effects of their interplay are still elusive. Research Design and Methods We investigated whether central administered insulin influences dopaminergic activity in striatal regions and whole-brain neural activity. Using a PET/MRI hybrid scanner, we simultaneously performed [ 11C]-raclopride-PET and resting state fMRI in 10 healthy normal weight men after application of intranasal insulin or placebo on two separate days in a randomized, placebo-controlled, blinded, crossover trial. Results In response to central insulin compared to placebo administration, we observed greater [ 11C]-raclopride binding potential (BPnd) in the bilateral ventral and dorsal striatum. This suggests an insulin-induced reduction in synaptic dopamine levels. Resting-state striatal activity was lower 15 and 30 min after nasal insulin compared to placebo. Functional connectivity of the mesocorticolimbic circuitry associated with differences in dopamine levels: individuals with a stronger insulin-induced effect on dopamine levels showed a stronger increase in functional connectivity 45 min after intranasal insulin. Conclusions This study indicates that central insulin modulates dopaminergic tone in the striatum, which may affect regional brain activity and connectivity. Our results deepen the understanding of the insulin-dopamine interaction and the complex network that underlies the regulation of whole-body metabolism.