Insulin Resistance and Insulin Resistance Syndrome (Frontiers in Animal Diabetes Research, 5)
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According to the binding model, the Rmax value is 8. SPR response correlates with change in mass concentration which depends on the molecular interaction of dmp in relation to the number of sites present in IR. SPR results were further evaluated by quantitative analysis of the interaction between IR and dmp through fluorimetric titration. Fluorescence intensity gradually quenched due to the interaction between IR and dmp.
Binding constant was found to be 1. Binding affinity of dmp to IR is represented by KD value 1. Rmax value is 8. C Fluorescence spectra of IR-dmp. All steady-state fluorescence measurements were carried out using an excitation wavelength of nm. The emission spectra were traced from to nm.
The concentration of IR was 0. Autophosphorylation of IR in L6 myotubes could be dose dependently increased by both dmp and insulin. Similar trend was observed with tyrosine kinase activity of IR by dmp and insulin Fig 3D. A comparison between insulin and dmp was then examined with insulin downstream molecules, both stimulated the downstream kinases Fig 3E to effect translocation of GLUT4 from cytosol to membrane. The same was also reflected in glucose uptake by primary muscle cells and L6 myotubes Fig 3G.
Both insulin and dmp significantly stimulated fatty acid uptake by adipocytes Fig 3H. A dmp fails to activate EGFR. L6 myotubes or 3T3L1 adipocytes were treated with or without nM dmp for 4h. B,C dmp can induce IR phosphorylation in a dose dependent manner. D IR kinase activity was determined in L6 myotubes which were incubated with varied concentrations of insulin or dmp. E dmp stimulates IR and its downstream kinases phosphorylation.
L6 myotubes or 3T3L1 adipocytes were treated with or without Insulin nM or dmp nM for 4h and the IR phosphorylation and its downstream signalling were monitored by immunoblotting. G dmp like insulin promotes glucose uptake. L6 myotubes or skeletal muscle cells from soleus muscle of neonatal mice days were incubated with n m insulin or n m dmp for 25 min. H dmp augments fatty acid uptake. Primary culture adipocytes or 3T3L1 adipocytes were treated with n m insulin or n m dmp for 4h followed by incubation with [ 3 H] Palmitate for 15 min.
Fig 4A shows that in STZ induced Type1 diabetes mice blood glucose level was markedly elevated while oral administration of dmp could reduce it significantly. Decrease of skeletal muscle IR phosphorylation was also improved by dmp Fig 4B. Same was observed with glucose uptake by skeletal muscle and fatty acid uptake by adipose tissue of STZ treated mice, dmp treatment considerably improved the defects caused due to the dearth of insulin Fig 4C. Another advantage of dmp was that its stimulatory effect on [ 14 C] 2-DOG uptake could be noted for longer period whereas with insulin the plateau was reached at 75 min Fig 4D.
Pharmacodyanamics study of dmp demonstrated that its presence in the blood after oral administration 5mg kg bw -1 could be detected at 1 h, peak reached at 5 h and it was retained till 7 h Fig 4E. Maximum concentration Cmax in plasma was These findings suggest that bioavailability of dmp would not be a problem. A Blood glucose level was detected at different times. C [ 14 C] 2-DOG uptake top and [ 3 H] Fatty acid uptake bottom by skeletal muscle or adipose tissue from above mentioned mice were determined in a liquid scintillation counter. E dmp was orally administered to BL6 mice 5mg kg -1 bw and plasma dmp level was measured at different time intervals.
To test this, we performed experiments with 3T3L1 adipocytes. Fig 5C demonstrates that dmp significantly reduced Wnt3a gene and protein expression. It also decreased the expression of Wnt target genes i. A peptide inhibitor of IR which efficiently blocks insulin induced IR activation i. Fig 5G demonstrates the results obtained with primary mice adipocytes, there was a significant increase of Wnt3a expression in HFD mice adipocytes as compared to SD mice adipocytes, dmp markedly suppressed it and this effect remained undisturbed when IR was blocked with a peptide inhibitor, HNMPA- AM 3, indicating that dmp inhibition of Wnt3a is not mediated through IR.
In vitro incubation of 3T3L1 cells were conducted in the absence control or presence of nM dmp along with 0.
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C Wnt3a gene top and protein bottom expression levels were estimated. D mRNA expressions of Wnt target genes, axin2 and wisp2 were estimated. The same was also reported with insulin [ 39 , 44 ]. This coincided with the lowering of blood glucose, free fatty acid FFA and TG levels Fig 6B and increased the uptake of glucose and fatty acid by skeletal muscle and adipose tissue respectively Fig 6C.see
Insulin Resistance and Insulin Resistance Syndrome (Frontiers in Animal Diabetes Research, 5)
Orally fed dmp also increased adiponectin expression in the adipose tissue in a dose dependent manner Fig 6D. Administration of dmp significantly improved energy expenditure EE Fig 7D indicating that dmp could prevent diet induced impairment of energy homeostasis. Adiponectin is known to regulate AMPK activation which is the master regulator of energy homeostasis [ 45 ].
Body weight was recorded on the days mentioned in the figure. Weight of the abdominal fat was recorded. Blood glucose concentration GTT was measured before and after oral gavages of 1g glucose kg bw -1 at the indicated time points. ITT was performed after injecting mice with 0. Toxicity of dmp single dose-5mg kg bw -1 to Wistar rats Rattus norvegicus was evaluated as per the guideline of OECD [ 46 ]. To determine dmp toxicity blood parameters such as WBC counts, total leukocyte count, hemoglobin, total lymphocytes, monocytes and neutrophils were measured after 14th day of the treatment and it was found that all these parameters are in normal range Fig 8A , indicating that dmp does not have any adverse effects.
In addition to these parameters we have also determined some important biochemical markers of liver, kidney including lipid profile. Fig 8B demonstrates that there was no alteration of these parameters due to dmp treatment Fig 8B. Histopathology of the liver and kidney did not show abnormality Fig 8C. Besides in vivo validation of dmp toxicity, we also tested its toxic effect at cellular level. We have taken skeletal muscle cell line L6 myotubes and 3T3L1 adipocytes and observed whether there was any toxic effect of dmp through MTT cell viability assay, level of proinflammatory cytokines i.
It would be evident from the results that dmp did not show any abnormality in cell viability, there was also no notable changes in proinflammatory cytokine levels and ATP production between control and dmp treated cells Fig 8D—8F. These findings suggest that dmp did not produce toxic effects in the above mentioned experimental models.
In addition, according to the GHS Global Harmonization system , dmp was found to be under category 2. Rats were fed with dmp 5 mg kg bw -1 for 14 days. A Hematological, B Biochemical analysis, C Liver and kidney histopathology were performed on 0 and 14 day to test toxic effect of dmp. F ATP production was measured in L6 myotubes incubated in the absence or presence of nM dmp for 4 h. Anti-diabetic effect of vanadium salt, Na 2 VO 4 sodium orthovanadate has been reported 22 years before the discovery of insulin. It is Lyonnet et al.
Several studies followed thereafter showed various insulin-mimetic effects of vanadium compounds both in vitro and in vivo , which include stimulation of glucose transport and glucose oxidation [ 47 , 48 ] glycogen synthesis and lipogenesis [ 49 ]. In animal experiments, glucose homeostasis in diabetic rats [ 50 ], normalization of hyperglycemia in diabetic mice [ 51 ] and insulin sensitization effect in Type2 diabetes patients [ 52 ] are few examples from numerous reports on anti-diabetic effects of various vanadium compounds.
Primary reason for which vanadium compounds are not recommended for clinical therapy is their toxic side effects. The toxic side effects of Vanadium are reported by several authors which includes dehydration, hepatic and renal toxicity [ 53 ]. Some Vanadium compounds have been found to interact with DNA and have considerable toxicity [ 54 ]. Domingo et al. To use vanadium as a therapy because it showed significant efficacy in dealing with diabetic problems, attempts were made by several investigators to minimize the toxicity by preparing a peroxy vanadium compound which showed encouraging results.
One of such compounds has been prepared by Crans et al [ 26 ], that showed considerable increase in anti-diabetic activity with minimized toxicity, but its stability remains a problem.
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Major issues those are concerned with the use of vanadium salt for diabetes treatment is to fulfill the following requirements: a it should possess high sensitivity so that even a low dose can produce desired anti-diabetic effects, b free from toxicity, c stable at room temperature, d better retention in the circulation and e reasonable bioavailability when administered through oral route.
To meet these objectives, we prepared a hexacordinated peroxyvanadium V compound with 3,5-dimethyl imidazole dmp ligand. Dmp could satisfy these requirements with significantly high insulin mimetic activity and improve the loss of insulin sensitivity that occurs in Type2 diabetes. By binding to IR insulin produces both metabolic as well as mitogenic effects, while dmp only showed metabolic activities, it does not exhibit mitogenic activity as evident from unaltered EGFR expression and activation.
Previous reports with vanadium described translocation of GLUT4 for increasing glucose transport, without altering GLUT4 transcription or protein expression [ 56 ]. We also could not detect increase in GLUT4 expression with dmp data not shown. It possibly effects efficient translocation of GLUT4 due to the increase in intrinsic activity. Vanadium inhibitory effect on non-specific protein tyrosine phosphatase PTPase has been focused as one of its major function which permitted its insulin like activity [ 57 ].
This indicates that vanadium effect on IR activation has been indirectly mediated [ 57 ]. Although vanadium inhibitory effect on PTPase is important in mediating the metabolic effects, number of evidences suggests that inhibition of PTPase is insufficient to cover plethora of activities by various vanadium compounds. Vanadium effects glycogen metabolism and gluconeogenesis, lipogenesis, insulin sensitization in Type 2 diabetes etc. But some studies with vanadium demonstrate its stimulatory effect could be independent of insulin or IR activation [ 47 , 58 , 59 ]. Again, such multifunctional actions of vanadium compounds have shown preferential increase in metabolic effects [ 60 ].
It is indeed difficult to consider the view that such various kinds of activities executed by different vanadium compounds belong to post receptor effects. Demonstration of dmp binding to IR in this report is a strong evidence in favour of this. Moreover our contribution will provide a better understanding of vanadium compound-induced insulin mimetic action, a search for which is continuing for last 45 years. We have demonstrated that dmp significantly enhanced insulin sensitivity in obese diabetic mice. Previous reports showed that vanadyl sulphate could markedly improve insulin sensitivity of muscle and liver in Type 2 diabetes human patients [ 52 ].
Insulin sensitizing effect of vanadium has also been examined in animal models, administration of it has been found to increase insulin sensitivity in diabetic mice and rat models [ 51 , 56 ]. However, underlying mechanism involved in insulin sensitization by vanadium compounds remains unclear. TZDs which attenuate lipid induced defects by controlling fat metabolism thus causing improvement of insulin sensitivity. Insulin resistance in human skeletal muscle has been shown to be associated with decreased mitochondrial oxidative capacity and downregulation of genes which regulate mitochondrial activity thus resulting in decreased ATP synthesis.
Number of recent reports emphasize a strong link between impaired mitochondrial function and Type 2 diabetes [ 61 ]. There is practically no compound to reverse this except resveratrol which by improving mitochondrial function could protect mice from obesity and insulin resistance [ 62 ]. In this connection dmp showed a promise, it stimulated mitochondrial biogenesis and bioenergetics through increased adiponectin and could effectively regulate energy homeostasis which has an impact on insulin sensitivity.
In both in vitro and in vivo studies dmp produces insulin like activity in insulin target tissues or for Type2 diabetes mice with considerable low dose. Dose response study for in vitro and in vivo effects is very important because some of the insulin mimetic effects of vanadium observed in vitro failed to produce results with therapeutic doses when examined in in vivo experiments therefore lacks relevance for clinical application [ 53 ].
We are thankful to Dr. We sincerely acknowledge the help of Dr. Subrata K. The authors duly acknowledge the Head, Dept. Data curation: S. Formal analysis: S. Mukherjee MC Sushmita Bhattacharya. Methodology: S. Software: S. Additionally, in the experiment by Hoeks et al.
Overall, the human studies mimicking shift-work seem to find more profound disturbances than the animal studies mimicking shift-work. The prolonged protocols likely allow the animals' sufficient time to partly adapt to the initial disturbances caused by circadian misalignment or shift work. The results from Experiment-2 where we fasted ad libitum fed rats acutely for 17 h are also in line with this idea.
The changes seen after an acute 17 h fast period clearly differ from those of the TRF animals that were fasted for 17 h. By experimental design the TRF animals were daily fasted for 14 h, whereas ad libitum fed animals usually only have a daily fasting period of 6—8 h at the beginning of the light phase. During the TRF protocol especially glucose tolerance seems to improve again, i. As recently nicely demonstrated in humans 29 , 30 , the present results clearly show that also in rats the well-known daily variation in glucose tolerance and insulin sensitivity is not only due to the daily variation in feeding condition, but also has a circadian component.
In fact, we observed that the daily variation in glucose responses was lost in both the dark and light fed group, whereas the daily variation in insulin responses was enhanced in the dark fed animals, but lost in light fed animals. It should be noted, however, that during ivGTTs insulin sensitivity is measured indirectly. Therefore, we cannot rule out the possibility that the smaller insulin release we find in our groups that are absolutely fasted for 17 h are due to e.
Surprisingly, feeding restricted to the inactive phase only marginally affected glucose tolerance and the concomitant insulin response compared to ad libitum conditions. For future experiments, it will be necessary to investigate how rapid and persistent these effects are when animals are switched back and forth between TRF and ad libitum feeding conditions, as such a situation more closely resembles shift work in humans. On the other hand, feeding restricted to the active phase did improve insulin sensitivity, but only during the active phase. Most likely this effect is due to the long fasting period coinciding with the regular sleep and fasting phase.
This also means that when applying TRF for therapeutic means eating should be restricted to the prescribed eating period, as glucose tolerance is worsened outside the regular eating hours. The datasets generated for this study are available on request to the corresponding author.
PdG and AK orchestrated the research project, performed the analyses, and wrote the manuscript. AK and C-XY provided both intellectual and financial support and helped writing and revising the manuscript. The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. We would like to thank the Endocrinology diagnostic department of the AMC for measuring the insulin concentrations.
We also thank Aurea Blancas, Anneloes Opperhuizen and Leslie Eggels for their assistance during surgeries and the experiment in general. Supplemental Figure 1. Control experiment in which 2 groups of animals were tested both in the 5 h fasted and 17 h fasted condition with a wash-out period of 1 week in between measurements either at ZT4 or ZT Diabetes mellitus, fasting blood glucose concentration, and risk of vascular disease: a collaborative meta-analysis of prospective studies. Knutsson A, Kempe A. Shift work and diabetes — A systematic review.
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Increased levels of IRS1 phosphorylated at serine residues are observed in the hippocampus and in the hypothalamus of AD mouse models.
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In the AD context, activation of stress-response kinases was shown to regulate brain insulin signaling impairment and memory behavior tests 12 , 13 , 75 , Interestingly, both measures plus depressive-like behavior were counteracted by the administration of probiotics Interestingly, TLR4 expression correlates with depression in humans 83 , 84 and followed anxiety and depressive-like behavior in mice fed a high-cholesterol diet Figure 1. Proposed mechanism of insulin resistance in the brain of diabetic patients prompting the onset of depression.
Activation of those stress pathways leads to the phosphorylation of insulin receptor substrate 1 IRS1 at serine residues, impacting proper insulin signaling response. Lack of proper central insulin signaling would affect hippocampal neurogenesis, synaptic plasticity, hypothalamic-pituitary-adrenal HPA axis response, and the reward system. Due to the heterogeneity of depression and the lack of specific biomarkers, the management of this condition in the primary care setting remains challenging 88 , 89 and treatment frequently involves trial and error experimentation.
Different types of antidepressants are applied in clinical practices, usually directed to neurotransmitters reuptake and monoamine oxidase inhibition. It is not uncommon to observe cases of treatment-resistant depression despite adequate dosing and duration of antidepressants More effective treatments are required, and some overlapping mechanisms between T2D and depression, suggested above, opens up new avenues for the identification of novel pharmacological targets for the treatment of those comorbid disorders.
Regarding this topic, anti-depressant effects of anti-diabetic and anti-inflammatory medications are currently being explored in the field. Insulin based medications can be considered first-line treatments in T2D in cases of severe basal hyperglycemia or elevated serum glycated hemoglobin.
Clinical studies administering intranasal insulin in healthy human subjects have reported improvements in mood and memory 92 , as well as better HPA axis response to a social stress test, assessed by decreased saliva and plasma cortisol levels But when evaluated in a cohort of depressive patients, intranasal insulin had no improvements on the depressive scores and neurocognition indexes applied compared to the placebo group Lack of effective response to insulin amongst patients could be related to an intracellular insulin resistance Figure 1 , suggesting that approaches that bypass the first steps of the insulin signaling might show better results.
Liraglutide, another anti-diabetic medication, is an incretin analog that binds to the Glucagon-like peptide 1 receptor and ameliorates insulin signaling. This injectable anti-diabetic medication is capable of crossing the blood-brain barrier 95 and shows positive effects on brain insulin signaling and memory performance on animal models of AD 78 , 96 , When tested in animal models of depression, liraglutide also had beneficial effects 98 , Clinical trials using this drug as a treatment for neurodegenerative diseases, like Alzheimer's disease are ongoing ClinicalTrials.
A 4-week pilot study adding liraglutide as a treatment for patients with mood disorders observed better scores on measures of cognitive function compared to baseline But more robust trials involving liraglutide and a placebo group in depressive patients are still warranted. Metformin is a commonly used treatment for T2D with mechanisms of action not fully understood, but it involves key regulators of cellular energy status, including mitochondrial proteins and the AMP kinase AMPK , In a cohort of patients with comorbid depression and T2D, metformin was reported to ameliorate depressive behavior when compared to baseline Nonetheless, in a study involving overweight participants with impaired glucose tolerance, metformin had no effect on the Beck Depression Inventory score when compared to the placebo group The effects of metformin in the antidepressant response to sertraline in a group of obese people is currently being evaluated in a phase 4 clinical trial ClinicalTrials.
Rosiglitazone administration provides antidepressant-like effects in mouse models of depression and T2D 31 , Pioglitazone has been evaluated in several clinical trials involving depressed patients and analysis indicated that the drug was more effective in patients with insulin resistance — Interestingly, pioglitazone effectiveness was age-dependent, being more efficacious in younger subjects Recent studies have also shown that immunosuppressive agents can improve outcomes in depression.
But, when delivery subcuteously, etanercept had no beneficial effects on cognition , possibly due to restricted transport across the blood-brain barrier A randomized double-blind placebo-controlled trial using an indwelling catheter to deliver infliximab in depressed patients showed no significant changes in Hamilton-Depression HAM-D score when compared with the placebo group. Since the treatment decreased circulating CRP levels within the responder vs. Finally, changes in the gut microbiota are associated with stress disorders Probiotics can modulate the HPA axis , neurotransmitters , inflammatory markers and, as previously mentioned, insulin signaling in the brain Probiotics are emerging as promising treatments for depression, showing positive results in different clinical studies [for a systematic review see ].
The association between depression and diabetes is supported by several evidences, but the mechanistic links between both diseases are still emerging. The development of brain insulin resistance is a possible candidate connecting both diseases, but further studies focusing on this issue are warranted in the field. Unraveling this connection is a matter of a great value in order to pursue alternative treatments or to optimize anti-depressants response.
NL: development of the subject matter, drafting of the article, conception, and design of the figure, critical revision of the article, final approval of the version to be published; ML: development of the subject matter, drafting of the article, critical revision of the article, final approval of the version to be published; CS and DM: critical revision of the article, final approval of the version to be published; RM and FD: development of the subject matter, drafting of the article, critical revision of the article, final approval of the version to be published.
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