Key Strategies for Overcoming Psychological Insulin Resistance in Adults with Type 2 Diabetes: The UK Subgroup in the EMOTION Study.

INTRODUCTION: Many patients with type 2 diabetes mellitus (T2DM) delay initiation of insulin therapy despite healthcare professional (HCP) advice. This phenomenon has been referred to as 'psychological insulin resistance' (PIR), and various contributing factors have been identified. Studies discussing approaches to overcoming PIR are lacking. Our aim was to identify the key strategies used by HCPs that most helped adults with T2DM and PIR in the UK to initiate insulin. METHODS: As part of a global study, UK adults with T2DM and PIR were recruited (N = 125) to take a survey that included 38 HCP statements and actions about insulin initiation. Data assessed were perceived occurrence and helpfulness of these strategies in facilitating insulin initiation. RESULTS: The most helpful strategies involved demonstrating the injection process (e.g. HCP talked patient through the process of taking insulin [83.6%]) and adopting a collaborative approach (HCP encouraged patient to contact the clinic immediately in case of any problems/questions [80.5%]). Additionally, HCPs highlighting the benefits of insulin (HCP explained that insulin was a natural substance needed by patient's body [81.2%]) and allaying patients' concerns (HCP explained that patient might not have to take insulin forever [78.0%]) helped patients initiate insulin. The least helpful action was HCPs repeatedly persuading patients to initiate insulin (40.9%). CONCLUSIONS: The study recommends key strategies that HCPs can adopt to help adults with T2DM overcome PIR in the UK.

Many patients with type 2 diabetes (T2DM) are reluctant to start insulin therapy despite it being recommended by their doctor. This can lead to a delay in receiving effective treatment to control blood sugar. There are many reasons to explain this reluctance­which is also referred to as psychological insulin resistance (PIR)­including fear of injections and lack of understanding. EMOTION was a global study which set out to identify strategies to overcome PIR. It looked at 38 things, identified by people with diabetes, that doctors/nurses can do or say to encourage a patient to try insulin. Analysis of results for the 125 UK patients with T2DM who were reluctant to start insulin showed that the most helpful approach was demonstrating the injection procedure. Actually talking a patient through how to inject insulin and demonstrating how the pen works can help reduce their fears about the injection process. Adopting a collaborative approach was found to be important, encouraging patients to get in touch with any problems or questions. Other helpful strategies included highlighting the benefits of insulin­explaining that it is a natural substance the body needs­and addressing any specific concerns a patient may have about insulin. The least helpful strategy was taking an authoritarian approach and repeatedly trying to persuade a patient to start insulin. This is the first study which provides evidence-based clinical strategies that UK healthcare professionals can use to help overcome PIR in their patients with T2DM.

Antispasmodic and antidiarrheal activities of rhizomes of Polygonatum verticillatum maneuvered predominately through activation of K⁺ channels: Components identification through TLC.

Polygonatum verticillatum has traditionally been used for various purposes. The present study was aimed to validate the antispasmodic and antidiarrheal properties of crude methanolic extract of rhizomes of P. verticillatum (PR). Isolated rabbit jejunum preparations were suspended in tissue baths to measure the isotonic responses using Power Lab data acquisition system for the antispasmodic activity of PR, while the antidiarrheal activity was conducted in vivo in mice. PR caused complete relaxation of the spontaneous contractions of isolated rabbit jejunum preparations in a dose-dependent mode. A complete inhibition was observed against low potassium (K(+); 25 mM)-induced contractions, while the plant extract partially inhibited the high K(+)(80 mM)-induced contractions. From a mechanistic point of view, the spasmolytic effect of PR against low K(+)was antagonized by glibenclamide similar to the effect of cromakalim, thus showing the presence of constituents in PR mediating spasmolytic activity predominantly through the activation of adenosine triphosphate-sensitive K(+)channels. When tested against castor oil-induced diarrhea in mice, oral administration of the plant extract manifested marked antidiarrheal activity at the doses of 500 and 1000 mg/kg similar to loperamide. This study provided a pharmacological basis for the medicinal use of PR in abdominal colic and diarrhea.

In vivo antinociceptive and anticonvulsant activity of extracts of Heliotropium strigosum.

Natural healing agents are primarily focused to overcome unwanted side effects with synthetic drugs worldwide. In the proposed study, crude extracts and subsequent solvent fractions of Heliotropium strigosum were evaluated for antinociceptive and anticonvulsant activity in animal paradigms. In post acetic acid-induced writhing test, crude extract and fractions (hexane, ethyl acetate, and aqueous) demonstrated marked attenuation of nociception at test doses (50, 100, and 200 mg/kg i.p.). When challenged against thermally induced pain model, pretreatment of extracts exhibited prominent amelioration at test dose (50, 100, and 200 mg/kg i.p.). In both tests, inhibition of noxious stimulation was in a dose-dependent manner, and ethyl acetate fraction was most dominant. However, extracts did not antagonize the seizures and mortality induced by pentylenetetrazole. In conclusion, the extracts of H. strigosum illustrated significant antinociceptive effect in both centrally and peripherally acting pain models.

Anti-inflammatory activity of Heliotropium strigosum in animal models.

The current project was designed to evaluate the anti-inflammatory activity of crude extract of Heliotropium strigosum and its subsequent solvent fractions in post carrageenan-induced edema and post xylene-induced ear edema at 50, 100, and 200 mg/kg intraperitoneally. The results revealed marked attenuation of edema induced by carrageenan injection in a dose-dependent manner. The ethyl acetate fraction was most dominant with 73.33% inhibition followed by hexane fraction (70.66%). When the extracts were challenged against xylene-induced ear edema, again ethyl acetate and hexane fractions were most impressive with 38.21 and 35.77% inhibition, respectively. It is concluded that various extracts of H. strigosum possessed strong anti-inflammatory activity in animal models.

Modulation of c-Fos and BDNF protein expression in pentylenetetrazole-kindled mice following the treatment with novel antiepileptic compound HHL-6.

Brain-derived neurotrophic factor (BDNF) and c-Fos are shown to promote epileptogenesis and are taken as a marker of neuronal activity. The present study investigated the expression of BDNF and c-Fos in mice brain with pentylenetetrazol- (PTZ-) induced generalized seizure and evaluated the effect of novel tryptamine derivative HHL-6 on the expression of these two markers. The subconvulsive dose of PTZ (50 mg/kg) was administered on alternate days in the experimental groups until the seizure scores 4-5 developed in the PTZ-control group. At the end of each experiment, animals were sacrificed, brain samples were collected and cryosectioned, and immunohistochemical analysis of BDNF and c-Fos protein was performed. Data obtained from two sections per mouse (n = 12 animals/group) is presented as means ± S.E.M. The test compound HHL-6 demonstrated a potent anticonvulsant activity in the PTZ-induced seizure in mice. Significant reduction in the BDNF (P < 0.003) and c-Fos (P < 0.01) protein expression was observed in the HHL-6 treated group. Based on these results we suggest that one of the possible mechanisms of HHL-6 to inhibit epileptogenesis might be due to its controlling effect on the cellular and molecular expression of the factors that contribute to the development of epileptogenic plasticity in the CNS.

Inflammatory abdominal aortic aneurysm: a persistent painful hip.

The presentation of an abdominal aortic aneurysm (AAA) with isolated hip pain is a rare phenomenon. We present an atypical case of a 58-year-old previously fit man who presented with a 6-month history of progressively worsening left hip pain associated with unintentional weight loss, tender bilateral testicular swellings and a large non-tender palpable mass on abdominal examination. Urgent abdominal CT scan findings revealed a 15 cm infrarenal abdominal aortic aneurysm extending to the aortic bifurcation associated with an extensive left hydronephrosis. In theatre, the diagnosis of inflammatory AAA (IAAA) was confirmed following the presence of pyuria and a successful repair with an open approach using a bifurcated dacron graft was performed.

Studies on tracheorelaxant and anti-inflammatory activities of rhizomes of Polygonatum verticillatum.

BACKGROUND: The present study describes the tracheorelaxant and anti-inflammatory effects of Polygonatum verticillatum which may support its medicinal use in hyperactive airway complaints and inflammatory disorders. METHODS: The tracheorelaxant activity of crude extract of the rhizomes of P. verticillatum (PR) was assessed in isolated guinea-pig tracheal tissues immersed in tissue organ bath filled with Tyrode's solution and a continuous supply of carbogen gas (95% O2 and 5% CO2). The contractile and relaxant responses of the tissue were measured using isometric transducers coupled with Power-Lab data acquisition system. The anti-inflammatory effect was evaluated in carrageenan-induced rat paw edema model, while the lipoxygenase inhibitory activity was performed in the in-vitro assay. Various chromatographic and spectroscopic techniques were used for the isolation and characterization of pure molecules. RESULTS: In isolated guinea-pig tracheal preparations, PR caused complete inhibition of the high K+ (80 mM) and carbachol-induced contractions however, it was more potent against K+ than CCh, similar to verapamil. Pretreatment of the tissue with PR, displaced the Ca2+ concentration-response curves to the right, similar to that induced by verapamil, indicating the presence of Ca2+ channel blocking like activity. When tested on carrageenan-induced rat paw edema, PR demonstrated a marked reduction in edema with 65.22% protection at 200 mg/kg, similar to aspirin. In the in-vitro assay, PR showed lipoxygenase inhibitory activity (IC50: 102 ± 0.19 µg/mL), similar to baicalein. Bioactivity-guided fractionation led to the isolation of 2-hydroxybenzoic acid and ß-sitosterol. CONCLUSIONS: These results indicate that the plant possesses tracheorelaxant, mediated possibly through a Ca2+ channel blockade mechanism, and anti-inflammatory activities, which may explain the medicinal use of this plant in airway disorders and inflammation.

Antipyretic and anticonvulsant activity of Polygonatum verticillatum: comparison of rhizomes and aerial parts.

The current study was undertaken to explore the antipyretic and anticonvulsant profile of the Polygonatum verticillatum in established pharmacological paradigms. The crude methanol extract of rhizomes (PR) and aerial parts (PA) of the plant were tested in Brewer's-yeast-induced pyrexia and pentylenetetrazole-induced convulsion test. PR and PA both evoked prominent antipyretic activity (p < 0.01) in a dose-dependent manner during all assessment times at the dose of 50, 100, and 200 mg/kg intraperitoneally. The protection elicited by PR (82.20%) at 200 mg/kg was comparable with aspirin (88.48%) as a standard drug at 100 mg/kg. However, PA was less potent, and maximum protection was 64% at 200 mg/kg. Both PR and PA were devoid of any anticonvulsant activity. Our results demonstrated prominent evidence of antipyretic activity of P. verticillatum that is consistent with the folk uses of the plant. In addition from a biodiversity point of view, PA of the plant can also be used as an alternate of PR.

The anti-arthritic and anti-oxidative effect of NBD (6-nitro-1,3-benzodioxane) in adjuvant-induced arthritis (AIA) in rats.

OBJECTIVES: The present study evaluated the anti-arthritic and anti-oxidative effects of 6-nitro-1,3-benzodioxane in the adjuvant-induced arthritis model in rats. METHODS: Arthritis was induced in female rats by intradermal injection of MT37Ra. Arthritis was evaluated by arthritic score, body weight loss, paw volume measurement, and histological changes. The plantar test was used to evaluate the effect of NBD on hyperalgesia. RESULTS: The hyperalgesia (p < 0.0001) and hind paw inflammation (p < 0.034) was significantly decreased with parallel increase in the body weight of the NBD-treated (25 mg/kg) group compared to arthritic control rats. The antioxidant activity analysis demonstrated that the treatment of NBD significantly suppressed the levels of nitric oxide (p < 0.001) and peroxide (p < 0.002) with a significant increase in the glutathione (p < 0.021) compared to the arthritic control group. Since the IL-1ß and TNF-α are key pro-inflammatory cytokines in arthritis, we therefore measured their levels in the serum samples. In comparison to the arthritic control group, the NBD treatment significantly reduced the levels of IL-1ß (p < 0.003) and TNF-α (p < 0.026). CONCLUSION: Our results suggests that NBD is an anti-arthritic agent that not only reduces the severity of the disease process but also affects contributing factors of arthritic inflammation including free radicals and inflammatory cytokines production.

Suppression of c-Fos protein and mRNA expression in pentylenetetrazole-induced kindled mouse brain by isoxylitones.

An early immediate gene c-fos has been proposed as the gene responsible for turning on molecular events that might underlie the long-term neural changes occurring during kindling. We have evaluated the effects of novel anticonvulsant isomeric compounds isoxylitones [(E/Z)-2-propanone-1,3,5,5-trimethyl-2-cyclohexen-1-ylidine] on the c-Fos protein and mRNA expression in the brain samples of kindled mice and compared it with the normal and untreated kindled groups. Kindling was induced in male NMRI mice by repeated administration of sub-convulsive dose (50 mg/kg) of pentylenetetrazole (PTZ) until a seizure score of 4-5 was achieved. The c-Fos expression was quantified by combination of immunohistochemistry and RT-PCR protocols. Both the immunohistochemical and RT-PCR analysis revealed a marked increase in the expression of c-fos mRNA and protein in the brain regions tested in case of PTZ-kindled control group compared to normal control. In contrast, the isoxylitone (30 mg/kg)-treated group demonstrated significant reduction of c-Fos expression compared to PTZ-kindled control animals. However, low expression of c-fos mRNA was only detected in the thalamus of the isoxylitone-treated brain samples. Based on these observations, we suggest that isoxylitones may have the capacity to control the seizure pattern by mechanism such as the suppression of c-Fos protein and mRNA levels in different regions of the brain. Further investigations to explore the mechanism of action of these compounds are under process.

Antinociceptive activity of aerial parts of Polygonatum verticillatum: attenuation of both peripheral and central pain mediators.

Polygonatum verticillatum All. is used traditionally as an analgesic and plant diuretic. The methanol extract of aerial parts of Polygonatum verticillatum (PA) was assessed in various experimental paradigms. The pain threshold in the form of abdominal constriction induced by acetic acid was significantly (p < 0.01) inhibited by PA at test doses (50, 100 and 200 mg/kg). In the formalin test, PA elicited a significant (p < 0.01) analgesic activity in both phases and strongly attenuated the formalin-induced flinching behaviour. The hot plate test was used to evaluate central involvement in the analgesic profile of PA. The PA significantly relieved thermal-induced pain. From a mechanistic point of view, the central antihyperalgesic activity was tested for antagonism with naloxone, but no antagonism was observed. The current investigations suggest that the active constituent(s) in PA has an analgesic profile with predominant peripheral activity which is augmented by an opioid independent central effect. In the diuretic assay, PA (300 and 600 mg/kg) showed mild insignificant diuretic activity. Our study rationalized the traditional use of Polygonatum verticillatum in the treatment of painful conditions.