Heat therapy shows benefit in patients with type 2 diabetes mellitus: a systematic review and meta-analysis.

AIMS: Type-2 diabetes mellitus (T2DM) is a common health condition which prevalence increases with age. Besides lifestyle modifications, passive heating could be a promising intervention to improve glycemic control. This study aimed to assess the efficacy of passive heat therapy on glycemic and cardiovascular parameters, and body weight among patients with T2DM. METHODS: A systematic review and meta-analysis were reported according to PRISMA Statement. We conducted a systematic search in three databases (MEDLINE, Embase, CENTRAL) from inception to 19 August 2021. We included interventional studies reporting on T2DM patients treated with heat therapy. The main outcomes were the changes in pre-and post-treatment cardiometabolic parameters (fasting plasma glucose, glycated plasma hemoglobin, and triglyceride). For these continuous variables, weighted mean differences (WMD) with 95% confidence intervals (CIs) were calculated. Study protocol number: CRD42020221500. RESULTS: Five studies were included in the qualitative and quantitative synthesis, respectively. The results showed a not significant difference in the hemoglobin A1c [WMD -0.549%, 95% CI (-1.262, 0.164), p = 0.131], fasting glucose [WMD -0.290 mmol/l, 95% CI (-0.903, 0.324), p = 0.355]. Triglyceride [WMD 0.035 mmol/l, 95% CI (-0.130, 0.200), p = 0.677] levels were comparable regarding the pre-, and post intervention values. CONCLUSION: Passive heating can be beneficial for patients with T2DM since the slight improvement in certain cardiometabolic parameters support that. However, further randomized controlled trials with longer intervention and follow-up periods are needed to confirm the beneficial effect of passive heat therapy.

The ophthalmic surgical backlog associated with the COVID-19 pandemic: a population-based and microsimulation modelling study.

BACKGROUND: Jurisdictions worldwide ramped down ophthalmic surgeries to mitigate the effects of COVID-19, creating a global surgical backlog. We sought to predict the long-term impact of COVID-19 on the timely delivery of non-emergent ophthalmology sub-specialty surgical care in Ontario. METHODS: This is a microsimulation modelling study. We used provincial population-based administrative data from the Wait Time Information System database in Ontario for January 2019 to May 2021 and facility-level data for March 2018 to May 2021 to estimate the backlog size and wait times associated with the COVID-19 pandemic. For the postpandemic recovery phase, we estimated the resources required to clear the backlog of patients accumulated on the wait-list during the pandemic. Outcomes were accrued over a time horizon of 3 years. RESULTS: A total of 56 923 patients were on the wait-list in the province of Ontario awaiting non-emergency ophthalmic surgery as of Mar. 15, 2020. The number of non-emergency surgeries performed in the province decreased by 97% in May 2020 and by 80% in May 2021 compared with the same months in 2019. By 2 years and 3 years since the start of the pandemic, the overall estimated number of patients awaiting surgery grew by 129% and 150%, respectively. The estimated mean wait time for patients for all subspecialty surgeries increased to 282 (standard deviation [SD] 91) days in March 2023 compared with 94 (SD 97) days in 2019. The provincial monthly additional resources required to clear the backlog by March 2023 was estimated to be a 34% escalation from the prepandemic volumes (4626 additional surgeries). INTERPRETATION: The estimates from this microsimulation modelling study suggest that the magnitude of the ophthalmic surgical backlog from the COVID-19 pandemic has important implications for the recovery phase. This model can be adapted to other jurisdictions to assist with recovery planning for vision-saving surgeries.

Surgical Outcomes among Focused versus Diversified Cataract Surgeons.

PURPOSE: Narrowly focused surgical practice has become increasingly common in ophthalmology and may have an effect on surgical outcomes. Previous research evaluating the influence of surgical focus on cataract surgical outcomes has been lacking. This study aimed to evaluate whether surgeons' exclusive surgical focus on cataract surgery influences the risk of cataract surgical adverse events. DESIGN: Population-based cohort study. PARTICIPANTS: All patients 66 years of age or older undergoing cataract surgery in Ontario, Canada, between January 1, 2002, and December 31, 2013. METHODS: Outcomes of isolated cataract surgery performed by exclusive cataract surgeons (no other types of surgery performed), moderately diversified cataract surgeons (1%-50% noncataract procedures), and highly diversified cataract surgeons (>50% noncataract procedures) were evaluated using linked healthcare databases and controlling for patient-, surgeon-, and institution-level covariates. Surgeon-level covariates included both surgeon experience and surgical volume. MAIN OUTCOME MEASURES: Composite outcome incorporating 4 adverse events: posterior capsule rupture, dropped lens fragments, retinal detachment, and suspected endophthalmitis. RESULTS: The study included 1 101 864 cataract operations. Patients had a median age of 76 years, and 60.2% were female. Patients treated by the 3 groups of surgeons were similar at baseline. Adverse events occurred in 0.73%, 0.78%, and 2.31% of cases performed by exclusive cataract surgeons, moderately diversified surgeons, and highly diversified surgeons, respectively. The risk of cataract surgical adverse events for patients operated on by moderately diversified surgeons was not different than for patients operated on by exclusive cataract surgeons (odds ratio [OR], 1.08; 95% confidence interval [CI], 1.00-1.18). Patients operated on by highly diversified surgeons had a higher risk of adverse events than patients operated on by exclusive cataract surgeons (OR, 1.52; 95% CI, 1.09-2.14). This resulted in an absolute risk difference of 0.016 (95% CI, 0.012-0.020) and a number needed to harm of 64 (95% CI, 50-87). CONCLUSIONS: Exclusive surgical focus did not affect the safety of cataract surgery when compared with moderate levels of surgical diversification. The risk of cataract surgical adverse events was higher among surgeons whose practice was dedicated mainly to noncataract surgery.

Exclusive cataract surgical focus among ophthalmologists: a population-based analysis.

OBJECTIVE: An important potential unintended consequence of the growth of surgical subspecialization is the narrowing of surgical practice among comprehensive ophthalmologists. We investigated trends in the narrowing of surgical practice and the exclusive provision of cataract surgery. DESIGN: Population-based, retrospective study. PARTICIPANTS: All ophthalmologists and all ophthalmologic surgical patients in Ontario from 1994 to 2016. METHODS: We linked several health care databases to evaluate the proportion of ophthalmologists who exclusively provided cataract surgery (and no other ophthalmologic surgery) and the proportion who provided other types of ophthalmologic surgical care. To further investigate surgical focus, we evaluated the proportion of surgical cases within each surgical area for each ophthalmologist. RESULTS: Between 1994 and 2016, the proportion of ophthalmologists who exclusively provided cataract surgery rose from 10.0% to 34.9% (p < 0.0001). In contrast, the proportions of ophthalmologists providing other types of subspecialized surgical care were stable over the study period. Cataract surgeons showed high degrees of focus with a median percentage of surgical cases approaching 100% in all years. Among exclusive cataract surgeons, the median annual cataract case volume increased from 138 (interquartile range: 87-214) to 529 (interquartile range: 346-643) between 1994 and 2009 (p < 0.0001) and then plateaued. CONCLUSIONS: Between 1994 and 2016, exclusive cataract surgical focus among ophthalmologists in Ontario rose dramatically from 1 in 10 to 1 in 3 surgeons. This evolution was similar among recent graduates and established ophthalmologists. Our data may have important implications for policies regarding surgeon human resources as well as residency and fellowship training programs.

COVID-19 and heme oxygenase: novel insight into the disease and potential therapies.

The COVID-19 pandemic needs therapies that are presently available and safe. We propose that subjects with metabolic syndrome, old age, and male gender have the greatest morbidity and mortality and have low stress proteins, in particular, low intracellular heme oxygenase (HO-1), making them particularly vulnerable to the disease. Additionally, COVID-19's heme reduction may contribute to even lower HO-1. Low-grade inflammation associated with these risk factors contributes to triggering a cytokine storm that spreads to multi-organ failure and near death. The high mortality of those treated with ventilator assistance may partially be explained by ventilator-induced inflammation. The cytoprotective and anti-inflammatory properties of HO-1 can limit the infection's damage. A paradox of COVID-19 hospital admissions data suggests that fewer cigarette-smokers are admitted compared with non-smokers in the general population. This unexpected observation may result from smoke induction of HO-1. Therapies with anti-viral properties that raise HO-1 include certain anesthetics (sevoflurane or isoflurane), hemin, estrogen, statins, curcumin, resveratrol, and melatonin. Controlled trials of these HO-1 inducers should be done in order to prevent or treat COVID-19 disease.

Cataract Surgery Quality and Capacity.

Cataract surgery is the most common operation performed in most developed countries, including Canada. Nuanced, evidence-driven policies are needed to ensure appropriate access to this sight-saving operation while maintaining the highest standards in quality of care. The Vision Health Services Research Program at Queen's University, in partnership with members of the Ontario Provincial Vision Task Force, has developed evidence to inform policies aimed at optimizing both access and quality across the eye care spectrum.

Evolution in the Risk of Cataract Surgical Complications among Patients Exposed to Tamsulosin: A Population-Based Study.

PURPOSE: Tamsulosin is associated with intraoperative floppy iris syndrome (IFIS), an important risk factor for complications during cataract surgery. Significant efforts have been made to increase awareness of the risks associated with tamsulosin, and educational initiatives have fostered the uptake of technical adjustments to decrease adverse event rates among tamsulosin-exposed patients. However, the effectiveness of these efforts at the population level has not been studied. DESIGN: Population-based study to evaluate cataract surgical adverse event rates over time among patients exposed to tamsulosin and those not exposed to this drug. PARTICIPANTS: All male patients 66 years of age and older undergoing cataract surgery in Ontario, Canada, between January 1, 2003, and December 31, 2013, were included in the study. METHODS: Linked healthcare databases were used to study the evolution in the risk of cataract surgical adverse events over time among tamsulosin-exposed and non-tamsulosin-exposed patients adjusting for patient-, surgeon-, and institution-level covariates. The study timeframe incorporated periods before and after the first reports of tamsulosin-associated IFIS. MAIN OUTCOME MEASURES: Four important cataract surgical adverse events were evaluated: posterior capsule rupture, dropped lens fragments, retinal detachment, and suspected endophthalmitis. RESULTS: Among patients exposed to tamsulosin, the risk of surgical adverse events decreased over time (odds ratio, 0.95 per year; 95% confidence interval, 0.91-0.99 per year). This trend was observed across patient age strata. Among patients not recently exposed to tamsulosin, the risk of surgical adverse events also decreased over time (odds ratio, 0.96 per year; 95% confidence interval, 0.95-0.98 per year). CONCLUSIONS: The risk of cataract surgical complications among both tamsulosin-exposed and non-tamsulosin-exposed patients declined between 2003 and 2013. Tamsulosin remains an important risk factor for cataract surgical adverse events, and ongoing efforts will be needed to develop and disseminate surgical approaches that mitigate the risks posed by tamsulosin.

Association of Cataract Surgical Outcomes With Late Surgeon Career Stages: A Population-Based Cohort Study.

Importance: Evidence suggests that the quality of some aspects of care provided by physicians may decrease during their late career stage. However, to our knowledge, data regarding the association of advancing surgeon career phase with cataract surgical outcomes have been lacking. Objective: To investigate whether an increase in cataract surgical adverse events occurs during later surgeon career stages. Design, Setting, and Participants: This population-based study of 499 650 cataract operations performed in Ontario, Canada, between January 1, 2009, and December 31, 2013, investigated the association between late surgeon career stage and the risk of surgical adverse events. Linked health care databases were used to study cataract surgical complications while controlling for patient-, surgeon-, and institution-level covariates. All ophthalmologists who performed cataract surgery in Ontario within the study period were included in the analysis. Exposures: Isolated cataract surgery performed by surgeons at early, mid, and late career stages. Main Outcomes and Measures: Four serious adverse events were evaluated: dropped lens fragments, posterior capsule rupture, suspected endophthalmitis, and retinal detachment. Results: Of 416 502 participants, 244 670 (58.7%) were women, 90 429 (21.7%) were age 66 to 70 years, 111 530 (26.8%) were age 71 to 75 years, 90 809 (21.8%) were age 76 to 80 years, and 123 734 (29.7%) were 81 years or older. Late-career surgeons performed 143 108 of 499 650 cataract operations (28.6%) during the study period. Late surgeon career stage was not associated with an increased overall risk of surgical adverse events (odds ratio [OR] vs midcareer, 1.06; 95% CI, 0.85-1.32). In a sensitivity analysis with surgeon volume removed from the model, late career stage was still not associated with overall adverse surgical events (OR, 1.10; 95% CI, 0.88-1.38). Among individual complications, late surgeon career stage was associated with an increased risk of dropped lens fragment (OR, 2.30; 95% CI, 1.50-3.54) and suspected endophthalmitis (OR, 1.41; 95% CI, 1.01-1.98). These corresponded with small absolute risk differences of 0.11% (95% CI, 0.085%-0.130%) and 0.045% (95% CI, 0.028%-0.063%) for dropped lens fragment and suspected endophthalmitis, respectively. Conclusions and Relevance: These findings suggest that later-career surgeons are performing a substantial proportion of cataract operations with overall low surgical adverse event rates. Future studies might extend evaluations to the frequency of secondary surgical interventions as additional measures of surgical care quality.

Effect of cataract surgery volume constraints on recently graduated ophthalmologists: a population-based cohort study.

BACKGROUND: Across Canada, graduates from several medical and surgical specialties have recently had difficulty securing practice opportunities, especially in specialties dependent on limited resources such as ophthalmology. We aimed to investigate whether resource constraints in the health care system have a greater impact on the volume of cataract surgery performed by recent graduates than on established physicians. METHODS: We used population-based administrative data from Ontario for the period Jan. 1, 1994, to June 30, 2013, to compare health services provided by recent graduates and established ophthalmologists. The primary outcome was volume of cataract surgery, a resource-intensive service for which volume is controlled by the province. RESULTS: When cataract surgery volume in Ontario entered a period of government-mandated zero growth in 2007, the mean number of cataract operations performed by recent graduates dropped significantly (-46.37 operations/quarter, 95% confidence interval [CI] -62.73 to -30.00 operations/quarter), whereas the mean rate for established ophthalmologists remained stable (+5.89 operations/quarter, 95% CI 95% CI -1.47 to +13.24 operations/quarter). Decreases in service provision among recent graduates did not occur for services without volume control. The proportion of recent graduates providing exclusively cataract surgery increased over the study period, and recent graduates in this group were 5.24 times (95% CI 2.15 to 12.76 times) more likely to fall within the lowest quartile for cataract surgical volume during the period of zero growth in provincial cataract volume (2007-2013) than in the preceding period (1996-2006). INTERPRETATION: Recent ophthalmology graduates performed many fewer cataract surgery procedures after volume controls were implemented in Ontario. Integrated initiatives involving multiple stakeholders are needed to address the issues facing recently graduated physicians in Canada.

Adequacy of the ophthalmology workforce under Ontario's Local Health Integration Networks.

OBJECTIVE: To determine the current distribution of ophthalmologists across Ontario's Local Health Integration Networks (LHINs) and the influence on LHIN-specific cataract surgery wait times. DESIGN: Cross-sectional study. PARTICIPANTS: Ophthalmologists listed in the College of Physicians and Surgeons (CPSO) database and the Canadian population. METHODS: A list of ophthalmologists and their practice locations were obtained from the CPSO website. The total population count for Ontario was obtained from the Statistics Canada census. The population counts for the population aged 65 years and older were generated using the Canadian Socioeconomic Information Management System (CANSIM) table 109-5425. Cataract surgery wait times were obtained from the Ontario Ministry of Health. Statistical analysis was completed using Microsoft Excel using StatPlus software. RESULTS: There are currently 3.28 ophthalmologists per 100 000 total population in Ontario. LHIN-specific ratios ranged from 8.87 (Toronto Central) to 1.67 (Central West), with 3 out of 14 LHINs having met the previously recommended ratio of 3.37. Median cataract surgery wait times ranged from 30 to 72 days. Although the number of cataract surgeries performed was positively correlated with the population aged 65 years and older (p < 0.001), there was no statistically significant association between wait times and number of cataract cases per 1000 population (p = 0.41). CONCLUSIONS: Although Ontario appears to have a sufficient number of ophthalmologists overall, there is significant variation in the distribution of the ophthalmology workforce at the LHIN level. This variation did not appear to significantly influence LHIN-specific cataract surgery wait times.

Dihydropyridine Derivatives Modulate Heat Shock Responses and have a Neuroprotective Effect in a Transgenic Mouse Model of Alzheimer's Disease.

Heat shock proteins (Hsps) have chaperone activity and play a pivotal role in the homeostasis of proteins by preventing misfolding, by clearing aggregated and damaged proteins from cells, and by maintaining proteins in an active state. Alzheimer's disease (AD) is thought to be caused by amyloid-ß peptide that triggers tau hyperphosphorylation, which is neurotoxic. Although proteostasis capacity declines with age and facilitates the manifestation of neurodegenerative diseases such as AD, the upregulation of chaperones improves prognosis. Our research goal is to identify potent Hsp co-inducers that enhance protein homeostasis for the treatment of AD, especially 1,4-dihydropyridine derivatives optimized for their ability to modulate cellular stress responses. Based on favorable toxicological data and Hsp co-inducing activity, LA1011 was selected for the in vivo analysis of its neuroprotective effect in the APPxPS1 mouse model of AD. Here, we report that 6 months of LA1011 administration effectively improved the spatial learning and memory functions in wild type mice and eliminated neurodegeneration in double mutant mice. Furthermore, Hsp co-inducer therapy preserves the number of neurons, increases dendritic spine density, and reduces tau pathology and amyloid plaque formation in transgenic AD mice. In conclusion, the Hsp co-inducer LA1011 is neuroprotective and therefore is a potential pharmaceutical candidate for the therapy of neurodegenerative diseases, particularly AD.

Prospective evaluation of teleophthalmology in screening and recurrence monitoring of neovascular age-related macular degeneration: a randomized clinical trial.

IMPORTANCE: Teleophthalmology has the potential to reduce costs and inconveniences associated with frequent patient visits. Evaluating teleophthalmology in the management of age-related macular degeneration (AMD) will allow for future implementation of this technology. OBJECTIVE: To evaluate teleophthalmology as a tool for the screening and monitoring of neovascular AMD. DESIGN, SETTING, AND PARTICIPANTS: Prospective, randomized clinical trial that included 106 referral eyes for suspected neovascular AMD and 63 eyes with stable neovascular AMD. New referrals for patients with suspected neovascular AMD and patients with stable neovascular AMD were randomized into either routine or teleophthalmologic groups. In the routine group, patients received clinical assessment and diagnostic imaging at a tertiary hospital-based retina clinic. In the teleophthalmologic group, patients received basic examination and diagnostic imaging at a stand-alone teleophthalmologic site, where patient information and imaging studies were acquired and electronically sent over to tertiary hospital-based retina specialists. Patients in the teleophthalmologic group were called back to the tertiary treatment center if the teleophthalmologic data set suggested pathology or was inconclusive for diagnosis. MAIN OUTCOMES AND MEASURES: Patient wait times for diagnosis and/or treatment, referral accuracy, and visual outcome. RESULTS: For neovascular AMD screening, the average referral-to-diagnostic imaging time was 22.5 days for the teleophthalmologic group and 18.0 days for the routine group, for a difference of 4.5 days (95% CI, 11.8 to -2.8 days; P = .23). The average diagnostic imaging to treatment time was 16.4 days for the teleophthalmologic group and 11.6 days for the routine group, for a difference of 4.8 days (95% CI, 10.7 to -1.1 days; P = .11). For neovascular AMD monitoring, the average recurrence to treatment time was shorter for the routine group (0.04 days) compared with 13.6 days for the teleophthalmologic group, for a difference of -13.5 days (95% CI, -18.2 to -9.0 days; P < .01). There was no difference identified between end-of-study visual acuities in the 2 groups (P = .99). CONCLUSIONS AND RELEVANCE: A delay of referral to treatment time could not be identified when comparing teleophthalmologic screening for suspected neovascular AMD with retinal specialist-based screening. Teleophthalmologic monitoring for neovascular AMD recurrence resulted in longer wait times for treatment reinitiation, but no adverse visual outcomes were identified. TRIAL REGISTRATION: clinicaltrials.gov Identifier:NCT01581606.

Intravitreal ranibizumab for the treatment of fibrovascular pigment epithelial detachment in age-related macular degeneration.

OBJECTIVE: To determine the response of predominantly fibrovascular pigment epithelial detachments (PED)-type lesions (secondary to age-related macular degeneration [AMD]) to intravitreal ranibizumab. DESIGN: This was an open-label prospective study. PARTICIPANTS: Thirty-two patients with predominantly fibrovascular PED-type lesions secondary to AMD were included in this study. Three patients were excluded from the final analysis. METHODS: Patients received monthly intravitreal ranibizumab injections for 6 months (induction). At 6 months, patients not experiencing a visual improvement from baseline Early Treatment of Diabetic Retinopathy Study (ETDRS) visual acuity or not showing a reduction in PED height (based on optical coherence tomography [OCT]) were deemed ranibizumab nonresponders and received no further injections but underwent re-evaluation at 12 months. Patients deemed responders continued with OCT-guided active treatment on an as-needed basis for an additional 6 months. RESULTS: Twenty-four patients (82.8%) were ranibizumab responders and 5 were (17.2%) nonresponders. For ranibizumab responders, mean ETDRS visual acuity improved by 7.2 ± 9.8 letters at 6 months (p = 0.002) and 6.3 ± 8.6 letters at 12 months (p = 0.002). Ranibizumab nonresponders experienced a decline in mean visual acuity of 8.2 ± 4.6 letters at 6 months (p = 0.02) and 18.2 ± 10.11 letters at 12 months (p = 0.02). At baseline, responders had a mean PED height of 345.8 ± 96.0 µm, which decreased to 111.6 ± 133.2 µm at 6 months (p < 0.001) and had a slight increase at 12 months to 144.8 ± 146.3 µm (p < 0.001). Two responders (8.3%) and 2 nonresponders (40%) developed retinal pigment epithelium tears while on treatment. CONCLUSIONS: Intravitreal ranibizumab appears to be a well-tolerated treatment option for patients with fibrovascular PED. Further large-scale, prospective studies may assist in delineating the best treatment protocol.

Hydroximic acid derivatives: pleiotropic HSP co-inducers restoring homeostasis and robustness.

According to the "membrane sensor" hypothesis, the membrane's physical properties and microdomain organization play an initiating role in the heat shock response. Clinical conditions such as cancer, diabetes and neurodegenerative diseases are all coupled with specific changes in the physical state and lipid composition of cellular membranes and characterized by altered heat shock protein levels in cells suggesting that these "membrane defects" can cause suboptimal hsp-gene expression. Such observations provide a new rationale for the introduction of novel, heat shock protein modulating drug candidates. Intercalating compounds can be used to alter membrane properties and by doing so normalize dysregulated expression of heat shock proteins, resulting in a beneficial therapeutic effect for reversing the pathological impact of disease. The membrane (and lipid) interacting hydroximic acid (HA) derivatives discussed in this review physiologically restore the heat shock protein stress response, creating a new class of "membrane-lipid therapy" pharmaceuticals. The diseases that HA derivatives potentially target are diverse and include, among others, insulin resistance and diabetes, neuropathy, atrial fibrillation, and amyotrophic lateral sclerosis. At a molecular level HA derivatives are broad spectrum, multi-target compounds as they fluidize yet stabilize membranes and remodel their lipid rafts while otherwise acting as PARP inhibitors. The HA derivatives have the potential to ameliorate disparate conditions, whether of acute or chronic nature. Many of these diseases presently are either untreatable or inadequately treated with currently available pharmaceuticals. Ultimately, the HA derivatives promise to play a major role in future pharmacotherapy.

Loss of stress response as a consequence of viral infection: implications for disease and therapy.

Herein, we propose that viral infection can induce a deficient cell stress response and thereby impairs stress tolerance and makes tissues vulnerable to damage. Having a valid paradigm to address the pathological impacts of viral infections could lead to effective new therapies for diseases that have previously been unresponsive to intervention. Host response to viral infections can also lead to autoimmune diseases like type 1 diabetes. In the case of Newcastle disease virus, the effects of viral infection on heat shock proteins may be leveraged as a therapy for cancer. Finally, the search for a specific virus being responsible for a condition like chronic fatigue syndrome may not be worthwhile if the disease is simply a nonspecific response to viral infection.

HSP72 protects against obesity-induced insulin resistance.

Patients with type 2 diabetes have reduced gene expression of heat shock protein (HSP) 72, which correlates with reduced insulin sensitivity. Heat therapy, which activates HSP72, improves clinical parameters in these patients. Activation of several inflammatory signaling proteins such as c-jun amino terminal kinase (JNK), inhibitor of kappaB kinase, and tumor necrosis factor-alpha, can induce insulin resistance, but HSP 72 can block the induction of these molecules in vitro. Accordingly, we examined whether activation of HSP72 can protect against the development of insulin resistance. First, we show that obese, insulin resistant humans have reduced HSP72 protein expression and increased JNK phosphorylation in skeletal muscle. We next used heat shock therapy, transgenic overexpression, and pharmacologic means to overexpress HSP72 either specifically in skeletal muscle or globally in mice. Herein, we show that regardless of the means used to achieve an elevation in HSP72 protein, protection against diet- or obesity-induced hyperglycemia, hyperinsulinemia, glucose intolerance, and insulin resistance was observed. This protection was tightly associated with the prevention of JNK phosphorylation. These findings identify an essential role for HSP72 in blocking inflammation and preventing insulin resistance in the context of genetic obesity or high-fat feeding.

Insulin Signaling, GSK-3, Heat Shock Proteins and the Natural History of Type 2 Diabetes Mellitus: A Hypothesis.

Metabolic syndrome and type 2 diabetes are progressive, indolent, multi-organ diseases. Understanding the abnormalities of heat shock proteins (HSPs) in these diseases is paramount to understanding their pathogenesis. In insulin resistant states and diabetes, heat shock factor 1(HSF-1) is low in insulin sensitive tissues, resulting in low Hsp 60, 70, and 90 levels. We propose that low Hsps levels are the result of decreased insulin action leading to less phosphorylation of PI3K, PKB, and glycogen synthase kinase-3 (GSK-3). Importantly, less GSK-3 phosphorylation (and thus more GSK-3 activity) will lower HSF-1. Low Hsps make organs vulnerable to injury, impair the stress response, accelerate systemic inflammation, raise islet amyloid polypeptide, and increase insulin resistance. Feeding this cycle is excess saturated fat and calorie consumption, hypertension, inactivity, aging, and genetic predisposition- all of which are a associated with high GSK-3 activity and low Hsps. Support for the proposed "vicious" cycle is based on the observation that GSK-3 inhibition and Hsp stimulation result in increased insulin sensitivity, reduced accumulation of degenerative proteins with in the cell, improved wound healing, decreased organ damage and improved recovery from vascular ischemia. Recognizing GSK-3 and Hsps in the pathogenesis of insulin resistance, the central common feature of the metabolic syndrome, and type 2 diabetes will expand our understanding of the disease, offering new therapeutic options.