DataSheet_1_TIMP3 overexpression in myeloid lineage alleviates pancreatic damage and confers resistance to the development of type 1 diabetes in the MLDS -induced model.pdf

IntroductionType 1 diabetes mellitus (T1DM) development involves a complex interplay of genetic, environmental, and immunological factors. By modulating the activity of proteases and receptors, the protein tissue inhibitor of metalloproteinase 3 (TIMP3) plays a role in limiting the expression and function of pro-inflammatory cytokines, which have been implicated in the advancement of T1DM. This study was aimed at examining the effect of TIMP3 overexpression in myeloid cells on the development of T1DM.Methods and resultsTwelve weeks after multiple low doses of streptozotocin (MLDS) treatment, diabetic mice overexpressing TIMP3 specifically in myeloid cells under the CD68 promoter (MacT3 mice) showed improved insulin secretion, islet morphology and vascularization, antioxidant defense system, and regulatory factors of mitochondrial biosynthesis and function. To get mechanistic insights into the origin of this protection, the severity of insulitis and inflammatory parameters were evaluated in pancreatic tissues 11 days after MLSD treatment, showing significantly reduced insulitis and levels of the pro-inflammatory cytokine tumor necrosis factor-α, interleukin -1β, and interferon -γ in MacT3 mice.DiscussionThe results indicate that TIMP3 is involved in maintaining islet architecture and functions, at least in part, through modulation of pro-inflammatory cytokine production associated with insulitis and may represent a novel therapeutic strategy for T1DM.</p

Effect of High- versus Low-Intensity Supervised Aerobic and Resistance Training on Modifiable Cardiovascular Risk Factors in Type 2 Diabetes; The Italian Diabetes and Exercise Study (IDES)

<div><h3>Background</h3><p>While current recommendations on exercise type and volume have strong experimental bases, there is no clear evidence from large-sized studies indicating whether increasing training intensity provides additional benefits to subjects with type 2 diabetes.</p> <h3>Objective</h3><p>To compare the effects of moderate-to-high intensity (HI) versus low-to-moderate intensity (LI) training of equal energy cost, i.e. exercise volume, on modifiable cardiovascular risk factors.</p> <h3>Design</h3><p>Pre-specified sub-analysis of the Italian Diabetes and Exercise Study (IDES), a randomized multicenter prospective trial comparing a supervised exercise intervention with standard care for 12 months (2005–2006).</p> <h3>Setting</h3><p>Twenty-two outpatient diabetes clinics across Italy.</p> <h3>Patients</h3><p>Sedentary patients with type 2 diabetes assigned to twice-a-week supervised progressive aerobic and resistance training plus exercise counseling (n = 303).</p> <h3>Interventions</h3><p>Subjects were randomized by center to LI (n = 142, 136 completed) or HI (n = 161, 152 completed) progressive aerobic and resistance training, i.e. at 55% or 70% of predicted maximal oxygen consumption and at 60% or 80% of predicted 1-Repetition Maximum, respectively, of equal volume.</p> <h3>Main Outcome Measure(s)</h3><p>Hemoglobin (Hb) A_1c and other cardiovascular risk factors; 10-year coronary heart disease (CHD) risk scores.</p> <h3>Results</h3><p>Volume of physical activity, both supervised and non-supervised, was similar in LI and HI participants. Compared with LI training, HI training produced only clinically marginal, though statistically significant, improvements in HbA_1c (mean difference −0.17% [95% confidence interval −0.44,0.10], P = 0.03), triglycerides (−0.12 mmol/l [−0.34,0.10], P = 0.02) and total cholesterol (−0.24 mmol/l [−0.46, −0.01], P = 0.04), but not in other risk factors and CHD risk scores. However, intensity was not an independent predictor of reduction of any of these parameters. Adverse event rate was similar in HI and LI subjects.</p> <h3>Conclusions</h3><p>Data from the large IDES cohort indicate that, in low-fitness individuals such as sedentary subjects with type 2 diabetes, increasing exercise intensity is not harmful, but does not provide additional benefits on cardiovascular risk factors.</p> <h3>Trial Registration</h3><p><a href="http://www.ISRCTN.org">www.ISRCTN.org</a><a href="http://isrctn.org/ISRCTN04252749"> ISRCTN-04252749</a>.</p> </div

Average monthly energy expenditure from supervised exercise.

<p>Energy expenditure data in LI (circles, dotted line; n = 136) and HI (squares, continuous line; n = 152) participants [mean values; means (SD) are reported below]. LI = low intensity; HI = high intensity.</p

Medications at baseline and at the end of the 12-month study period.

<p>Values are n (%); LI = low-intensity group; HI = high-intensity group.</p>*<p>McNemar test; † Logistic regression adjusted for baseline.</p

Subjects on-target for traditional cardiovascular risk factors at baseline and at the end of the 12-month study period and probability of reaching targets at 12 months.

<p>Values are n (%); LI = low-intensity group; HI = high-intensity group; OR = odd ratio; CI = confidence interval; TG = triglycerides; C = cholesterol; SBP = systolic blood pressure; DBP = diastolic blood pressure.</p>*<p>Mc Nemar test; † Logistic regression adjusted for baseline status (on-target vs. not-on-target), treatment at baseline and change during the study.</p

Physical activity, physical fitness, anthropometric, clinical and biochemical parameters and risk scores at baseline and at the end of the 12-month study period.

<p>Values are mean (SD); LI = low-intensity subgroup; HI = high-intensity subgroup; PA = physical activity; METs = metabolic equivalents; VO_2max = maximal oxygen consumption; BMI = body mass index; BP = blood pressure; HOMA-IR = Homeostasis Model Assessment-Insulin Resistance; hs-CRP = high sensitivity C-reactive protein; UKPDS = United Kingdom Prospective Diabetes Study; CHD = coronary heart disease.</p>*<p>Wilcoxon signed ranks test; † Mann Whitney U-test; ‡ Total PA = non-supervised+supervised PA.</p

Study flow diagram.

<p>* Patients were randomly allocated by center and, within each center, by age (<60 versus ≥60 years) and type of diabetes treatment (no insulin versus insulin) to CON or EXE group and then † EXE participants were further randomized to LI or HI subgroup by center only. CON = control group; EXE = exercise group; LI = low intensity; HI = high intensity.</p

Adverse events.

*<p>χ² test; † Fisher’s exact test.</p

Changes in glucose homeostasis from baseline to end-of-follow-up.

<p>Changes in glucose homeostasis from baseline to end-of-follow-up.</p

Changes in BMI category from baseline to end-of-follow-up.

<p>Changes in BMI category from baseline to end-of-follow-up.</p