Type 2 diabetes mellitus in the Goto-Kakizaki rat impairs microvascular function and contributes to premature skeletal muscle fatigue

Despite extensive investigation into the impact of metabolic disease on vascular function and, by extension, tissue perfusion and organ function, interpreting results for specific risk factors can be complicated by the additional risks present in most models. To specifically determine the impact of type 2 diabetes without obesity on skeletal muscle microvascular structure/function and on active hyperemia with elevated metabolic demand, we used 17-wk-old Goto-Kakizaki (GK) rats to study microvascular function at multiple levels of resolution. Gracilis muscle arterioles demonstrated blunted dilation to acetylcholine (both ex vivo proximal and in situ distal arterioles) and elevated shear (distal arterioles only). All other alterations to reactivity appeared to reflect compromised endothelial function associated with increased thromboxane (Tx)A2 production and oxidant stress/inflammation rather than alterations to vascular smooth muscle function. Structural changes to the microcirculation of GK rats were confined to reduced microvessel density of ~12%, with no evidence for altered vascular wall mechanics. Active hyperemia with either field stimulation of in situ cremaster muscle or electrical stimulation via the sciatic nerve for in situ gastrocnemius muscle was blunted in GK rats, primarily because of blunted functional dilation of skeletal muscle arterioles. The blunted active hyperemia was associated with impaired oxygen uptake (V̇o2) across the muscle and accelerated muscle fatigue. Acute interventions to reduce oxidant stress (TEMPOL) and TxA2 action (SQ-29548) or production (dazmegrel) improved muscle perfusion, V̇o2, and muscle performance. These results suggest that type 2 diabetes mellitus in GK rats impairs skeletal muscle arteriolar function apparently early in the progression of the disease and potentially via an increased reactive oxygen species/inflammation-induced TxA2 production/action on network function as a major contributing mechanism. NEW & NOTEWORTHY The impact of type 2 diabetes mellitus on vascular structure/function remains an area lacking clarity. Using diabetic Goto-Kakizaki rats before the development of other risk factors, we determined alterations to vascular structure/function and skeletal muscle active hyperemia. Type 2 diabetes mellitus reduced arteriolar endothelium-dependent dilation associated with increased thromboxane A2 generation. Although modest microvascular rarefaction was evident, there were no other alterations to vascular structure/function. Skeletal muscle active hyperemia was blunted, although it improved after antioxidant or anti-thromboxane A2 treatment.

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The Impact of Obesity on Incidence of Type 2 Diabetes Mellitus (T2DM) among Women with Polycystic Ovary Syndrome (PCOS)

Diabetes ◽

10.2337/db18-1612-p ◽

2018 ◽

Vol 67 (Supplement 1) ◽

pp. 1612-P

Author(s):

NADIRA SULTANA KAKOLY ◽

ARUL EARNEST ◽

HELENA TEEDE ◽

LISA MORAN ◽

DEBORAH LOXTON ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Polycystic Ovary Syndrome ◽

Polycystic Ovary ◽

Ovary Syndrome ◽

The Impact

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The Impact of Bariatric Surgery in Patients with Type-2 Diabetes Mellitus

Current Diabetes Reviews ◽

10.2174/157339911795843087 ◽

2011 ◽

Vol 7 (3) ◽

pp. 185-189 ◽

Cited By ~ 6

Author(s):

Richdeep S. Gill ◽

Arya M. Sharma ◽

David P. Al-Adra ◽

Daniel W. Birch ◽

Shahzeer Karmali

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Bariatric Surgery ◽

Type 2 Diabetes Mellitus ◽

The Impact

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Effects of ertugliflozin on kidney composite outcomes, renal function and albuminuria in patients with type 2 diabetes mellitus: an analysis from the randomised VERTIS CV trial

Diabetologia ◽

10.1007/s00125-021-05407-5 ◽

2021 ◽

Author(s):

David Z. I. Cherney ◽

◽

Bernard Charbonnel ◽

Francesco Cosentino ◽

Samuel Dagogo-Jack ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Kidney Disease ◽

Serum Creatinine ◽

Renal Dialysis ◽

Composite Endpoint ◽

Composite Outcome ◽

The Impact

Abstract Aims/hypothesis In previous work, we reported the HR for the risk (95% CI) of the secondary kidney composite endpoint (time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death) with ertugliflozin compared with placebo as 0.81 (0.63, 1.04). The effect of ertugliflozin on exploratory kidney-related outcomes was evaluated using data from the eValuation of ERTugliflozin effIcacy and Safety CardioVascular outcomes (VERTIS CV) trial (NCT01986881). Methods Individuals with type 2 diabetes mellitus and established atherosclerotic CVD were randomised to receive ertugliflozin 5 mg or 15 mg (observations from both doses were pooled), or matching placebo, added on to existing treatment. The kidney composite outcome in VERTIS CV (reported previously) was time to first event of doubling of serum creatinine from baseline, renal dialysis/transplant or renal death. The pre-specified exploratory composite outcome replaced doubling of serum creatinine with sustained 40% decrease from baseline in eGFR. In addition, the impact of ertugliflozin on urinary albumin/creatinine ratio (UACR) and eGFR over time was assessed. Results A total of 8246 individuals were randomised and followed for a mean of 3.5 years. The exploratory kidney composite outcome of sustained 40% reduction from baseline in eGFR, chronic kidney dialysis/transplant or renal death occurred at a lower event rate (events per 1000 person-years) in the ertugliflozin group than with the placebo group (6.0 vs 9.0); the HR (95% CI) was 0.66 (0.50, 0.88). At 60 months, in the ertugliflozin group, placebo-corrected changes from baseline (95% CIs) in UACR and eGFR were −16.2% (−23.9, −7.6) and 2.6 ml min−1 [1.73 m]−2 (1.5, 3.6), respectively. Ertugliflozin was associated with a consistent decrease in UACR and attenuation of eGFR decline across subgroups, with a suggested larger effect observed in the macroalbuminuria and Kidney Disease: Improving Global Outcomes in Chronic Kidney Disease (KDIGO CKD) high/very high-risk subgroups. Conclusions/interpretation Among individuals with type 2 diabetes and atherosclerotic CVD, ertugliflozin reduced the risk for the pre-specified exploratory composite renal endpoint and was associated with preservation of eGFR and reduced UACR. Trial registration ClinicalTrials.gov NCT01986881 Graphical abstract

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Impact of timing of randomization after an acute coronary syndrome and subsequent events in patients with type 2 diabetes mellitus: an analysis of the EXAMINE trial

European Heart Journal ◽

10.1093/ehjci/ehaa946.3067 ◽

2020 ◽

Vol 41 (Supplement_2) ◽

Author(s):

M Elharram ◽

A Sharma ◽

W White ◽

G Bakris ◽

P Rossignol ◽

...

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Clinical Trials ◽

Type 2 Diabetes Mellitus ◽

Acute Coronary Syndrome ◽

Primary Outcome ◽

Funding Source ◽

Coronary Syndrome ◽

The Impact

Abstract Background The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes. Methods EXAMINE was a randomized trial of alogliptin versus placebo in 5380 patients with T2DM and a recent ACS. The primary outcome was a composite of CV death, non-fatal myocardial infarction [MI], or non-fatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8–34, 35–56, and 57–141 days. Results Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs. 33.0%), prior coronary artery bypass graft (9.6% vs. 15.9%), or atrial fibrillation (5.9% vs. 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio [aHR] 1.47; 95% CI 1.21–1.74) (Figure 1). Similarly, patients randomized early had an increased risk of recurrent MI (aHR 1.51; 95% CI 1.17–1.96) and HF hospitalization (1.49; 95% CI 1.05–2.10). Conclusion In a contemporary cohort of T2DM with a recent ACS, early randomization following the ACS increases the risk of CV events including recurrent MI and HF hospitalization. This should be taken into account when designing future clinical trials. Figure 1 Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): Takeda Pharmaceutical

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Prevalence of depression in patients with type 2 diabetes mellitus in Irish primary care and the impact of depression on the control of diabetes

Irish Journal of Medical Science (1971 -) ◽

10.1007/s11845-014-1110-7 ◽

2014 ◽

Vol 184 (2) ◽

pp. 319-322 ◽

Cited By ~ 11

Author(s):

E. Foran ◽

A. Hannigan ◽

L. Glynn

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Primary Care ◽

Type 2 Diabetes Mellitus ◽

Prevalence Of Depression ◽

Control Of Diabetes ◽

The Impact

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Evaluating the impact of type 2 diabetes mellitus on CYP450 metabolic activities: protocol for a case–control pharmacokinetic study

BMJ Open ◽

10.1136/bmjopen-2017-020922 ◽

2018 ◽

Vol 8 (2) ◽

pp. e020922 ◽

Cited By ~ 2

Author(s):

Sophie Gravel ◽

Jean-Louis Chiasson ◽

Suzanne Dallaire ◽

Jacques Turgeon ◽

Veronique Michaud

Keyword(s):

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Adult Population ◽

Study Groups ◽

Primary Objective ◽

Research Centre ◽

Probe Drug ◽

The Impact

IntroductionDiabetes affects more than 9% of the adult population worldwide. Patients with type 2 diabetes mellitus (T2DM) show variable responses to some drugs which may be due, in part, to variability in the functional activity of drug-metabolising enzymes including cytochromes P450 (CYP450s). CYP450 is a superfamily of enzymes responsible for xenobiotic metabolism. Knowledge must be gained on the impact of T2DM and related inflammatory processes on drug metabolism and its consequences on drug response. The aim of this study is to characterise the activity of CYP1A2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A4/5 in T2DM versus non-T2DM subjects following the administration of a cocktail of probe drug substrates.Methods and analysisThis single-centre clinical study proposes the first detailed characterisation of T2DM impacts on major CYP450 drug-metabolising enzyme activities. We intend to recruit 42 patients with controlled T2DM (A1C≤7%), 42 patients with uncontrolled T2DM (A1C>7%) and 42 non-diabetic control subjects. The primary objective is to determine and compare major CYP450 activities in patients with T2DM versus non-diabetic subjects by dosing in plasma and urine probe drug substrates and metabolites following the oral administration of a drug cocktail: caffeine (CYP1A2), bupropion (CYP2B6), tolbutamide (CYP2C9), omeprazole (CYP2C19), dextromethorphan (CYP2D6), chlorzoxazone (CYP2E1) and midazolam (CYP3A4/5). Secondary objectives will evaluate the influence of variables such as glycaemia, insulinaemia, genetic polymorphisms and inflammation. The value of an endogenous biomarker of CYP3A activity is also evaluated. The first patient was recruited in May 2015 and patients will be enrolled up to completion of study groups.Ethics and disseminationApproval was obtained from the ethic review board of the CHUM research centre (Montreal, Canada).Trial registration numberNCT02291666.

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