Chronic type 2 but not type 1 diabetes impairs myocardial ischaemic tolerance and preconditioning in C57Bl/6 mice

Abstract

New Findings What is the central question of this study?What is the impact of chronic adult‐onset diabetes on cardiac ischaemic outcomes and preconditioning? What is the main finding and its importance?Chronic adult‐onset type 2 but not type 1 diabetes significantly impairs myocardial ischaemic tolerance and ischaemic preconditioning. Preconditioning may be detrimental in type 2 diabetes, exaggerating nitrosative stress and apoptotic protein expression. Abstract Effects of diabetes on myocardial responses to ischaemia–reperfusion (I–R) and cardioprotective stimuli remain contentious, potentially reflecting influences of disease duration and time of onset. Chronic adult‐onset type 1 diabetes (T1D) and type 2 diabetes (T2D) were modelled non‐genetically in male C57Bl/6 mice via 5 × 50 mg kg−1 daily streptozotocin (STZ) injections + 12 weeks’ standard chow or 1 × 75 mg kg−1 STZ injection + 12 weeks’ obesogenic diet (32% calories as fat, 57% carbohydrate, 11% protein), respectively. Systemic outcomes were assessed and myocardial responses to I–R ± ischaemic preconditioning (IPC; 3 × 5 min I–R) determined in Langendorff perfused hearts. Uncontrolled T1D was characterised by pronounced hyperglycaemia (25 mm fasting glucose), glucose intolerance and ∼10% body weight loss, whereas T2D mice exhibited moderate hyperglycaemia (15 mm), hyperinsulinaemia, glucose intolerance and 17% weight gain. Circulating ghrelin, resistin and noradrenaline were unchanged with T1D, while leptin increased and noradrenaline declined in T2D mice. Ischaemic tolerance and IPC were preserved in T1D hearts. In contrast, T2D worsened post‐ischaemic function (∼40% greater diastolic and contractile dysfunction) and cell death (100% higher troponin efflux), and abolished IPC protection. Whereas IPC reduced post‐ischaemic nitrotyrosine and pro‐apoptotic Bak and Bax levels in non‐diabetic hearts, these effects were reduced in T1D and IPC augmented Bax and nitrosylation in T2D hearts. The data demonstrate chronic T1D does not inhibit myocardial I–R tolerance or IPC, whereas metabolic and endocrine disruption in T2D is associated with ischaemic intolerance and inhibition of IPC. Indeed, normally protective IPC may exaggerate damage mechanisms in T2D hearts.

Dietary α-Linolenic Acid Counters Cardioprotective Dysfunction in Diabetic Mice: Unconventional PUFA Protection

“…Data confirm metabolic compromise and a T2D-like phenotype in the present model, including elevated glucose and insulin levels, and impaired glucose clearance and insulin sensitivity (Figure 1). The outcomes are consistent with our prior findings [44] and other studies employing this model [63,64,66,82,83]. These metabolic factors are well-established risks for ischemic heart disease [89] and were unaltered by ALA supplementation (Figure 1).…”

“…Consistent with metabolic outcomes reported in similar T2D models [44,63,64,66,82,83], mice exhibited high body weights ( Figure 1A), moderate fasting hyperglycemia ( Figure 1B) and glucose intolerance ( Figure 1B,C). Although trends to increased fasting insulin levels ( Figure 1D) in T2D mice did not reach statistical significance compared to controls prior to ALA supplementation (p = <0.10), the HOMA and QUICKI calculations indicate mice were insulin-resistant ( Figure 1E) and had impaired insulin sensitivity ( Figure 1F), respectively.…”

“…The basis of this selective benefit with ALA is unclear, arising independently of systemic metabolic phenotype, expression/localization of caveolins and cavins, and baseline mitochondrial function, and AKT and GSK3β expression/phosphorylation. We recently found that post-ischemic AKT levels and phosphorylation are unaltered by IPC or T2D [44], leaving the possibility that phosphorylation patterns during the IPC stimulus and/or initial minutes of reperfusion might be modified with ALA; AKT phosphorylation at these times is linked to I-R outcomes and cardioprotection. Shifts in select inflammatory mediators and VEGF could participate in improved IPC with ALA, while excess TNF-α and HMGB1 are both linked to myocardial injury; TNF-α signaling is also implicated in cardiac preconditioning [131] and HMGB1 may additionally precondition hearts via up-regulating protective VEGF [132], which was augmented by ALA here.…”

Cardiomyoblast caveolin expression: effects of simulated diabetes, α-linolenic acid, and cell signaling pathways

“…(though appears disproportionately high with HG alone), consistent with known stimulatory effects of caveolin-3 on glucose transport and insulin signaling (44,46,65) and suggestive of a role for caveolin-3 in modulating glucose handling in metabolically stressed cells (44,46,65). Findings also suggest differential caveolin changes in T1D vs. T2D, potentially contributing to distinct shifts in ischemic tolerance and cardioprotection (66).…”

“…Again, insulin-resistance (49) Although assessed in an in vitro cardiomyoblast model, the present data provide insight into differing effects of T1D vs. T2D on myocardial caveolins and ischemic tolerance (66). High glucose alone (reflective of acute/uncontrolled T1D) may initially elevate caveolin-1 and -3, consistent with cardioprotection with 1-6 wks hyperglycemia in vivo (17,58,79).…”