Glycemic control and outcome after carotid intervention in patients with T2D: A Swedish nationwide cohort study.

AIMS: To investigate the association between glycemic control and outcome in people with type 2 diabetes (T2D) after carotid intervention due to carotid stenosis. METHODS: Observational nationwide population-based cohort study using inverse probability treatment weighting (IPTW) and Cox regressions with covariates, that is, 4 stepwise models, investigating the relationship between terciles of glycated hemoglobin (HbA1c) levels and stroke or death. RESULTS: 1115 subjects with T2D undergoing carotid intervention were included during Jan 1st 2009 to Dec 31st 2015. Divided into terciles, with a mean HbA1c level of 44 (tercile 1), 53 (tercile 2), and 72 (tercile 3) mmol/mol. By using IPTW and Cox regression, each model was stepwise introduced for the investigating of relative risks, that is, hazard ratios (HRs) with associated 95% confidence intervals (CI). There was a significant increased risk for stroke or death, in every model observed for tercile 3, compared to tercile 1: HR for model 4: 1.35 (95% CI 1.02-1.78). No difference for stroke or death within 30 days was observed between the groups. CONCLUSION: Poor glycemic control in people with T2D after carotid intervention is associated with an increased long-term risk for stroke or death.

The Pre-Stroke Induction and Normalization of Insulin Resistance Respectively Worsens and Improves Functional Recovery.

Type 2 diabetes (T2D) impairs post-stroke recovery, and the underlying mechanisms are unknown. Insulin resistance (IR), a T2D hallmark that is also closely linked to aging, has been associated with impaired post-stroke recovery. However, whether IR worsens stroke recovery is unknown. We addressed this question in mouse models where early IR, with or without hyperglycemia, was induced by chronic high-fat diet feeding or sucrose supplementation in the drinking water, respectively. Furthermore, we used 10-month-old mice, spontaneously developing IR but not hyperglycemia, where IR was normalized pharmacologically pre-stroke with Rosiglitazone. Stroke was induced by transient middle cerebral artery occlusion and recovery was assessed by sensorimotor tests. Neuronal survival, neuroinflammation and the density of striatal cholinergic interneurons were also assessed by immunohistochemistry/quantitative microscopy. Pre-stroke induction and normalization of IR, respectively, worsened and improved post-stroke neurological recovery. Moreover, our data indicate a potential association of this impaired recovery with exacerbated neuroinflammation and a decreased density of striatal cholinergic interneurons. The global diabetes epidemic and population aging are dramatically increasing the percentage of people in need of post-stroke treatment/care. Our results suggest that future clinical studies should target pre-stroke IR to reduce stroke sequelae in both diabetics and elderly people with prediabetes.

Normalisation of glucose metabolism by exendin-4 in the chronic phase after stroke promotes functional recovery in male diabetic mice.

BACKGROUND AND PURPOSE: Glucagon-like peptide-1 (GLP-1) receptor activation decreases stroke risk in people with Type 2 diabetes (T2D), while animal studies have shown the efficacy of this strategy to counteract stroke-induced acute brain damage. However, whether GLP-1 receptor activation also improves recovery in the chronic phase after stroke is unknown. We investigated whether post-acute, chronic administration of the GLP-1 receptor agonist, exendin-4, improves post-stroke recovery and examined possible underlying mechanisms in T2D and non-T2D mice. EXPERIMENTAL APPROACH: We induced stroke via transient middle cerebral artery occlusion (tMCAO) in T2D/obese mice (8 months of high-fat diet) and age-matched controls. Exendin-4 was administered for 8 weeks from Day 3 post-tMCAO. We assessed functional recovery by weekly upper-limb grip strength tests. Insulin sensitivity and glycaemia were evaluated at 4 and 8 weeks post-tMCAO. Neuronal survival, stroke-induced neurogenesis, neuroinflammation, atrophy of GABAergic parvalbumin+ interneurons, post-stroke vascular remodelling and fibrotic scar formation were investigated by immunohistochemistry. KEY RESULTS: Exendin-4 normalised T2D-induced impairment of forepaw grip strength recovery in correlation with normalised glycaemia and insulin sensitivity. Moreover, exendin-4 counteracted T2D-induced atrophy of parvalbumin+ interneurons and decreased microglia activation. Finally, exendin-4 normalised density and pericyte coverage of micro-vessels and restored fibrotic scar formation in T2D mice. In non-T2D mice, the exendin-4-mediated recovery was minor. CONCLUSION AND IMPLICATIONS: Chronic GLP-1 receptor activation mediates post-stroke functional recovery in T2D mice by normalising glucose metabolism and improving neuroplasticity and vascular remodelling in the recovery phase. The results warrant clinical trial of GLP-1 receptor agonists for rehabilitation after stroke in T2D. LINKED ARTICLES: This article is part of a themed issue on GLP1 receptor ligands (BJP 75th Anniversary). To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.4/issuetoc.

Diet-induced weight loss in obese/diabetic mice normalizes glucose metabolism and promotes functional recovery after stroke.

BACKGROUND: Post-stroke functional recovery is severely impaired by type 2 diabetes (T2D). This is an important clinical problem since T2D is one of the most common diseases. Because weight loss-based strategies have been shown to decrease stroke risk in people with T2D, we aimed to investigate whether diet-induced weight loss can also improve post-stroke functional recovery and identify some of the underlying mechanisms. METHODS: T2D/obesity was induced by 6 months of high-fat diet (HFD). Weight loss was achieved by a short- or long-term dietary change, replacing HFD with standard diet for 2 or 4 months, respectively. Stroke was induced by middle cerebral artery occlusion and post-stroke recovery was assessed by sensorimotor tests. Mechanisms involved in neurovascular damage in the post-stroke recovery phase, i.e. neuroinflammation, impaired angiogenesis and cellular atrophy of GABAergic parvalbumin (PV)+ interneurons were assessed by immunohistochemistry/quantitative microscopy. RESULTS: Both short- and long-term dietary change led to similar weight loss. However, only the latter enhanced functional recovery after stroke. This effect was associated with pre-stroke normalization of fasting glucose and insulin resistance, and with the reduction of T2D-induced cellular atrophy of PV+ interneurons. Moreover, stroke recovery was associated with decreased T2D-induced neuroinflammation and reduced astrocyte reactivity in the contralateral striatum. CONCLUSION: The global diabetes epidemic will dramatically increase the number of people in need of post-stroke treatment and care. Our results suggest that diet-induced weight loss leading to pre-stroke normalization of glucose metabolism has great potential to reduce the sequelae of stroke in the diabetic population.

Estimated glucose disposal rate and risk of stroke and mortality in type 2 diabetes: a nationwide cohort study.

BACKGROUND AND AIMS: Insulin resistance contributes to the development of type 2 diabetes (T2D) and is also a cardiovascular risk factor. The aim of this study was to investigate the potential association between insulin resistance measured by estimated glucose disposal rate (eGDR) and risk of stroke and mortality thereof in people with T2D. MATERIALS AND METHODS: Nationwide population based observational cohort study that included all T2D patients from the Swedish national diabetes registry between 2004 and 2016 with full data on eGDR and categorised as following: < 4, 4-6, 6-8, and ≥ 8 mg/kg/min. We calculated crude incidence rates and 95% confidence intervals (CIs) and used multiple Cox regression to estimate hazard ratios (HRs) to assess the association between the risk of stroke and death, according to the eGDR categories in which the lowest category < 4 (i.e., highest grade of insulin resistance), served as a reference. The relative importance attributed of each factor in the eGDR formula was measured by the R2 (± SE) values calculating the explainable log-likelihoods in the Cox regression. RESULTS: A total of 104 697 T2D individuals, 44.5% women, mean age of 63 years, were included. During a median follow up-time of 5.6 years, 4201 strokes occurred (4.0%). After multivariate adjustment the HRs (95% CI) for stroke in patients with eGDR categories between 4-6, 6-8 and > 8 were: 0.77 (0.69-0.87), 0.68 (0.58-0.80) and 0.60 (0.48-0.76), compared to the reference < 4. Corresponding numbers for the risk of death were: 0.82 (0.70-0.94), 0.75 (0.64-0.88) and 0.68 (0.53-0.89). The attributed relative risk R2 (± SE) for each variable in the eGDR formula and stroke was for: hypertension (0.045 ± 0.0024), HbA1c (0.013 ± 0.0014), and waist (0.006 ± 0.0009), respectively. CONCLUSION: A low eGDR (a measure of insulin resistance) is associated with an increased risk of stroke and death in individuals with T2D. The relative attributed risk was most important for hypertension.

Early and long-term prognosis in patients with and without type 2 diabetes after carotid intervention: a Swedish nationwide propensity score matched cohort study.

OBJECTIVES: To investigate early and long-term outcomes after treatment of carotid artery stenosis in patients with type 2 diabetes (T2D) compared to patients without T2D. DESIGN/METHOD: This observational nationwide population-based retrospective cohort study investigated all T2D patients treated for carotid stenosis registered in the National Swedish Vascular Surgery and the National Diabetes Registries. Data was collected prospectively for all patients after carotid intervention, during 2009-2015. We estimated crude early (within 30-days) hazard ratios (HRs) risk of stroke and death, and long-term HRs risk, adjusted for confounders with 95% confidence intervals (CIs), for stroke and death and major adverse cardiovascular events (MACE) by using inverse probability of treatment weighting matching. RESULTS: A total of 1341 patients with T2D and 4162 patients without T2D were included; 89% treated for symptomatic carotid stenosis, 96% with carotid endarterectomy. There was an increased early risk, HRs (95% CI), for stroke in T2D patients 1.65 (1.17-2.32), whereas risk for early death 1.00 (0.49-2.04) was similar in both groups. During a median follow-up of 4.3 (T2D) and 4.6 (without T2D), with a maximum of 8.0 years; after propensity score matching there was an increased HRs (95% CI) of stroke 1.27 (1.05-1.54) and death 1.27 (1.10-1.47) in T2D patients compared to patients without T2D. Corresponding numbers for MACE were 1.21 (1.08-1.35). CONCLUSIONS: Patients with T2D run an increased risk for stroke, death, and MACE after carotid intervention. They also have an increased perioperative risk for stroke, but not for death.

Risk of first stroke in people with type 2 diabetes and its relation to glycaemic control: A nationwide observational study.

AIMS: To compare stroke incidence in people with type 2 diabetes (T2D) with that in a matched control group, and to investigate whether glucose exposure in people with T2D can predict a first-time stroke event and mortality. MATERIAL AND METHODS: In a nationwide observational cohort study, individuals with T2D were linked in the Swedish National Diabetes Register and matched with five individual population-based control subjects. We calculated crude incidence rates and 95% confidence intervals (CIs), and used Cox regression and multivariable hazard ratios (HRs), to estimate the risk of stroke and mortality in relation to glycated haemoglobin (HbA1c) levels. RESULTS: A total of 406 271 people with T2D (age 64.1 ± 12.4 years, 45.7% women) and 2086 440 control subjects (age 64.0 ± 12.4 years, 45.7% women) were included. During a median follow-up of 7.3 years, 26 380 people with T2D (6.5%) versus 92 375 control subjects (4.4%) were diagnosed with a stroke. The incidence rate was 10.12 events per 1000 person-years versus 7.26 events per 1000 person-years (HR 1.54, 95% CI 1.52-1.56). In the T2D group after multivariable adjustments, the HRs for stroke stratified by HbA1c level were: 54-64 mmol/mol: 1.27 (95% CI 1.22-1.32); 65-75 mmol/mol: 1.68 (95% CI 1.60-1.76); 76-86 mmol/mol: 1.89 (95% CI, 1.75-2.05); and > 87 mmol/mol: 2.14 (95% CI 1.90-2.42), respectively, compared with the reference category of HbA1c ≤53 mmol/mol. There was a stepwise increased risk of death after stroke, for every 10-mmol/mol categorical increment of HbA1c (HR 1.71; 95% CI 1.47-2.00) for the highest HbA1c category. CONCLUSIONS: An increased risk of stroke and death was associated with poor glycaemic control in people with T2D.