Cardiometabolic effects of a novel SIRT1 activator, SRT2104, in people with type 2 diabetes mellitus

Background: The cardiometabolic effects of SRT2104, a novel SIRT1 activator, were investigated in people with type 2 diabetes mellitus (T2DM). Methods: Fifteen adults with T2DM underwent a randomised, double-blind, placebo-controlled cross-over trial and received 28 days of oral SRT2104 (2.0 g/day) or placebo. Forearm vasodilatation (measured during intrabrachial bradykinin, acetylcholine and sodium nitroprusside infusions) as well as markers of glycaemic control, lipid profile, plasma fibrinolytic factors, and markers of platelet-monocyte activation, were measured at baseline and at the end of each treatment period. Results: Lipid profile and platelet-monocyte activation were similar in both treatment arms (p>0.05 for all). Forearm vasodilatation was similar on exposure to acetylcholine and sodium nitroprusside (p>0.05,respectively). Bradykinin-induced vasodilatation was less during treatment with SRT2104 versus placebo (7.753vs9.044, respectively, mean difference=−1.291,(95% CI −2.296 to −0.285, p=0.012)). Estimated net plasminogen activator inhibitor type 1 antigen release was reduced in the SRT2104 arm versus placebo (mean difference=−38.89 ng/100mL tissue/ min, (95%CI −75.47, to –2.305, p=0.038)). There were no differences in other plasma fibrinolytic factors (p>0.05 for all). After 28 days, SRT2104 exposure was associated with weight reduction (−0.93 kg (95% CI −1.72 to −0.15), p=0.0236), and a rise in glycated haemoglobin (5 mmol/ mol or 0.48% (0.26 to 0.70), p=0.004) Conclusions: In people with T2DM, SRT2104 had inconsistent, predominantly neutral effects on endothelial and fibrinolytic function, and no discernible effect on lipids or platelet function. In contrast, weight loss was induced along with deterioration in glycaemic control, suggestive of potentially important metabolic effects. Clinical trial registration: NCT01031108; Results

The impact of diabetes on cognitive decline:potential vascular, metabolic, and psychosocial risk factors

Older people with type 2 diabetes are at increased risk of developing cognitive impairment, for which several potential risk factors have been proposed. The present article reviews evidence in people with type 2 diabetes for associations of cognitive impairment with a range of vascular, metabolic, and psychosocial risk factors, many of which have a higher prevalence in people with type 2 diabetes than in non-diabetic adults of a similar age. Definitive research studies in this field are few in number. The risk factors may be involved in causal pathways or may act as useful markers of cerebrovascular damage (or both), and for which relatively consistent evidence is available, include poor glycemic control, hypoglycemia, microvascular disease, inflammation, and depression. For macrovascular disease, the strength of the association with cognitive impairment appears to depend on which vascular system has been examined. A role for pre-morbid ability in young adulthood as influencing the risk of both diabetes and cognitive impairment has also been suggested. The importance of considering inter-relationships between risk factors when investigating their potential contribution to cognitive impairment in future investigations is discussed. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s13195-015-0130-5) contains supplementary material, which is available to authorized users

Distribution and characteristics of newly-defined subgroups of type 2 diabetes in randomised clinical trials : Post hoc cluster assignment analysis of over 12,000 study participants

Publisher Copyright: © 2022Aims: Newly-defined subgroups of type 2 diabetes mellitus (T2DM) have been reported from real-world cohorts but not in detail from randomised clinical trials (RCTs). Methods: T2DM participants, uncontrolled on different pre-study therapies (n = 12.738; 82 % Caucasian; 44 % with diabetes duration > 10 years) from 14 RCTs, were assigned to new subgroups according to age at onset of diabetes, HbA1c, BMI, and fasting C-peptide using the nearest centroid approach. Subgroup distribution, characteristics and influencing factors were analysed. Results: In both, pooled and single RCTs, “mild-obesity related diabetes” predominated (45 %) with mean BMI of 35 kg/m2. “Severe insulin-resistant diabetes” was found least often (4.6 %) and prevalence of “mild age-related diabetes” (23.9 %) was mainly influenced by age at onset of diabetes and age cut-offs. Subgroup characteristics were widely comparable to those from real-world cohorts, but all subgroups showed higher frequencies of diabetes-related complications which were associated with longer diabetes duration. A high proportion of “severe insulin-deficient diabetes” (25.4 %) was identified with poor pre-study glycaemic control. Conclusions: Classification of RCT participants into newly-defined diabetes subgroups revealed the existence of a heterogeneous population of T2DM. For future RCTs, subgroup-based randomisation of T2DM will better define the target population and relevance of the outcomes by avoiding clinical heterogeneity.Peer reviewe

Effect of hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with and without type 1 diabetes:A prospective, randomised, open-label, blinded endpoint, cross-over study

Abstract Aims This study examined the effect of experimentally‐induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes. Methods In a prospective, randomised, open‐label, blinded, endpoint cross‐over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non‐diabetic volunteers, underwent hyperinsulinaemic‐euglycaemic (blood glucose 4.5–5.5 mmol/L) and hypoglycaemic (2.2–2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high‐sensitivity cardiac troponin I (hs‐cTnI) concentration. Results During hypoglycaemia, coronary flow reserve trended non‐significantly lower in those with type 1 diabetes than in the non‐diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed‐model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status (p = .23) or between euglycaemia and hypoglycaemia (p = .31). No changes in hs‐cTnI occurred during hypoglycaemia or in the recovery period (p = .86). Conclusions A small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem

Effects of sleep deprivation on hypoglycemia-induced cognitive impairment and recovery in adults with type 1 diabetes

OBJECTIVE To ascertain whether hypoglycemia in association with sleep deprivation causes greater cognitive dysfunction than hypoglycemia alone and protracts cognitive recovery after normoglycemia is restored. RESEARCH DESIGN AND METHODS Fourteen adults with type 1 diabetes underwent a hyperinsulinemic, hypoglycemic clamp on two separate occasions. Before one glucose clamp, the participants stayed awake overnight to induce sleep deprivation. Participants were randomized and counterbalanced to the experimental condition. Cognitive function tests were performed before and during hypoglycemia and for 90 min after restoration of normoglycemia. RESULTS Cognitive impairment during hypoglycemia did not differ significantly between the sleep-deprived and non–sleep-deprived conditions. However, in the sleep-deprived state, digit symbol substitution scores and choice reaction times were significantly poorer during recovery (P &amp;lt; 0.001) and hypoglycemia symptom scores were significantly higher (P &amp;lt; 0.001), even when symptoms that may have been caused by sleep deprivation, such as tiredness, were removed. CONCLUSIONS Hypoglycemia per se produced a significant decrement in cognitive function; coexisting sleep deprivation did not have an additive effect. However, after restoration of normoglycemia, preceding sleep deprivation was associated with persistence of hypoglycemic symptoms and greater and more prolonged cognitive dysfunction during the recovery period. </jats:sec

Effects of the small molecule SIRT1 activator, SRT2104 on arterial stiffness in otherwise healthy cigarette smokers and subjects with type 2 diabetes mellitus

Objective: Arterial stiffness increases with age, and is associated with adverse cardiovascular outcome including increased mortality. The effect of the oral small molecule SIRT1 activator, SRT2104, on arterial stiffness was examined in otherwise healthy cigarette smokers and participants with type 2 diabetes mellitus. Methods: 24 otherwise healthy cigarette smokers and 15 people with stable type 2 diabetes were randomised in a double-blind placebo-controlled crossover trial and received 28 days of oral SRT2104 (2.0 g/day) or matched placebo. Blood pressure was measured using non-invasive oscillatory sphygmomanometry. Pulse wave analysis and velocity were measured using applanation tonometry at baseline and the end of each treatment period. Owing to the small sample size and similar trends for both groups, data for the two groups were pooled (post hoc analysis). Results: Compared to placebo, treatment with SRT2104 was associated with a significant reduction in augmentation pressure (p=0.0273) and a trend towards improvement in the augmentation index and corrected augmentation index (p&gt;0.05 for both). However, no changes were observed in pulse wave velocity and time to wave reflection (p&gt;0.05). Systolic and diastolic blood pressures remained unchanged throughout the study. Treatment by cohort interaction was not significant for any of the pulse wave parameters, suggesting that the response to SRT2104 in otherwise healthy smokers and people with diabetes was consistent. Conclusions: SRT2104 may improve measures of arterial stiffness in otherwise healthy cigarette smokers and in participants with type 2 diabetes. Definitive conclusions are not possible given the small sample size and exploratory nature of this analysis. Trial registration number: NCT01031108

Effects of acute hypoglycemia on working memory and language processing in adults with and without type 1 diabetes

OBJECTIVE To examine the effects of hypoglycemia on language processing in adults with and without type 1 diabetes. RESEARCH DESIGN AND METHODS Forty adults were studied (20 with type 1 diabetes and 20 healthy volunteers) using a hyperinsulinemic glucose clamp to lower blood glucose to 2.5 mmol/L (45 mg/dL) (for 60 min, or to maintain blood glucose at 4.5 mmol/L (81 mg/dL) (euglycemia), on separate occasions. Language tests were applied to assess the effects of hypoglycemia on the relationship between working memory and language (reading span), grammatical decoding (self-paced reading), and grammatical encoding (subject-verb agreement). RESULTS Hypoglycemia caused a significant deterioration in reading span (P < 0.001; eta(2) = 0.37; Cohen d = 0.65) and a fall in correct responses (P = 0.005; eta(2) = 0.19; Cohen d = 0.41). On the self-paced reading test, the reading time for the first sentence fragment increased during hypoglycemia (P = 0.039; eta(2) = 0.11; Cohen d = 0.25). For the reading of the next fragment, hypoglycemia affected the healthy volunteer groupmore than the adults with type 1 diabetes (P = 0.03; eta(2) = 0.12; Cohen d = 0.25). However, hypoglycemia did not significantly affect the number of errors in sentence comprehension or the time taken to answer questions. Hypoglycemia caused a deterioration of subject-verb agreement (correct responses: P = 0.011; eta(2) = 0.159; Cohen d = 0.31). CONCLUSIONS Hypoglycemia caused a significant deterioration in reading span and in the accuracy of subject-verb agreement, both of which are practical aspects of language involved in its everyday use. Language processing is therefore impaired during moderate hypoglycemia

Top research priorities in liver and gallbladder disorders in the UK

OBJECTIVES: There is a mismatch between research questions considered important by patients, carers and healthcare professionals and the research performed in many fields of medicine. The non-alcohol-related liver and gallbladder disorders priority setting partnership was established to identify the top research priorities in the prevention, diagnostic and treatment of gallbladder disorders and liver disorders not covered by the James-Lind Alliance (JLA) alcohol-related liver disease priority setting partnership. DESIGN: The methods broadly followed the principles of the JLA guidebook. The one major deviation from the JLA methodology was the final step of identifying priorities: instead of prioritisation by group discussions at a consensus workshop involving stakeholders, the prioritisation was achieved by a modified Delphi consensus process. RESULTS: A total of 428 unique valid diagnostic or treatment research questions were identified. A literature review established that none of these questions were considered 'answered' that is, high-quality systematic reviews suggest that further research is not required on the topic. The Delphi panel achieved consensus (at least 80% Delphi panel members agreed) that a research question was a top research priority for six questions. Four additional research questions with highest proportion of Delphi panel members ranking the question as highly important were added to constitute the top 10 research priorities. CONCLUSIONS: A priority setting process involving patients, carers and healthcare professionals has been used to identify the top 10priority areas for research related to liver and gallbladder disorders. Basic, translational, clinical and public health research are required to address these uncertainties

Addition of hyaluronic acid to the FIB-4 liver fibrosis score improves prediction of incident cirrhosis and hepatocellular carcinoma in Type 2 diabetes: The Edinburgh Type 2 Diabetes Study

Background: Type 2 diabetes is associated with increased risk of progression to cirrhosis and hepatocellular carcinoma (HCC) in people with chronic liver diseases, particularly non-alcoholic fatty liver disease (NAFLD). However, the absolute risk of progression is low so it is crucial to accurately identify patients who would benefit most from hepatology referral and intensified management. Current risk-stratification tools are sub-optimal and perform worse in people with diabetes.Aims: To determine whether the addition of complementary biomarker(s) to current NAFLD risk-stratification tools in people with Type 2 diabetes could improve the identification of people who are at increased risk of developing incident cirrhosis or HCC.Methods: The Edinburgh Type 2 diabetes Study (ET2DS) is a cohort study of men and women with Type 2 diabetes (n=1066, age 60-75 at baseline). Cases of cirrhosis and HCC were identified over 11-years of follow-up. Biomarkers were measured at baseline and year one and association with incident disease assessed using logistic regression.Results: Of existing risk-stratification scores tested, the Fibrosis-4 (FIB-4) index and the AST:platelet ratio index (APRI) performed best in this cohort. Addition of hyaluronic acid (cut-point ≥50μg/L) to FIB-4 (cut-point ≥1.3) maintained a false negative rate ≤25% and reduced the number of people incorrectly identified as ‘high-risk’ for incident disease by ~50%.Conclusions: The addition of hyaluronic acid to FIB-4 reduced the proportion of people inappropriately identified as ‘high-risk’ for development of cirrhosis/HCC in a community population of otherwise asymptomatic people with Type 2 diabetes. These findings require validation in independent cohorts