The effect of acute and 14-day exogenous ketone supplementation on glycemic control in adults with type 2 diabetes: two randomized controlled trials.

Acute ingestion of the exogenous ketone monoester supplement [(R)-3-hydroxybutyl-(R)-3-hydroxybutyrate] lowers blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, it is unknown how acute or repeated ingestion of exogenous ketones affects blood glucose control in individuals with type 2 diabetes (T2D). We conducted two randomized, counterbalanced, double-blind, placebo-controlled crossover trials to determine if 1) acute exogenous ketone monoester (0.3 g/kg body mass; N = 18) or 2) 14-day thrice daily premeal exogenous ketone monoester (15 g; N = 15) supplementation could lower blood glucose in individuals living with T2D. A single dose of the ketone monoester supplement elevated blood ß-OHB to ∼2 mM. There were no differences in the primary outcomes of plasma glucose concentration (acutely) or serum fructosamine (glycemic control across 14 days) between conditions. Ketone monoester ingestion acutely increased insulin and lowered nonesterified fatty acid concentrations; plasma metabolomics confirmed a reduction in multiple free fatty acids species and select gluconeogenic amino acids. In contrast, no changes were observed in fasting metabolic outcomes following 14 days of supplementation. In the context of these randomized controlled trials, acute or repeated ketone monoester ingestion in adults with T2D did not lower blood glucose when consumed acutely in a fasted state and did not improve glycemic control following thrice daily premeal ingestion across 14 days. Future studies exploring the mechanistic basis for the (lack of) glucose-lowering effect of exogenous ketone supplementation in T2D and other populations are warranted.NEW & NOTEWORTHY Exogenous ketone supplements can acutely lower blood glucose, suggesting therapeutic potential in individuals with impaired glucose metabolism. However, the effect of exogenous ketones on glucose metabolism in adults with type 2 diabetes has not been investigated in a controlled setting. In adults with type 2 diabetes, ketone monoester ingestion did not lower blood glucose acutely in a fasted state and did not improve glycemic control across thrice daily premeal ingestion across 14 days.

Reduction in mitochondrial ATP synthesis mimics the effect of low glucose in depolarizing neurons from the subpostremal nucleus of the solitary tract of rats.

Neurons of the subpostremal nucleus of the solitary tract (NTS) respond to changes in extracellular glucose with alterations in membrane potential with both depolarization and hyperpolarization. From 5 mM glucose, a rapid shift to 0.5 mM glucose produces a membrane depolarization by an unknown mechanism in most neurons. However, the mechanism involved in this response needs to be known. Here, we investigated if the low glucose-induced depolarization could be mimicked by reducing ATP synthesis and possible mediators of this effect. We showed that applying the mitochondrial uncoupler CCCP (1 µM) reproduced the effects of low glucose depolarizing the membrane, generating an inward current, and decreasing membrane resistance. On the other hand, activation of AMPK did not alter these parameters. To test if low glucose and CCCP could depolarize the membrane by affecting the ionic gradient, we inhibited the electrogenic Na/K pump with 10 µM of ouabain. We observed a similar membrane depolarization but not a decrease in membrane resistance. We conclude that perfusion of neurons of the subpostremal NTS with a low glucose solution depolarizes the membrane by probably reducing intracellular ATP, but not by activating AMPK or decreasing the ionic gradient across the membrane.

A comparison of dry bean and pea consumption on serum cholesterol: A randomized controlled trial in adults with mild hypercholesterolemia.

BACKGROUND: Diets including pulses are associated with better cardiovascular profiles, including lipid, glycemia and hemodynamics, however, evidence is lacking regarding the contributions of individual pulse varieties. OBJECTIVE: This randomized, controlled trial examined the effects of beans or peas individually, relative to rice, on LDL-cholesterol levels (primary outcome) and other indices of cardiovascular disease risk (secondary outcomes) at 6 weeks in adults with mild hypercholesterolemia. METHODS: This randomized, controlled, single-blind, three-arm parallel-group study was conducted in two Canadian cities (Edmonton, Alberta; Winnipeg, Manitoba). Participants (n=60/group) were randomly assigned to 6 weeks of regular consumption of foods containing either 120g (∼¾ cups) of beans (mixture of black, great northern, navy, pinto,) or 120 g (∼¾ cups) peas (mixture of yellow, green) or identical foods containing white, parboiled rice (control foods). LDL-cholesterol (primary outcome) and indices of lipid metabolism, glycemia and hemodynamics (secondary outcomes) were assessed. RESULTS: LDL-cholesterol was lower (mean, (95%CI)) in the bean (-0.21,-0.39 - -0.03) but not the pea (-0.11, -0.29 - 0.07) group, relative to rice after 6 weeks. Non-HDL-cholesterol (-0.20, -0.40 - -0.002) and total cholesterol (-0.28, -0.49- -0.06) were also lower in bean vs. rice groups. No changes were noted in triglycerides (-0.07, -0.28-0.14), glucose (0.02, -0.17-0.14), insulin (4.94, -5.51-11.38), or blood pressure (systolic: -1.39, -5.18-2.40; diastolic: -1.89, -4.65-0.88). Dietary fiber intake (g/day or g/1000 kcal) was not correlated with the LDL-cholesterol (g/d: r2=0.209, p=0.142; g/1000 kcal: r2=0.126, p=0.379) in the bean group. Gastrointestinal effects were transient and most often not related to the study foods. CONCLUSIONS: Beans, but not peas, lowered LDL-cholesterol, relative to rice, in adults with mild hypercholesterolemia. Fibre may not be responsible for the effect of beans, suggesting other phytochemicals may be the active component(s). Strategies incorporating 120g of pulses in a meal are feasible for managing some cardiometabolic risk factors. CLINICAL TRIAL REGISTRY: Clinical Trials.Gov NCT01661543.

Continuous glucose monitoring for glycaemic control and cardiovascular risk reduction in patients with type 2 diabetes not on insulin therapy: A clinical trial.

AIM: To evaluate the impact of the Dexcom G6 continuous glucose monitoring (CGM) device on glycaemic control and cardiometabolic risk in patients with type 2 diabetes mellitus (T2DM) at high cardiovascular risk who are not on insulin therapy. MATERIALS AND METHODS: Adults with T2DM with glycated haemoglobin (HbA1c) >7% and body mass index (BMI) ≥30 kg/m2 not using insulin were enrolled in a two-phase cross-over study. In phase 1, CGM data were blinded, and participants performed standard glucose self-monitoring. In phase 2, the CGM data were unblinded, and CGM, demographic and cardiovascular risk factor data were collected through 90 days of follow-up and compared using paired tests. RESULTS: Forty-seven participants were included (44% women; 34% Black; mean age 63 years; BMI 37 kg/m2; HbA1c 8.4%; 10-year predicted atherosclerotic cardiovascular disease risk 24.0%). CGM use was associated with a reduction in average glucose (184.0 to 147.2 mg/dl, p < .001), an increase in time in range (57.8 to 82.8%, p < .001) and a trend towards lower glucose variability (26.2 to 23.8%). There were significant reductions in HbA1c, BMI, triglycerides, blood pressure, total cholesterol, diabetes distress and 10-year predicted risk for atherosclerotic cardiovascular disease (p < .05 for all) and an increase in prescriptions for sodium-glucose cotransporter 2 inhibitors (36.2 to 83.0%) and glucagon-like peptide-1 receptor agonists (42.5 to 87.2%, p < .001 for both). CONCLUSIONS: Dexcom G6 CGM was associated with improved glycaemic control and cardiometabolic risk in patients with T2DM who were not on insulin. CGM can be a safe and effective tool to improve diabetes management in patients at high risk for adverse cardiovascular outcomes.

Healthy dietary pattern is associated with lower glycemia independently of the genetic risk of type 2 diabetes: a cross-sectional study in Finnish men.

PURPOSE: Hyperglycemia is affected by lifestyle and genetic factors. We investigated if dietary patterns associate with glycemia in individuals with high or low genetic risk for type 2 diabetes (T2D). METHODS: Men (n = 1577, 51-81 years) without T2D from the Metabolic Syndrome in Men (METSIM) cohort filled a food-frequency questionnaire and participated in a 2-hour oral glucose tolerance test. Polygenetic risk score (PRS) including 76 genetic variants was used to stratify participants into low or high T2D risk groups. We established two data-driven dietary patterns, termed healthy and unhealthy, and investigated their association with plasma glucose concentrations and hyperglycemia risk. RESULTS: Healthy dietary pattern was associated with lower fasting and 2-hour plasma glucose, glucose area under the curve, and better insulin sensitivity (Matsuda insulin sensitivity index) and insulin secretion (disposition index) in unadjusted and adjusted models, whereas the unhealthy pattern was not. No interaction was observed between the patterns and PRS on glycemic measures. Healthy dietary pattern was negatively associated with the risk for hyperglycemia in an adjusted model (OR 0.69, 95% CI 0.51-0.95, in the highest tertile), whereas unhealthy pattern was not (OR 1.08, 95% CI 0.79-1.47, in the highest tertile). No interaction was found between diet and PRS on the risk for hyperglycemia (p = 0.69 for healthy diet, p = 0.54 for unhealthy diet). CONCLUSION: Our findings suggest that healthy diet is associated with lower glucose concentrations and lower risk for hyperglycemia in men with no interaction with the genetic risk.

Use of a decision support tool and quick start onboarding tool in individuals with type 1 diabetes using advanced automated insulin delivery: a single-arm multi-phase intervention study.

BACKGROUND: Multiple clinician adjustable parameters impact upon glycemia in people with type 1 diabetes (T1D) using Medtronic Mini Med 780G (MM780G) AHCL. These include glucose targets, carbohydrate ratios (CR), and active insulin time (AIT). Algorithm-based decision support advising upon potential settings adjustments may enhance clinical decision-making. METHODS: Single-arm, two-phase exploratory study developing decision support to commence and sustain AHCL. Participants commenced investigational MM780G, then 8 weeks Phase 1-initial optimization tool evaluation, involving algorithm-based decision support with weekly AIT and CR recommendations. Clinicians approved or rejected CR and AIT recommendations based on perceived safety per protocol. Co-design resulted in a refined algorithm evaluated in a further identically configured Phase 2. Phase 2 participants also transitioned to commercial MM780G following "Quick Start" (algorithm-derived tool determining initial AHCL settings using daily insulin dose and weight). We assessed efficacy, safety, and acceptability of decision support using glycemic metrics, and the proportion of accepted CR and AIT settings per phase. RESULTS: Fifty three participants commenced Phase 1 (mean age 24.4; Hba1c 61.5mmol/7.7%). The proportion of CR and AIT accepted by clinicians increased between Phases 1 and 2 respectively: CR 89.2% vs. 98.6%, p < 0.01; AIT 95.2% vs. 99.3%, p < 0.01. Between Phases, mean glucose percentage time < 3.9mmol (< 70mg/dl) reduced (2.1% vs. 1.4%, p = 0.04); change in mean TIR 3.9-10mmol/L (70-180mg/dl) was not statistically significant: 72.9% ± 7.8 and 73.5% ± 8.6. Quick start resulted in stable TIR, and glycemic metrics compared to international guidelines. CONCLUSION: The co-designed decision support tools were able to deliver safe and effective therapy. They can potentially reduce the burden of diabetes management related decision making for both health care practitioners and patients. TRIAL REGISTRATION: Prospectively registered with Australia/New Zealand Clinical Trials Registry(ANZCTR) on 30th March 2021 as study ACTRN12621000360819.

Low glycemic index diet restrains epileptogenesis in a gender-specific fashion.

Dietary restriction, such as low glycemic index diet (LGID), have been successfully used to treat drug-resistant epilepsy. However, if such diet could also counteract antiepileptogenesis is still unclear. Here, we investigated whether the administration of LGID during the latent pre-epileptic period, prevents or delays the appearance of the overt epileptic phenotype. To this aim, we used the Synapsin II knockout (SynIIKO) mouse, a model of temporal lobe epilepsy in which seizures manifest 2-3 months after birth, offering a temporal window in which LGID may affect epileptogenesis. Pregnant SynIIKO mice were fed with either LGID or standard diet during gestation and lactation. Both diets were maintained in weaned mice up to 5 months of age. LGID delayed the seizure onset and induced a reduction of seizures severity only in female SynIIKO mice. In parallel with the epileptic phenotype, high-density multielectrode array recordings revealed a reduction of frequency, amplitude, duration, velocity of propagation and spread of interictal events by LGID in the hippocampus of SynIIKO females, but not mutant males, confirming the gender-specific effect. ELISA-based analysis revealed that LGID increased cortico-hippocampal allopregnanolone (ALLO) levels only in females, while it was unable to affect ALLO plasma concentrations in either sex. The results indicate that the gender-specific interference of LGID with the epileptogenic process can be ascribed to a gender-specific increase in cortical ALLO, a neurosteroid known to strengthen GABAergic transmission. The study highlights the possibility of developing a personalized gender-based therapy for temporal lobe epilepsy.

Glycemic control and cancer outcomes in oncologic patients with diabetes: an Italian Association of Medical Oncology (AIOM), Italian Association of Medical Diabetologists (AMD), Italian Society of Diabetology (SID), Italian Society of Endocrinology (SIE), Italian Society of Pharmacology (SIF) multidisciplinary critical view.

BACKGROUND:  Increasing evidence suggests that diabetes increases the risk of developing different types of cancer. Hyperinsulinemia, hyperglycemia and chronic inflammation, characteristic of diabetes, could represent possible mechanisms involved in cancer development in diabetic patients. At the same time, cancer increases the risk of developing new-onset diabetes, mainly caused by the use of specific anticancer therapies. Of note, diabetes has been associated with a ∼10% increase in mortality for all cancers in comparison with subjects who did not have diabetes. Diabetes is associated with a worse prognosis in patients with cancer, and more recent findings suggest a key role for poor glycemic control in this regard. Nevertheless, the association between glycemic control and cancer outcomes in oncologic patients with diabetes remains unsettled and poorly debated. PURPOSE:  The current review seeks to summarize the available evidence on the effect of glycemic control on cancer outcomes, as well as on the possibility that timely treatment of hyperglycemia and improved glycemic control in patients with cancer and diabetes may favorably affect cancer outcomes.

An open label randomized controlled trial of the effects of rice bran oil on cardiometabolic risk factors, lipid peroxidation and antioxidant status in overweight/obese adults with metabolic syndrome.

INTRODUCTION: We previously documented the beneficial effects of rice bran oil (RBO) on cardiac function and atherogenic cardiometabolic factors in men with coronary artery disease. Therefore, the existing evidence in this area aims to be expanded by investigating the impact of adding RBO to a daily standard diet on emerging insulin resistance surrogate markers, lipid peroxidation, antioxidant status, and metabolic disturbances in individuals with metabolic syndrome (MetSyn) through an open-label controlled trial. METHODS: A total of 50 overweight/obese adults (mean body mass index (BMI) = 31.08 kg/m2) with at least 3 MetSyn components were randomly allocated to either the control group, which received a standard diet plan, or the intervention group, which was supplemented with 30 g/d RBO for 8 weeks. BMI, MetSyn components, metabolic score for insulin resistance (METS-IR), triglyceride‒glucose‒BMI (TyG‒BMI), malondialdehyde (MDA), total antioxidant capacity (TAC), and plasma polyphenol levels were measured before and after this open-label trial. RESULTS: Analysis of covariance (ANCOVA) adjusted for baseline values revealed that, compared with patients who received only a standard diet, those who were supplemented with 30 g/d RBO presented significantly lower total cholesterol (P value = 0.005; effect size (ES):-0.92), LDL-cholesterol (P value = 0.048; ES:-0.62), fasting blood glucose (P value = 0.014; ES:-0.77), MDA (P value = 0.002; ES: -1.01), METS-IR (P value < 0.001; ES: -1.24), and TyG-BMI (P value = 0.007; ES:-0.85) after 8 weeks. Additionally, RBO consumption resulted in significantly higher levels of HDL-C (P value = 0.004; ES:0.94) and TAC (P value < 0.0001; ES:2.05). However, no significant changes were noted in BMI, waist circumference, serum triglycerides, plasma polyphenols, or blood pressure. CONCLUSION: Although the current findings suggest that the hypocholesterolemic, antihyperglycemic, and antioxidative effects of 30 g/d RBO seem to be promising for MetSyn patients, they should be considered preliminary. Therefore, further well-designed clinical trials with larger sample sizes and longer durations are needed to confirm these findings.

Enhanced muscle activity during interrupted sitting improves glycemic control in overweight and obese men.

The efficacy of interrupting prolonged sitting may be influenced by muscle activity patterns. This study examined the effects of interrupting prolonged sitting time with different muscle activity patterns on continuously monitored postprandial glycemic response. Eighteen overweight and obese men (21.0 ± 1.2 years; 28.8 ± 2.2 kg/m2) participated in this randomized four-arm crossover study, including uninterrupted sitting for 8.5 h (SIT) and interruptions in sitting with matched energy expenditure and duration but varying muscle activity: 30-min walking at 4 km/h (ONE), sitting with 3-min walking at 4 km/h (WALK) or squatting (SQUAT) every 45 min for 10 times. Net incremental area under the curve (netiAUC) for glucose was compared between conditions. Quadriceps, hamstring, and gluteal muscles electromyogram (EMG) patterns including averaged muscle EMG amplitude (aEMG) and EMG activity duration were used to predict the effects on glucose netiAUC. Compared with SIT (10.2 mmol/L/h [95%CI 6.3 to 11.7]), glucose netiAUC was lower during sitting interrupted with any countermeasure (ONE 9.2 mmol/L/h [8.0 to 10.4], WALK 7.9 mmol/L/h [6.4 to 9.3], and SQUAT 7.9 mmol/L/h [6.4 to 9.3], all p < 0.05). Furthermore, WALK and SQUAT resulted in a lower glucose netiAUC compared with ONE (both p < 0.05). Only increased aEMG in quadriceps (-0.383 mmol/L/h [-0.581 to -0.184], p < 0.001) and gluteal muscles (-0.322 mmol/L/h [-0.593 to -0.051], p = 0.022) was associated with a reduction in postprandial glycemic response. Collectively, short, frequent walking or squatting breaks effectively enhance glycemic control in overweight and obese men compared to a single bout of walking within prolonged sitting. These superior benefits seem to be associated with increased muscle activity intensity in the targeted muscle groups during frequent transitions from sitting to activity.