Postprandial glucose-management strategies in type 1 diabetes: Current approaches and prospects with precision medicine and artificial intelligence.

Postprandial glucose control can be challenging for individuals with type 1 diabetes, and this can be attributed to many factors, including suboptimal therapy parameters (carbohydrate ratios, correction factors, basal doses) because of physiological changes, meal macronutrients and engagement in postprandial physical activity. This narrative review aims to examine the current postprandial glucose-management strategies tested in clinical trials, including adjusting therapy settings, bolusing for meal macronutrients, adjusting pre-exercise and postexercise meal boluses for postprandial physical activity, and other therapeutic options, for individuals on open-loop and closed-loop therapies. Then we discuss their challenges and future avenues. Despite advancements in insulin delivery devices such as closed-loop systems and decision-support systems, many individuals with type 1 diabetes still struggle to manage their glucose levels. The main challenge is the lack of personalized recommendations, causing suboptimal postprandial glucose control. We suggest that postprandial glucose control can be improved by (i) providing personalized recommendations for meal macronutrients and postprandial activity; (ii) including behavioural recommendations; (iii) using other personalized therapeutic approaches (e.g. glucagon-like peptide-1 receptor agonists, sodium-glucose co-transporter inhibitors, amylin analogues, inhaled insulin) in addition to insulin therapy; and (iv) integrating an interpretability report to explain to individuals about changes in treatment therapy and behavioural recommendations. In addition, we suggest a future avenue to implement precision recommendations for individuals with type 1 diabetes utilizing the potential of deep reinforcement learning and foundation models (such as GPT and BERT), employing different modalities of data including diabetes-related and external background factors (i.e. behavioural, environmental, biological and abnormal events).

Increased proton leak and SOD2 expression in myotubes from obese non-diabetic subjects with a family history of type 2 diabetes.

Muscle insulin resistance is linked to oxidative stress and decreased mitochondrial function. However, the exact cause of muscle insulin resistance is still unknown. Since offspring of patients with type 2 diabetes mellitus (T2DM) are susceptible to developing insulin resistance, they are ideal for studying the early development of insulin resistance. By using primary muscle cells derived from obese non-diabetic subjects with (FH+) or without (FH-) a family history of T2DM, we aimed to better understand the link between mitochondrial function, oxidative stress, and muscle insulin resistance. Insulin-stimulated glucose uptake and glycogen synthesis were normal in FH+ myotubes. Resting oxygen consumption rate was not different between groups. However, proton leak was higher in FH+ myotubes. This was associated with lower ATP content and decreased mitochondrial membrane potential in FH+ myotubes. Surprisingly, mtDNA content was higher in FH+ myotubes. Oxidative stress level was not different between FH+ and FH- groups. Reactive oxygen species content was lower in FH+ myotubes when differentiated in high glucose/insulin (25mM/150pM), which could be due to higher oxidative stress defenses (SOD2 expression and uncoupled respiration). The increased antioxidant defenses and mtDNA content in FH+ myotubes suggest the existence of compensatory mechanisms, which may provisionally prevent the development of insulin resistance.

Advanced decision support system for individuals with diabetes on multiple daily injections therapy using reinforcement learning and nearest-neighbors: In-silico and clinical results.

Many individuals with diabetes on multiple daily insulin injections therapy use carbohydrate ratios (CRs) and correction factors (CFs) to determine mealtime and correction insulin boluses. The CRs and CFs vary over time due to physiological changes in individuals' response to insulin. Errors in insulin dosing can lead to life-threatening abnormal glucose levels, increasing the risk of retinopathy, neuropathy, and nephropathy. Here, we present a novel learning algorithm that uses Q-learning to track optimal CRs and uses nearest-neighbors based Q-learning to track optimal CFs. The learning algorithm was compared with the run-to-run algorithm A and the run-to-run algorithm B, both proposed in the literature, over an 8-week period using a validated simulator with a realistic scenario created with suboptimal CRs and CFs values, carbohydrate counting errors, and random meals sizes at random ingestion times. From Week 1 to Week 8, the learning algorithm increased the percentage of time spent in target glucose range (4.0 to 10.0 mmol/L) from 51 % to 64 % compared to 61 % and 58 % with the run-to-run algorithm A and the run-to-run algorithm B, respectively. The learning algorithm decreased the percentage of time spent below 4.0 mmol/L from 9 % to 1.9 % compared to 3.4 % and 2.3 % with the run-to-run algorithm A and the run-to-run algorithm B, respectively. The algorithm was also assessed by comparing its recommendations with (i) the endocrinologist's recommendations on two type 1 diabetes individuals over a 16-week period and (ii) real-world individuals' therapy settings changes of 23 individuals (19 type 2 and 4 type 1) over an 8-week period using the commercial Bigfoot Unity Diabetes Management System. The full agreements (i) were 89 % and 76 % for CRs and CFs for the type 1 diabetes individuals and (ii) was 62 % for mealtime doses for the individuals on the commercial Bigfoot system. Therefore, the proposed algorithm has the potential to improve glucose control in individuals with type 1 and type 2 diabetes.

Low-Dose Empagliflozin as Adjunct to Hybrid Closed-Loop Insulin Therapy in Adults With Suboptimally Controlled Type 1 Diabetes: A Randomized Crossover Controlled Trial.

OBJECTIVE: To assess whether low doses of empagliflozin as adjunct to hybrid closed-loop therapy improve glycemia compared with placebo in adults with type 1 diabetes (T1D) who are not able to achieve targets with the system alone. RESEARCH DESIGN AND METHODS: A double-blind crossover randomized controlled trial was performed in adults with suboptimally controlled T1D (HbA1c 7.0-10.5%) who were not able to achieve a target time in range (3.9-10.0 mmol/L) ≥70% after 14 days of hybrid closed-loop therapy. Three 14-day interventions were performed with placebo, 2.5 mg empagliflozin, or 5 mg empagliflozin as adjunct to the McGill artificial pancreas. Participants were assigned at a 1:1:1:1:1:1 ratio with blocked randomization. The primary outcome was time in range (3.9-10.0 mmol/L). Analysis was by intention to treat, and a P value <0.05 was regarded as significant. RESULTS: A total of 24 participants completed the study (50% male; age 33 ± 14 years; HbA1c 8.1 ± 0.5%). The time in range was 59.0 ± 9.0% for placebo, 71.6 ± 9.7% for 2.5 mg empagliflozin, and 70.2 ± 8.0% for 5 mg empagliflozin (P < 0.0001 between 2.5 mg empagliflozin and placebo and between 5 mg empagliflozin and placebo). Mean daily capillary ketone levels were not different between arms. There were no serious adverse events or cases of diabetic ketoacidosis or severe hypoglycemia in any intervention. CONCLUSIONS: Empagliflozin at 2.5 and 5 mg increased time in range during hybrid closed-loop therapy by 11-13 percentage points compared with placebo in those who otherwise were unable to attain glycemic targets. Future studies are required to assess long-term efficacy and safety.

Care Endpoints in Adults With Type 2 Diabetes: Screening and Therapeutic Targets at a Canadian Tertiary Diabetes Care Centre.

OBJECTIVES: Although national diabetes guidelines recommend targets for various health parameters, studies have demonstrated a gap between recommendations and real-life practice. The objectives of the present study were to 1) assess measurements in type 2 diabetes (T2DM) care performed by diabetologists in tertiary care, 2) determine whether these measurements were within recommended targets by Canadian guidelines, and 3) identify how these measurements compare with previously published Canadian studies. METHODS: A retrospective chart review analyzed electronic medical records of patients seen by diabetes specialists at the McGill University Health Centre (MUHC). Patients 18 to 75 years of age and diagnosed with T2DM were assessed for blood pressure <130/80 mmHg, low-density lipoprotein cholesterol (LDL-C) ≤2 mmol/L and glycated hemoglobin (A1C) ≤7%. Urinary albumin:creatinine ratio (uACR) was also assessed. Comparisons were made with existing literature data. RESULTS: The percentages of patients with recent screening of A1C, LDL-C, blood pressure and uACR were higher compared with the earlier studies. The calculated means for A1C, LDL-C and blood pressure were comparable with those studies. The percentage of measurements achieving target was comparable with subspecialty care data but differed from primary care data. CONCLUSIONS: Patients with T2DM at the MUHC receive guideline-based measurements of health parameters more frequently than at other institutions. Achievement of target values was closer to that seen by Canadian specialists than by primary care. Although further analyses are necessary to help implement effective strategies for improvement, quality assurance is nonetheless an essential part of ensuring the standards of tertiary care.

Participant Experiences of Low-Dose Empagliflozin Use as Adjunct Therapy to Hybrid Closed Loop: Findings From a Randomized Controlled Trial.

BACKGROUND: Very few patient-reported outcomes have been published in regard to opinions of individuals with type 1 diabetes concerning adjunctive therapy. The aim of this subanalysis was to qualitatively and quantitatively assess the thoughts and experiences of participants with type 1 diabetes who have used low doses of empagliflozin as an adjunct to hybrid closed-loop therapy. METHODS: Semi-structured interviews were performed with adult participants who completed a double-blinded, crossover, randomized controlled trial using low-dose empagliflozin as an adjunct to hybrid closed-loop therapy. Participant experiences were captured through qualitative and quantitative methods. A descriptive analysis was performed using a qualitative approach; attitudes toward relevant topics were extracted from interview transcripts. RESULTS: Twenty-four participants were interviewed; 15 (63%) perceived differences between interventions despite blinding, due to glycemic control or side effects. Advantages that arose were better glycemic control, in particular postprandially, requiring less insulin, and ease of use. Disadvantages were thought to be adverse effects, increased incidence of hypoglycemia, and increased pill burden. Thirteen (54%) participants were interested in using low-dose empagliflozin beyond the study. CONCLUSIONS: Many participants had positive experiences with low-dose empagliflozin as an adjunct to the hybrid closed-loop therapy. A dedicated study with unblinding would be beneficial to better characterize patient-reported outcomes.

Strategically Playing with Fire: SGLT Inhibitors as Possible Adjunct to Closed-Loop Insulin Therapy.

As closed-loop insulin therapies emerge into clinical practice and evolve in medical research for type 1 diabetes (T1D) treatment, the limitations in these therapies become more evident. These gaps include unachieved target levels of glycated hemoglobin in some patients, postprandial hyperglycemia, the ongoing need for carbohydrate counting, and the lack of non-glycemic benefits (such as prevention of metabolic syndrome and complications). Multiple adjunct therapies have been examined to improve closed-loop systems, yet none have become a staple. Sodium-glucose-linked cotransporter inhibitors (SGLTi's) have been extensively researched in T1D, with average reductions in placebo-adjusted HbA1c by 0.39%, and total daily dose by approximately 10%. Unfortunately, many trials revealed an increased risk of diabetic ketoacidosis, as high as 5 times the relative risk compared to placebo. This narrative review discusses the proven benefits and risks of SGLTi in patients with T1D with routine therapy, what has been studied thus far in closed-loop therapy in combination with SGLTi, the potential benefits of SGLTi use to closed-loop systems, and what is required going forward to improve the benefit to risk ratio in these insulin systems.