Impact of Nutrient Type and Sequence on Glucose Tolerance: Physiological Insights and Therapeutic Implications

Pharmacological and dietary interventions targeting postprandial glycemia have proved effective in reducing the risk for type 2 diabetes and its cardiovascular complications. Besides meal composition and size, the timing of macronutrient consumption during a meal has been recently recognized as a key regulator of postprandial glycemia. Emerging evidence suggests that premeal consumption of non-carbohydrate macronutrients (i.e., protein and fat “preloads”) can markedly reduce postprandial glycemia by delaying gastric emptying, enhancing glucose-stimulated insulin release, and decreasing insulin clearance. The same improvement in glucose tolerance is achievable by optimal timing of carbohydrate ingestion during a meal (i.e., carbohydrate-last meal patterns), which minimizes the risk of body weight gain when compared with nutrient preloads. The magnitude of the glucose-lowering effect of preload-based nutritional strategies is greater in type 2 diabetes than healthy subjects, being comparable and additive to current glucose-lowering drugs, and appears sustained over time. This dietary approach has also shown promising results in pathological conditions characterized by postprandial hyperglycemia in which available pharmacological options are limited or not cost-effective, such as type 1 diabetes, gestational diabetes, and impaired glucose tolerance. Therefore, preload-based nutritional strategies, either alone or in combination with pharmacological treatments, may offer a simple, effective, safe, and inexpensive tool for the prevention and management of postprandial hyperglycemia. Here, we survey these novel physiological insights and their therapeutic implications for patients with diabetes mellitus and altered glucose tolerance

Abnormal Glucose Tolerance Is Associated with a Reduced Myocardial Metabolic Flexibility in Patients with Dilated Cardiomyopathy

Dilated cardiomyopathy (DCM) is characterized by a metabolic shift from fat to carbohydrates and failure to increase myocardial glucose uptake in response to workload increments. We verified whether this pattern is influenced by an abnormal glucose tolerance (AGT). In 10 patients with DCM, 5 with normal glucose tolerance (DCM-NGT) and 5 with AGT (DCM-AGT), and 5 non-DCM subjects with AGT (N-AGT), we measured coronary blood flow and arteriovenous differences of oxygen and metabolites during Rest, Pacing (at 130 b/min), and Recovery. Myocardial lactate exchange and oleate oxidation were also measured. At Rest, DCM patients showed a reduced nonesterified fatty acids (NEFA) myocardial uptake, while glucose utilization increased only in DCM-AGT. In response to Pacing, glucose uptake promptly rose in N-AGT (from 72 ± 21 to 234 ± 73 nmol/min/g, p<0.05), did not change in DCM-AGT, and slowly increased in DCM-NGT. DCM-AGT sustained the extra workload by increasing NEFA oxidation (from 1.3 ± 0.2 to 2.9 ± 0.1 mol/min/gO2 equivalents, p<0.05), while DCM-NGT showed a delayed increase in glucose uptake. Substrate oxidation rates paralleled the metabolites data. The presence of AGT in patients with DCM exacerbates both the shift from fat to carbohydrates in resting myocardial metabolism and the reduced myocardial metabolic flexibility in response to an increased workload. This trial is registered with ClinicalTrial.gov NCT02440217

Evaluation of the Incidence and Potential Mechanisms of Tracheal Complications in Patients With COVID-19

Full-thickness tracheal lesions and tracheoesophageal fistulas are severe complications of invasive mechanical ventilation. The incidence of tracheal complications in ventilated patients with coronavirus disease 2019 (COVID-19) is unknown

Incidence and types of laryngotracheal sequelae of prolonged invasive ventilation in COVID-19 patients

Purpose The COVID-19 outbreak has led to an increasing number of acute laryngotracheal complications in patients subjected to prolonged mechanical ventilation, but their incidence in the short and mid-term after ICU discharge is still unknown. The main objective of this study is to evaluate the incidence of these complications in a COVID-19 group of patients and to compare these aspects with non-COVID-19 matched controls. Methods In this cohort study, we retrospectively selected patients from November 1 to December 31, 2020, according to specific inclusion and exclusion criteria. The follow-up visits were planned after 6 months from discharge. All patients were subjected to an endoscopic evaluation and completed two questionnaires (VHI-10 score and MDADI score). Results Thirteen men and three women were enrolled in the COVID-19 group while nine men and seven women were included in the control group. The median age was 60 [56-66] years in the COVID-19 group and 64 [58-69] years in the control group. All the patients of the control group showed no laryngotracheal lesions, while five COVID-19 patients had different types of lesions, two located in the vocal folds and three in the trachea. No difference was identified between the two groups regarding the VHI-10 score, while the control group showed a significantly worse MDADI score. Conclusions COVID-19 patients subjected to prolonged invasive ventilation are more likely to develop a laryngotracheal complication in the short and medium term. A rigorous clinical follow-up to allow early identification and management of these complications should be set up after discharge

Disruption of fasting and post-load glucose homeostasis are largely independent and sustained by distinct and early major beta-cell function defects: a cross-sectional and longitudinal analysis of the relationship between insulin sensitivity and cardiovascular risk (RISC) study cohort

Background/aims: Uncertainty still exists on the earliest beta-cell defects at the bases of the type 2 diabetes. We assume that this depends on the inaccurate distinction between fasting and post-load glucose homeostasis and aim at providing a description of major beta-cell functions across the full physiologic spectrum of each condition. Methods: In 1320 non-diabetic individuals we performed an OGTT with insulin secretion modeling and a euglycemic insulin clamp, coupled in subgroups to glucose tracers and IVGTT; 1038 subjects underwent another OGTT after 3.5 years. Post-load glucose homeostasis was defined as mean plasma glucose above fasting levels (δOGTT). The analysis was performed by two-way ANCOVA. Results: Fasting plasma glucose (FPG) and δOGTT were weakly related variables (stβ = 0.12) as were their changes over time (r = −0.08). Disruption of FPG control was associated with an isolated and progressive decline (approaching 60%) of the sensitivity of the beta-cell to glucose values within the normal fasting range. Disruption of post-load glucose control was characterized by a progressive decline (approaching 60%) of the slope of the full beta-cell vs glucose dose-response curve and an early minor (30%) decline of potentiation. The acute dynamic beta-cell responses, neither per se nor in relation to the degree of insulin resistance appeared to play a relevant role in disruption of fasting or post-load homeostasis. Follow-up data qualitatively and quantitatively confirmed the results of the cross-sectional analysis. Conclusion: In normal subjects fasting and post-load glucose homeostasis are largely independent, and their disruption is sustained by different and specific beta-cell defects

Manipulating the sequence of food ingestion improves glycemic control in type 2 diabetic patients under free-living conditions

Lipid and protein ingested before carbohydrate reduce postprandial hyperglycemia. We tested feasibility, safety and clinical efficacy of manipulating the sequence of nutrient ingestion in patients with type 2 diabetes (T2D). After a 4-week run-in, 17 T2D patients were randomized to either a control diet (CD) or to an experimental diet (ED) allowing the consumption of high-carbohydrate foods only after high-protein and high-fat foods at each main meal (lunch+dinner). Both diets were accurately followed and neutral on arterial blood pressure, plasma lipids and indices of hepatic and kidney function. After 8 weeks, in spite of a similar reduction of body weight (ED-1.9 95% confidence interval (-3.4/-0.4)kg, P<0.03; CD-2.0 (-3.6/-0.5)kg, P<0.02) and waist circumference (ED-2.9 (-4.3/-1.5)cm, P<0.002; CD-3.3 (-5.9/- 0.7)cm, P<0.02), the ED only was associated with significant reductions of HbA1c (-0.3 (-0.50/-0.02)%, P<0.04), fasting plasma glucose (-1.0 (-1.8/-0.3)mmol l-1, P<0.01), postprandial glucose excursions (lunch - 1.8 (-3.2/-0.4)mmol l-1, P<0.01; dinner: -1.0 (-1.9/-0.1)mmol l-1, P<0.04) and other indices of glucose variability (s.d.: - 0.5 (-0.7/-0.2)mmol l-1, P<0.02; Coefficient of variation: - 6.6 (-10.4/-2.7)%, P<0.02). When compared with the CD, the ED was associated with lower post-lunch glucose excursions (P<0.02) and lower glucose coefficients of variation (P<0.05). Manipulating the sequence of nutrient ingestion might reveal a rapid, feasible, economic and safe strategy for optimizing glucose control in T2D

Glucagon-Like Peptide-1 Receptor Agonists—Use in Clinical Practice

In the past 2 decades, eight glucagon-like peptide-1 receptor agonists (GLP-1RAs) have been approved for the management of type 2 diabetes, each with its peculiar molecular structure, pharmacokinetics, and metabolic effects. Along with their marked glucose-lowering actions, which occur both at fasting and in the postprandial phase without an increased risk of hypoglycemia, GLP-1RAs have provided marked reductions in body weight and ancillary improvements in blood pressure and lipid profile. Recent cardiovascular outcome trials have established the benefits of GLP-1RAs on major cardiovascular events and all-cause mortality, independent of glucose control, with minor effects on preventing hospitalization for heart failure. Novel evidence is also emerging on the protection of GLP-1RAs against diabetic kidney disease, mainly preventing the onset of macroalbuminuria. Several mechanisms have been proposed to explain the cardiorenal protective properties of GLP-1RAs, which may be direct or mediated by additional hemodynamic and anti-inflammatory/antioxidant effects. With their favorable cardiometabolic properties and safety profile, GLP-1RAs may offer an ideal pharmacological option for the management of diabetic kidney disease. In this review, we discuss pharmacokinetic properties, glucometabolic effects, and cardioprotective actions of GLP-1RAs, highlighting the available evidence for a kidney protective role and the proposed mechanisms