Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling.

OBJECTIVE: Obesity is a global health concern with management strategies encompassing bariatric surgery and anti-obesity drugs; however, concerns regarding complexities and side effects persist, driving research for more effective, low-risk strategies. The promotion of white adipose tissue (WAT) browning has emerged as a promising approach. Moreover, alisol B 23-acetate (AB23A) has demonstrated efficacy in addressing metabolic disorders, suggesting its potential as a therapeutic agent in obesity management. Therefore, in this study, we aimed to investigate the therapeutic potential of AB23A for mitigating obesity by regulating metabolic phenotypes and lipid distribution in mice fed a high-fat diet (HFD). METHODS: An obesity mouse model was established by administration of an HFD. Glucose and insulin metabolism were assessed via glucose and insulin tolerance tests. Adipocyte size was determined using hematoxylin and eosin staining. The expression of browning markers in WAT was evaluated using Western blotting and quantitative real-time polymerase chain reaction. Metabolic cage monitoring involved the assessment of various parameters, including food and water intake, energy metabolism, respiratory exchange rates, and physical activity. Moreover, oil red O staining was used to evaluate intracellular lipid accumulation. A bioinformatic analysis tool for identifying the molecular mechanisms of traditional Chinese medicine was used to examine AB23A targets and associated signaling pathways. RESULTS: AB23A administration significantly reduced the weight of obese mice, decreased the mass of inguinal WAT, epididymal WAT, and perirenal adipose tissue, improved glucose and insulin metabolism, and reduced adipocyte size. Moreover, treatment with AB23A promoted the expression of browning markers in WAT, enhanced overall energy metabolism in mice, and had no discernible effect on food intake, water consumption, or physical activity. In 3T3-L1 cells, AB23A inhibited lipid accumulation, and both AB23A and rapamycin inhibited the mammalian target of rapamycin-sterol regulatory element-binding protein-1 (mTOR-SREBP1) signaling pathway. Furthermore, 3-isobutyl-1-methylxanthine, dexamethasone and insulin, at concentrations of 0.25 mmol/L, 0.25 µmol/L and 1 µg/mL, respectively, induced activation of the mTOR-SREBP1 signaling pathway, which was further strengthened by an mTOR activator MHY1485. Notably, MHY1485 reversed the beneficial effects of AB23A in 3T3-L1 cells. CONCLUSION: AB23A promoted WAT browning by inhibiting the mTOR-SREBP1 signaling pathway, offering a potential strategy to prevent obesity. Please cite this article as: Han LL, Zhang X, Zhang H, Li T, Zhao YC, Tian MH, Sun FL, Feng B. Alisol B 23-acetate promotes white adipose tissue browning to mitigate high-fat diet-induced obesity by regulating mTOR-SREBP1 signaling. J Integr Med. 2024; 22(1): 83-92.

Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus.

Islet ß-cell dysfunction is a basic pathophysiological characteristic of type 2 diabetes mellitus (T2DM). Appropriate assessment of islet ß-cell function is beneficial to better management of T2DM. Protecting islet ß-cell function is vital to delay the progress of type 2 diabetes mellitus. Therefore, the Pancreatic Islet ß-cell Expert Panel of the Chinese Diabetes Society and Endocrinology Society of Jiangsu Medical Association organized experts to draft the "Clinical expert consensus on the assessment and protection of pancreatic islet ß-cell function in type 2 diabetes mellitus." This consensus suggests that ß-cell function can be clinically assessed using blood glucose-based methods or methods that combine blood glucose and endogenous insulin or C-peptide levels. Some measures, including weight loss and early and sustained euglycemia control, could effectively protect islet ß-cell function, and some newly developed drugs, such as Sodium-glucose cotransporter-2 inhibitor and Glucagon-like peptide-1 receptor agonists, could improve islet ß-cell function, independent of glycemic control.

Assessment of executive function in a rodent model of Type 1 diabetes.

This study examined the impact of Type 1 Diabetes Mellitus (T1DM) on executive function using a series of operant conditioning-based tasks in rats. Sprague Dawley rats were randomized to either non-diabetic (n = 12; 6 male) or diabetic (n = 14; 6 male) groups. Diabetes was induced using multiple low-dose streptozotocin injections. All diabetic rodents were insulin-treated using subcutaneous insulin pellet implants (9-15 mM). At week 14 of the study, rats were placed on a food restricted diet to induce 5-10 % weight loss. Rodents were familiarized and their set-shifting ability was tested on a series of tasks that required continuous adjustments to novel stimulus-reward paradigms in order to receive food rewards. Results showed no differences in the number of trials, nor number and type of errors made to successfully complete each task between groups. Therefore, we report no differences in executive function, or more specifically set-shifting abilities between non-diabetic and diabetic rodents that receive insulin.

Mathematical Model of Glucagon Kinetics for the Assessment of Insulin-Mediated Glucagon Inhibition During an Oral Glucose Tolerance Test.

Glucagon is secreted from the pancreatic alpha cells and plays an important role in the maintenance of glucose homeostasis, by interacting with insulin. The plasma glucose levels determine whether glucagon secretion or insulin secretion is activated or inhibited. Despite its relevance, some aspects of glucagon secretion and kinetics remain unclear. To gain insight into this, we aimed to develop a mathematical model of the glucagon kinetics during an oral glucose tolerance test, which is sufficiently simple to be used in the clinical practice. The proposed model included two first-order differential equations -one describing glucagon and the other describing C-peptide in a compartment remote from plasma - and yielded a parameter of possible clinical relevance (i.e., SGLUCA(t), glucagon-inhibition sensitivity to glucose-induced insulin secretion). Model was validated on mean glucagon data derived from the scientific literature, yielding values for SGLUCA(t) ranging from -15.03 to 2.75 (ng of glucagon·nmol of C-peptide-1). A further validation on a total of 100 virtual subjects provided reliable results (mean residuals between -1.5 and 1.5 ng·L-1) and a negative significant linear correlation (r = -0.74, p < 0.0001, 95% CI: -0.82 - -0.64) between SGLUCA(t) and the ratio between the areas under the curve of suprabasal remote C-peptide and glucagon. Model reliability was also proven by the ability to capture different patterns in glucagon kinetics. In conclusion, the proposed model reliably reproduces glucagon kinetics and is characterized by sufficient simplicity to be possibly used in the clinical practice, for the estimation in the single individual of some glucagon-related parameters.

Antidiabetic Therapy and Rate of Severe Hypoglycaemia in Patients with Type 2 Diabetes and Chronic Kidney Disease of Different Stages - A Follow-up Analysis of Health Insurance Data from Germany.

BACKGROUND: The presence of chronic kidney disease (CKD) influences the type of antiglycaemic therapy and the risk for hypoglycaemia. METHODS: In 2006, 2011 and 2016 health insurance data of people with diabetes type 2 were screened for CKD and the presence of severe hypoglycaemia (sHypo). The type of antihyperglycaemic therapy was recorded due to Anatomical Therapeutic Chemical (ATC) codes up to 3 months before suffering sHypo. RESULTS: The prevalence of CKD increased from 5.3% in 2006 to 7.3% in 2011 and 11.2% in 2016. Insulin-based therapies were used in 39.0, 39.1, and 37.9% of patients with, but only in 17.7, 17.4, and 18.8% of patients without CKD. Although the proportion of the CKD stages 1, 2 and 5 decreased, CKD stages 3 and 4 increased. The proportion of sHypo in CKD declined from 2006 (3.5%) to 2011 (3.0%) and 2016 (2.2%) but was still more than 10 times higher as compared to type 2 diabetic patients without CKD (0.3/0.2/0.2%) conferring a significantly higher probability of sHypo (OR 9.30, 95%CI 9.07-9.54) in CKD. The probability of sHypo was significantly lower in 2016 than in 2006 both in patients with (OR 0.58; CI 0.55-0.61) and without CKD (OR 0.70; CI 0.68-0.73). CONCLUSION: The prevalence of CKD increased from 2006 to 2016. Patients with CKD exhibited a 9-fold increased probability of sHypo, especially in patients treated with insulin plus oral anti-diabetic drugs. However, the rate and risk for sHypo decreased over time, probably as a consequence of new antidiabetic treatment options, better awareness of sHypo, and changed therapy goals.

Assessment of Insulin Tolerance Ex Vivo.

Insulin is a hormone produced and secreted by the ß-cells of the pancreatic islets of Langerhans in response to increased blood glucose levels after a meal. The hormone binds to its receptor located on the plasma membrane triggering an intracellular signaling cascade. This signaling pathway is responsible for the pleiotropic actions of insulin on different tissues, such as regulation of glucose and lipid metabolism, proliferation, and differentiation. Although considerable efforts have been made to understand the molecular mechanism linking the action of the hormone to biological processes, our knowledge is incomplete. Of note, under certain conditions, physiological circulating levels of the hormone are insufficient to properly regulate these processes, a term coined as insulin resistance. The ex vivo analysis of insulin action provides valuable information to decipher intracellular signaling events downstream of the insulin receptor under physiological and pathophysiological conditions. In this chapter, we focus on the analysis of intracellular insulin action ex vivo.

The burden of type 2 diabetes in Europe: Current and future aspects of insulin treatment from patient and healthcare spending perspectives.

Due to the progressive nature of type 2 diabetes (T2DM), initiation of insulin therapy is very likely in the disease continuum. This article aims at highlighting the current situation with regard to insulin therapy in people with T2DM in Europe and at presenting the associated unmet need. Challenges for both people with T2DM and healthcare professionals include clinical inertia also derived from fear of hypoglycaemia, weight gain and injections as well as increased need for a comprehensive diabetes management. We compare national and international guidelines and recommendations for the initiation and intensification of insulin therapy with the real-world situation in six European countries, demonstrating that glycaemic targets are only met in a minority of people with T2DM on insulin therapy. Furthermore, this work evaluates currently recorded numbers of people with T2DM treated with insulin in Europe, the proportion not achieving the stated glycaemic targets and thus in need to enhance insulin therapy e.g. by a change in means of insulin delivery including, but not limited to, insulin pens, wearable mealtime insulin delivery patches, patch pumps, and conventional insulin pumps with continuous subcutaneous insulin infusion.

[De-escalation of antihyperglycemic treatment in patients with type 2 diabetes - when less is more]. / Az antihyperglykaemiás terápia deeszkalációja 2-es típusú diabetesben ­ amikor a kevesebb több.

Type 2 diabetes - due to its natural course - should be considered as a progressive chronic disease. Owing to this fact, antihyperglycemic treatment should be continuously increased stepwise in order to achieve proper glycemic control. Lifestyle modification should be initiated immediately after manifestation, shortly followed by metformin monotherapy, and later, dual or triple combinations and, finally, injectable derivatives - only insulin in the past - should be used for appropriate glycemic control. Guidelines about treatment approach of patients with type 2 diabetes unequivocally emphasize and describe in detail the need of treatment intensification, in other words, stepwise escalation in clinical practice. In the last couple of years, evidences provided that step down therapy, simplification of complex treatment regimens should also be considered in certain cases. This approach was generally called de-escalation in antihyperglycemic treatment which should be considered in patients with type 2 diabetes 1) after bariatric (metabolic) surgery; 2) with significant weight reduction irrespective of its origin; 3) with complex insulin regimens where re-evaluation of this treatment was missed; 4) with continuously decreasing renal function; 5) among elderly patients with comorbidities; 6) in social deprivation. In this article, data about therapeutic de-escalation of antihyperglycemic treatment in patients with type 2 diabetes and first experiences with this treatment approach are summarized. Orv Hetil. 2019; 160(31): 1207-1215.

Appropriate Titration of Basal Insulin in Type 2 Diabetes and the Potential Role of the Pharmacist.

A substantial proportion of patients with suboptimal control of their type 2 diabetes experience delays in treatment intensification. Additionally, patients often experience overuse of basal insulin, commonly referred to as "over-basalization," whereby basal insulin continues to be uptitrated in order to meet targets, when addition of a mealtime bolus insulin dose may be a more appropriate option. In order to overcome these challenges, there is a need to develop the capacity of allied healthcare professionals to provide appropriate support to these patients, such as during initiation or titration of basal insulin. Pharmacists play an integral role in healthcare delivery, with patients seeing their pharmacist, on average, seven times more often than their primary care physician. This places pharmacists in a unique position to provide diabetes education and care, which may help patients avoid clinical inertia. Nevertheless, the management of the disease with basal insulin is becoming increasingly complex, with growing numbers of treatment options (such as recent second-generation longer-acting basal insulin formulations) and frequently updated titration algorithms. The two most common titration schedules specify either increasing doses by a set amount every 2-3 days or a treat-to-target strategy. Neither schedule has been shown to be superior, and the decision to use one or the other should be based on a discussion between the clinician and patient after assessment of mental and physical acumen, comfort of both parties, and follow-up plans. This review article discusses basal insulin therapy options and titration algorithms from the unique perspective of the pharmacist in order to help ensure that optimal antidiabetes therapy is initiated, appropriately titrated, and maintained.Funding: Sanofi US, Inc.

In Silico Assessment of Literature Insulin Bolus Calculation Methods Accounting for Glucose Rate of Change.

BACKGROUND: The standard formula (SF) used in bolus calculators (BCs) determines meal insulin bolus using "static" measurement of blood glucose concentration (BG) obtained by self-monitoring of blood glucose (SMBG) fingerprick device. Some methods have been proposed to improve efficacy of SF using "dynamic" information provided by continuous glucose monitoring (CGM), and, in particular, glucose rate of change (ROC). This article compares, in silico and in an ideal framework limiting the exposition to possibly confounding factors (such as CGM noise), the performance of three popular techniques devised for such a scope, that is, the methods of Buckingham et al (BU), Scheiner (SC), and Pettus and Edelman (PE). METHOD: Using the UVa/Padova Type 1 diabetes simulator we generated data of 100 virtual subjects in noise-free, single-meal scenarios having different preprandial BG and ROC values. Meal insulin bolus was computed using SF, BU, SC, and PE. Performance was assessed with the blood glucose risk index (BGRI) on the 9 hours after meal. RESULTS: On average, BU, SC, and PE improve BGRI compared to SF. When BG is rapidly decreasing, PE obtains the best performance. In the other ROC scenarios, none of the considered methods prevails in all the preprandial BG conditions tested. CONCLUSION: Our study showed that, at least in the considered ideal framework, none of the methods to correct SF according to ROC is globally better than the others. Critical analysis of the results also suggests that further investigations are needed to develop more effective formulas to account for ROC information in BCs.

Cost-effectiveness Analysis of Routine Screening Using Massively Parallel Sequencing for Maturity-Onset Diabetes of the Young in a Pediatric Diabetes Cohort: Reduced Health System Costs and Improved Patient Quality of Life.

OBJECTIVE: Maturity-onset diabetes of the young (MODY) is an autosomal dominant form of diabetes, with multiple causative genes. Some MODY subtypes can be treated with sulfonylureas instead of insulin, improving glycemic control, complication rates, quality of life (QoL), and costs. Using massively parallel sequencing (MPS), we recently determined the prevalence of pathogenic/likely pathogenic MODY variants in an Australian pediatric diabetes cohort. Here, these data are used to estimate cost-effectiveness of using MPS for MODY in all pediatric diabetes cases compared with standard practice (sequencing limited to individuals with specific clinical features). RESEARCH DESIGN AND METHODS: A Markov decision model was developed to estimate incremental costs and quality-adjusted life-years (QALYs) of MPS screening, modeled over 30 years. We used our observed prevalence of 2.14% compared with 0.7% for standard practice, based on published data. The probabilities and utility weightings of long-term diabetes complications were based on HbA1c and estimated from published data. A series of one-way sensitivity analyses were performed using the net monetary benefit framework. RESULTS: Routine MPS screening for MODY was more effective and less costly than standard care screening, with 26 QALYs gained and 1,016,000 AUD (782,000 USD) saved per 1,000 patients. Cost of screening was fully offset within 10 years. Routine MPS screening remained dominant until MODY prevalence fell to <1.1%. CONCLUSIONS: Routine MPS screening for MODY in the pediatric population with diabetes could reduce health system costs and improve patient QoL. Our results make a compelling argument for routine genetic screening in all children with presumed type 1 diabetes mellitus.

Technology in the management of type 1 diabetes mellitus - current status and future prospects.

Type 1 diabetes mellitus (T1DM) represents 5-10% of diabetes cases worldwide. The incidence of T1DM is increasing, and there is no immediate prospect of a cure. As such, lifelong management is required, the burden of which is being eased by novel treatment modalities, particularly from the field of diabetes technologies. Continuous glucose monitoring has become the standard of care and includes factory-calibrated subcutaneous glucose monitoring and long-term implantable glucose sensing. In addition, considerable progress has been made in technology-enabled glucose-responsive insulin delivery. The first hybrid insulin-only closed-loop system has been commercialized, and other closed-loop systems are under development, including dual-hormone glucose control systems. This Review focuses on well-established diabetes technologies, including glucose sensing, pen-based insulin delivery, data management and data analytics. We also cover insulin pump therapy, threshold-based suspend, predictive low-glucose suspend and single-hormone and dual-hormone closed-loop systems. Clinical practice recommendations for insulin pump therapy and continuous glucose monitoring are presented, and ongoing research and future prospects are highlighted. We conclude that the management of T1DM is improved by diabetes technology for the benefit of the majority of people with T1DM, their caregivers and guardians and health-care professionals treating patients with T1DM.

Direct and indirect health economic impact of hypoglycaemia in a global population of patients with insulin-treated diabetes.

AIMS: The Hypoglycaemia Assessment Tool (HAT) study investigated the health economic impact of hypoglycaemic events in 24 countries, including countries without previously published data on hypoglycaemia. METHODS: Self-assessment questionnaires and patient diaries (4-week prospective period) were completed by adults with type 1 (T1D) or type 2 diabetes (T2D) treated with insulin for more than 12 months (N = 27,585). RESULTS: Direct economic impacts of hypoglycaemia during the 4-week prospective period, included increased blood glucose monitoring (reported by 69.7% [T1D] and 60.9% [T2D] of patients), hospitalisation (T1D 2.1%; T2D 3.4% of patients) and medical contact (clinic or telephone; T1D 3.8%; T2D 6.8% of patients). Regional variation in medical contact and hospitalisation was found, with the highest usage in Russia (T1D 17.1%; T2D 17.3%), and Latin America (T1D 5.2%; T2D 6.8%) respectively. Indirect economic impacts following hypoglycaemia included loss of productivity due to absence from work or study; 3.9% (T1D) and 6.2% (T2D) of patients. Regional differences in work productivity were noted among patients with T2D, with a low prevalence in Northern Europe and Canada (0.9%) and high in Southeast Asia (14.6%). CONCLUSIONS: This study shows that hypoglycaemia has a significant but variable impact on the economics of diabetes healthcare globally.

The impact of ethnicity, educational and economic status on the prescription of insulin therapeutic regimens and on glycemic control in patients with type 1 diabetes. A nationwide study in Brazil.

AIMS: Establish the relationship between demographic, educational and economic status on insulin therapeutic regimens (ITRs) and on glycemic control in patients with type 1 diabetes. METHODS: This was a cross-sectional, multicenter study with 1760 patients conducted between August 2011 and August 2014 in 10 Brazilian cities. RESULTS: Patients were stratified according to ITRs as follows: only NPH insulin (group 1, n=80(4.5%)); only long-acting insulin analogs (group 2, n=6(0.3%)); continuous subcutaneous insulin infusion (CSII) (group 3, n=62(3.5%)); NPH plus regular insulin (group 4, n=710(40.3%)); NPH plus ultra-rapid insulin analogs (group 5, n=259(14.8%)); long-acting insulin analogs plus regular insulin (group 6, n=25(4.4%)) and long-acting plus ultra-rapid insulin analogs (group 7, n=618 (35.1%)). As group A (provided free of charge by the government) we considered groups 1 and 4, and as group B (obtained through lawsuit or out-of-pocket) groups 2, 3 and 7. Multivariate logistic analysis showed that independent variables related to group B were older age, more years of school attendance, higher economic status and ethnicity (Caucasians). The independent variables related to better glycemic control were older age, higher adherence to diet, higher frequency of self-monitoring of blood glucose, more years of school attendance and belonging to group B. CONCLUSIONS: In Brazilian National Health Care System, prescriptions of insulin analogs or CSII are more frequent in Caucasian patients with type 1 diabetes, with higher economic status and more years ofschool attendance. Among these variables years of school attendance was the only one associated with better glycemic control.

Prevalence of ketosis, ketonuria, and ketoacidosis during liberal glycemic control in critically ill patients with diabetes: an observational study.

BACKGROUND: It is uncertain whether liberal glucose control in critically ill diabetic patients leads to increased ketone production and ketoacidosis. Therefore, we aimed to assess the prevalence of ketosis, ketonuria and ketoacidosis in critically ill diabetic patients treated in accordance with a liberal glycemic control protocol. METHODS: We performed a prospective observational cohort study of 60 critically ill diabetic patients with blood and/or urine ketone bodies tested in ICU. All patients were treated according to a liberal glucose protocol targeting a blood glucose level (BGL) between 10 and 14 mmol/l in a single tertiary intensive care unit in Australia. We measured quantitative bedside blood 3-beta-hydroxybutyrate (ß-OHB) and semi-quantitative urine ketones on ICU admission and daily during ICU stay, for a maximum of 10 consecutive days. RESULTS: Median blood ß-OHB level on admission was 0.3 (0.1, 0.8) mmol/l. Ketoacidosis was rare (3 %), but some level of ketosis (ß-OHB ≥0.6 mmol/l) was found in 38 patients (63 %) early during their ICU stay. However, there was no significant difference in prevalence or severity of ketonemia and ketonuria among patients with BGL above (permissive hyperglycemia) or below 10 mmol/l. On multivariable linear regression analysis there was no association between blood ketone levels and BGL, HbA1c, lactate levels, hematocrit, catecholamine infusion or APACHE III score. In contrast, blood ketone levels tended to be higher after cardiopulmonary bypass surgery (P = 0.06). CONCLUSIONS: Liberal glycemic control in critically ill diabetic patients does not appear to be associated with a high prevalence of ketoacidosis or ketonemia. Moreover, ketosis is typically present on admission and resolves rapidly. Finally, cardiopulmonary bypass surgery may be an important trigger of ketone body production. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry ( ACTRN12615000216516 ; trial registration date 5 March 2015).

Long-lived hypopituitary Ames dwarf mice are resistant to the detrimental effects of high-fat diet on metabolic function and energy expenditure.

Growth hormone (GH) signaling stimulates the production of IGF-1; however, increased GH signaling may induce insulin resistance and can reduce life expectancy in both mice and humans. Interestingly, disruption of GH signaling by reducing plasma GH levels significantly improves health span and extends lifespan in mice, as observed in Ames dwarf mice. In addition, these mice have increased adiposity, yet are more insulin sensitive compared to control mice. Metabolic stressors such as high-fat diet (HFD) promote obesity and may alter longevity through the GH signaling pathway. Therefore, our objective was to investigate the effects of a HFD (metabolic stressor) on genetic mechanisms that regulate metabolism during aging. We show that Ames dwarf mice fed HFD for 12 weeks had an increase in subcutaneous and visceral adiposity as a result of diet-induced obesity, yet are more insulin sensitive and have higher levels of adiponectin compared to control mice fed HFD. Furthermore, energy expenditure was higher in Ames dwarf mice fed HFD than in control mice fed HFD. Additionally, we show that transplant of epididymal white adipose tissue (eWAT) from Ames dwarf mice fed HFD into control mice fed HFD improves their insulin sensitivity. We conclude that Ames dwarf mice are resistant to the detrimental metabolic effects of HFD and that visceral adipose tissue of Ames dwarf mice improves insulin sensitivity in control mice fed HFD.

Enhancement of oral insulin bioavailability: in vitro and in vivo assessment of nanoporous stimuli-responsive hydrogel microparticles.

OBJECTIVE: Oral insulin administration suffers gastrointestinal tract (GIT) degradation and inadequate absorption from the intestinal epithelium resulting in poor bioavailability. This study entails in vitro and in vivo assessment of stimuli-responsive hydrogel microparticles (MPs) in an attempt to circumvent GI barrier and enhance oral insulin bioavailability. METHODS: Bacterial cellulose-g-poly(acrylic acid) (BC-g-P(AA)) hydrogel MPs were evaluated for morphology, swelling, entrapment efficiency (EE), in vitro insulin release and enzyme inhibition. The ex vivo mucoadhesion, insulin degradation and transport were investigated in excised intestinal tissues. The effect of MPs on paracellular transport was studied in Caco-2/HT29-MTX monolayers. The in vivo hypoglycemic effect and pharmacokinetics of insulin-loaded MPs were investigated in diabetic rats. RESULTS: Hydrogel MPs efficiently entrapped insulin (EE up to 84%) and exhibited pH-responsive in vitro release. The MPs decreased the proteolytic activity of trypsin (up to 60%). Insulin transport across monolayers was increased up to 5.9-times by MPs. Histological assessment of GI tissues confirmed the non-toxicity of MPs. Orally administered insulin-loaded MPs showed higher hypoglycemic effect as compared to insulin solution and enhanced relative oral bioavailability of insulin up to 7.45-times. CONCLUSION: These findings suggest that BC-g-P(AA) MPs are promising biomaterials to overcome the barriers of oral insulin delivery and enhancing its bioavailability.

Assessment of myocardial metabolic flexibility and work efficiency in human type 2 diabetes using 16-[18F]fluoro-4-thiapalmitate, a novel PET fatty acid tracer.

Altered myocardial fuel selection likely underlies cardiac disease risk in diabetes, affecting oxygen demand and myocardial metabolic flexibility. We investigated myocardial fuel selection and metabolic flexibility in human type 2 diabetes mellitus (T2DM), using positron emission tomography to measure rates of myocardial fatty acid oxidation {16-[(18)F]fluoro-4-thia-palmitate (FTP)} and myocardial perfusion and total oxidation ([(11)C]acetate). Participants underwent paired studies under fasting conditions, comparing 3-h insulin + glucose euglycemic clamp conditions (120 mU·m(-2)·min(-1)) to 3-h saline infusion. Lean controls (n = 10) were compared with glycemically controlled volunteers with T2DM (n = 8). Insulin augmented heart rate, blood pressure, and stroke index in both groups (all P < 0.01) and significantly increased myocardial oxygen consumption (P = 0.04) and perfusion (P = 0.01) in both groups. Insulin suppressed available nonesterified fatty acids (P < 0.0001), but fatty acid concentrations were higher in T2DM under both conditions (P < 0.001). Insulin-induced suppression of fatty acid oxidation was seen in both groups (P < 0.0001). However, fatty acid oxidation rates were higher under both conditions in T2DM (P = 0.003). Myocardial work efficiency was lower in T2DM (P = 0.006) and decreased in both groups with the insulin-induced increase in work and shift in fuel utilization (P = 0.01). Augmented fatty acid oxidation is present under baseline and insulin-treated conditions in T2DM, with impaired insulin-induced shifts away from fatty acid oxidation. This is accompanied by reduced work efficiency, possibly due to greater oxygen consumption with fatty acid metabolism. These observations suggest that improved fatty acid suppression, or reductions in myocardial fatty acid uptake and retention, could be therapeutic targets to improve myocardial ischemia tolerance in T2DM.