Lower Insulin Research Articles

The correlation of ABC goal attainment with insulin resistance/sensitivity in Syrian type 2 diabetes patients

BackgroundThe rising prevalence of type 2 diabetes (T2D) in Syria emphasizes the urgent requirement for effective management approaches. The ABC goals, which include maintaining glycated hemoglobin levels below 7 %, blood pressure below 140/90 mmHg, and low-density lipoprotein cholesterol levels below 100 mg/dl, serve as crucial benchmarks for managing T2D and its associated comorbidities. MethodsIn this cross-sectional study, the achievement of ABC goals was retrospectively examined among 681 clinically diagnosed T2D patients (not on Insulin) who participated in a six-year online lifestyle intervention program for diabetes management at the Freedom from Diabetes Clinic in Syria between January 2016 and December 2022. ResultsOut of the participants, 152 (22.3 %) successfully achieved all three ABC goals, while 306 (45.0 %) and 183 (26.9 %) achieved two or one goal(s) respectively. The factors influencing the attainment of all three ABC goals revealed a significant association with older age (>50 years), lower body mass index (<25 kg/m2), and lower insulin resistance (Homeostatic Model Assessment of Insulin Resistance < 2.5). Furthermore, patients who successfully achieved all three ABC goals exhibited lower insulin resistance, improved lipid profiles, and higher insulin sensitivity and beta cell function. ConclusionThis study offers new insights into the relationship between insulin resistance/sensitivity and the achievement of ABC goals in the Syrian population with T2D, underscoring the necessity for tailored strategies to enhance comprehensive diabetes management.

Lifestyle-based subtypes of childhood obesity and their association with cardiometabolic factors: A cluster analysis.

Lifestyle factors play an important role in the development and management of childhood obesity and its related cardiometabolic complications. We aimed to explore childhood obesity subtypes based on lifestyle factors and examine their association with cardiometabolic health. We included 1550 children with obesity from the National Health and Nutrition Examination Survey. Cluster analysis identified obesity subtypes based on four lifestyle factors (physical activity, diet quality, sedentary time and smoking). Multiple linear regression assessed their association with cardiometabolic factors. Five subtypes of childhood obesity were identified: unhealthy subtype (n = 571; 36.8%), physically active subtype (n = 185; 21.1%), healthy diet subtype (n = 404; 26.1%), smoking subtype (n = 125; 8.1%) and non-sedentary subtype (n = 265; 17.1%). Compared with the unhealthy subtype, the physically active subtype had lower insulin and HOMA-IR levels, and smoking subtype was associated with lower HDL levels. When compared with children with normal weight, all obesity subtypes had worse cardiometabolic profile, except the physically active subtype who had similar DBP, HbA1c and TC levels; smoking subtype who had similar TC levels; and healthy diet and non-sedentary subtypes who had similar DBP levels. Children of different lifestyle-based obesity subtypes might have different cardiometabolic risks. Our new classification system might help personalize assessment of childhood obesity.

A retrospective study comparing the results of continuous glucose monitoring to self-blood glucose monitoring for pregnant women with type 1 diabetes mellitus

ABSTRACT Background Type 1 diabetes mellitus (T1DM) is associated with adverse maternal and fetal outcomes. Continuous glucose monitoring (CGM) during pregnancy is associated with better glycemic control in women with T1DM. However, no clear benefits have been demonstrated in reducing adverse feto-maternal outcomes in pregnant women with T1DM. Design and Methods This is a retrospective, single-center study of pregnant women with T1DM to evaluate the impact of CGM use on glycemic control and feto-maternal outcomes in pregnant women with T1DM. Results Of 265 women with T1DM, 92 (34.7%) used CGM, and 173 (65.3%) were managed with capillary blood glucose (CBG) monitoring. The mean (SD) age and BMI at the first visit were 29.4 (4.7) years and 27.2 (5.2) kg/m2, respectively. The mean (SD) HbA1c at the first-trimester visit was 63 (1) mmol/mol, and in the last trimester was 51 (1%). There was no difference in the mean changes in HbA1c between the two groups. Women using CGM had lower insulin requirements (1.02 + 0.37 vs. 0.87 + 0.04 units/kg, p = 0.01). The two groups had no significant differences in maternal or fetal outcomes. Conclusion CGM use in pregnant T1DM women is not associated with improved fetomaternal outcomes.

Late-in-life Exercise Ameliorates the Aging Trajectory Metabolism Programmed by Maternal Obesity in Rats: It is Never Too Late

BackgroundMaternal obesity (MO) has been shown to adversely affect metabolic, oxidative, reproductive, and cognitive function in offspring. However, it is unclear whether lifestyle modification can ameliorate the metabolic and organ dysfunction programmed by MO and prevent the effects of metabolic syndrome in adulthood. This study aimed to evaluate whether moderate voluntary exercise in the offspring of rats born to obese mothers can ameliorate the adverse effects of MO programming on metabolism and liver function in mid-adulthood. MethodsOffspring of control (CF1) and MOF1 mothers were fed with a control diet from weaning. Adult males and females participated in 15 min exercise sessions five days/week. Metabolic parameters were analyzed before and after the exercise intervention. Liver oxidative stress biomarkers and antioxidant enzymes were analyzed before and after the intervention. ResultsMales showed that CF1ex ran longer than MOF1ex and increased the distance covered. In contrast, females in both groups ran similar distances and remained constant but ran further distances than males. At PND 300 and 450, male and female MOF1ex had higher leptin, triglycerides, insulin, and HOMA-IR levels than CF1. However, male MOF1ex had lower triglycerides, insulin, and HOMA-IR levels than MOF1. Improvements in liver fat and antioxidant enzymes were observed in CF1ex and MOF1ex males and females compared to their respective CF1 and MOF1 groups. ConclusionThese findings suggest that moderate voluntary exercise, even when started in mid-adulthood, can improve metabolic outcomes and delay accelerated metabolic aging in MO-programmed rats in a sex-dependent manner.

Clinico-Metabolic Profile and Follow-Up of Familial Cases Compared to Sporadic Cases in a Lyon Series of Type 1 Diabetic Children.

This study aimed to describe the clinical, biochemical, therapeutic, and progressive characteristics of children with familial type 1 diabetes (T1D) compared to those with non-familial T1D. Compare within the first group, the phenotype of type 1 diabetics inherited from the father with those inherited from the mother. We conducted a retrospective study lasting 10 years at the L'hôpital Femme Mère Enfant (Woman-Mother-Child Hospital) in Lyon, France. Cases were any child diagnosed with T1D for at least 12 months who had a parent with T1D. Each case was matched with a T1D control without a family history of T1D, of the same age, same sex and same year of discovery. Cases group was divided into two subgroups according to the sex of the parent with T1D. A total of 43 children had a TD1 parent (family group) of whom 27 cases were the father. Forty four T1D children without any T1D parent were matched (sporadic group). The family group had consulted earlier (p < 0.001), were less in initial diabetic ketoacidosis (p = 0.016), and had a lower HbA1C level lower (p < 0.001) and lower initial insulin requirements (p < 0.001). During follow-up, it was noted that the evolution of Hb1AC, insulin requirements, and chronic complications were similar in familial and non-familial cases (p = 0.943, p = 0.450, p = 0.664, respectively). The patients in the T1D mother group seemed better balanced than those of the T1D father with an average HbA1C at 10 years of follow-up of 7.82% in the maternal group compared to 9.10% in the paternal group (p = 0.021). This study shows that familial T1D is a protective factor against the initial severity of T1D in offspring. Paternal T1D presents a more severe initial and progressive clinico-biological character than T1D inherited from the mother. However, during follow-up, other psycho-environmental factors could modify this observation.

Impact of chickpea hummus on postprandial blood glucose, insulin and gut hormones in healthy humans combined with mechanistic studies of food structure, rheology and digestion kinetics

Slowing the rate of carbohydrate digestion leads to low postprandial glucose and insulin responses, which are associated with reduced risk of type 2 diabetes. There is increasing evidence that food structure plays a crucial role in influencing the bioaccessibility and digestion kinetics of macronutrients. The aims of this study were to compare the effects of two hummus meals, with different degrees of cell wall integrity, on postprandial metabolic responses in relation to the microstructural and rheological characteristics of the meals. A randomised crossover trial in 15 healthy participants was designed to compare the acute effect of 27 g of starch, provided as hummus made from either intact chickpea cells (ICC) or ruptured chickpea cells (RCC), on postprandial metabolic responses. In vitro starch digestibility, microstructural and rheological experiments were also conducted to evaluate differences between the two chickpea hummus meals. Blood insulin and GIP concentrations were significantly lower (P < 0.02, P < 0.03) after the consumption of the ICC meal than the meal containing RCC. In vitro starch digestion for 90 min was slower in ICC than in RCC. Microscopic examination of hummus samples digested in vitro for 90 min revealed more intact chickpea cells in ICC compared to the RCC sample. Rheological experiments showed that fracture for ICC hummus samples occurred at smaller strains compared to RCC samples. However, the storage modulus for ICC was higher than RCC, which may be explained by the presence of intact cells in ICC. Food structure can affect the rate and extent of starch bioaccessibility and digestion and may explain the difference in the time course of metabolic responses between meals. The rheological properties were measured on the two types of meals before ingestion, showing significant differences that may point to different breakdown mechanisms during subsequent digestion.This trial was registered at clinicaltrial.gov as NCT03424187.

Subacute cadmium exposure changes different metabolic functions, leading to type 1 and 2 diabetes mellitus features in female rats.

Cadmium (Cd) is a heavy metal that acts as endocrine disrupting chemical (EDC). Few studies have investigated the effects of Cd exposure on metabolic dysfunctions, such as type 1 and 2 diabetes mellitus (T1DM and T2DM). Thus, we assessed whether subacute Cd exposure at occupational levels causes abnormalities in white adipose tissue (WAT), liver, pancreas, and skeletal muscle. We administered cadmium chloride (CdCl2) (100 ppm in drinking water for 30 days) to female rats and evaluated Cd levels in serum and metabolic organs, morphophysiology, inflammation, oxidative stress, fibrosis, and gene expression. High Cd levels were found in serum, WAT, liver, pancreas, and skeletal muscle. Cd-exposed rats showed low adiposity, dyslipidemia, insulin resistance, systemic inflammation, and oxidative stress compared to controls. Cd exposure reduced adipocyte size, hyperleptinemia, increased cholesterol levels, inflammation, apoptosis and fibrosis in WAT. Cd-exposed rats had increased liver cholesterol levels, insulin receptor beta (IRβ) and peroxisome proliferator-activated receptor-gamma coactivator-1alpha (PGC1α) expression, karyomegaly, inflammation, and fibrosis. Cd exposure reduced insulin levels and pancreatic islet size and increased inflammation and fibrosis. Cd exposure reduced skeletal muscle fiber diameter and increased IR expression and inflammation. Finally, strong positive correlations were observed between serum, tissue Cd levels, abnormal morphology, tissue inflammation and fibrosis. Thus, these data suggest that subacute Cd exposure impairs WAT, liver, pancreas and skeletal muscle function, leading to T1DM and T2DM features and other complications in female rats.

Beyond Stages: Predicting Individual Time Dependent Risk for Type 1 Diabetes.

Essentially all individuals with multiple autoantibodies will develop clinical type 1 diabetes. Multiple AABs and normal glucose tolerance define Stage 1 diabetes; abnormal glucose tolerance defines Stage 2. However, the rate of progression within these stages is heterogeneous, necessitating personalized risk calculators to improve clinical implementation. We developed 3 models using TrialNet's Pathway to Prevention data to accommodate the reality that not all risk variables are clinically available. The Small model included AAB status, fasting glucose, HbA1c and age, while the Medium and Large models added predictors of disease progression measured via oral glucose tolerance testing. All models markedly improved granularity regarding personalized risk missing from current categories of stages of T1D. Model derived risk calculations are consistent with the expected reduction of risk with increasing age and increase in risk with higher glucose and lower insulin secretion, illustrating the suitability of the models. Adding glucose and insulin secretion data altered model predicted probabilities within Stages. In those with high 2-hour glucose, a high C-peptide markedly decreased predicted risk; lower C-peptide obviated the age-dependent risk of 2-hour glucose alone, providing a more nuanced estimate of rate of disease progression within Stage 2. While essentially all those with multiple AABs will develop type 1 diabetes, the rate of progression is heterogeneous and not explained by any individual single risk variable. The model-based probabilities developed here provide an adaptable personalized risk calculator to better inform decisions about how and when to monitor disease progression in clinical practice.

Metabolic-Associated Fatty Liver Disease is Characterized by a Post-Oral Glucose Load Hyperinsulinemia in Individuals with Mild Metabolic Alterations.

Metabolic-associated fatty liver disease (MAFLD) has been identified as risk factor of incident type 2 diabetes (T2D), but the underlying postprandial mechanisms remains unclear. We compared the glucose metabolism, insulin resistance, insulin secretion and insulin clearance post-oral glucose tolerance test (OGTT) between individuals with and without MAFLD. We included 50 individuals with a BMI between 25-40 kg/m2 and ≥1 metabolic alteration: increased fasting triglycerides or insulin, plasma glucose 5.5-6.9 mmol/L, or glycated hemoglobin 5.7-5.9%. Participants were grouped according to MAFLD status, defined as hepatic fat fraction (HFF) ≥5% on MRI. We used oral minimal model on a frequently sampled 3h 75g-OGTT to estimate insulin sensitivity, insulin secretion, and pancreatic ß-cell function. Fifty percents of participants had MAFLD. Median age (IQR) (57 (45-65) vs 57 (44-63) years) and gender (60% vs 56% female) were comparable between groups. Post-OGTT glucose concentrations did not differ between groups, whereas post-OGTT insulin concentrations were higher in the MAFLD group (p <0.03). Individuals with MAFLD exhibited lower insulin clearance, insulin sensitivity and first phase pancreatic β cell function. In all individuals, increased insulin incremental area under the curve and decreased insulin clearance were associated with HFF after adjusting for age, sex, and BMI (p <0.02). Amongst individuals with metabolic alterations, the presence of MAFLD was characterized mainly by post-OGTT hyperinsulinemia and reduced insulin clearance, while exhibiting lower first phase β-cell function and insulin sensitivity. This suggests that MAFLD is linked with impaired insulin metabolism that may precede type 2 diabetes.

Pre-Existing Metabolic Conditions Impair the Beneficial Effects of Estrogen on Memory and Cognition in Ovariectomized Mice

Loss of estrogen, as a result of menopause, has been associated with cognitive decline and memory loss. Intriguingly, studies conducted with postmenopausal healthy women suggest that hormone replacement therapy improves cognitive functions. In contrast, clinical data involving subjects with a wide range of health conditions indicate that the effect of estrogen treatment varies. In addition to the cognitive decline, postmenopausal women have an increased risk of developing metabolic disorders including obesity, insulin resistance, and diabetes. In this study, we tested the hypothesis that pre-existing metabolic conditions reduce the beneficial effects of estradiol treatment and are responsible for the conflicting findings in cognitive functions after menopause. Female, seven-month-old C57BL/6J mice were fed with either a high-fat diet (HFD, BioServ #F3282) or a control diet (LFD, BioServ #F4031) for 10 to 14 weeks, then ovariectomized (OVX). In a randomized manner, mice received a silastic tube implant containing either 17β-estradiol (E2) or vehicle (VEH, cholesterol) and stayed on their respective diets. Body composition and metabolic parameters were measured in the four groups (HFD+VEH, HFD+E2, LFD+VEH, LFD+E2) to assess metabolic status, and novel object recognition test was performed to assess memory and cognition. Before OVX, HFD fed mice had significantly increased body weight, fat mass, basal blood glucose and insulin levels compared to mice fed with LFD. After OVX, LFD-VEH mice developed obesity and had elevated blood glucose and insulin levels, whereas E2 treatment prevented the metabolic changes. Interestingly, HFD-VEH mice had a reduction in fat mass after OVX, which was further decreased with E2 treatment. Overall, mice treated with E2 had lower body weight, fat mass, blood glucose and insulin levels compared to VEH treated mice regardless of their diet, and HFD fed mice had a higher body weight than mice fed the LFD, irrespective of their treatment. The novel object recognition test revealed that LFD-E2 mice spent significantly more time exploring the novel object than LFD-VEH mice. In contrast, there was no difference in exploration time between HFD-VEH and HFD-E2 treated mice. These preliminary results suggest that 1) E2 treatment may be beneficial to prevent the development of metabolic changes and improve cognitive function in LFD fed mice; 2) OVX alone did not worsen the metabolic status of diet-induced obese mice; 3) E2 treatment partially improved the metabolic status of HFD fed mice by decreasing fat mass, blood glucose and insulin levels; and 4) E2 treatment did not improve memory and cognition of HFD fed mice. Source of funding: P01AG071746 8456. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Disrupted Phosphorylated Phosphoinositide 3-kinase in the NTS of Type 2 Diabetic Rats

The hallmark of type 2 diabetes mellitus (T2DM) is systemic insulin resistance, where insulin signaling is impaired, blood glucose is chronically elevated, and various pathophysiological processes ensue. Much is known about the cardiovascular and metabolic consequences of T2DM. However, the impact of T2DM on autonomic nervous system function remains to be fully elucidated. Increasing evidence suggests that in both human and animal models of T2DM, the exercise pressor reflex (EPR) is abnormally augmented, characterized by heightened cardiovascular and sympathetic responses to physical activity. The underlying mechanisms are still not completely understood. Our recent studies suggest that T2DM induces alterations in peripheral somatosensory nerve activity that could explain the augmented EPR function. However, it is possible that neurons within the cardiovascular control areas of the brainstem, such as the nucleus tractus solitarius (NTS), could also be impaired by this disease. In the central nervous system, insulin has been shown to hyperpolarize neurons through activation of the phosphoinositide 3-kinase (PI3K) pathway, resulting in reduced neuronal excitability. Therefore, we hypothesized that decreased insulin transport into the brain in T2DM rats, results in increased cellular excitability as evidenced by decreased activity of the PI3K pathway in the NTS. Purpose: The aim of this study was to examine alterations in brain insulin levels and the PI3K pathway in T2DM rats as compared to control rats. Methods: Control rats were fed a low fat control diet (13% fat, 67.8% carbohydrate, and 19.2% protein) for 12-16 wks, while T2DM were generated by two low dose bolus injections of i.p. streptozotocin (35mg/kg, week 1; 25mg/kg week 2) and then fed a high fat diet (42% fat, 42.8% carbohydrate, and 15.2% protein) for 12-16wks. Cerebrospinal fluid (CSF) were collected from control and T2DM rats after an overnight fast. NTS micro-punches were performed, and then total and phosphorylated PI3K protein expressions were examined by the western blot technique. Results: CSF insulin was significantly decreased in T2DM rats as compared to control rats (0.41 ± 0.19 vs 0.11 ± 0.05 (ng/mL), Control (n=14) vs T2DM (n=4), p&lt;0.01). Total PI3K expression in the NTS did not differ between control and T2DM (1.0 ± 0.2 vs 1.1 ± 0.2 (au), Control (n=9) vs T2DM (n=9), P=0.172). However, phosphorylated PI3K expression in the NTS of T2DM was significantly decreased as compared with control animals (1.0 ± 0.2 vs 0.8 ± 0.1 (au), Control (n=9) vs T2DM (n=9), p&lt;0.05). Conclusion: These results suggest that 1) in consistent with earlier studies, insulin transport into the brain is impaired in high fat diet/streptozotocin-induced T2DM animals, and 2) decreased phospho-PI3K signaling in the NTS of diabetic animals is associated with lower brain insulin. Taken together, these alterations may increase neuronal excitability in the NTS, thereby contributing, at least in part, to the exaggerated EPR response to exercise in this disease. Supported by NIH HL-151632 and NIH HL-151632-01S1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Effect of High Fructose Diet on Insulin Signaling in Pituitary Tissue of Liver Androgen Receptor Knockout in Female Mice

Intro: Insulin resistance affects up to a third of the US adult population and polycystic ovary syndrome affects up to 10% of reproductive-age adult women. Hyperandrogenism in females can increase predisposition to insulin resistance. Andrisse et al 2021 (PMCID: PMC9097557) showed that deleting the liver androgen receptor (LivARKO) prevented female mice from developing hyperandrogenemia (HA)-induced insulin resistance. This study placed female LivARKO mice on a high fructose diet (HFrD) to determine if LivARKO mice demonstrate blunted insulin resistance on HFrD compared to control diet. Hypothesize: It was hypothesized that (unlike HA-LivARKO) HFrD LivARKO female mice would display impaired insulin action (lowered insulin-stimulated p-AKT) in PIT tissue in comparison to the Control diet fed LivARKO female mice, suggesting that liver AR does not play a significant role in regulating HFrD-induced insulin resistance in the pituitary. Methods: Female LivARKO mice were placed on two diets: Control (Con, Research Diets Inc, RDI D12450J) and High Fructose (HFrD, RDI D02022704). After 3 months on the diet, the mice were sacrificed. Half of the mice were given a dose of 0.5 U/kg insulin before sacrificing to investigate the effects of the diets on insulin signaling. Western blots were used to determine protein expression in tissue from the pituitary tissue (PIT). BCA assays were used to standardize the protein concentration in each sample. Insulin action can be measured molecularly by examining p-AKT Serine 473 (positive regulator, Santa Cruz sc-514032). If p-AKT S473 levels increase in the presence of insulin, this indicates that insulin is likely functioning properly in the sample. Results:LivARKO female mice on a control diet (Con) for 3-months administered with insulin displayed a 3-fold significant increase in p-AKT levels in the pituitary compared to LivARKO-Con female mice not injected with insulin (basal), suggesting that LivARKO-Con mice pituitaries were insulin sensitive. However, LivARKO female mice fed a high fructose diet (HFrD) for 3-months and then administered with insulin displayed significantly lowered p-AKT levels in the pituitary compared to basal LivARKO-HFrD female mice and compared to insulin LivARKO-Con, indicating that LivARKO-HFrD female mice were experiencing insulin resistance (lowered insulin sensitivity compared to LivARKO-Con). Interestingly, p-AKT was significantly increased by 2.5 fold in LivARKO-HFrD female mice compared to LivARKO-Con, suggesting that HFrD increased insulin sensitivity in the pituitary. Conclusion: In conclusion, these data suggest that LivARKO indirectly disrupted insulin-stimulated p-AKT in PIT possibly via altering metabolites in the blood. Additionally, HFrD is known to cause insulin resistance, however, it is not known to alter p-AKT levels. Thus, the change in p-AKT levels is presumably associated with the LivARKO. Further research is required on what components of the Control Diet are prompting this difference in insulin action and if it only takes place in the LivARKO mouse model. We would like to thank the National Science Foundation for award # NSF 1931045 and the National Institutes of Health 1R01DK126892-01A1. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Effect of intermittent hypoxia on glucose tolerance in adults with type 2 diabetes

Hypoxia stimulates glucose uptake through an insulin-independent pathway. The purpose of this single-blind randomized study was to determine the acute effect of intermittent hypoxia, consisting of alternating short bouts of breathing hypoxic and normoxic air, on glucose and insulin concentrations during an oral glucose tolerance test in adults with type 2 diabetes. It was hypothesized that intermittent hypoxia would attenuate the increase in glucose and insulin concentrations during an oral glucose tolerance test. Six adults with type 2 diabetes (5 men, age: 51±15 years, HbA1c: 7.3±1.5%) visited the laboratory on two occasions. On both visits, a 2-hour oral glucose tolerance test was performed, with venous blood samples collected 0, 30, 60, 90, and 120 min after ingestion of a high-glucose drink. Following ingestion of the drink, participants were exposed to either an intermittent hypoxia (IH) protocol, consisting of eight 4-min hypoxic cycles at a targeted arterial oxygen saturation of 80% interspersed with breathing room air to resaturation, or an intermittent normoxia (IN) protocol consisting of eight 4-min normoxic cycles interspersed with breathing room air. By design, oxygen saturation was lower during intermittent hypoxia than intermittent normoxia (81±3 vs. 97±1%, p&lt;0.01). Relative changes in plasma glucose concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 42±15 vs. 35±15; 60: 57±26 vs. 65±30; 90: 73±32 vs. 88±30; and 120: 78±26 vs. 83±29 mg/dl, interaction effect: p=0.13). Similarly, the relative changes in insulin concentrations in response to the oral glucose tolerance tests were not different between conditions (IH vs. IN: 30: 14±17 vs. 25±17; 60: 42±36 vs. 48±35; 90: 70±58 vs. 86±60; and 120: 103±72 vs. 125±94 ulU/ml, main effect for condition: p=0.12). While these preliminary results did not reach statistical significance, the observed trends for reduced glucose concentrations in combination with lower insulin concentrations during intermittent hypoxia suggest that short bouts of hypoxia improve glucose tolerance by stimulating glucose uptake independently from the action of insulin. Data from a larger sample size of adults with type 2 diabetes are needed to confirm these preliminary findings. None. This is the full abstract presented at the American Physiology Summit 2024 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Sleep patterns are associated with cardiometabolic risk factors in nine-year-old Swedish children.

Sleep duration and bedtime may play a role in children's cardiometabolic health, but research is lacking. This study examined associations between sleep patterns and cardiometabolic risk factors in Swedish nine-year-olds. This cross-sectional study used data from three studies, where identical outcome measures were conducted in 411 nine-year-olds, 51% boys, between 2016 and 2020. Sleep was assessed with wrist-worn accelerometers and sleep journals. Children were grouped based on meeting the sleep guidelines of 9-11 h and going to bed early or late based on the median bedtime. Analysis of covariance was used to examine associations between sleep patterns and cardiometabolic risk factors. Meeting sleep guidelines and going to bed early were associated with lower metabolic syndrome score (-0.15 vs. 0.42, p = 0.029), insulin resistance (0.30 vs. 0.60, p = 0.025) and insulin levels (6.80 vs. 8.87 mIU/L, p = 0.034), compared with their peers who did not meet the guidelines and went to bed later. When adjusting for total sleep time, analyses still showed associations with the metabolic syndrome score (-0.19 vs. 0.50, p = 0.011). The findings indicate that good sleep patterns could help mediate positive overall cardiometabolic health in children.

Pancreatic β-Cell Identity Change through the Lens of Single-Cell Omics Research.

The main hallmark in the development of both type 1 and type 2 diabetes is a decline in functional β-cell mass. This decline is predominantly attributed to β-cell death, although recent findings suggest that the loss of β-cell identity may also contribute to β-cell dysfunction. This phenomenon is characterized by a reduced expression of key markers associated with β-cell identity. This review delves into the insights gained from single-cell omics research specifically focused on β-cell identity. It highlights how single-cell omics based studies have uncovered an unexpected level of heterogeneity among β-cells and have facilitated the identification of distinct β-cell subpopulations through the discovery of cell surface markers, transcriptional regulators, the upregulation of stress-related genes, and alterations in chromatin activity. Furthermore, specific subsets of β-cells have been identified in diabetes, such as displaying an immature, dedifferentiated gene signature, expressing significantly lower insulin mRNA levels, and expressing increased β-cell precursor markers. Additionally, single-cell omics has increased insight into the detrimental effects of diabetes-associated conditions, including endoplasmic reticulum stress, oxidative stress, and inflammation, on β-cell identity. Lastly, this review outlines the factors that may influence the identification of β-cell subpopulations when designing and performing a single-cell omics experiment.

Immunoproteasomal Inhibition With ONX-0914 Attenuates Atherosclerosis and Reduces White Adipose Tissue Mass and Metabolic Syndrome in Mice.

Atherosclerosis is the major underlying pathology of cardiovascular disease and is driven by dyslipidemia and inflammation. Inhibition of the immunoproteasome, a proteasome variant that is predominantly expressed by immune cells and plays an important role in antigen presentation, has been shown to have immunosuppressive effects. We assessed the effect of ONX-0914, an inhibitor of the immunoproteasomal catalytic subunits LMP7 (proteasome subunit β5i/large multifunctional peptidase 7) and LMP2 (proteasome subunit β1i/large multifunctional peptidase 2), on atherosclerosis and metabolism in LDLr-/- and APOE*3-Leiden.CETP mice. ONX-0914 treatment significantly reduced atherosclerosis, reduced dendritic cell and macrophage levels and their activation, as well as the levels of antigen-experienced T cells during early plaque formation, and Th1 cells in advanced atherosclerosis in young and aged mice in various immune compartments. Additionally, ONX-0914 treatment led to a strong reduction in white adipose tissue mass and adipocyte progenitors, which coincided with neutrophil and macrophage accumulation in white adipose tissue. ONX-0914 reduced intestinal triglyceride uptake and gastric emptying, likely contributing to the reduction in white adipose tissue mass, as ONX-0914 did not increase energy expenditure or reduce total food intake. Concomitant with the reduction in white adipose tissue mass upon ONX-0914 treatment, we observed improvements in markers of metabolic syndrome, including lowered plasma triglyceride levels, insulin levels, and fasting blood glucose. We propose that immunoproteasomal inhibition reduces 3 major causes underlying cardiovascular disease, dyslipidemia, metabolic syndrome, and inflammation and is a new target in drug development for atherosclerosis treatment.

Smart Algorithms for Efficient Insulin Therapy Initiation in Individuals With Type 2 Diabetes: An in Silico Study.

Insulin-naive subjects with type 2 diabetes (T2D) start basal insulin titration from a low initial insulin dose (IID), which is adjusted weekly or twice per week based on fasting plasma glucose (FPG) measurement as recommended by the American Diabetes Association (ADA). The procedure to reach the optimal insulin dose (OID) is time-consuming, especially in subjects with high insulin needs (HIN). The aim of this study is to provide a fast and effective, but still safe, insulin titration algorithm in insulin-naive T2D subjects with HIN. To do that, we in silico cloned 300 subjects, matching a real population of insulin-naive T2D and used a logistic regression model to classify them as subjects with HIN or subjects with low insulin needs (LIN). Then, we applied to the subjects with HIN both a more aggressive insulin dose initiation (SMART-IID) and two newly developed titration algorithms (continuous glucose monitoring [CGM]-BASED and SMART-CGM-BASED) in which CGM was used to guide the decision-making process. The new titration algorithm applied to HIN-classified individuals guaranteed a faster reaching of OID, with significant improvements in time in range (TIR) and reduction in time above range (TAR) in the first months of the trial, without any clinically significant increase in the risk of hypoglycemia. Smart basal insulin titration algorithms enable insulin-naive T2D individuals to achieve OID and improve their glycemic control faster than standard guidelines, without jeopardizing patient safety.

IMO-PSO FO-PID controller based insulin infusion system for type 1 diabetes patients during post-operation condition

Blood Glucose level controls of type 1 diabetic patients (T1D) in post operative conditions are extremely important. This work proposes controllers for management and control of insulin injections to T1D in post operative care. Proposed work investigated IMO-PSO FO-PID controller as a novel approach to improve insulin delivery. The controller utilizes optimization algorithms to regulate insulin levels in real time. Particle swarm optimization (PSO) based tuning is already a proven method in insulin regulation and multiobjective PSO is well suited when combined with FO-PID which is tested. Additionally, system aims to achieve lower insulin levels, as high insulin levels have been linked to increase risks of complications for T1D patients. Results showed that IMO-PSO FO-PID controller is effective in improving glucose control, with patients experiencing fewer fluctuations and instances of hypoglycemia or hyperglycemia. Simulation results show that the use of the controller is very useful in managing blood glucose levels over a longer period and corresponding insulin infusion levels are also controlled well, which is much less than the previously reported control methodologies. This paper highlights potential benefits of using this controller in managing T1D and improving glucose control.

Spontaneous Akt2 deficiency in a colony of NOD mice exhibiting early diabetes.

Diabetes constitutes a major public health problem, with dramatic consequences for patients. Both genetic and environmental factors were shown to contribute to the different forms of the disease. The monogenic forms, found both in humans and in animal models, specially help to decipher the role of key genes in the physiopathology of the disease. Here, we describe the phenotype of early diabetes in a colony of NOD mice, with spontaneous invalidation of Akt2, that we called HYP. The HYP mice were characterised by a strong and chronic hyperglycaemia, beginning around the age of one month, especially in male mice. The phenotype was not the consequence of the acceleration of the autoimmune response, inherent to the NOD background. Interestingly, in HYP mice, we observed hyperinsulinemia before hyperglycaemia occurred. We did not find any difference in the pancreas' architecture of the NOD and HYP mice (islets' size and staining for insulin and glucagon) but we detected a lower insulin content in the pancreas of HYP mice compared to NOD mice. These results give new insights about the role played by Akt2 in glucose homeostasis and argue for the ß cell failure being the primary event in the course of diabetes.

Sustained insulin treatment restoring metabolic status, body weight, and cognition in an anorexia nervosa-like animal model in mice

IntroductionAnorexia Nervosa (AN) is a psycho-socio-biological disease characterized by severe weight loss as result of dieting and hyperactivity. Effective treatments are scarce, despite its significant prevalence and mortality. AN patients show lower basal insulin levels and increased metabolic clearance, leading to weight loss, cognitive deficits, and hormonal imbalances. Low-dose polymer insulin could potentially reverse these effects by restoring brain function, reducing fear of weight gain, encouraging food intake, and restoring fat depots. This study evaluates an insulin delivery system designed for sustained release and AN treatment. MethodsAN-like model was established through dietary restriction (DR). On days 1–25, mice were on DR, and on days 26–31 they were on ad libitum regimen. An insulin-loaded delivery system was administered subcutaneously (1% w/w insulin). The impact of insulin treatment on gene expression in the hippocampus (cognition, regulation of stress, neurogenesis) and hypothalamus (eating behavior, mood) was assessed. Behavioral assays were conducted to evaluate motor activity and cognitive function. ResultsThe delivery system demonstrated sustained insulin release, maintaining therapeutic plasma levels. Diet restriction mice treated with the insulin delivery system showed body weight restoration. Gene expression analysis revealed enhanced expression of CB1 and CB2 genes associated with improved eating behavior and cognition, while POMC expression was reduced. Insulin-polymer treatment restored cognitive function and decreased hyperactivity in the AN-like model. ConclusionThe PSA-RA-based insulin delivery system effectively restores metabolic balance, body weight, and cognitive function in the AN model. Its ability to steadily release insulin makes it a promising candidate for AN treatment."