Short Insulin Research Articles

Insulin resistance assessed by short insulin tolerance test and its association with obesity and insulin resistance-related parameters in humans: A pilot randomized trial.

The aim of this study was to examine the association of insulin resistance (evaluated by the short insulin tolerance test [SITT]) with parameters related to obesity and insulin resistance. We prospectively recruited controls and patients with type 2 diabetes mellitus (T2DM), subjected them to the SITT, and calculated the K indices of the intravenous insulin tolerance test (KITT(iv)) and the subcutaneous insulin tolerance test (KITT(sc)). We compared KITT(iv) results between the volunteers and patients and examined its correlation with KITT(sc). We also examined the association of KITT(iv) with obesity, insulin resistance-related parameters, and the insulin dose required for glycemic control. A total of 24 participants (seven controls and 17 patients with T2DM) were studied. The mean KITT(iv) was significantly lower in patients with T2DM than in the controls (2.5%±2.1% vs. 4.5%±1.8%). In all participants, KITT(iv) was significantly correlated with the homeostasis model assessment for insulin resistance (HOMA-IR) values (r = -0.601, p<0.05) but not with KITT(sc) (p = 0.62). KITT(iv) was correlated positively with the serum adiponectin concentration, but negatively with the visceral fat area and serum concentrations of tumor necrosis factor-α and branched-chain amino acids. In patients with T2DM, KITT(iv) and HOMA-IR values were significantly correlated with the total insulin dose required for glycemic control. Insulin resistance evaluated using KITT(iv) was correlated with the HOMA-IR values, but not with the resistance evaluated using KITT(sc). The degree of insulin resistance was associated with biomarkers, such as adiponectin, tumor necrosis factor-α, branched-chain amino acids, the visceral fat area, and the dose of insulin required for glycemic control.

SAT673 Novel Mutation Of TBX3 Associated With Morbid Obesity In Human

Abstract Disclosure: H.R. Alkaissi: None. B. Ji: None. S. McFarlane: None. Background: TBX3 is a transcription involved in the development of the heart conduction system, apocrine and mammary glands, limbs, and lung development and maturation, with variable oncogenic roles. Recently, the role of TBX3 and body weight control has been demonstrated in animal models, showing an essential role for TBX3 in hypothalamic arcuate neuronal maturation, function, and identity [1]. Case: 26-year-old woman referred for the management of morbid obesity and menstrual irregularities. The patient weighed 330 lbs, with a BMI of 55 kg/m2, with hypertension T2DM. The patient had a normal development until age five, after which she experienced regression in milestones and lost the ability to communicate, and was diagnosed with autism. She had a history of food-seeking behavior, leading to progressive weight gain, which was managed by blocking access to food, such as locking the fridge. The patient's weight fluctuated from 290 lbs to 330 lbs. Family history of T2DM in her maternal relatives. She was diagnosed with T2DM at the age of 18, with HbA1c level of 9.4%. Autoantibody testing was negative for glutamic acid decarboxylase (GAD), islet cell antibody (ICA), and zinc transporter 8 (ZnT8). The fasting C-peptide level was detectable at 1.87 ng/mL. T2DM was well controlled with an HbA1C range of 6.0-6.7% with the use of short and long-acting insulin regimen. However, with improved glycemic control, short-acting insulin was stopped and she was started on liraglutide. Syndromic obesity was suspected due to early-onset of the disease and the developmental regression. Testing for Prader-Willi syndrome was negative, based on a normal chromosome 15 methylation study. Leptin levels were elevated at 66 ng/mL, prompting further testing for obesity-related genetic mutations. Next-generation sequencing and targeted Sanger sequencing for 79 genes associated with obesity in human and animal models was performed. A novel mutation was identified in TBX3 activation domain, c. C1513T (p.P505S). UniProt peptide sequence alignment analyzed for sequence conservation. ClinVar, HGMD and GWAS Catalogue databases screened for similar variants. Discussion: We present the first case in human, where novel TBX3 mutation results in hypothalamic dysfunction, leptin resistance manifesting as morbid obesity, hyperphagia, and menstrual irregularities. The reported mutation in the activation domain (A) of TBX3. In silico analysis showed high evolutionary conservation of the mutated domain (across vertebrate species), indicating the mutation is likely pathogenic.

Insulin therapy and blood glucose management in critically ill patients: a 1-day cross-sectional observational study in 69 French intensive care units

BackgroundHyperglycaemia is common in critically ill patients, but blood glucose and insulin management may differ widely among intensive care units (ICUs). We aimed to describe insulin use practices and the resulting glycaemic control in French ICUs. We conducted a multicentre 1-day observational study on November 23, 2021, in 69 French ICUs. Adult patients hospitalized for an acute organ failure, severe infection or post-operative care were included. Data were recorded from midnight to 11:59 p.m. the day of the study by 4-h periods.ResultsTwo ICUs declared to have no insulin protocol. There was a wide disparity in blood glucose targets between ICUs with 35 different target ranges recorded. In 893 included patients we collected 4823 blood glucose values whose distribution varied significantly across ICUs (P < 0.0001). We observed 1135 hyperglycaemias (> 1.8 g/L) in 402 (45.0%) patients, 35 hypoglycaemias (≤ 0.7 g/L) in 26 (2.9%) patients, and one instance of severe hypoglycaemia (≤ 0.4 g/L). Four hundred eight (45.7%) patients received either IV insulin (255 [62.5%]), subcutaneous (SC) insulin (126 [30.9%]), or both (27 [6.6%]). Among patients under protocolized intravenous (IV) insulin, 767/1681 (45.6%) of glycaemias were above the target range. Among patients receiving insulin, short- and long-acting SC insulin use were associated with higher counts of hyperglycaemias as assessed by multivariable negative binomial regression adjusted for the propensity to receive SC insulin: incidence rate ratio of 3.45 (95% confidence interval [CI] 2.97–4.00) (P < 0.0001) and 3.58 (95% CI 2.84–4.52) (P < 0.0001), respectively.ConclusionsPractices regarding blood glucose management varied widely among French ICUs. Administration of short or long-acting SC insulin was not unusual and associated with more frequent hyperglycaemia. The protocolized insulin algorithms used failed to prevent hyperglycaemic events.Graphical

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

Twice-daily injections and multiple daily injections of insulin in toddlers with type 1 diabetes: a retrospective cohort study.

The Cognitive Improvement and Alleviation of Brain Hypermetabolism Caused by FFAR3 Ablation in Tg2576 Mice Is Persistent under Diet-Induced Obesity.

Obesity and aging are becoming increasingly prevalent across the globe. It has been established that aging is the major risk factor for Alzheimer's disease (AD), and it is becoming increasingly evident that obesity and the associated insulin resistance are also notably relevant risk factors. The biological plausibility of the link between high adiposity, insulin resistance, and dementia is central for understanding AD etiology, and to form bases for prevention efforts to decrease the disease burden. Several studies have demonstrated a strong association between short chain fatty acid receptor FFAR3 and insulin sensitivity. Interestingly, it has been recently established that FFAR3 mRNA levels are increased in early stages of the AD pathology, indicating that FFAR3 could play a key role in AD onset and progression. Indeed, in the present study we demonstrate that the ablation of the Ffar3 gene in Tg2576 mice prevents the development of cognitive deficiencies in advanced stages of the disease. Notably, this cognitive improvement is also maintained upon a severe metabolic challenge such as the exposure to high-fat diet (HFD) feeding. Moreover, FFAR3 deletion restores the brain hypermetabolism displayed by Tg2576 mice. Collectively, these data postulate FFAR3 as a potential novel target for AD.

The effect of krill oil supplementation on skeletal muscle function and size in older adults: A randomised controlled trial

The aim of this study was to determine the effect of krill oil supplementation, on muscle function and size in healthy older adults. Men and women, aged above 65 years, with a BMI less than 35kg/m2, who participated in less than 1h per week of structured self-reported exercise, were enrolled in the study (NCT04048096) between March 2018 and March 2020. Participants were randomised to either control or krill oil supplements (4g/day) for 6 months in this double blind randomised controlled trial. At baseline, 6 weeks and 6 months, knee extensor maximal torque was measured as the primary outcome of the study. Secondary outcomes measured were grip strength, vastus lateralis muscle thickness, short performance physical battery test, body fat, muscle mass, blood lipids, glucose, insulin, and C-Reactive Protein, neuromuscular (M-Wave, RMS and voluntary activation), and erythrocyte fatty acid composition. A total of 102 men and women were enrolled in the study. Ninety-four participants (krill group (26 women and 23 men) and placebo group (27 women and 18 men)) completed the study (mean (SD): age 71.2 (5.1) years and weight 71.8 (12.3) kg). Six months supplementation with krill oil resulted in, an increase in knee extensor maximal torque, grip strength and vastus lateralis muscle thickness, relative to control (p<0.05). The 6-month treatment effects were 9.3% (95%CI: 2.8, 15.8%), 10.9% (95%CI: 8.3, 13.6%) and 3.5% (95%CI: 2.1, 4.9%) respectively. Increases in erythrocyte fatty acid profile were seen with krill oil for EPA 214% (95%CI: 166, 262%), DHA 36% (95%CI: 24, 48%) and the omega-3 index 61% (95%CI: 49, 73%), relative to control (p<0.05). Krill oil resulted in an increased, relative to control (p<0.05), M-Wave of 17% (95%CI: 12.7, 38.1%) but there was no effect of krill oil on RMS, voluntary activation, or on any other secondary outcomes such as performance of the short performance physical battery test or quality of life. Krill oil supplementation for 6 months results in statistically and clinically significant increases in muscle function and size in healthy older adults. NCT04048096.

Biallelic POC1A variants cause syndromic severe insulin resistance with muscle cramps.

ObjectiveTo describe clinical, laboratory, and genetic characteristics of three unrelated cases from Chile, Portugal, and Saudi Arabia with severe insulin resistance, SOFT syndrome, and biallelic pathogenic POC1A variants.DesignObservational study.MethodsProbands’ phenotypes, including short stature, dysmorphism, and insulin resistance, were compared with previous reports.ResultsCases 1 (female) and 3 (male) were homozygous for known pathogenic POC1A variants: c.649C>T, p.(Arg217Trp) and c.241C>T, p.(Arg81*), respectively. Case 2 (male) was compound heterozygous for p.(Arg217Trp) variant and the rare missense variant c.370G>A, p.(Asp124Asn). All three cases exhibited severe insulin resistance, acanthosis nigricans, elevated serum triglycerides and decreased HDL, and fatty liver, resembling three previously reported cases. All three also reported severe muscle cramps. Aggregate analysis of the six known cases with biallelic POC1A variants and insulin resistance showed decreased birth weight and length mean (s.d.): −2.8 (0.9) and −3.7 (0.9) SDS, respectively), severe short stature mean (s.d.) height: −4.9 (1.7) SDS) and moderate microcephaly (mean occipitofrontal circumference −3.0 (range: −4.7 to −1.2)). These findings were similar to those reported for patients with SOFT syndrome without insulin resistance. Muscle biopsy in Case 3 showed features of muscle involvement secondary to a neuropathic process.ConclusionsPatients with SOFT syndrome can develop severe dyslipidaemic insulin resistance, independent of the exonic position of the POC1A variant. They also can develop severe muscle cramps. After diagnosis, patients should be regularly screened for insulin resistance and muscle complaints.

Comparing clinical outcomes between two continuous glucose monitors: similar diabetes-related events, all-cause hospitalizations and HbA1c reductions in type 1 and type 2 diabetes

ObjectivesWe compared clinical outcomes after acquiring a FreeStyle Libre© Flash Continuous Glucose Monitoring System (FSL) or Dexcom (DEX) continuous glucose monitoring (CGM) device in individuals with type 1 diabetes (T1D) and type 2 diabetes (T2D) treated with intensive insulin therapy. Design and MethodsThis retrospective analysis of the IBM® MarketScan® Research Databases and IBM® Explorys® Electronic Health Records Database assessed differences in acute diabetes-related events (ADE), all-cause hospitalizations (ACH) and glycated hemoglobin (HbA1c) in T1D and T2D populations 6 months post CGM acquisition. Analyses were conducted in two study cohorts (Cohort 1, n = 7,494; Cohort 2, n = 678). Participants were T1D or T2D, age ≥ 18 years, treated with short or rapid-acting insulin and naïve to CGM, who acquired a CGM system. Users were propensity score matched on demographics and clinical factors. ResultsCohort 1: Post-CGM ADE-free rates at 6 months ranged from 94.8 to 96.7% and ACH-free rates ranged from 90.4 to 95.4%, for both T1D and T2D groups, with no significant differences between CGM systems. Cohort 2: Significant HbA1c reductions were associated with use of the DEX and FSL devices in the T1D (-0.35% and -0.37%, respectively) and T2D (-0.73% and -0.79%, respectively) cohorts, both p < 0.001, with no significant differences in the magnitude of reduction between systems (T1D p = 0.99 and T2D p = 0.84). ConclusionsAcquisition of the FSL and DEX systems was associated with similar rates of acute diabetes-related events and all-cause hospitalizations and similar HbA1c reductions in adults with T1D and T2D.

Insulin biosimilars in clinical practice

Diabetes mellitus (DM) is an important medical and social problem throughout the world due to its high prevalence. At the same time, the majority of patients have type 2 diabetes. The onset of the disease is gradual, with a prolonged asymptomatic preclinical stage. Therefore, it is necessary to conduct screening among patients at risk. Therapy for type 2 diabetes is carried out with oral hypoglycemic drugs. If it is impossible with their help to achieve adequate glycemic control, it is possible to add basal insulin to therapy, and if the own insulin secretion is depleted, an intensive insulin therapy regimen must be prescribed. Insulin preparations differ in the source of receipt, as well as in the duration of action: background, or basal (insulin of medium duration, long-term or ultra-long-acting) and prandial, or food (ultrashort and short insulin). Currently, along with original insulin preparations, their analogues, or biosimilars (biosimilars), appear on the pharmaceutical market. Biosimilar (biosimilar) is a biological product similar in quality, efficacy and safety parameters to a reference biological medicinal product in the same dosage form and having an identical route of administration. Biosimilars are used all over the world, and this applies not only to insulin preparations, but also to other biological preparations. Proof of bioequivalence is a long-term process that ensures comparability and the absence of clinically significant differences between the study and the reference drug, and includes preclinical and clinical studies. The task of studies of biosimilars of insulin is to confirm the comparability with a reference, previously well-studied biological product. The efficacy and safety of domestically produced biosimilars has been studied in a number of clinical studies, during which the bioequivalence of the drugs was shown. These drugs are of high quality and safe, and their pharmacological characteristics, immunogenicity and effectiveness do not differ from the original drugs.

Insulin regulates arginine-stimulated insulin secretion in humans

AimsInsulin potentiates glucose-stimulated insulin secretion. These effects are attenuated in beta cell–specific insulin receptor knockout mice and insulin resistant humans. This investigation examines whether short duration insulin exposure regulates beta cell responsiveness to arginine, a non-glucose secretagogue, in healthy humans. Materials and methodsArginine-stimulated insulin secretion was studied in 10 healthy humans. In each subject arginine was administered as a bolus followed by continuous infusion on two occasions one month apart, after sham/saline or hyperinsulinemic-isoglycemic clamp, respectively providing low and high insulin pre-exposure conditions. Arginine-stimulated insulin secretion was measured by C-peptide deconvolution, and by a selective immunogenic (DAKO) assay for direct measurement of endogenous but not exogenous insulin. ResultsPre-exposure to exogenous insulin augmented arginine-stimulated insulin secretion. The effect was seen acutely following arginine bolus (endogenous DAKO insulin incremental AUC240-255min 311.6 ± 208.1 (post-insulin exposure) versus 120.6 ± 42.2 μU/ml•min (sham/saline) (t-test P = 0.021)), as well as in response to continuous arginine infusion (DAKO insulin incremental AUC260-290min 1095.3 ± 592.1 (sham/saline) versus 564.8 ± 207.1 μU/ml•min (high insulin)(P = 0.009)). Findings were similar when beta cell response was assessed using C-peptide, insulin secretion rates by deconvolution, and the C-peptide to glucose ratio. ConclusionsWe demonstrate a physiologic role of insulin in regulation of the beta cell secretory response to arginine.

A comparative study between topical short and long-acting insulin preparations in management of wounds in diabetic patients

Wounds of diabetic patients often require weeks of adequate and appropriate care for full recovery. The use of systemic insulin in diabetic patients was reported to enhance wound healing. Thus, the present study was conducted to evaluate the effect of topical insulin on diabetic wounds. Our objective was to compare the effectiveness of topical short and long acting insulin combined with standard wound dressings in healing of wounds in diabetic patients. Thirty adult patients of both sexes from the outpatient settings of the General and Plastic surgery wards at Minia University Hospital were included in the study. Patients were assigned into three groups; control, patients applying short acting insulin and those applying long-acting insulin. The wounds were compared for healing time, inflammation and pain at days 0, 14, and 21. The mean age of patients included in the study was 58.9±5.3 years. The unit healing time for diabetic control group was 25.1±22.9 which was significantly higher than the two other groups (10.02±5.4 and 5.1±2.4, respectively) with no significant difference between topical short and long-acting insulin applying groups. Upon scoring of wounds, the long acting score of the short acting insulin was significantly lower than the control group at day 14 (p=0.001) while both topical insulin groups showed significantly reduced scores at day 21 compared to the control group (p=0.001 and p=0.009 for short and long-acting insulin, respectively). Both topical insulin treatments resulted in an acceleration of the wound healing process with no significant difference between short and long-acting insulin.

Combined Effects of Insulin Resistance and Inflammation on Comorbidities of Type 2 Diabetes

Background: Insulin resistance (IR) and inflammation are closely related to each other and share common pathophysiological and metabolic mechanisms. We aimed to investigate the combined effect of IR and inflammation on comorbidities of type 2 diabetes mellitus (T2DM). Methods: A total 3,758 patients with T2DM were recruited through Huh’s Diabetes Center from January 2003 to June 2009. Insulin sensitivity was measured by a rate constant for plasma glucose disappearance (&lt;i&gt;Kitt&lt;/i&gt; , %/min) using short insulin tolerance test. High sensitivity C-reactive protein (hs-CRP) was used as a surrogate for inflammation.Results: Patients with the lowest tertile of &lt;i&gt;Kitt&lt;/i&gt; (IR group) showed worse cardio-metabolic parameters while those with the highest tertile of hs-CRP levels had worse cardio-metabolic parameters. The prevalence of metabolic syndrome, fatty liver, albuminuria, and carotid atherosclerosis decreased with &lt;i&gt;Kitt&lt;/i&gt; tertile, but increased with hs-CRP tertile. In multiple regression analysis, both &lt;i&gt;Kitt&lt;/i&gt; and hs-CRP were independent risk factors for comorbidities of T2DM. In addition, they showed synergistic effects on these comorbidities. Conclusion: Both IR and inflammation were significantly associated with comorbidities of T2DM in a dose dependent manner. In addition, the coexistence of IR and inflammation may synergistically contribute to increased comorbidities of T2DM.

Discrepancy between short synacthen test (sst) and insulin stimulation test (ist)

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

STUDY OF THE SPECIFIC ACTIVITY OF THE PHYTOCOMPOSITION ON THE DEXAMETHASONE-INDUCED INSULIN RESISTANCE

Introduction. Type 2 diabetes mellitus (DM2) has recently become an epidemic in the population. There are approximately 463 million patients in the world, and according to experts from the International Diabetes Federation, it is expected to increase to 700 million people by 2045, of which more than 90 % will fall on DM2. Despite the significant progress made in studying the pathogenesis of DM, the presence of a wide range of antidiabetic drugs, diabetes remains an acute medical and social problem.&#x0D; The aim of the study – to investigate the specific activity of the phytocomposition, which contains dry extracts of white mulberry leaves (Morus alba L.), common beans shells (Phaseolus vulgaris L.), bilberry sprouts (Vaccinium myrtillus L.) in the experimental model of insulin resistance caused by dexamethasone injections.&#x0D; Research Methods. The experiments were performed on male rats aged three months and weight (200±20) g. Experimental animals were divided into the following groups: negative and positive control, two reference groups, which received Arfazetin and metformin respectively, and experimental group, which received phytocomposition. Insulin resistance was modeled by intramuscular administration of glucocorticosteroid dexamethasone (0.125 mg/kg daily for 13 days in the morning). The state of glucose homeostasis was assessed by changes in basal glycemia and under oral glucose tolerance test, short insulin and adrenalin test. Functional glycemic coefficients were also calculated. Statistical processing was performed using computer programs IBM SPSS Statistics v.10.1 and MS Excel 2010.&#x0D; Results and Discussion. Basal glycemia after modeling insulin resistance in the experimental group, which received the phytocomposition, was significantly lower by 19.0 % from the positive control group and did not differ from the activity of metformin. During the oral glucose tolerance test, the phytocomposition significantly inhibited the growth of glycemia in all studied periods relative to the indicators of the positive control group. Functional glycemic coefficients, which were obtained based on test data, did not exceed the norm. Insulin sensitivity under the influence of phytomedicine increased by 16.2 % above the positive control group, indicating inhibition of insulin resistance development under its influence. The studied phytocomposition inhibited the development of adrenaline glycemia by 42.9, 70.2 % after 30 and 90 min, respectively, relative to the positive control group, which corresponds to the indicators of the negative control group and reference group, which received Arfazetin, but this decrease is not enough to exceed the effect of metformin.&#x0D; Conclusions. The obtained results indicate that the studied phytocomposition inhibits the development of insulin resistance and carbohydrate tolerance in the conditions of insulin resistance caused by the introduction of dexamethasone.

A Comparison of Short Sleep Duration and Insulin Resistance Association in Children Aged 13-15 Years Old and 16-18 Years Old

Background: Adolescents have unique sleep patterns and reduced sleep duration due to hormonal, activity, and environmental influences. Short sleep duration could be a factor in obesity, and insulin resistance might cause various metabolic problems. Several previous studies have conveyed different results. The present study analyzed the relationship between sleep duration and insulin resistance in obese adolescents with metabolic syndrome. Methods: A total of 62 adolescents aged 13-15 years and 62 adolescents aged 16-18 years who met the criteria for metabolic syndrome based on the International Diabetes Federation 2007 from 12 secondary schools in Surabaya and Sidoarjo. Insulin resistance was determined using the Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) with a cutoff value of >3.54. Sleep duration was determined based on direct interviews with research subjects and classified as short sleep duration when sleep duration was < 8 hours. The obtained data were analyzed using Chi-Square, Mann-Whitney, and T-test (significant at p<0.05). Results: The subjects were dominated by male adolescents (67.7%). There was a meaningful relationship between age and sleep duration (p = 0.035). The 16-18 year age group had more short sleep duration. The results of the analysis showed that there was a relationship between short sleep duration and the incidence of insulin resistance in both age groups, in the 13-15 year age group (PR 1.78; phi coefficient 0.430; p<0.001) and in the 16-18 year age group (PR 2.90; phi coefficient 0.478; p<0.001). Conclusion: Short sleep duration is associated with insulin resistance in obese adolescents with metabolic syndrome.

STUDY OF SPECIFIC ANTIDIABETIC EFFECT OF PERSPECTIVE SIRTUIN-1 ACTIVATOR PYRABENTIN ON THE MODEL OF METABOLIC MEMORY IN RATS

Pharmacological activation of sirtuin-1 (SIRT1), which can mimic calorie restriction, reduce fat deposition along with stimulating its utilization, and possibly erase "metabolic memory", is a promising goal for the prevention and treatment of obesity and type 2 diabetes. The aim of the study was to evaluate the specific antidiabetic effect of the original heterocyclic compound with the proprietary name pyrabentin with in situ proven ability to activate human sirtuin-1 on the experimental model of "metabolic memory" in rats.&#x0D; The study was conducted on adult male Wistar rats (n=24), which were kept on a high-fat diet (HFD) for 5 months, control sex- and age-matched animals (n=6) were received standard diet (StD). At the end of the 5-mo HFD-period, the animals were randomized for the study over the next two months into 4 groups as follows: HFD/HFD+placebo, HFD/StD+placebo, HFD/StD+pyrabentin (PB), HFD/StD+metformin (MF). PB was administered orally at 50 mg/kg body weight as an aqueous suspension with Tween-80 daily, the reference drug metformin was administered in a similar way at 100 mg/kg body weight, the control group received a placebo. Glucose tolerance test and short insulin test were performed, body weight, abdominal adipose tissue weight by fraction and blood pressure were assessed. Shapiro-Wilk test, paired and unpaired Student’s t-test, and Mann-Whitney U-test were used.&#x0D; It was found that 60-day administration of pyrabentin to rats with a model of "metabolic memory", insulin resistance and obesity, was realized in a statistically significant decrease in basal glycemia, glucose intolerance, body weight and weight of abdominal adipose tissue fractions with comparable efficacy to the reference drug. This was accompanied by improved insulin sensitivity and blood pressure.

Menstrual dysfunction in polycystic ovary syndrome: association with dynamic state insulin resistance rather than hyperandrogenism

To examine the relation of menstrual cyclicity abnormalities to hyperandrogenism (HA) and dynamic state insulin resistance (IR) in oligo-ovulatory women with polycystic ovary syndrome (PCOS). Prospective cross-sectional study. Tertiary-care academic center. Fifty-seven women with PCOS (1990 National Institutes of Health criteria) and 57 healthy control women matched by body mass index (BMI). Short insulin tolerance test (ITT). Menstrual cyclicity, sex hormone-binding globulin (SHBG), measures of HA (i.e., modified Ferriman-Gallwey score, total and free testosterone, dehydroepiandrosterone sulfate), and the rate constant for plasma glucose disappearance (kITT) derived from the short ITT. Adjusting for age, BMI, and ethnicity, the mean androgen measures were higher and SHBG trended lower, kITT was lower, and the prevalence of IR was higher in PCOS than in controls, independent of menstrual cyclicity. The optimal cutoff point for IR was set at kITT value of 3.57%/minute or lower. Overall, 79% of the women with PCOS had IR. To control further for the effect of ethnicity, a subgroup of 46 non-Hispanic white PCOS participants were studied; those who exhibited amenorrhea (n = 15) or oligomenorrhea (n = 19) had or tended toward having a lower kITT and a higher prevalence of IR than the women with PCOS and oligo-ovulatory eumenorrhea (n = 12). The kITT trended lower and the prevalence of IR trended higher in women with PCOS and amenorrhea than those with oligomenorrhea. The measures of SHBG and HA were similar across the three menstrual groups. Oligo-ovulatory women with PCOS and overt oligo/amenorrhea have greater degrees of IR but not HA when compared with oligo-ovulatory eumenorrheic women with PCOS, suggesting that IR and hyperinsulinemia but not HA play a role in determining the degree of menstrual dysfunction, which can be used as a clinical marker for the degree of IR in oligo-ovulatory PCOS.

Artificial pancreas under stable pulsatile MPC: Improving the closed-loop performance

This work presents a pulsatile Zone Model Predictive Control (pZMPC) for the control of blood glucose concentration (BGC) in patients with Type 1 Diabetes Mellitus (T1DM). The main novelties of the algorithm – in contrast to other existing strategies – are: (i) it controls the patient glycemia by injecting short duration insulin boluses for both, the basal and bolus infusions, in an unified manner, (ii) it performs the predictions and estimations (critical to anticipate both, hypo and hyperglycemia) based on a physiological individualized long-term model, (iii) it employs disturbance observers to compensate plant-model mismatches, (iv) it ensures, under standard assumptions, closed-loop stability, and (v) it can be used – under minor modifications – as an optimal basal–bolus calculator to emulate conventional therapies. Because of the latter characteristic, a significantly better performance is achieved, not only in terms of classical indexes (time in the normoglycemia zone, avoidance of hypoglycemia in the short term, avoidance of hyperglycemia in the long term) but also in terms of its applicability (use of the pump or injections). Such a performance is tested in a cohort of in-silico patients from the FDA-accepted UVA/Padova simulation platform, considering the most challenging scenarios.

Associations between sleep duration and insulin resistance in European children and adolescents considering the mediating role of abdominal obesity.

Short sleep duration has been suggested to lead to insulin resistance both directly by altering glucose metabolism and indirectly through obesity. This study aims to investigate associations between nocturnal sleep duration and insulin resistance considering abdominal obesity as a mediator. We analysed data of 3 900 children aged 2-15 years participating in the second (2009/10) and third (2013/14) examination wave of the European IDEFICS/I.Family study (hereafter referred to as baseline and follow-up). Information on nocturnal sleep duration was collected by questionnaires and age-standardised (SLEEP z-score). The homeostasis model assessment (HOMA) was calculated from fasting insulin and fasting glucose obtained from blood samples; waist circumference (WAIST) was measured with an inelastic tape. HOMA and WAIST were used as indicators for insulin resistance and abdominal obesity, respectively, and transformed to age- and sex-specific z-scores. Cross-sectional and longitudinal associations between SLEEP z-score and HOMA z-score were investigated based on a path model considering WAIST z-score as a mediator adjusting for relevant confounders. Cross-sectionally, baseline SLEEP z-score was negatively associated with baseline WAIST z-score (unstandardised effect estimate -0.120, 95% confidence interval [-0.167; -0.073]). We observed no direct effect of baseline SLEEP z-score on baseline HOMA z-score but a negative indirect effect through baseline WAIST z-score (-0.042 [-0.058; -0.025]). Longitudinally, there was no direct effect of baseline SLEEP z-score on HOMA z-score at follow-up but a negative indirect effect through both baseline WAIST z-score and WAIST z-score at follow-up (-0.028 [-0.040; -0.016]). Our results do not support the hypothesis of an association between short sleep duration and insulin resistance independent of abdominal obesity. However, longer sleep duration may exert short and long term beneficial effects on insulin resistance through its beneficial effects on abdominal obesity.

19-LB: Treatment Intensification and Risk of Cardiovascular Events in Insulin-Treated Patients with Type 2 Diabetes: A United Kingdom Retrospective Cohort Study

Using the Clinical Practice Research Datalink, adults diagnosed with T2DM newly initiated with a basal long/intermediate-acting insulin from January 2004 to December 2016 were identified. First change or add on of short or premix insulin and/or OADs was defined as intensification. Patients were categorized into three groups; uncontrolled glycaemia at baseline (≥7% HbA1c) and early (within 1-year) intensifiers, and uncontrolled glycaemia at baseline and delayed (&amp;gt;1-year) intensifiers and uncontrolled-non-intensifiers as a reference groups. A total of n=8,538 patients were included; 32.95% (n=2,813) were uncontrolled-glycaemic-early intensifiers, 28.91% (n=2,468) were uncontrolled glycaemic-delayed intensifiers, and 38.15% (n=3,257) were non-intensifiers. Majority of the early and delayed intensified patients were males (54.60% and 57.41% respectively) and the average age was 62.40years. Non-intensifiers were older (67.72 years) and had a greater number of risk factors. Median baseline HbA1c was 85.90mmol/mol [10.01%] (IQR, 73.9-101.0 mmol/mol; 8.91-11.39%) and 82.50mmol/mol [9.70%] (IQR, 71.60-96.70mmol/mol, 8.70-11.00%) in the early and delayed treatment intensified group respectively. Early treatment intensification within 1-year post basal insulin therapy was linked to 18% (HR CI: 0.65, 1.03), 23% (HR CI: 0.58, 1.02) and 28% (HR CI: 0.58, 0.93) reduction in the risk of HF, MI and stroke respectively. CVE risk was also reduced in the delayed versus non-intensified group. In conclusion, large proportion of patients remain non-intensified post basal insulin despite poor glycemic control, timely intensification in primary care is thus central in minimising CVE complications. Disclosure M. Adan: None. S. Seidu: Advisory Panel; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Servier. Board Member; Self; Novartis Pharmaceuticals Corporation, Novo Nordisk Inc. Research Support; Self; AstraZeneca, Janssen Pharmaceuticals, Inc., Sanofi-Aventis. Speaker’s Bureau; Self; Amgen, Lilly Diabetes, Merck Sharp &amp; Dohme Corp. K. Khunti: Advisory Panel; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Board Member; Self; AstraZeneca, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novo Nordisk A/S, Sanofi-Aventis. Consultant; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. Research Support; Self; AstraZeneca, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Merck Sharp &amp; Dohme Corp., Novartis AG, Novo Nordisk A/S, Pfizer Inc., Sanofi-Aventis, Servier. Speaker’s Bureau; Self; Amgen, AstraZeneca, Bayer AG, Berlin-Chemie AG, Boehringer Ingelheim International GmbH, Eli Lilly and Company, Menarini Group, Merck Sharp &amp; Dohme Corp., Napp Pharmaceuticals, Novartis AG, Novo Nordisk A/S, Roche Pharma, Sanofi-Aventis, Servier. F. Zaccardi: Speaker’s Bureau; Self; Napp Pharmaceuticals. C.L. Gillies: None. R. Lubwama: Employee; Self; Sanofi US. A.H. Boss: Employee; Self; Sanofi. Stock/Shareholder; Self; Novo Nordisk Inc., Sanofi. T.A. Dex: Consultant; Self; Sanofi US. Stock/Shareholder; Self; Bayer Healthcare Pharmaceuticals Inc., Pfizer Inc., Teva Pharmaceutical Industries Ltd.