Fasting Plasma Insulin Concentrations Research Articles

P-633 Impact of insulin resistance on reproductive medicine outcomes

Abstract Study question Does Homeostasis Model Assessment for insulin resistance (HOMA-IR) have an influence in reproductive medicine outcomes? Summary answer HOMA-IR is associated with fertility treatment parameters and has a significant influence on reproductive medicine outcomes. What is known already The HOMA model is used to yield an estimate of insulin sensitivity from basal (fasting) plasma insulin and glucose concentrations. Currently, the model has become a widely used clinical tool to evaluate glucose metabolism. Regarding fertility, the relation between polycystic ovary syndrome (PCOS) and insulin resistance (IR) has been studied. Insulin resistance may be potential contributor to impaired treatment outcomes in artificial reproductive technology (ART). Although a few studies have recently been published on the topic the association of HOMA-IR with fertility treatment parameters remains a black box in reproductive medicine research. Study design, size, duration The observational study was designed and conducted at the Kinderwunsch Institut Schenk GmbH (Dobl, Austria). The study included 175 patients (25 men and 150 women), aged 18-45. HOMA-IR was determined for each patient and then correlated with patient’s medical history, fertility treatment parameters and outcomes. Participants/materials, setting, methods HOMA-IR was determined by taking a blood sample during fasting state and measuring plasma values of glucose (mg/dl) and insulin (mU/ml). A HOMA-IR of ≥ 2 was considered as insulin resistance. HOMA-IR was correlated with medical history (polycystic ovarian syndrome (PCOS), endometriosis, Body-Mass-Index (BMI), nicotine abuse) and fertility treatment parameters (sperm quality, number of retrieved oocytes after controlled ovarian stimulation, number of mature and fertilized oocytes, embryo quality and pregnancy rate). Main results and the role of chance An increased HOMA-IR (³2) was observed in 90 patients (51.4%). They suffered from obesity (n = 36; 80%), PCOS (n = 22; 70.97%), ovarian hyperstimulation syndrome (n = 17; 77.27%) and experienced poor embryo quality (n = 249; 91.54%). A significant positive correlation was found between HOMA-IR and PCOS (p < 0.001), obesity (p < 0.001) and number of retrieved oocytes (p < 0.05). The pregnancy rate correlated negatively with the HOMA-IR (p < 0.001). Furthermore, trends of positive correlations of high HOMA-IR in endometriosis, BMI, pathological spermiogram, nicotine abuse and increased number of mature oocytes were determined. The relation between HOMA-IR and the number of retrieved and mature oocytes is consistent with its relation to PCOS. The data show that HOMA-IR is associated with fertility treatment parameters and has a significant influence on ART outcome. Limitations, reasons for caution The number of patients may be seen as a study limitation. Results should be confirmed with a bigger sample size. An interventional study should confirm the role of HOMA-IR in IVF outcomes. Wider implications of the findings These findings may help to better understand the importance of glucose and insulin metabolism in reproduction and suggest that evaluation of HOMA-IR may be a valuable parameter to be considered when collecting patients’ anamnesis prior to starting ART treatment. Trial registration number not applicable

The impact of short-term eucaloric low- and high-carbohydrate diets on liver triacylglycerol content in males with overweight and obesity: a randomized crossover study

BackgroundIntrahepatic triacylglycerol (liver TG) content is associated with hepatic insulin resistance and dyslipidemia. Liver TG content can be modulated within days under hypocaloric conditions. ObjectivesWe hypothesized that 4 d of eucaloric low-carbohydrate/high-fat (LC) intake would decrease liver TG content, whereas a high-carbohydrate/low-fat (HC) intake would increase liver TG content, and further that alterations in liver TG would be linked to dynamic changes in hepatic glucose and lipid metabolism. MethodsA randomized crossover trial in males with 4 d + 4 d of LC and HC, respectively, with ≥2 wk of washout. 1H-magnetic resonance spectroscopy (1H-MRS) was used to measure liver TG content, with metabolic testing before and after intake of an LC diet (11E% carbohydrate corresponding to 102 ± 12 {mean ± standard deviation [SD]) g/d, 70E% fat} and an HC diet (65E% carbohydrate corresponding to 537 ± 56 g/d, 16E% fat). Stable [6,6-2H2]-glucose and [1,1,2,3,3-D5]-glycerol tracer infusions combined with hyperinsulinemic-euglycemic clamps and indirect calorimetry were used to measure rates of hepatic glucose production and lipolysis, whole-body insulin sensitivity and substrate oxidation. ResultsEleven normoglycemic males with overweight or obesity (BMI 31.6 ± 3.7 kg/m2) completed both diets. The LC diet reduced liver TG content by 35.3% (95% confidence interval: −46.6, −24.1) from 4.9% [2.4–11.0] (median interquartile range) to 2.9% [1.4–6.9], whereas there was no change after the HC diet. After the LC diet, fasting whole-body fat oxidation and plasma beta-hydroxybutyrate concentration increased, whereas markers of de novo lipogenesis (DNL) diminished. Fasting plasma TG and insulin concentrations were lowered and the hepatic insulin sensitivity index increased after LC. Peripheral glucose disposal was unchanged. ConclusionsReduced carbohydrate and increased fat intake for 4 d induced a marked reduction in liver TG content and increased hepatic insulin sensitivity. Increased rates of fat oxidation and ketogenesis combined with lower rates of DNL are suggested to be responsible for lowering liver TG. This trial was registered at clinicaltrials.gov as NCT04581421.

Short-term high-calorie high-fat feeding induces hyperinsulinemia and blunts skeletal muscle microvascular blood flow in healthy humans.

Skeletal muscle microvascular blood flow (MBF) plays an important role in glucose disposal in muscle. Impairments in muscle MBF contribute to insulin resistance and prediabetes. Animal studies show that short-term (3 day) high-fat feeding blunts skeletal muscle MBF before impairing insulin-stimulated glucose disposal. It is not known whether this occurs in humans. We investigated the temporal impact of a 7-day high-calorie high-fat (HCHF) diet intervention (+52% kJ; 41% fat) on fasting and postprandial cardiometabolic outcomes in 14 healthy adults (18-37 yr). Metabolic health and vascular responses to a mixed-meal challenge (MMC) were measured at pre (day 0)-, mid (day 4)- and post (day 8)-intervention. There were no significant differences in body weight, body fat %, fasting blood glucose, and fasting plasma insulin concentrations at pre-, mid- and postintervention. Compared with preintervention there was a significant increase in insulin (but not glucose) total area under the curve in response to the MMC at midintervention (P = 0.041) and at postintervention (P = 0.028). Unlike at pre- and midintervention, at postintervention muscle MBF decreased at 60 min (P = 0.024) and 120 min (P = 0.023) after the MMC. However, macrovascular blood flow was significantly increased from 0 to 60 min (P < 0.001) and 120 min (P < 0.001) after the MMC at pre-, mid- and postintervention. Therefore, short-term HCHF feeding in healthy individuals leads to elevated postprandial insulin but not glucose levels and a blunting of meal-induced skeletal muscle MBF responses but not macrovascular blood flow responses.NEW & NOTEWORTHY This is the first study to investigate skeletal muscle microvascular blood flow (MBF) responses in humans after short-term high-calorie high-fat (HCHF) diet. The main findings were that HCHF diet causes elevated postprandial insulin in healthy individuals within 3 days and blunts meal-induced muscle MBF within 7 days, despite no impairments in postprandial glucose or macrovascular blood flow.

Cluster analysis based on fasting and postprandial plasma glucose and insulin concentrations

Cluster analysis based on fasting and postprandial plasma glucose and insulin concentrations

Insulin's Function in Health and Disease

Insulin is a polypeptide hormone that is primarily released by cells in the pancreatic islets of Langerhans. The hormone may work in tandem with glucagon to control blood sugar levels; glucagon has catabolic properties while insulin has anabolic ones. Insulin controls blood glucose levels and causes the liver, muscles, and adipose tissue to store glucose, which causes total weight gain. Insulin plays a crucial role in the initiation and development of many chronic diseases because it modulates a variety of physiological processes. Other techniques are based on the exogenous infusion of glucose or insulin, or both, either under steady-state (the insulin suppression test) or under dynamic conditions (the insulin tolerance test, intravenous glucose-tolerance test with minimal model analysis, and constant infusion of glucose with model analysis). Homeostatic model assessment uses fasting plasma glucose and insulin concentrations to derive indices of insulin sensitivity and secretion from a mathematical model.

FRI364 A Case Of Carcinoid Syndrome Symptoms Masked By Niacin Use

Abstract Disclosure: S. Yang: None. R. Sharag Eldin: None. D. Teves Qualler: None. Case Presentation: A 72 male presented with worsening of facial flushing and diarrhea for 10 years. The patient described episodic feeling of hotness in the face associated with red- purplish discoloration of his facial skin lasting for 2 to 3 minutes. He has had 5 to 6 episodes per day. The patient reported the use of Niacin in the past and it was believed that it was the cause of his flushing episodes despite its persistence for years after stopping it. The patient also suffered from long standing diarrhea which started around the same time of the flushing. Diarrhea has been watery or loose and he has 5 to 6 bowel movements a day. His symptoms were concerning for Carcinoid syndrome and a 24-hour urine collection for HIAA showed elevated HIAA to 108.7 mg/24 hour (&amp;lt;6 mg/24 hour). A CT scan of the abdomen revealed a 1.8 cm wall thickness in the cecum and a 3.6 cm spiculated mesenteric mass with central calcification with multiple hypervascular masses in the liver concerning for a metastatic neuroendocrine tumor. Core biopsy of one of the liver masses showed a well differentiated neuroendocrine tumor. He was also found to have tricuspid valve regurgitation as well as a Glycohemoglobin of 9%. The patient was treated medically with octreotide rather than surgery due to the significant disease burden. Interestingly, he was initially started on Lanreotide but developed foreign body granulomas at the injection sites. Discussion: Carcinoid-syndrome is a category of well-differentiated neuroendocrine neoplasms. The overproduction of serotonin is most used to assess the presence of carcinoid syndrome via its breakdown product 5- HIAA in the urine. Symptoms from niacin supplementation are variable and may include flushing and constipation. Patient’s flushing presented for years after discontinuing niacin supplementation. However, clinicians continued to attribute it to its use despite typical resolution of symptoms within 3 hours of discontinuing use. Niacin exposure may have been a mimicker of his underlying neuro endocrine neoplasia (NEN) as diarrhea is also an overlapping feature as seen in our patient’s presentation. DM as seen in our patient is not well documented in relation to carcinoid syndrome. One study (n=10) of the patients with functionally active NENs, 70% had borderline to diabetic-level blood glucose. Of the patients with carcinoid syndrome, there was no significant difference in fasting plasma glucose concentration or fasting plasma insulin concentration when compared to age-matched normal volunteers. Conclusion: Clinicians should have low level of suspicion in diagnosing carcinoid syndrome in the presence of typical symptoms of flushing and diarrhea. Due to the past use of niacin, our patient’s diagnosis was delayed despite the persistence of flushing years after stopping it. Presentation: Friday, June 16, 2023

Serum alanine transaminase is predictive of fasting and postprandial insulin and glucagon concentrations in type 2 diabetes

The liver plays a key role in glucose homeostasis. Serum liver enzyme levels, including alanine transaminase (ALT), aspartate transaminase (AST) and gamma-glutamyl transferase (GGT), are reportedly predictive of the risk of type 2 diabetes (T2D). However, the link between the liver enzyme profile and metabolic derangements in T2D, particularly the secretion of both insulin and glucagon, is not clear. This study evaluated its relationships with glycemia, insulin and glucagon both during fasting and after an oral glucose load or a mixed meal in T2D. 15 healthy and 43 T2D subjects ingested a 75 g glucose drink. 86 T2D subjects consumed a mixed meal. Venous blood was sampled for measurements of blood glucose and plasma insulin, C-peptide and glucagon. Blood glucose, plasma insulin, C-peptide and glucagon concentrations, both fasting and after oral glucose, correlated directly with ALT, while fewer and weaker correlations were observed with GGT or AST. Subgroup analysis in T2D subjects ascertained that plasma insulin, C-peptide and glucagon concentrations after oral glucose were higher with increasing ALT. Similar findings were observed in the T2D subjects who received a mixed meal. In conclusion, serum liver enzyme profile, particularly ALT, reflects dysregulated fasting and nutrient-stimulated plasma insulin and glucagon concentrations in T2D.

Association of tyrosine hydroxylase 01 (TH01) microsatellite and insulin gene (INS) variable number of tandem repeat (VNTR) with type 2 diabetes and fasting insulin secretion in Mexican population

PurposeA variable number of tandem repeats (VNTR) in the insulin gene (INS) control region may be involved in type 2 diabetes (T2D). The TH01 microsatellite is near INS and may regulate it. We investigated whether the TH01 microsatellite and INS VNTR, assessed via the surrogate marker single nucleotide polymorphism rs689, are associated with T2D and serum insulin levels in a Mexican population.MethodsWe analyzed a main case–control study (n = 1986) that used univariate and multivariate logistic regression models to calculate the risk conferred by TH01 and rs689 loci for T2D development; rs689 results were replicated in other case–control (n = 1188) and cross-sectional (n = 1914) studies.ResultsTH01 alleles 6, 8, 9, and 9.3 and allele A of rs689 were independently associated with T2D, with differences between sex and age at diagnosis. TH01 alleles with ≥ 8 repeats conferred an increased risk for T2D in males compared with ≤ 7 repeats (odds ratio, ≥ 1.46; 95% confidence interval, 1.1–1.95). In females, larger alleles conferred a 1.5-fold higher risk for T2D when diagnosed ≥ 46 years but conferred protection when diagnosed ≤ 45 years. Similarly, rs689 allele A was associated with T2D in these groups. In males, larger TH01 alleles and the rs689 A allele were associated with a significant decrease in median fasting plasma insulin concentration with age in T2D cases; the reverse occurred in controls.ConclusionLarger TH01 alleles and rs689 A allele may potentiate insulin synthesis in males without T2D, a process disabled in those with T2D.

Fasting plasma insulin in normal-weight apparently healthy adults in a Nigerian population: Reference intervals and influence of age, gender and anthropometric variables

Introduction: In Nigeria, there is paucity of data regarding indigenously established reference intervals for fasting plasma or serum insulin concentrations in the local populations. This study was designed to establish the reference interval of fasting plasma insulin (FPI) among apparently healthy young and middle-aged adults in a Nigerian population. The influence of age, gender, and anthropometric variables on FPI concentration were examined. Materials and Methods: The study was a cross-sectional descriptive study involving 210 reference individuals aged 18 to 64 years. Physical, anthropometric and biochemical variables were measured including FPI and fasting plasma glucose (FPG). The reference interval for FPI was determined using the non-parametric percentile method. Correlation studies between FPI and age, anthropometric indices, and HOMA-IR were carried out. Results: The study involved a total of 210 healthy normal-weight non-diabetic adults consisting of 110 males (52.4%) and 100 females (47.6%) as reference individuals. Reference intervals for FPI for the male, female, and total study participants were 0.1 –11.1mIU/L, 1.3 –13.2mIU/L and 0.1 – 13.03mIU/L respectively. There were statistically significant positive correlations between FPI and age (r = 0.001), WC (r = 0.0.302, p = 0.0001), WHR (r = 0.220, p = 0.0001), SBP (r = 0.137, p = 0.047) FPG (r = 0.165, p = 0.017) and HOMA-IR (r = 0.985, p = 0.0001). Conclusion: The reference interval of FPI using the Biointecho human insulin ELISA kit is 0.1–13.0mIU/L. This is not much at variance with 0.7–9.0mIU/L quoted by the kit manufacturer, but valued widely with that of other commercially available insulin assay kits from different manufacturers. Similar to reports of similar studies, FPI correlated positively with FPG, BMI. WC, BP and age.

235-LB: Incretin-Linked Adipose Tissue Microvascular Blood Flow in Healthy People With and Without a Family History of Type 2 Diabetes

Adipose tissue microvascular blood flow (ATMBF) increases in response to a mixed meal challenge (MMC) to promote nutrient storage. This vascular action is impaired in apparently healthy people with a parent with type 2 diabetes (FH+). The mechanisms for this vascular impairment in FH+ are unknow. We aimed to investigate whether incretins [glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1)] are associated with ATMBF responses to a MMC. Thirteen healthy (FH-, no parents or grandparents with type 2 diabetes) and fourteen FH+ underwent a 2-hr MMC after an overnight fast. Age, BMI, fasting and peak postprandial blood glucose and plasma insulin concentrations were similar between FH- and FH+ (Table 1). Baseline ATMBF, assessed by contrast ultrasound, was similar between groups, but was impaired in FH+ in response to the MMC (Table 1). Peak plasma GLP-1 and GIP concentrations, but not their ratio (GLP-1:GIP), were higher in FH+ in response to the MMC (Table 1). GLP-1 and GIP concentrations were not associated with ATMBF, however, GLP-1:GIP was significantly associated with postprandial ATMBF at 1-hr (p=0.025, r=0.46). We conclude that impaired postprandial ATMBF in FH+ is not exclusively linked to incretin levels. However, lower GLP-1:GIP ratios may be linked to impaired ATMBF responses in the postprandial state. Disclosure K. Roberts-thomson: None. L. Parker: None. M. Keske: None.

Acute insulin response following exercise and its association to lipid changes in sedentary African-American women

Sedentary African-American (AA) women are at increased risk of hypertension, dyslipidemias, metabolic syndrome, and impaired insulin response to exercise. The purpose of the study was to determine the effects of a single bout of aerobic exercise on fasting serum insulin and glucose concentrations following 1464 kJ (350 kcal) of exercise and to determine if this response was associated with serum lipid concentrations in overweight AA women. Premenopausal AA women (n = 11, mean ± SD, age = 32.5 ± 4.8 yr., BMI = 29.8 ± 4.8 kg·m-2, % fat = 35.6 ± 6.3, VO2peak = 21.5 ± 3.6 ml·kg-1·min-1, total cholesterol = 4.8 ± 0.6 mmol·L-1, triglycerides = 0.60 ± 0.2 mmol·L-1, HDLC = 3.3 ± 0.5 mg·dL-1) performed 1464 kJ (350 kcal) of treadmill exercise at 60%-70%VO2peak. Fasting plasma insulin and glucose concentrations were collected 24-h prior to, and immediately, 24-h, and 48 h following exercise. Fasting insulin concentration increased immediately following exercise (Baseline=77.1 ± 10.42 vs. Immediately=117.4 ± 15.28 μU·mL-1, 95%CI= 32.71, 47.89; P&lt;0.05). The change in insulin concentration from 24-h pre- to 24-h post-exercise was correlated with BMI (r= 0.51), VO2peak (r= -0.47), and the change in lipoprotein lipase activity (r=0.37) (P&lt;0.05 for all). In conclusion, in sedentary AA women, the insulin response immediately following exercise may be elevated, and is not suppressed below pre-exercise concentrations during the 48-h following exercise. The insulin response 24-h following exercise is modestly associated with markers of lipoprotein metabolism.

Exercise Training to Improve Brain Health in Older People Living With HIV: Study Protocol for a Randomized Controlled Trial.

With the advent of antiretrovirals, people living with HIV are living near-normal lifespans. However, people living with HIV are at greater risk of experiencing cognitive impairment and reduced brain integrity despite well-controlled viremia. A robust literature supports exercise interventions as a method of improving cognition and structural brain integrity in older individuals without HIV. The effects of exercise on cardiometabolic, neurocognitive, and neural structures in middle-aged to older people living with HIV are less well known, with few prospective studies examining these measures. This prospective randomized clinical trial will examine the effects of a 6-month exercise training intervention compared to a 6-month stretching intervention (control) on cardiorespiratory fitness, physical function and strength, cognition, and neuroimaging measures of brain volumes and cerebral blood flow in people living with HIV. Sedentary middle-aged to older people living with HIV (ages≥40; n=150) with undetectable HIV viral load (<20 copies/mL) will be enrolled in the study. At the baseline and final visit, fasting plasma lipid, insulin, glucose, and brain neurotrophic factor concentrations; cardiorespiratory fitness; cognitive performance; brain volumes; and cerebral blood flow via a magnetic resonance imaging scan will be measured. Participants will be randomized in a 2:1 ratio to either the exercise or control stretching intervention. All participants will complete their assigned programs at a community fitness center 3 times a week for 6 months. A professional fitness trainer will provide personal training guidance at all sessions for individuals enrolled in both arms. Individuals randomized to the exercise intervention will perform endurance and strength training exercises, while those randomized to the control intervention will perform stretches to increase flexibility. A midpoint visit (at 3 months) will assess cognitive performance, and at the end point visit, subjects will undergo cardiorespiratory fitness and cognition testing, and a magnetic resonance imaging scan. Physical activity throughout the duration of the trial will be recorded using an actigraph. Recruitment and data collection are complete as of December 2020. Data processing, cleaning, and organization are complete as of December 2021. Data analysis began in January 2022, with the publication of study results for primary aims 1 and 2 expected by early 2023. This study will investigate the effects of a 6-month aerobic and resistance exercise training intervention to improve cardiometabolic risk factors, cognitive performance, cerebral structure, and blood flow in sedentary people living with HIV. Results will inform clinicians and patients of the potential benefits of a structured aerobic exercise training program on the cognitive, functional, and cardiometabolic health status of older people living with HIV. Assessment of compliance will inform the development and implementation of future exercise programs for people living with HIV. ClinicalTrials.gov NCT02663934; https://clinicaltrials.gov/ct2/show/NCT02663934. DERR1-10.2196/41421.

Associations of Plasma 25-Hydroxy Vitamin D and Dietary Vitamin D Intake with Insulin Resistance in Healthy Japanese Women.

We investigated the associations of plasma 25-hydroxy vitamin D (25(OH)D) concentration and the dietary intake of vitamin D with insulin resistance in Japanese women. Study participants were 406 Japanese women attended a health examination. They were not taking hormones or medications for diabetes and had no history of cancer, ischemic heart disease, or stroke. Information regarding medical history and lifestyle factors was obtained by a self-administered questionnaire, while hours of sun exposure were determined through interviews. Dietary intake of vitamin D was evaluated using a validated food frequency questionnaire. Fasting plasma glucose and insulin concentrations were measured, and insulin resistance (HOMA-IR) scores were calculated based on homeostasis model assessment. Women with vitamin D deficiency (25(OH)D<20 ng/mL) had significantly higher fasting plasma insulin concentration and HOMA-IR than did the other women. Plasma 25(OH)D concentration was significantly and inversely associated with fasting plasma insulin level and HOMA-IR after controlling for age, season, menopausal status, BMI, smoking status, alcohol intake, physical exercise, and intakes of fat and calcium. Dietary vitamin D intake was not associated with HOMA-IR concentration after adjusting for these covariates and hours of sun exposure. Although significant inverse association between plasma 25(OH)D concentration and HOMA-IR was observed in women with a low BMI, low fat intake, or a high calcium intake, the interaction terms were not statistically significant. Data suggest that plasma vitamin D, but not dietary vitamin D, is inversely associated with fasting plasma insulin concentration and HOMA-IR in non-diabetic Japanese women.

The impact of physical inactivity on glucose homeostasis when diet is adjusted to maintain energy balance in healthy, young males

It is unclear if dietary adjustments to maintain energy balance during reduced physical activity can offset inactivity-induced reductions in insulin sensitivity and glucose disposal to produce normal daily glucose concentrations and meal responses. Therefore, the aim of the present study was to examine the impact of long-term physical inactivity (60 days of bed rest) on daily glycemia when in energy balance. Interstitial glucose concentrations were measured using Continuous Glucose Monitoring Systems (CGMS) for 5 days before and towards the end of bed rest in 20 healthy, young males (Age: 34±8 years; BMI: 23.5±1.8kg/m2). Energy intake was reduced during bed rest to match energy expenditure, but the types of foods and timing of meals was maintained. Fasting venous glucose and insulin concentrations were determined, as well as the change in whole-body glucose disposal using a hyperinsulinemic-euglycemic clamp (HIEC). Following long-term bed rest, fasting plasma insulin concentration increased 40% (p=0.004) and glucose disposal during the HIEC decreased 24% (p<0.001). Interstitial daily glucose total area under the curve (tAUC) from pre-to post-bed rest increased on average by 6% (p=0.041), despite a 20 and 25% reduction in total caloric and carbohydrate intake, respectively. The nocturnal period (00:00-06:00) showed the greatest change to glycemia with glucose tAUC for this period increasing by 9% (p=0.005). CGMS measures of daily glycemic variability (SD, J-Index, M-value and MAG) were not changed during bed rest. Reduced physical activity (bed rest) increases glycemia even when daily energy intake is reduced to maintain energy balance. However, the disturbance to daily glucose homeostasis was much more modest than the reduced capacity to dispose of glucose, and glycemic variability was not negatively affected by bed rest, likely due to positive mitigating effects from the contemporaneous reduction in dietary energy and carbohydrate intake. NCT03594799 (registered July 20, 2018) (https://clinicaltrials.gov/ct2/show/NCT03594799).

PECULIARITIES OF PULMONARY VENTILATION RESPONSE TO DOSED HYPOXIA IN ELDERLY PEOPLE WITH IMPAIRED GLUCOSE TOLERANCE.

The aim: To determine the peculiarities of the response of pulmonary ventilation to hypoxia in elderly people with impaired glucose tolerance. Materials and methods: Forty-three elderly people were examined, including 20 patients with impaired glucose tolerance and 23 healthy individuals with preserved glucose tolerance. Fasting plasma glucose and insulin concentrations were determined, and the HOMA-IR insulin resistance index was calculated. Under conditions of normoxia and during a dosed hypoxic test (12% oxygen, duration 20 min), blood saturation and lung ventilation parameters were monitored. Results: Under conditions of normoxia, the indicators of lung ventilation function did not differ between the groups of elderly people with impaired and preserved glucose tolerance. Under conditions of hypoxia, elderly people with impaired glucose tolerance had a less significant increase in ventilation, despite the development of more severe arterial hypoxemia. This leads to a decrease in the ventilatory response to hypoxia in case of impaired carbohydrate metabolism. Conclusions: In people with impaired glucose tolerance, a less significant ventilatory response to hypoxia is combined with more pronounced insulin resistance.

Effect of acute TLR4 inhibition on insulin resistance in humans.

BackgroundStudies in cell cultures and rodents suggest that TLR4 is involved in the pathogenesis of insulin resistance, but direct data in humans are limited. We tested the hypothesis that pharmacologic blockade of TLR4 with the competitive inhibitor eritoran would improve insulin resistance in humans.MethodsIn protocol I, 10 lean, healthy individuals received the following 72-hour i.v. infusions in a randomized crossover design: saline (30 mL/h) plus vehicle; Intralipid (30 mL/h) plus vehicle; or Intralipid (30 mL/h) plus eritoran (12 mg i.v. every 12 hours). In protocol II, also a randomized crossover design, 9 nondiabetic individuals with obesity received eritoran or vehicle for 72 hours. The effect of eritoran was assessed with euglycemic hyperinsulinemic clamps.ResultsIn protocol I, lipid infusion significantly decreased peripheral insulin sensitivity (M value) by 14% and increased fasting plasma glucose (FPG) concentrations, fasting plasma insulin (FPI) concentrations, and the homeostatic model assessment of insulin resistance (HOMA-IR) index by 7%, 22%, and 26%, respectively. Eritoran did not prevent lipid-induced alterations of these metabolic parameters. Eritoran also failed to improve any baseline metabolic parameters (M, FPG, FPI, HOMA-IR) in individuals with obesity and insulin resistance (protocol II).ConclusionsAcute TLR4 inhibition with eritoran did not protect against lipid-induced insulin resistance. Short-term eritoran administration also failed to improve obesity-associated insulin resistance. These data do not support a role for TLR4 in insulin resistance. Future studies with a different class of TLR4 inhibitors, longer drug exposure, and/or lipid-enhancing interventions richer in saturated fats may be needed to further clarify the role of TLR4 in metabolic dysfunction in humans.Trial registrationClinicalTrials.gov NCT02321111 and NCT02267317.FundingNIH grants R01DK080157, P30AG044271, P30AG013319, and UL1TR002645.

Perhexiline Therapy in Patients with Type 2 Diabetes: Incremental Insulin Resistance despite Potentiation of Nitric Oxide Signaling.

Perhexiline (Px) inhibits carnitine palmitoyltransferase 1 (CPT1), which controls uptake of long chain fatty acids into mitochondria. However, occasional cases of hypoglycaemia have been reported in Px-treated patients, raising the possibility that Px may also increase sensitivity to insulin. Furthermore, Px increases anti-aggregatory responses to nitric oxide (NO), an effect which may theoretically parallel insulin sensitization. We therefore sought to examine these relationships in patients with stable Type 2 diabetes (T2D) and cardiovascular disease (n = 30). Px was initiated, and dosage was titrated, to reach the therapeutic range and thus prevent toxicity. Investigations were performed before and after 2 weeks, to examine changes in insulin sensitivity and, utilizing aggregometry in whole blood, platelet responsiveness to the anti-aggregatory effects of the NO donor sodium nitroprusside (SNP). Other parameters that affect may affect NO signalling were also evaluated. Px substantially potentiated inhibition of platelet aggregation by SNP (from 16.7 ± 3.0 to 27.3 ± 3.7%; p = 0.005). Px did not change fasting blood glucose concentrations but reduced insulin sensitivity (HOMA-IR score increased from median of 4.47 to 6.08; p = 0.028), and increased fasting plasma insulin concentrations (median 16.5 to 19.0 mU/L; p = 0.014). Increases in SNP responses tended (r = −0.30; p = 0.11) to be reciprocally related to increases in HOMA-IR, and increases in HOMA-IR were greater (p = 0.002) in patients without NO-sensitizing effects. No patient developed symptomatic hypoglycaemia, nor was there any other short-term toxicity of Px. Thus, in patients with stable T2D and cardiovascular disease, Px increases anti-aggregatory responsiveness to NO, but is not an insulin sensitizer, and does not induce hypoglycaemia. Absence of NO-sensitizing effect occurs in approximately 30% of Px-treated patients with T2D, and is associated with induction of insulin resistance in these patients.

Neonatal orally administered curcumin: impact on the metabolic response and renal histology of Sprague-Dawley rats fed a high-fructose diet until adolescence

BackgroundFructose-rich diets are linked to the epidemic of metabolic syndrome and co-morbidities including nephropathy. Phytochemicals are increasingly being used for medicinal purposes due to their perceived safety compared to conventional drugs. Although previously shown to beneficially programme metabolism, these phytochemicals might have a negative impact on metabolic health when introduced early in life. We investigated whether neonatal administration of curcumin to rats would impact their response in adolescence to a high-fructose diet. Sprague-Dawley pups (n = 128) were administered either 0.5% dimethyl sulphoxide, curcumin (500 mg kg−1), fructose (20%, w/v) or a combination of curcumin and fructose from post-natal day 6 to 21. Each group was then subdivided into two; one had tap water, while the other had fructose (20%, w/v) to drink for 6 weeks.ResultsThere were no differences (p > 0.05) in the fasting blood glucose, triglycerides, cholesterol, plasma insulin and adiponectin concentrations across the groups. The renal corpuscular, glomerular tuft and Bowman capsular areas were similar (p > 0.05) across the treatment groups, in both sexes. Post-weaning fructose alone induced tubular secretions and mesangial proliferation in the kidneys which were prevented by curcumin.ConclusionsDespite the observed benefits in adolescence, the impact of curcumin on renal health beyond adolescence needs to be explored.

Is calorie restriction beneficial for normal-weight individuals? A narrative review of the effects of weight loss in the presence and absence of obesity.

Calorie restriction regimens are popular for their purported health-promoting effects. However, it is unclear whether chronic reduction in energy intake and subsequent weight loss have beneficial effects in the absence of obesity. To this end, the results of studies that examined the effects of the same diet-induced weight loss in individuals with and without obesity were reviewed. The contribution of lean mass to the total amount of weight lost is greater in participants without obesity than in those with obesity, but the reductions in resting, nonresting, and total energy expenditure are of similar magnitude. Both in the presence as well as in the absence of obesity, weight loss decreases visceral adipose tissue and liver fat, increases insulin sensitivity in skeletal muscle (insulin-mediated whole-body glucose disposal rate) and in adipose tissue (meal-induced or insulin-induced suppression of plasma free fatty acid concentration), and augments insulin clearance rate, without affecting pancreatic insulin secretion. These effects are of similar magnitude in participants with and without obesity and result in reductions in fasting plasma glucose and insulin concentrations. These data suggest that the same degree of calorie restriction and the same amount of weight loss have multiple beneficial effects on health outcomes in individuals without obesity, similar to those observed in individuals with obesity.

Clinical correlates of plasma insulin levels over the life course and association with incident type 2 diabetes: the Framingham Heart Study

IntroductionInsulin is a glucose-lowering hormone that affects carbohydrate, lipid, and protein metabolism. Limited data exist on the correlates of insulin levels over the life course in healthy community-dwelling individuals.Research design...