Variation In Glucose Tolerance Research Articles

Early time-restricted carbohydrate consumption vs conventional dieting in type 2 diabetes: a randomised controlled trial

Aims/hypothesisEarly time-restricted carbohydrate consumption (eTRC) is a novel dietary strategy that involves restricting carbohydrate-rich food intake to the morning and early afternoon to align with circadian variations in glucose tolerance. We examined the efficacy, feasibility and safety of eTRC in individuals with type 2 diabetes under free-living conditions.MethodsIn this randomised, parallel-arm, open label, controlled trial, participants with type 2 diabetes and overweight/obesity (age 67.2±7.9 years, 47.8% women, BMI 29.4±3.7 kg/m2, HbA1c 49±5 mmol/mol [6.6±0.5%]) were randomised, using computer-generated random numbers, to a 12 week eTRC diet or a Mediterranean-style control diet with matched energy restriction and macronutrient distribution (50% carbohydrate, 30% fat and 20% protein). The primary outcome was the between-group difference in HbA1c at 12 weeks. Body composition, 14 day flash glucose monitoring and food diary analysis were performed every 4 weeks. Mixed meal tolerance tests with mathematical beta cell function modelling were performed at baseline and after 12 weeks.ResultsTwelve (85.7%) participants in the eTRC arm and 11 (84.6%) participants in the control arm completed the study, achieving similar reductions in body weight and fat mass. The two groups experienced comparable improvements in HbA1c (−3 [−6, −0.3] mmol/mol vs −4 [−6, −2] mmol/mol, corresponding to −0.2 [−0.5, 0]% and −0.3 [−0.5, −0.1]%, respectively, p=0.386), fasting plasma glucose, flash glucose monitoring-derived glucose variability and mixed meal tolerance test-derived glucose tolerance, insulin resistance, insulin clearance and plasma glucagon levels, without changes in model-derived beta cell function parameters, glucagon-like peptide-1, glucose-dependent insulinotropic polypeptide and non-esterified fatty acid levels. The two diets similarly reduced liver function markers and triglyceride levels, being neutral on other cardiometabolic and safety variables. In exploratory analyses, diet-induced changes in body weight and glucometabolic variables were not related to the timing of carbohydrate intake.Conclusions/interpretationThe proposed eTRC diet provides a feasible and effective alternative option for glucose and body weight management in individuals with type 2 diabetes, with no additional metabolic benefits compared with conventional dieting.Trial registrationClinicalTrials.gov NCT05713058FundingThis study was supported by the European Society for Clinical Nutrition and Metabolism (ESPEN) and the Italian Society of Diabetology (SID).Graphical

Michaelis-Menten kinetic modeling of hemoglobin A1c status facilitates personalized glycemic control

IntroductionDiscrepancy between measured HbA1c and HbA1c calculated from plasma glucose is associated with higher risk for diabetic complications. However, quantification of this difference is inaccurate due to the imperfect linear conversion models. We propose to introduce a mathematical formula that correlates with the observational data and supports individualized glycemic control. MethodsWe analysed 175,437 simultaneous plasma glucose and HbA1c records stored in our laboratory database. Employing the Michaelis-Menten (MM) equation, we compared the calculated HbA1c levels to the measured HbA1c levels. Data from patients with multiple records were used to establish the patients’ glycemic status and to assess the predictive power of our MM model. ResultsHbA1c levels calculated with the MM equation closely matched the population’s average HbA1c levels. The Michaelis constant (Km) had a negative correlation with HbA1c (r2 = 0.403). Using personalized Km values in the MM equation, 85.1% of HbA1c predictions were within 20% error (ADAG calculation: 78.4%). MM prediction also performed better in predicting pathologic HbA1c levels (0.904 AUC vs. 0.849 AUC for ADAG). ConclusionMM equation is an improvement over linear models and could be readily employed in routine diabetes management. Km is a reliable and quantifiable marker to characterize variations in glucose tolerance.

Increased Variation in Body Weight and Food Intake Is Related to Increased Dietary Fat but Not Increased Carbohydrate or Protein in Mice.

A variety of inbred mouse strains have been used for research in metabolic disorders. Despite being inbred, they display large inter-individual variability for many traits like food intake and body weight. However, the relationship between dietary macronutrients and inter-individual variation in body weight and food intake of different mouse strains is still unclear. We investigated the association between macronutrient content of the diet and variations in food intake, body composition, and glucose tolerance by exposing five different mouse strains (C57BL/6, BALB/c, C3H, DBA/2, and FVB) to 24 different diets with variable protein, fat, and carbohydrate contents. We found only increasing dietary fat, but not protein or carbohydrate had a significant association (positive) with variation in both food intake and body weight. The highest variation in both body weight and food intake occurred with 50% dietary fat. However, there were no significant relationships between the variation in fat and lean mass with dietary protein, fat, or carbohydrate levels. In addition, none of the dietary macronutrients had significant impacts on the variation in glucose tolerance ability in C57BL/6 mice. In conclusion, the variations in food intake and body weight changes increased with the elevation of dietary fat levels.

Constant light alters serum hormone levels related to thyroid function in male CD-1 mice

ABSTRACTDisruptions to the circadian rhythm can lead to altered metabolism. Modification of thyroid function may be a reason why circadian misalignment may contribute to future metabolic disorders. We investigated whether circadian disruption through constant light (LL) can lead to variations in hormone levels associated with thyroid function. Mice were exposed to LL or a 12:12 Light:Dark (LD) cycle for 6 weeks; then glucose tolerance and thyroid hormone levels were measured at ZT 6 and ZT 18. There was day/night variation in glucose tolerance, but LL had no effect. LL reduced TSH, increased fT4, and abolished day/night variation in fT3 and leptin. These findings illustrate that LL alters thyroid-related hormones, providing evidence of a link between circadian disruption and thyroid function.

Impact of Seasonality on Gestational Diabetes Mellitus.

Gestational diabetes mellitus (GDM) is a major health concern that seems to be influenced by seasonality. To assess the impact of seasonality on the incidence of GDM in an Italian population. This is a retrospective cohort study of 5,473 pregnant women attending the Operative Unit of Diabetes, who underwent GDM screening by means of the 75-g oral glucose tolerance test (OGTT), during the period from August 2011 to December 2016. Screening was performed at 16-18 or 24-28 weeks&amp;apos; gestation, following the Health Italian Minister guidelines. All blood samples were undertaken in the Hospital itself, under the same temperature conditions, and analyzed in the nearby biochemical laboratory. Statistical analysis was performed by SPSS software. 1,559 of 5,473 enrolled women (28.5%) were affected by GDM. The incidence of GDM was significantly higher during the summer season (33.7%) (P<0.001), and significantly lower during the winter (23.3%), compared with spring (P=0.035) and fall seasons (P=0.002). When the year was divided on a 24-hr temperature basis into two parts only, the warm half and the cold half, GDM was considerably lower in cold months compared to warm ones (P<0.0001). No difference was observed between the medians of fasting glycemia throughout the four seasons; instead, serum glucose levels at 1-h and 2-h after OGTT were higher in summer than in spring, autumn and winter. Results from multiple linear regression analysis supported the hypothesis that glucose levels at 1-h and 2-h following OGTT could be influenced by ambient temperature. Our data indicate that seasonal changes may influence variations in glucose tolerance during pregnancy, with GDM incidence increasing during the summer and declining during cold months.

Abstract 404: NLR Family, Pyrin Domain-containing 3 Knockout Rescues Cardiac Dysfunction Induced by High-fat Diet Feeding

NLR family, pyrin domain-containing 3 (NLRP3) is a pattern recognition receptor responsible for perpetuating an inflammatory response through production of pro-inflammatory cytokines IL-1β and IL-18. It has been implicated in the sustained inflammatory response in obesity and multiple cardiovascular disease conditions. In order to investigate NLRP3 as a potential therapeutic target in metabolic syndrome, C57BL/6 wild-type (WT) and NLRP3 knockout (NLRP3-\-) mice were fed a normal diet (ND; 12% fat chow) or a high fat diet (HFD; 45% fat chow) for 5 months. At 5 months, echocardiography and glucose tolerance tests (GTTs) were performed. Cardiac function assessed by fractional shortening (FS) was significantly impaired by HFD feeding in the WT group (0.335 HFD vs. 0.456 ND; p&lt;0.05) but not in the NLRP3-\- (0.449 HFD vs. 0.492 ND; p&gt;0.05). FS was higher in NLRP3-\-HFD than in WT-HFD (p&lt;0.05). Two-dimensional analysis shows the FS difference between NLRP3-\-HFD and WT-HFD was primarily explained by the difference in left ventricular end-systolic dimension (0.2716 cm WT vs. 0.1883 cm NLRP3-\-; p&lt;0.05). Glucose tolerance measured by area under the curve (AUC) was significantly impaired by HFD feeding for both WT (23183 ND vs. 57298 HFD; p&lt;0.001) and NLRP3-\- (23197 ND vs. 44626 HFD; p&lt;0.001), but significantly better in the NLRP3-\-HFD than in WT-HFD (p&lt;0.01). HFD feeding increased fasting blood glucose (FBG) for both WT (97.7 mg . dl -1 ND vs. 164.7 mg . dl -1 HFD; p&lt;0.01) and NLRP3-\- (80.50 mg . dl -1 ND vs. 108.8 mg . dl -1 HFD; p&lt;0.05), but significantly less in NLRP3-\- mice (NLRP3-\- vs. WT; p&lt;0.05). For GTTs, body weight was significantly higher in the WT than NLRP3-\- fed HFD (47.93 g vs. 36.5 g; p&lt;0.001). Body weight explained 92% of variation in glucose tolerance (p&lt;0.0001) and 69% of variation in fasting blood glucose (p&lt;0.0001). WT-HFD averaged 1.31X heavier than NLRP3-\-HFD, while the AUC for the IGTT was 1.28X larger for the WT-HFD than NLRP3-\-HFD. Body weights were not significantly different between genotypes at the time of echo. The results suggest that knockout of NLRP3 may be protective against HFD induced cardiovascular dysfunction. A protective effect on glucose tolerance is not strongly supported.

Glucose tolerance female-specific QTL mapped in collaborative cross mice

Type-2 diabetes (T2D) is a complex metabolic disease characterized by impaired glucose tolerance. Despite environmental high risk factors, host genetic background is a strong component of T2D development. Herein, novel highly genetically diverse strains of collaborative cross (CC) lines from mice were assessed to map quantitative trait loci (QTL) associated with variations of glucose-tolerance response. In total, 501 mice of 58 CC lines were maintained on high-fat (42% fat) diet for 12weeks. Thereafter, an intraperitoneal glucose tolerance test (IPGTT) was performed for 180min. Subsequently, the values of Area under curve for the glucose at zero and 180min (AUC0-180), were measured, and used for QTL mapping. Heritability and coefficient of variations in glucose tolerance (CVg) were calculated. One-way analysis of variation was significant (P<0.001) for AUC0-180 between the CC lines as well between both sexes. Despite Significant variations for both sexes, QTL analysis was significant, only for females, reporting a significant female-sex-dependent QTL (~2.5 Mbp) associated with IPGTT AUC0-180 trait, located on Chromosome 8 (32-34.5 Mbp, containing 51 genes). Gene browse revealed QTL for body weight/size, genes involved in immune system, and two main protein-coding genes involved in the Glucose homeostasis, Mboat4 and Leprotl1. Heritability and coefficient of genetic variance (CVg) were 0.49 and 0.31 for females, while for males, these values 0.34 and 0.22, respectively. Our findings demonstrate the roles of genetic factors controlling glucose tolerance, which significantly differ between sexes requiring independent studies for females and males toward T2D prevention and therapy.

Circadian Transcription from Beta Cell Function to Diabetes Pathophysiology.

The mammalian circadian clock plays a central role in the temporal coordination of physiology across the 24-h light-dark cycle. A major function of the clock is to maintain energy constancy in anticipation of alternating periods of fasting and feeding that correspond with sleep and wakefulness. While it has long been recognized that humans exhibit robust variation in glucose tolerance and insulin sensitivity across the sleep-wake cycle, experimental genetic analysis has now revealed that the clock transcription cycle plays an essential role in insulin secretion and metabolic function within pancreatic beta cells. This review addresses how studies of the beta cell clock may elucidate the etiology of subtypes of diabetes associated with circadian and sleep cycle disruption, in addition to more general forms of the disease.

Variation of glucose tolerance in adult patients with cystic fibrosis: What is the potential contribution of insulin sensitivity?

BackgroundReduced insulin secretion is a key factor to explain high prevalence of glucose intolerance in patients with cystic fibrosis (CF). However, the role of insulin sensitivity remains unclear. The aim of this study is to investigate the association of insulin secretion and sensitivity with the evolution of glucose tolerance. MethodsA total of 152 patients without known diabetes from the Montreal CF cohort underwent two 2-h oral glucose tolerance tests (OGTT) at baseline and again after 21.2±5.5months. Pulmonary function and anthropometric measurements were also collected at each visit. At both visits, based on their OGTT results, patients were categorized in glucose tolerance groups (normal glucose tolerance, impaired glucose tolerance or CF-related diabetes) and stratified in 3 groups according to the variation of their glucose tolerance: stable, improved or deteriorated. ResultsAt baseline, patients in the deteriorated group had a better sensitivity to insulin than those in the improved group (P=0.029). At follow-up glucose tolerance remained stable in 55.3%, improved in 14.5% and deteriorated in 30.3% of patients. During follow-up, insulin secretion remained stable in all 3 groups. While insulin sensitivity remained stable in patients without changes in glucose tolerance it worsened in patients who deteriorated glucose tolerance (P<0.001) and improved in patients who improved their glucose tolerance (P=0.003). ConclusionIn a context of significantly reduced insulin secretion, variations of insulin sensitivity are associated with variations of glucose tolerance in adult patients with CF.

Effects of the Internal Circadian System and Circadian Misalignment on Glucose Tolerance in Chronic Shift Workers.

Shift work is a risk factor for diabetes. The separate effects of the endogenous circadian system and circadian misalignment (ie, misalignment between the central circadian pacemaker and 24-hour environmental/behavioral rhythms such as the light/dark and feeding/fasting cycles) on glucose tolerance in shift workers are unknown. The objective of the study was to test the hypothesis that the endogenous circadian system and circadian misalignment separately affect glucose tolerance in shift workers, both independently from behavioral cycle effects. A randomized, crossover study with two 3-day laboratory visits. Center for Clinical Investigation at Brigham and Women's Hospital. Healthy chronic shift workers. The intervention included simulated night work comprised of 12-hour inverted behavioral and environmental cycles (circadian misalignment) or simulated day work (circadian alignment). Postprandial glucose and insulin responses to identical meals given at 8:00 am and 8:00 pm in both protocols. Postprandial glucose was 6.5% higher at 8:00 pm than 8:00 am (circadian phase effect), independent of behavioral effects (P = .0041). Circadian misalignment increased postprandial glucose by 5.6%, independent of behavioral and circadian effects (P = .0042). These variations in glucose tolerance appeared to be explained, at least in part, by different insulin mechanisms: during the biological evening by decreased pancreatic β-cell function (18% lower early and late phase insulin; both P ≤ .011) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 10% higher late phase insulin; P = .015) without change in early-phase insulin (P = .38). Internal circadian time affects glucose tolerance in shift workers. Separately, circadian misalignment reduces glucose tolerance in shift workers, providing a mechanism to help explain the increased diabetes risk in shift workers.

Effects of Growth Hormone on Diurnal Insulin Sensitivity in Normal and Type 2 Diabetic Patients and Animal Models

This review addresses the effects of growth hormone on diurnal insulin sensitivity in normal, patients with type 2 diabetes mellitus (T2DM) and animal models described in our previous studies. Results confirmed the presence of diurnal insulin sensitivity, or greater insulin sensitivity in the morning, in normal subjects. The exact cause of this circadian rhythm in plasma glucose levels in healthy subjects has not been established, and nocturnal surges in growth hormone secretion remain a possible explanation. Results showed that growth hormone is an important factor controlling the diurnal variation of glucose tolerance and insulin sensitivity in rats. Data from our previous study provided direct evidence that the role of growth hormone in regulating insulin sensitivity in healthy subjects may be related to changes in the metabolic clearance rate of insulin and the metabolism of non-esterified fatty acids. A different circadian rhythm for plasma glucose appears to be present in patients with T2DM with nadirs in the early evening and peaks in the early morning, indicating greater insulin sensitivity in the evening. As in normal subjects, the exact cause of these circadian rhythms in the plasma glucose levels of patients with T2DM provided direct evidence that the reduction in insulin sensitivity may be due to the nocturnal surge of growth hormone in the early morning hours.

Endogenous circadian system and circadian misalignment impact glucose tolerance via separate mechanisms in humans

Glucose tolerance is lower in the evening and at night than in the morning. However, the relative contribution of the circadian system vs. the behavioral cycle (including the sleep/wake and fasting/feeding cycles) is unclear. Furthermore, although shift work is a diabetes risk factor, the separate impact on glucose tolerance of the behavioral cycle, circadian phase, and circadian disruption (i.e., misalignment between the central circadian pacemaker and the behavioral cycle) has not been systematically studied. Here we show--by using two 8-d laboratory protocols--in healthy adults that the circadian system and circadian misalignment have distinct influences on glucose tolerance, both separate from the behavioral cycle. First, postprandial glucose was 17% higher (i.e., lower glucose tolerance) in the biological evening (8:00 PM) than morning (8:00 AM; i.e., a circadian phase effect), independent of the behavioral cycle effect. Second, circadian misalignment itself (12-h behavioral cycle inversion) increased postprandial glucose by 6%. Third, these variations in glucose tolerance appeared to be explained, at least in part, by different mechanisms: during the biological evening by decreased pancreatic β-cell function (27% lower early-phase insulin) and during circadian misalignment presumably by decreased insulin sensitivity (elevated postprandial glucose despite 14% higher late-phase insulin) without change in early-phase insulin. We explored possible contributing factors, including changes in polysomnographic sleep and 24-h hormonal profiles. We demonstrate that the circadian system importantly contributes to the reduced glucose tolerance observed in the evening compared with the morning. Separately, circadian misalignment reduces glucose tolerance, providing a mechanism to help explain the increased diabetes risk in shift workers.

PM.84 The Association Between Severity of Impaired Glucose Tolerance in Gestational Diabetes with Age, BMI and Ethnicity

IntroductionGestational diabetes (GDM) has been shown to cause adverse fetal outcomes including macrosomia, shoulder dystocia and stillbirth. The multinational Hyperglycaemia and Pregnancy Outcome (HAPO) Study has shown there is a...

Variation in Glucose Tolerance in Health and Disease : Especially Pre-diabetes and Early Type 2 Diabetes

Variation in Glucose Tolerance in Health and Disease : Especially Pre-diabetes and Early Type 2 Diabetes

Intrauterine Growth Retardation Leads to the Functional Change of Insulin Secretion in the Newborn Rats

To investigate the observed variation in glucose tolerance and insulin secretion in intrauterine growth retarded newborn rats and to explore the mechanism of the variations, Sprague-Dawley pregnant rats were allocated into two groups: a control group and an intrauterine energy restricted group. The intrauterine growth retardation (IUGR) in the rats was induced by 50% calorie restriction in pregnant rats from gestational day 15 until term as compared to the control group. The pancreata of control and IUGR newborn rats were dissected respectively. RT-PCR was used to study the mRNA level related to insulin synthesis and exocytosis. Intraperitoneal glucose tolerance tests were done to study the function of the pancreatic islet. We found that birth weight and pancreas mass of IUGR newborn rats were significantly lower than those of controls. Although no significant differences were observed in mRNA level of insulin and PDX-1, the expression of genes related to insulin exocytosis such as munc13-1, vamp-2, syntaxin1a, rab3a were reduced significantly in IUGR newborn rats. IUGR animals were glucose-intolerant. The observed blood insulin level and insulin secretion response to glucose challenge were both found to be at reduced level in IUGR newborn rats as compared with the normal control group rats. With these findings, we hypothesize that IUGR can induce changes in glucose homeostasis due to, at least in part, a reduced function of insulin exocytosis in newborn rats.

Daytime variations in glucose tolerance in people with impaired glucose tolerance

To determine whether glucose tolerance varies throughout the day in people with impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched normal glucose tolerant (NGT) individuals. Blood samples were taken every 30–120 min during a 24 h period in which all individuals had three mixed meals and nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact proinsulin, cortisol and growth hormone. Variable responses were considered as concentrations and areas under the curves. Comparison between the groups was by Student's t-test, Mann–Whitney, and analysis of variance. Higher total glucose response, inappropriate normal total insulin response, and unproportionally increased proinsulin total response were observed in the IGT group. Lower glucose tolerance occurred in IGT after dinner, as in the NGT, and after breakfast associated with increased insulin response after breakfast, and similar proinsulin response after all three meals. IGT had higher glucose response than NGT after breakfast and lunch, similar insulin responses, and increased proinsulin–insulin ratio after all three meals. Data from this study demonstrate that IGT individuals present lower glucose tolerance in the evening, as those with NGT, and in the morning, as reported in patients with type 2 diabetes.

BMAL1 and CLOCK, Two Essential Components of the Circadian Clock, Are Involved in Glucose Homeostasis

Circadian timing is generated through a unique series of autoregulatory interactions termed the molecular clock. Behavioral rhythms subject to the molecular clock are well characterized. We demonstrate a role for Bmal1 and Clock in the regulation of glucose homeostasis. Inactivation of the known clock components Bmal1 (Mop3) and Clock suppress the diurnal variation in glucose and triglycerides. Gluconeogenesis is abolished by deletion of Bmal1 and is depressed in Clock mutants, but the counterregulatory response of corticosterone and glucagon to insulin-induced hypoglycaemia is retained. Furthermore, a high-fat diet modulates carbohydrate metabolism by amplifying circadian variation in glucose tolerance and insulin sensitivity, and mutation of Clock restores the chow-fed phenotype. Bmal1 and Clock, genes that function in the core molecular clock, exert profound control over recovery from insulin-induced hypoglycaemia. Furthermore, asynchronous dietary cues may modify glucose homeostasis via their interactions with peripheral molecular clocks.

Diabetes Mellitus in the Arabian Peninsula

Diabetes Mellitus in the Arabian Peninsula

A daily rhythm in glucose tolerance: a role for the suprachiasmatic nucleus.

The suprachiasmatic nucleus (SCN), the biological clock, is responsible for a 24-h rhythm in plasma glucose concentrations, with the highest concentrations toward the beginning of the activity period. To investigate whether the SCN is also responsible for daily fluctuations in glucose uptake and to examine how these fluctuations relate to the rhythm in plasma glucose concentrations, SCN-intact rats and SCN-lesioned rats were injected intravenously with a glucose bolus at different time points. We found an increase in glucose uptake toward the beginning of the activity period, followed by a gradual reduction in glucose uptake toward the end of the activity period. The daily variation in glucose tolerance seemed not to be caused by fluctuations in insulin responses of the pancreas but by a daily variation in insulin sensitivity. Lesioning the SCN resulted in the disappearance of the daily fluctuation in glucose uptake and insulin sensitivity. Interestingly, SCN-lesioned rats showed an enhancement in glucose tolerance that could not be explained by higher insulin responses or enhanced insulin sensitivity. Therefore, these findings suggest a role for the SCN in insulin-independent glucose uptake. The present results further show that the daily rhythm in glucose tolerance follows the same pattern as the daily rhythm in plasma glucose concentrations. We hypothesized that the biological clock prepares the individual for the upcoming activity period by two separate mechanisms: increasing plasma glucose concentrations and making tissue more tolerant to glucose.

Roles of circadian rhythmicity and sleep in human glucose regulation.

I. Introduction II. Characteristics and Causal Mechanisms of 24-h Rhythms of Glucose Regulation in Normal Young Subjects A. 24-h variations in glucose tolerance B. Causal mechanisms III. Alterations of 24-h Rhythms of Glucose Regulation in Normal Aging A. Daytime variations in glucose tolerance B. Nighttime variations in glucose tolerance C. Respective roles of sleep and time of day D. Significance and clinical implications IV. Diurnal Variations of Glucose Regulation in Obesity A. Daytime variations in glucose tolerance B. Nighttime variations in glucose tolerance C. Significance and clinical implications V. Alterations in 24-h Rhythmicity of Glucose Regulation in Non-Insulin-Dependent Diabetes Mellitus (NIDDM) A. Alterations in daytime variations in glucose tolerance B. Alterations in nighttime variations in glucose levels during fasting C. Significance and clinical implications VI. Alterations in 24-h Rhythmicity of Glucose Regulation in Insulin-Dependent Diabetes Mellitus (IDDM) A. Alterations in dayt...