Higher Insulin Response Research Articles

Baseline phenotypes with preserved β-cell function and high insulin concentrations have the best improvements in glucose tolerance after weight loss: results from the prospective DEXLIFE and EGIR-RISC studies

BackgroundWeight loss and lifestyle intervention improve glucose tolerance delaying the onset of type 2 diabetes (T2D), but individual responses are highly variable. Determining the predictive factors linked to the beneficial effects of weight loss on glucose tolerance could provide tools for individualized prevention plans. Thus, the aim was to investigate the relationship between pre-intervention values of insulin sensitivity and secretion and the improvement in glucose metabolism after weight loss. MethodsIn the DEXLIFE cohort (373 individuals at high risk of T2D, assigned 3:1 to a 12-week lifestyle intervention or a control arm, Trial Registration: ISRCTN66987085), K-means clustering and logistic regression analysis were performed based on pre-intervention indices of insulin sensitivity, insulin secretion (AUC-I), and glucose-stimulated insulin response (ratio of incremental areas of insulin and glucose, iAUC I/G). The response to the intervention was evaluated in terms of reduction of OGTT-glucose concentration. Clusters' validation was done in the prospective EGIR-RISC cohort (n = 1538). ResultsFour replicable clusters with different glycemic and metabolomic profiles were identified. Individuals had similar weight loss, but improvement in glycemic profile and β-cell function was different among clusters, highly depending on pre-intervention insulin response to OGTT. Pre-intervention high insulin response was associated with the best improvement in AUC-G, while clusters with low AUC-I and iAUC I/G showed no beneficial effect of weight loss on glucose control, as also confirmed by the logistic regression model. ConclusionsIndividuals with preserved β-cell function and high insulin concentrations at baseline have the best improvement in glucose tolerance after weight loss.

Modern ideas about the consequences of sympathoadrenal hyperactivation in hypertensive patients with metabolic disorders: modulation possibilities

The prevalence of hypertension (HTN) in the Russian Federation and the world continues to grow. This is largely due to the epidemic of obesity and related conditions — metabolic syndrome and type 2 diabetes. The most common and proven hypothesis of the relationship between hypertension and obesity is the activation of the sympathetic nervous system. However, modern research shows that the consequences of sympathetic hyperactivation are not limited only to hemodynamic effects, but extend to many organs and systems. Long-term sympathetic hyperactivation can lead to insulin resistance and type 2 diabetes. Neurotransmitters affect fat cells by increasing lipolysis and leading to increased fatty acid release, the liver by increasing gluconeogenesis, and pancreatic β-cells by decreasing insulin secretion. The sympathetic nervous system plays an important role in energy management by regulating metabolic rate. Obese individuals have significantly less pronounced postprandial thermogenesis, despite a higher insulin response, while the hemodynamic response to isometric or heterometric exercise is reduced. Chronic stress serves not only as a trigger for behavioral disorders, but also directly leads to various physiological disorders, including through sympathetic activation. However, the choice of antihypertensive agents affecting the sympathetic activity in patients with obesity and metabolic disorders is very limited. According to current guidelines, β-blockers are not the drugs of choice in patients with uncomplicated HTN, since it has a weaker evidence base compared to other classes of drugs and have metabolic and other side effects. Therefore, selective I1-imidazoline receptor agonists, and in particular, moxonidine may be the drugs of choice in this category of patients. Moxonidine in combination therapy of patients with HTN and metabolic disorders, including metabolic disorders in menopause, as well as with a physiological estrogen decrease, significantly improves the effectiveness of antihypertensive therapy and increases the achievement of target blood pressure. In addition, its metabolic effects improve prognosis of such patients.

Arepas Made from High Amylose Corn Flour Produce Favorably Low Glucose and Insulin Responses in Healthy Humans

The importance of the amylose: amylopectin ratio in the postprandial glycemic and insulinemic responses to corn was studied in food products that might realistically be consumed. Healthy subjects were given test meals in the form of arepas made from ordinary (25% amylose) or high amylose (70% amylose) corn flour. The ordinary corn meal contained 45 g of potentially available starch. To exclude the possible influence of a lowered content of potentially available starch due to formation of resistant starch in the high amylose product, this product was evaluated at two levels and included either on the basis of potentially available starch (45 g) or total starch (including resistant starch) (45 g, i.e., 29 g potentially available starch), respectively. The rate of starch hydrolysis, measured in vitro employing a method based on chewing, was studied. In addition, the content of in vitro resistant starch was analyzed in all products. The meals containing high amylose corn flour produced lower areas under the glucose and insulin response curves (57 and 42% lower, respectively) than did the meals containing ordinary cornmeal. This could not be explained by a lower amount of potentially available starch. No differences were noted when subjects consumed the two high amylose meals of arepas, despite 36% lower potentially available starch in one of the meals. The rate of starch hydrolysis measured in vitro was slower in the high amylose corn products than in the ordinary corn product. Resistant starch in the ordinary product was 3 g/100 g dry matter, vs. -20 g/100 g dry matter in the high amylose products. We concluded that high amylose corn products have a potential to promote favorably low metabolic responses and high resistant starch contents.

Peptide Tyrosine-Tyrosine Triggers GLP-2-Mediated Intestinal Hypertrophy After Roux-en-Y Gastric Bypass

Purpose Intestinal remodeling and adaptation of the alimentary limb after Roux-en-Y gastric bypass (RYGB) play an important role in the pathophysiological events that lead to type 2 diabetes mellitus (T2DM) improvement. Intestinal absorptive loop hypertrophy and growth following surgery have been related to GLP-2 secretion by ileal L-cells. The secretion of peptide tyrosine-tyrosine (PYY) enterohormone after a meal has been proposed as a trigger for ileal secretion of GLP-1. Our aim is to determine the role of PYY as a GLP-2 secretion modulator as an adaptation result in the alimentary limb after RYGB.MethodWe used a non-obese euglycemic rodent model. Circulating glucose, insulin, PYY, and GLP-2 were measured in the experimental and control groups. We used four groups: fasting control, Sham-operated, RYGB-operated (RYGB), and RYGB-operated and treated with BIIE0246 (RYGB + BII). BIIE0246 is a NPY2 receptor antagonist in L-cells. Intestinal glucose transporters and GLP-1 and PYY gut expression and hypertrophy were analyzed after 12 weeks of surgery.ResultsRYGB increased PYY3-36 plasma levels in rats with or without BII treatment. A high-insulin response was observed in the RYGB group but not in the control or RYGB + BII groups. BIIE0246 treatment limited plasma GLP-2 levels. In the alimentary intestinal limb, hypertrophy and SGLT1 and GLUT1 expression appeared to be reduced after RYGB compared to controls.ConclusionThe postprandial ileal PYY secretion is enhanced after RYGB. This increase mediates GLP-2 release through its binding to the Y2 receptor on L-cells. This mechanism plays a role in alimentary limb hypertrophy after surgery.Graphical abstract

Postprandial glycemic responses to a high-protein dairy snack and energy-enriched berry snacks in older adults.

We have previously shown that regular consumption of high-protein dairy- and energy-enriched berry-based products consumed as snacks improved nutritional status, functional status, and quality of life among vulnerable older people. These products contain protein, sugar and other components which may have acute effects on glycemic control. The aim of the present study was to determine the effects of these snack products on postprandial glycemic responses in older adults. In a randomized, single-blinded crossover design, 25 subjects aged 71.4±4.6 years consumed either a high-protein dairy drink or one of the two energy-enriched berry purées, as well as corresponding reference products, as mid-morning snacks, each containing 25g of available carbohydrates. Baseline and postprandial blood samples for measurements of glucose, insulin, and non-esterified fatty acids (NEFA) were collected at regular intervals up to 3h. In comparison with a protein-free reference, consumption of the dairy product resulted in a remarkably high insulin response, a fall in glucose concentration and suppression of late postprandial NEFA rebound. In comparison with a low-berry reference, both berry products led to significantly lower glucose, insulin and NEFA responses. The high-protein dairy product which induces short-term hyperinsulinemia, accompanied with reduced glycemia, may help to improve muscle protein and energy metabolism. The energy-enriched berry products maintain balanced postprandial glycemia. These are beneficial effects in older adults who may suffer from impaired muscle performance or glycemic control. NCT04175353.

Effects of omega fatty acids on the short-term postprandial satiety related peptides in rats.

We aimed to assess the effects of omega fatty acids on time depending on responses of satiety hormones. Sixty adult rats were randomly divided into 4 groups; linoleic acid (LA), α-linolenic acid (ALA), eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) groups. For each fatty acid, the dose of 400 mg/kg was applied by oral gavage. Blood samples were taken after the 15, 30, 60 and 120 minutes. Ghrelin, cholecystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY (PYY), leptin and insulin hormones were analyzed by ELISA. We observed the significant increases (p<0.05) of the levels of CCK between n-3 (ALA, at 60th min; EPA, at 30th and 60th min and DHA, at 60 min) and n-6 (LA) supplemented rats. The highest GLP-1 levels were in ALA (0.70 ng/mL) and DHA (0.67 ng/mL) supplemented groups at 60th and 120th min indicating n-3 fatty acids efficiency on satiety compared to LA. It seems that ALA at 60th min and EPA at 120th min could provide the highest satiety effect with the highest insulin response, while the efficiency of LA supplementation on insulin-induced satiety diminished. The only significant change in AUC values among all hormones was in the CCK of the ALA group (p=0.004). The level of leptin increased in DHA and EPA supplemented rats (p=0.140). Our results showed that dietary omega fatty acids influenced the releasing of hormones in different ways possibly depending on chain length or saturation degree. Comprehensive studies need to be addressed for each fatty acid on satiety-related peptide hormones.

The different patterns of insulin response during Oral Glucose Tolerance Test (OGTT) in transfused young patients with β-Thalassemia.

Background and aim:Dysregulation of glucose metabolism is a common complication of transfusions in Transfusion Dependent Thalassemia (TDT) patients. For early diagnosis of glucose disturbances, screening is recommended. The age of starting and the type of screening vary; the more common methods are assessment of RPG, FPG, 2h PG and 2 hours OGTT. The combined assessment of glucose tolerance and insulin response during OGTT is rarely recommended. The main objective of the study is the evaluation of simultaneous assessment of Glucose Tolerance (GT) and Insulin Response (IR) during OGTT in patients with TDT.Methods:43 TDT patients aged 12-28years, without clinical evidence of glucose disturbances, were randomly selected for the study. The 2-hour OGTT in 30 minutes intervals was applied. Plasma glucose and insulin were assessed in all samples using routine laboratory methods.Results:Of 43 patients 31(72%) had Normal GT; of them 9 (29%) had normal insulin response (NIR), 14 (45%) high IR and 8(26%) delayed peak IR. Delayed peak IR was found in 8 of the 9 patients with Impaired GT and in 2 of the 3 with diabetic GT. Deficient IR (hypoinsulinemia) was found in two patients.Conclusions:Simultaneous assessment of GT and IR during OGTT in TDT patients, seems to be a most sensitive and creditable screening test for early diagnosis of glucose disturbances. High IR and delayed peak IR in normoglycemic patients are valuable indices for diagnosis of the pre-diabetic state that precede the development of glucose disturbances in TDT patients and start proper follow and management. (www.actabiomedica.it).

Metabolic changes induced by oral glucose tests in horses and their diagnostic use.

BackgroundLittle is known about the implications of hyperinsulinemia on energy metabolism, and such knowledge might help understand the pathophysiology of insulin dysregulation.ObjectivesDescribe differences in the metabolic response to an oral glucose test, depending on the magnitude of the insulin response.AnimalsTwelve Icelandic horses in various metabolic states.MethodsHorses were subjected to 3 oral glucose tests (OGT; 0.5 g/kg body weight glucose). Basal, 120 and 180 minutes samples were analyzed using a combined liquid chromatography tandem mass spectrometry and flow injection analysis tandem mass spectrometry metabolomic assay. Insulin concentrations were measured using an ELISA. Analysis was performed using linear models and partial least‐squares regression.ResultsThe kynurenine : tryptophan ratio increased over time during the OGT (adjusted P‐value = .001). A high insulin response was associated with lower arginine (adjusted P‐value = .02) and carnitine (adjusted P‐value = .03) concentrations. A predictive model using only baseline samples performed well with as few as 7 distinct metabolites (sensitivity, 86%; 95% confidence interval [CI], 81%‐90%; specificity, 88%; 95% CI, 84%‐92%).Conclusions and Clinical ImportanceOur results suggest induction of low‐grade inflammation during the OGT. Plasma arginine and carnitine concentrations were lower in horses with high insulin response and could constitute potential therapeutic targets. Development of screening tools to identify insulin‐dysregulated horses using only baseline blood sample appears promising.

Relationship between biochemical and symptomatic hypoglycemia after RYGB. Responses to a mixed meal test: a case-control study.

Postprandial hypoglycemia is a relatively common complication after Roux-en-Y gastric bypass (RYGB). The cause remains incompletely understood, and the association between biochemical hypoglycemia and hypoglycemic symptoms is unclear. To evaluate the association between postprandial hormonal responses and biochemical and symptomatic hypoglycemia after RYGB. University Hospital, Denmark. A case-control study with 3 groups: (1) RYGB group with postprandial hypoglycemic symptoms (HS), n = 13; (2) RYGB-group with no symptoms of hypoglycemia (NHS), n = 13; and (3) nonoperated body mass index-matched controls (CON), n = 7. Plasma glucose (PG) and hormonal responses (insulin, glucagon-like peptide-1, gastric inhibitory polypeptide, glucagon) were measured after a mixed meal test (MMT), and hypoglycemic symptoms were determined by a questionnaire. The primary outcomes were differences in subjective and biochemical responses related to hypoglycemia among the 3 groups. Nadir PG was lower (3.1 versus 4.0 mmol/L (56 versus 72 mg/dL); P = .0002) and peak insulin higher in HS than NHS patients (1073 versus 734 pmol/L; P = .0499). Of the 13 patients with a peak insulin >850 pmol/L, 8 patients developed symptoms whereas only 2 out of the 13 patients with peak insulin ≤850 pmol/L developed symptoms, corresponding to an odds ratio of 12 (1.8; 81.7). Post hoc analyses comparing all RYGB patients with biochemical hypoglycemia after the MMT (nadir glucose ≤3.0 mmol/L [54 mg/dL]) with those with glucose >3 mmol/L (54 mg/dL) revealed a difference in both peak insulin (1138 versus 760 pmol/L; P = .042) and peak glucagon-like peptide-1 (182 versus 86 pmol/L; P = .016) concentrations. Patients with HS had lower nadir PG and higher insulin responses than NHS patients after MMT. Regarding PG, PG ≤3.0 mmol/L (54 mg/dL) was the best discriminator of having hypoglycemic symptoms after the MMT. However, high insulin level seems the most important predictor for having both biochemical and symptomatic hypoglycemia.

Preliminary examination of insulin and amylin levels in women with purging disorder.

This preliminary study explored whether differences in meal-stimulated insulin or amylin release are linked to altered ingestive behaviors in individuals with bulimia nervosa (BN) or purging disorder (PD). Women with BN (n = 15), PD (n = 16), or no eating disorder (n = 18) underwent structured clinical interviews and assessments of gut hormone and subjective responses to a fixed test meal. Multilevel model analyses were used to explore whether gut hormone responses contribute to subjective responses to the test meal and whether these associations differed by group. Insulin and amylin levels significantly increased following the test meal. Women with PD showed greater insulin release compared to those with BN, but not controls. Multilevel models support significant group X insulin interactions predicting subjective ratings of nausea and urge to vomit, with a stronger association between higher insulin responses and higher nausea and urge to vomit in women with PD and BN. Amylin responses did not differ by group. Increased sensitivity to the effects of insulin on nausea and urge to vomit may be linked to purging in both PD and BN. Differences in postprandial insulin levels may be linked to purging behavior in the absence versus presence of binge eating.

Pharmacodynamic Effects of Pioglitazone on High Molecular Weight Adiponectin Concentrations and Insulin Response After Oral Sugar in Equids

Chronic insulin dysregulation is challenging to manage with pharmaceuticals in horses. Pioglitazone improves insulin sensitivity in humans, and the pharmacokinetics of pioglitazone have been evaluated in horses. The objectives of this study were to assess the pharmacodynamic effects of oral pioglitazone on morphometric parameters, hepatic enzyme activity and function, adipokines, and enteroinsular response to oral sugar. A prospective pilot study was performed using fifteen adult equids (8 ponies, 7 horses) to evaluate the effects of short-term pioglitazone administration (2 mg/kg PO q 24 hours, 28 days). Oral sugar tests (OST) were performed before and after treatment. Adipokines were measured at day 0, 14, and 28 of administration. Plasma drug concentrations were measured at day 14 and 28 of administration. The subjects were grouped into horses, ponies, and insulin dysregulated (ID) animals. Baseline values for all parameters were compared with values obtained at day 14 and 28 using one-way or two-way analysis of variance. Mild changes were noted in morphometric parameters and hepatic enzymes. No differences were found in leptin concentrations or the blood glucose response to the OST. Significant decreases were found in the insulin response to OST at 90 and 120 minutes time points and the area under the curve after pioglitazone treatment in the pony and ID groups. High-molecular-weight (HMW) adiponectin concentrations were significantly increased in all groups after pioglitazone treatment. Decreased insulin concentrations in response to oral sugar and increased HMW adiponectin concentrations indicate positive effects of pioglitazone for treatment of metabolic derangements in equine metabolic syndrome, which warrant future clinical study.

Yogurt Is a Low–Glycemic Index Food

High yogurt intake is associated with a reduced risk of type 2 diabetes (T2DM). Although several mechanisms could explain this association, this paper addresses the glycemic and insulinemic impact of yogurt. There is evidence that low-glycemic index (GI) and low-glycemic load (GL) diets are associated with a reduced risk of T2DM. The 93 GI values for yogurt in the University of Sydney's GI database have a mean ± SD of 34 ± 13, and 92% of the yogurts are low-GI (≤55). The 43 plain yogurts in the database have a lower GI than the 50 sweetened yogurts, 27 ± 11 compared with 41 ± 11 (P < 0.0001). This difference is not explained by sugar, per se, but rather by the higher protein-to-carbohydrate ratio in plain yogurt. Although yogurt has a low GI, its insulinemic index (II) is higher than its GI. High insulin responses may be deleterious because hyperinsulinemia is associated with an increased risk of T2DM. Nevertheless, this may not be a concern for yogurt because, although its II is higher than its GI, the II of yogurt is within the range of II values for nondairy low-GI foods. In addition, mixed meals containing dairy protein elicit insulin responses similar to those elicited by mixed meals of similar composition containing nondairy protein. Because the GI of yogurt is lower than that of most other carbohydrate foods, exchanging yogurt for other protein and carbohydrate sources can reduce the GI and GL of the diet, and is in line with recommended dietary patterns, which include whole grains, fruits, vegetables, nuts, legumes, fish, vegetable oils, and yogurt.

Metabolic changes in serum metabolome in response to a meal.

The change in serum metabolic response from fasting state to postprandial state provides novel insights into the impact of a single meal on human metabolism. Therefore, this study explored changes in serum metabolite profile after a single meal. Nineteen healthy postmenopausal women with normal glucose tolerance participated in the study. They received a meal consisting of refined wheat bread (50g carbohydrates, 9g protein, 4.2g fat and 2.7g dietary fibre), 40g cucumber and 300mL noncaloric orange drink. Blood samples were collected at fasting and five postprandial time points. Metabolic profile was measured by nuclear magnetic resonance and targeted liquid chromatography-mass spectrometry. Changes over time were assessed with multivariate models and ANOVA, with baseline as control. The metabolomic analyses demonstrated alterations in phospholipids, amino acids and their breakdown products, glycolytic products, acylcarnitines and ketone bodies after a single meal. More specifically, phosphatidylcholines, lysophosphatidylcholines and citrate displayed an overall declining pattern, while leucine, isoleucine, methionine and succinate increased initially but declined thereafter. A sharp decline in acylcarnitines and ketone bodies and increase in glycolytic products postprandially suggest a switch in the body's energy source from β-oxidation to glycolysis. Moreover, individuals with relatively high postprandial insulin responses generated a higher postprandial leucine responses compared to participants with lower insulin responses. The study demonstrated complex changes from catabolic to anabolic metabolism after a meal and indicated that the extent of postprandial responses is different between individuals with high and low insulin response.

Relationship of insulin dynamics to body composition and resting energy expenditure following weight loss.

ObjectiveTo examine associations of baseline insulin dynamics with changes in body composition and resting energy expenditure (REE) following weight loss.MethodsTwenty-one participants with overweight or obesity achieved 10-15% weight loss and then received 3 weight-loss maintenance diets (high-carbohydrate, moderate-carbohydrate, low-carbohydrate) in random order, each for 4 weeks. Body composition was measured at baseline and after weight loss. Insulin 30 minutes after glucose consumption (insulin-30; insulin response), C-peptide deconvolution analysis, HOMA, hepatic insulin sensitivity (IS), and REE were assessed at baseline and after each maintenance diet.ResultsInsulin-30, but not maximal insulin secretion, hepatic IS or HOMA, predicted changes in fat mass (standardized β=0.385, 1.7 kg difference between 10th-90th centile of insulin-30, P=0.04) after weight loss. Insulin-30 (β=−0.341, −312 kcal/d, P=0.008), maximal insulin secretion (β=−0.216, −95 kcal/d, P=0.0002), HOMA (β=−0.394,−350 kcal/d, P=0.002) and hepatic IS (β=0.217, 225 kcal/d, P=0.0003) predicted change in REE during weight-loss maintenance, independent of changes in body composition. The inverse relationship between insulin-30 and REE was substantially attenuated when the low-carbohydrate diet was consumed first.ConclusionsThese findings distinguish a novel phenotype, characterized by high insulin response, at risk for weight regain, and identify a dietary approach to ameliorate this risk.

Adolescent and Early Adulthood Dietary Carbohydrate Quantity and Quality in Relation to Breast Cancer Risk.

We investigated quantity and quality of dietary carbohydrate as well as insulin load and insulin index during adolescence and also early adulthood in relation to risk of breast cancer in the Nurses' Health Study II. During 20 years of follow-up of 90,534 premenopausal women who completed a diet questionnaire in 1991, 2,833 invasive breast cancer cases were documented. In 1998, 44,263 of these women also completed a questionnaire about their diet during high school; among these women, we documented 1,118 cases of breast cancer. Multivariable-adjusted Cox proportional hazards regression was used to model relative risks (RR) and 95% confidence intervals (95% CI) for breast cancer across categories of dietary carbohydrate, glycemic index (GI), glycemic load (GL), as well as insulin load and insulin index scores. Adolescent or early adult intakes of GI or GL were not associated with risk of breast cancer. Comparing women in the highest versus lowest quintile, the multivariable-adjusted RRs were 1.14 (0.95-1.38) for adolescent GI scores and 1.03 (0.91-1.16) for early adulthood GI scores. We also did not observe associations with insulin index and insulin load scores in adolescence or early adulthood and breast cancer risk. We found that diets high in GI, GL, insulin index, and insulin load during adolescence or early adulthood were not associated with an increased risk of breast cancer in this cohort study. Diets with a high glucose or insulin response in adolescence or early adulthood were not significant predictors of breast cancer incidence.

The structure of wheat bread influences the postprandial metabolic response in healthy men.

Postprandial high glucose and insulin responses after starchy food consumption, associated with an increased risk of developing several metabolic diseases, could possibly be improved by altering food structure. We investigated the influence of a compact food structure; different wheat products with a similar composition were created using different processing conditions. The postprandial glucose kinetics and metabolic response to bread with a compact structure (flat bread, FB) was compared to bread with a porous structure (control bread, CB) in a randomized, crossover study with ten healthy male volunteers. Pasta (PA), with a very compact structure, was used as the control. The rate of appearance of exogenous glucose (RaE), endogenous glucose production, and glucose clearance rate (GCR) was calculated using stable isotopes. Furthermore, postprandial plasma concentrations of glucose, insulin, several intestinal hormones and bile acids were analyzed. The structure of FB was considerably more compact compared to CB, as confirmed by microscopy, XRT analysis (porosity) and density measurements. Consumption of FB resulted in lower peak glucose, insulin and glucose-dependent insulinotropic polypeptide (ns) responses and a slower initial RaE compared to CB. These variables were similar to the PA response, except for RaE which remained slower over a longer period after PA consumption. Interestingly, the GCR after FB was higher than expected based on the insulin response, indicating increased insulin sensitivity or insulin-independent glucose disposal. These results demonstrate that the structure of wheat bread can influence the postprandial metabolic response, with a more compact structure being more beneficial for health. Bread-making technology should be further explored to create healthier products.

Dietary insulin index and insulin load in relation to endometrial cancer risk in the Nurses' Health Study.

Although unopposed estrogen exposure is considered the main driver of endometrial carcinogenesis, factors associated with states of insulin resistance and hyperinsulinemia are independently associated with endometrial cancer risk. We used dietary insulin load and insulin index scores to represent the estimated insulin demand of overall diets and assessed their association with endometrial cancer risk in the prospective Nurses' Health Study. We estimated incidence rate ratios (RR) and 95% confidence intervals (CI) for risk of invasive endometrial cancer using Cox proportional hazards models. Between the baseline dietary questionnaire (1980) and 2010, we identified a total of 798 incident-invasive epithelial endometrial adenocarcinomas over 1,417,167 person-years of follow-up. Dietary insulin scores were not associated with overall risk of endometrial cancer. Comparing women in the highest with the lowest quintile, the multivariable-adjusted RRs of endometrial cancer were 1.07 (95% CI, 0.84-1.35) for cumulative average dietary insulin load and 1.03 (95% CI, 0.82-1.31) for cumulative average dietary insulin index. Findings did not vary substantially by alcohol consumption, total dietary fiber intake, or body mass index and/or physical activity (P(heterogeneity) ≥ 0.10). Intake of a diet predicted to stimulate a high postprandial insulin response was not associated with endometrial cancer risk in this large prospective study. Considering the complex interplay of diet, lifestyle, and genetic factors contributing to the hyperinsulinemic state, dietary measures alone may not sufficiently capture absolute long-term insulin exposure. This study is the first to investigate dietary insulin scores in relation to endometrial cancer risk.

Metabolomics Reveals Differences in Postprandial Responses to Breads and Fasting Metabolic Characteristics Associated with Postprandial Insulin Demand in Postmenopausal Women

Changes in serum metabolic profile after the intake of different food products (e.g., bread) can provide insight into their interaction with human metabolism. Postprandial metabolic responses were compared after the intake of refined wheat (RWB), whole-meal rye (WRB), and refined rye (RRB) breads. In addition, associations between the metabolic profile in fasting serum and the postprandial concentration of insulin in response to different breads were investigated. Nineteen postmenopausal women with normal fasting glucose and normal glucose tolerance participated in a randomized, controlled, crossover meal study. The test breads, RWB (control), RRB, and WRB, providing 50 g of available carbohydrate, were each served as a single meal. The postprandial metabolic profile was measured using nuclear magnetic resonance and targeted LC–mass spectrometry and was compared between different breads using ANOVA and multivariate models. Eight amino acids had a significant treatment effect (P < 0.01) and a significant treatment × time effect (P < 0.05). RWB produced higher postprandial concentrations of leucine (geometric mean: 224; 95% CI: 196, 257) and isoleucine (mean ± SD: 111 ± 31.5) compared with RRB (geometric mean: 165; 95% CI: 147, 186; mean ± SD: 84.2 ± 22.9) and WRB (geometric mean: 190; 95% CI: 174, 207; mean ± SD: 95.8 ± 17.3) at 60 min respectively (P < 0.001). In addition, 2 metabolic subgroups were identified using multivariate models based on the association between fasting metabolic profile and the postprandial concentration of insulin. Women with higher fasting concentrations of leucine and isoleucine and lower fasting concentrations of sphingomyelins and phosphatidylcholines had higher insulin responses despite similar glucose concentration after all kinds of bread (cross-validated ANOVA, P = 0.048). High blood concentration of branched-chain amino acids, i.e., leucine and isoleucine, has been associated with the increased risk of diabetes, which suggests that additional consideration should be given to bread proteins in understanding the beneficial health effects of different kinds of breads. The present study suggests that the fasting metabolic profile can be used to characterize the postprandial insulin demand in individuals with normal glucose metabolism that can be used for establishing strategies for the stratification of individuals in personalized nutrition.

Obesity - should we revise indications for treatment with metformin?

IntroductionTreatment of obesity with life style modifications often fails; therefore pharmacological treatment has become a very popular approach. Metformin is one of the examined possibilities. The aim of this study was to verify indications for metformin use in obese women based on metabolic and anthropometric parameters assessed by dual-X-ray absorptiometry (DXA), to establish the degree of insulin resistance and its correlations.Material and methodsAnthropometry, fat measurement by bioimpedance and metabolic profile, including lipids, and oral glucose tolerance test (OGTT) with insulin (0 and 120 min) were performed in 50 female patients diagnosed with simple obesity, aged 18-40 years. Homeostatic model assessment HOMA-R was calculated for insulin resistance, and area under the curve (AUC) for insulin response. Total, android and gynoid fat distribution, and their ratio (A/G), were measured by DXA.ResultsFrom 50 women who entered the study, 33 were classified as insulin resistant (IR subgroup) and 17 as non-insulin resistant (non-IR subgroup), according to their HOMA-R indices. IR women presented higher waist circumference and DXA A/G ratio. The IR subgroup demonstrated elevated fasting triglycerides and glucose (but in the normal range) and a higher insulin response in OGTT (4.1-fold vs 2.5-fold). From different insulin measurements HOMA index turned out to have the strongest correlations with the metabolic parameters triglycerides and glucose. We found significant positive correlations between android fat and insulin: waist circumference and HOMA-R, WHR and HOMA-R, android fat and HOMA-R, A/G ratio and insulin after OGTT, and A/G ratio and HOMA-R. We found a strong correlation between WHR and A/R ratio.Conclusions67% of premenopausal obese women were insulin resistant. Measures of DXA visceral fat determined by android fat percentage and android/gynoid ratio were the strongest determinants of insulin resistance. Waist-to-hip ratio might be a simple method for determining the indications for metformin treatment.

GLP-1 Responses Are Heritable and Blunted in Acquired Obesity With High Liver Fat and Insulin Resistance

OBJECTIVE Impaired incretin response represents an early and uniform defect in type 2 diabetes, but the contributions of genes and the environment are poorly characterized. RESEARCH DESIGN AND METHODS We studied 35 monozygotic (MZ) and 75 dizygotic (DZ) twin pairs (discordant and concordant for obesity) to determine the heritability of glucagon-like peptide 1 (GLP-1) responses to an oral glucose tolerance test (OGTT) and the influence of acquired obesity to GLP-1, glucose-dependent insulinotropic peptide (GIP), and peptide YY (PYY) during OGTT or meal test. RESULTS The heritability of GLP-1 area under the curve was 67% (95% CI 45-80). Cotwins from weight-concordant MZ and DZ pairs and weight-discordant MZ pairs but concordant for liver fat content demonstrated similar glucose, insulin, and incretin profiles after the OGTT and meal tests. In contrast, higher insulin responses and blunted 60-min GLP-1 responses during the OGTT were observed in the heavier as compared with leaner MZ cotwins discordant for BMI, liver fat, and insulin sensitivity. Blunted GLP-1 response to OGTT was observed in heavier as compared with leaner DZ cotwins discordant for obesity and insulin sensitivity. CONCLUSIONS Whereas the GLP-1 response to the OGTT is heritable, an acquired unhealthy pattern of obesity characterized by liver fat accumulation and insulin resistance is closely related to impaired GLP-1 response in young adults.