Matsuda Index Research Articles

In Obese Patients Without Diabetes, 12 Weeks of Time-Restricted Eating (TRE) Does Not Alter β-Cell Function: A Randomized Pilot Study

Abstract Impairment of β-cell function is a precursor to impaired glucose tolerance, which is a pathophysiological basis for the development of Type 2 Diabetes Mellitus (T2DM). Previous literature has reported varying effects of TRE on metabolic measures in different populations, yet the effect of TRE on β-cell function has not been well-characterized. We hypothesized that in obese patients without diabetes, 12 weeks of TRE (8-hour eating window) would improve β-cell function relative to baseline and the unrestricted eating group (non-TRE). Participants (17 women and 3 men; (mean ± SD); 45.5±12.1 years; BMI 34.1±7.5 kg/m2) with a prolonged eating window (15.4±0.9 hours) were randomized to either TRE (n=11) or non-TRE (n=9) for 12 weeks. Weight and 2-hour oral glucose tolerance (OGTT) were measured during at baseline and end-intervention. Β-cell function was assessed by multiple OGTT-based measures, including Glucose AUC, Insulin AUC, insulinogenic index, disposition index, QUICKI index, Matsuda index, Stumvoll index, and Avignon index. At baseline, these measures are within normal range across both groups. We found that TRE did not significantly alter these measures relative to baseline or the non-TRE group. In addition, the degree of eating window restriction did not correlate with any observed changes in β-cell function. We concluded that in obese patients without diabetes, TRE did not significantly alter β cell function; whether TRE may be beneficial in patients with dysglycemia warrants further investigation.

Comparison of islet cell function, insulin sensitivity, and incretin axis between Asian-Indians with either impaired fasting glucose or impaired glucose tolerance, and normal healthy controls

AimsThe objective of this study was to compare the islet cell function, insulin sensitivity, and incretin axis between Asian-Indian subjects with either impaired fasting glucose (IFG), or impaired glucose tolerance (IGT), and normal glucose tolerance (NGT). Materials and methodsPrediabetes subjects underwent a mixed meal tolerance test(MMTT) after overnight fasting. Samples for glucose, insulin, glucagon, and glucagon-like peptide-1 (GLP-1) were collected at 0, 30, 60, and 120 min. Insulin secretion sensitivity index -2 (ISSI-2) for beta-cell function and Matsuda index for insulin sensitivity were assessed. Alpha cell function was assessed by measuring the area under the curve (AUC) 0-120 glucagon/AUC0-120 glucose. ResultsA total of sixty subjects were recruited with 20 in each group. The beta-cell function represented by ISSI-2 was impaired in prediabetes subjects as compared to NGT group (IFG: 2.09 ± 0.44 vs. NGT: 3.04 ± 0.80, P < 0.0001, and IGT: 2.33 ± 0.59 vs. NGT: 3.04 ± 0.80, P = 0.002). Similarly, AUC0-120 glucagon/AUC0-120 glucose was also lower in prediabetes group as compared to healthy controls (IFG: 0.41(0.54) vs. NGT: 1.07(0.39), P = 0.003 and IGT: 0.57(0.38) vs. NGT: 1.07(0.39), P = 0.001). ConclusionAsian-Indian prediabetes subjects have reduced beta-cell function with lesser glucagon secretion during MMTT as compared to normal healthy controls.

Resting metabolic rate is increased in hypertensive patients with overweight or obesity: Potential mechanisms.

The purpose of this investigation was to determine whether differences in body composition, pharmacological treatment, and physical activity explain the increased resting metabolic rate (RMR) and impaired insulin sensitivity in hypertension. Resting blood pressure, RMR (indirect calorimetry), body composition (dual-energy X-ray absorptiometry), physical activity (accelerometry), maximal oxygen uptake (VO2 max) (ergospirometry), and insulin sensitivity (Matsuda index) were measured in 174patients (88men and 86women; 20-68years) with overweight or obesity. Hypertension (HTA) was present in 51men (58%) and 42women (49%) (p=.29). RMR was 6.9% higher in hypertensives than normotensives (1777±386 and 1663±383kcal d-1 , p=.044). The double product (systolic blood pressure × heart rate) was 18% higher in hypertensive than normotensive patients (p<.001). The observed differences in absolute RMR were non-significant after adjusting for total lean mass and total fat mass (estimated means: 1702kcal d-1 , CI: 1656-1750; and 1660kcal d-1 , CI: 1611-1710kcal d-1 , for the hypertensive and normotensive groups, respectively, p=.19, HTA × sex interaction p=.37). Lean mass, the double product, and age were the variables with the higher predictive value of RMR in hypertensive patients. Insulin sensitivity was lower in hypertensive than in normotensive patients, but these differences disappeared after accounting for physical activity and VO2max . In summary, hypertension is associated with increased RMR and reduced insulin sensitivity. The increased RMR is explained by an elevated myocardial oxygen consumption due to an increased resting double product, combined with differences in body composition between hypertensive and normotensive subjects.

Waist-to-height ratio and metabolic phenotype compared to the Matsuda index for the prediction of insulin resistance

Current screening algorithms for type 2 diabetes (T2D) rely on fasting plasma glucose (FPG) and/or HbA1c. This fails to identify a sizeable subgroup of individuals in early stages of metabolic dysregulation who are at high risk for developing diabetes or cardiovascular disease. The Matsuda index, a combination of parameters derived from a fasting and postprandial insulin assay, is an early biomarker for metabolic dysregulation (i.e. insulin resistance/compensatory hyperinsulinemia). The aim of this analysis was to compare four widely available anthropometric and biochemical markers indicative of this condition [waist-to-height ratio (WHtR), hypertriglyceridemic-waist phenotype (HTW), triglycerides-to-HDL-C ratio (TG/HDL-C) and FPG] to the Matsuda index. This cross-sectional analysis included 2231 individuals with normal fasting glucose (NFG, n = 1333), impaired fasting glucose (IFG, n = 599) and T2D (n = 299) from an outpatient diabetes clinic in Germany and thus extended a prior analysis from our group done on the first two subgroups. We analyzed correlations of the Matsuda index with WHtR, HTW, TG/HDL-C and FPG and their predictive accuracies by correlation and logistic regression analyses and receiver operating characteristics. In the entire group and in NFG, IFG and T2D, the best associations were observed between the Matsuda index and the WHtR (r = − 0.458), followed by HTW phenotype (r = − 0.438). As for prediction accuracy, WHtR was superior to HTW, TG/HDL-C and FPG in the entire group (AUC 0.801) and NFG, IFG and T2D. A multivariable risk score for the prediction of insulin resistance was tested and demonstrated an area under the ROC curve of 0.765 for WHtR and its interaction with sex as predictor controlled by age and sex. The predictive power increased to 0.845 when FPG and TG/HDL-C were included. Using as a comparator the Matsuda index, WHtR, compared to HTW, TG/HDL-C and FPG, showed the best predictive value for detecting metabolic dysregulation. We conclude that WHtR, a widely available anthropometric index, could refine phenotypic screening for insulin resistance/hyperinsulinemia. This may ameliorate early identification of individuals who are candidates for appropriate therapeutic interventions aimed at addressing the twin epidemic of metabolic and cardiovascular disease in settings where more extended testing such as insulin assays are not feasible.

Metformin for early comorbid glucose dysregulation and schizophrenia spectrum disorders: a pilot double-blind randomized clinical trial

Patients with schizophrenia have exceedingly high rates of metabolic comorbidity including type 2 diabetes and lose 15–20 years of life due to cardiovascular diseases, with early accrual of cardiometabolic disease. In this study, thirty overweight or obese (Body Mass Index (BMI) > 25) participants under 40 years old with schizophrenia spectrum disorders and early comorbid prediabetes or type 2 diabetes receiving antipsychotic medications were randomized, in a double-blind fashion, to metformin 1500 mg/day or placebo (2:1 ratio; n = 21 metformin and n = 9 placebo) for 4 months. The primary outcome measures were improvements in glucose homeostasis (HbA1c, fasting glucose) and insulin resistance (Matsuda index—derived from oral glucose tolerance tests and homeostatic model of insulin resistance (HOMA-IR)). Secondary outcome measures included changes in weight, MRI measures of fat mass and distribution, symptom severity, cognition, and hippocampal volume. Twenty-two patients (n = 14 metformin; n = 8 placebo) completed the trial. The metformin group had a significant decrease over time in the HOMA-IR (p = 0.043) and fasting blood glucose (p = 0.007) vs. placebo. There were no differences between treatment groups in the Matsuda index, HbA1c, which could suggest liver-specific effects of metformin. There were no between group differences in other secondary outcome measures, while weight loss in the metformin arm correlated significantly with decreases in subcutaneous, but not visceral or hepatic adipose tissue. Our results show that metformin improved dysglycemia and insulin sensitivity, independent of weight loss, in a young population with prediabetes/diabetes and psychosis spectrum illness, that is at extremely high risk of early cardiovascular mortality. Trial Registration: This protocol was registered with clinicaltrials.gov (NCT02167620).

Interactive effects of acute exercise and carbohydrate-energy replacement on insulin sensitivity in healthy adults.

This study investigated whether carbohydrate-energy replacement immediately after prolonged endurance exercise attenuates insulin sensitivity the following morning, and whether exercise improves insulin sensitivity the following morning independent of an exercise-induced carbohydrate deficit. Oral glucose tolerance and whole-body insulin sensitivity were compared the morning after 3 evening conditions, involving (1) treadmill exercise followed by a carbohydrate replacement drink (200 or 150g maltodextrin for males and females, respectively; CHO-replace); (2) treadmill exercise followed by a non-caloric, taste-matched placebo (CHO-deficit); or (3) seated rest with no drink provided (Rest). Treadmill exercise involved 90minutes at ∼80% age-predicted maximum heart rate. Seven males and 2 females (aged 23± 1years; body mass index 24.0± 2.7kg·m-2) completed all conditions in a randomised order. Matsuda index improved by 22% (2.2 [0.3, 4.0] au, p= 0.03) and HOMA2-IR improved by 10% (-0.04 [-0.08, 0.00] au, p= 0.04) in CHO-deficit versus CHO-replace, without corresponding changes in postprandial glycaemia. Outcomes were similar between Rest and other conditions. These data suggest that improvements to insulin sensitivity in healthy populations following acute moderate/vigorous intensity endurance exercise may be dependent on the presence of a carbohydrate-energy deficit. Novelty: Restoration of carbohydrate balance following acute endurance exercise attenuated whole-body insulin sensitivity. Exercise per se failed to enhance whole-body insulin sensitivity. Maximising or prolonging the post-exercise carbohydrate deficit may enhance acute benefits to insulin sensitivity.

Early menarche is associated with insulin-resistance and non-alcoholic fatty liver disease in adolescents with obesity.

Recent evidence linked early menarche to a higher risk of insulin-resistance (IR) and nonalcoholic fatty liver disease (NAFLD) in adulthood. We aimed to evaluate the impact of early menarche on glucose derangements and NAFLD in a sample of Italian adolescents with obesity. Anthropometric and biochemical evaluations were conducted in all the enrolled 318 obese patients (mean age 12.31±2.95years). NAFLD was defined by the presence of ultrasound detected liver steatosis and/or alanine transaminase (ALT) levels >40IU/L. Patients with early menarche showed both higher homeostasis model assessment of insulin-resistance (HOMA-IR) (p=0.008) and ALT (p=0.02) values, an increased prevalence of NAFLD (p=0.001), and lower Matsuda and Insulinogenic Index (IGI) values than the other obese patients. The association between early menarche and both ALT and Matsuda Index remained significant in General Linear Models (GLMs) in which respectively body mass index standard deviation score (BMI-SDS) and Matsuda Index, and BMI-SDS were included as covariates. Patients with early menarche also showed a higher risk of both HOMA-IR>3 (OR 1.69, CI 1.05-2.70, p=0.02) and NAFLD (OR 1.10, CI 1.01-1.21, p=0.03). Girls with obesity presenting early menarche showed higher HOMA-IR levels, lower Matsuda Index and IGI values, and higher risk of NAFLD compared to girls without early menarche.

Lack of Improvement in Insulin Sensitivity After Pancreas Transplantation in Recipients With a High Level of Calcineurin Inhibitors.

This study aimed to assess posttransplant changes in insulin sensitivity and β-cell function of pancreas transplant recipients according to the type of diabetes mellitus (DM) and the pretransplant insulin sensitivity measured by the Matsuda Index (MI). We analyzed 60 patients who underwent pancreas transplantation and oral glucose tolerance test pretransplant and at 1 month posttransplant. At 1 month posttransplant, insulin sensitivity did not show significant improvement; particularly, the MI was significantly lower after transplant in recipients with type 1 DM (T1DM) and those with pretransplant MI of 5 or greater. β-cell function was significantly improved after transplant in all recipients regardless of the type of DM and pretransplant MI values. Glucose control was significantly improved in recipients with T1DM and in all recipients regardless of the pretransplant MI values. Additional oral glucose tolerance test at 1 year posttransplant revealed that insulin sensitivity remained unimproved and β-cell function was higher compared with pretransplant. Glucose control had partially reverted to pretransplant levels in recipients with T1DM and those with pretransplant MI of 5 or greater. Unlike β-cell function and glucose control, insulin sensitivity did not significantly improve until posttransplant 1 year after pancreas transplantation regardless of the type of DM or the degree of pretransplant insulin sensitivity.

Visceral adiposity index is associated with insulin resistance, impaired insulin secretion, and β-cell dysfunction in subjects at risk for type 2 diabetes

BackgroundIncreased visceral adiposity, insulin resistance, and β-cell dysfunction predispose to type 2 diabetes (T2D). The Visceral Adiposity Index (VAI) is an indicator of visceral fat function obtained from the association between BMI, Triglycerides, HDL-C, and waist circumference, and is a reliable tool to assess the cardiometabolic risk, however, its association with insulin resistance and decreased β-cell function in primary prevention for T2D has not been fully yielded. MethodsThis is a retrospective cross-sectional study that included 354 asymptomatic subjects, without any known chronic disease, with at least two risk factors for T2D that underwent an oral glucose tolerance test. Patients with newly diagnosed T2D were excluded from the analysis. ResultsParticipants were 51 ± 8 years old, 72.2% were women, had a mean body mass index of 29.9 ± 6.5 kg/m2 and a median VAI of 3.00. The homeostasis model assessment of insulin resistance (HOMA-IR) (r = 0.324), Matsuda index (r = -0.325), first-phase insulin secretion (S1PhOGTT) (r = 0.138), second-phase insulin secretion (S2PhOGTT) (r = 0.137), HOMA-B (r = 0.224), and disposition index (r = -0.165) were significantly correlated with the VAI. After multiple linear regression analysis, the VAI was independently associated with HOMA-IR (β = 0.305), Matsuda Index (β = -0.303), S1PhOGTT (β = 0.143), S2PhOGTT (β = 0.140), HOMA-B (β = 0.204), and the disposition index (β = -0.146). Likewise, a VAI of 2.23 had a sensitivity/specificity of 81.9% and 41.5%, respectively, for identifying a HOMA-IR ≥ 2.5; and a VAI of 3.00 had a sensitivity/specificity of 61.3% and 41.8%, respectively, for identifying a disposition index ≤1.24. ConclusionsThe VAI was independently associated with insulin resistance, impaired insulin secretion and β-cell dysfunction in subjects at risk for developing T2D.

Metabolic effects of 1-week binge drinking and fast food intake during Roskilde Festival in young healthy male adults.

Metabolic effects of intermittent unhealthy lifestyle in young adults are poorly studied. We investigated the gluco-metabolic and hepatic effects of participation in Roskilde Festival (1 week of binge drinking and junk food consumption) in young, healthy males. Fourteen festival participants (FP) were studied before, during and after 1 week's participation in Roskilde Festival. Fourteen matched controls (CTRL) who did not participate in Roskilde Festival or change their lifestyle in other ways were investigated along a similar timeline. The FP group consumed more alcohol compared to their standard living conditions (2.0 ± 3.9 vs 16.3 ± 8.3 units/day, P < 0.001). CTRLs did not change their alcohol consumption. AUC for glucose during OGTT did not change in either group. C-peptide responses increased in the FP group (206 ± 24 vs 236 ± 17 min × nmol/L, P = 0.052) and the Matsuda index of insulin sensitivity decreased (6.2 ± 2.4 vs 4.7 ± 1.4, P = 0.054). AUC for glucagon during oral glucose tolerance test (OGTT) increased in the FP group (1037 ± 90 vs 1562 ± 195 min × pmol/L, P = 0.003) together with fasting fibroblast growth factor 21 (FGF21) (62 ± 30 vs 132 ± 72 pmol/L, P < 0.001), growth differentiation factor 15 (GDF5) (276 ± 78 vs 330 ± 83 pg/mL, P = 0.009) and aspartate aminotransferase (AST) levels (37.6 ± 6.8 vs 42.4 ± 11 U/L, P = 0.043). Four participants (29%) developed ultrasound-detectable steatosis and a mean strain elastography-assessed liver stiffness increased (P = 0.026) in the FP group. Participation in Roskilde Festival did not affect oral glucose tolerance but was associated with a reduction in insulin sensitivity, increases in glucagon, FGF21, GDF15 and AST and lead to increased liver stiffness and, in 29% of the participants, ultrasound-detectable hepatic steatosis.

Regional Variations of Insulin Secretion and Insulin Sensitivity in Japanese Participants With Normal Glucose Tolerance.

Purpose: Regional differences in dietary patterns in Asian countries might affect the balance of insulin response and sensitivity. However, this notion is yet to be validated. To clarify the regional differences in the insulin response and sensitivity and their relationship to nutrients, we compared the insulin secretory response during an oral glucose tolerance test in Japanese participants.Methods: This observational retrospective cohort study analyzed the data from participants with normal glucose tolerance (NGT) from four distinct areas of Japan with regard to the food environment: Fukushima, Nagano, Tokushima, and Okinawa based on data available in the Japanese National Health Insurance database.Results: Although the glucose levels were comparable among the four regions, the insulin responses were significantly different among the regions. This difference was observed even within the same BMI category. The plot between the insulin sensitivity index (Matsuda index) and insulinAUC/glucoseAUC or the insulinogenic index showed hyperbolic relationships with variations in regions. The indices of insulin secretion correlated positively with fat intake and negatively with the intake of fish, carbohydrate calories, and dietary fiber.Conclusions: We found that significant regional differences in insulin response and insulin sensitivity in Japanese participants and that nutritional factors may be linked to these differences independently of body size/adiposity. Insulin response and insulin sensitivity can vary among adult individuals, even within the same race and the same country, and are likely affected by environmental/lifestyle factors as well as genetic traits.

Islet isograft transplantation improves insulin sensitivity in a murine model of type 2 diabetes.

Type 2 diabetes develops in the presence of chronic overnutrition and genetic susceptibility, and causes insulin resistance and relative insulin deficiency. We hypothesized that islet transplantation can improve insulin sensitivity by modifying the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues. Eight-week-old male mice were used as both recipients and donors in this study. To induce type 2 diabetes with partial β-cell failure, the mice were fed a high-fat diet for 4 weeks and then injected with low-dose streptozotocin. Approximately 400 islet cells from a donor mouse were injected into the renal capsule of a recipient mouse for islet transplantation. After 6 weeks following transplantation, the mediators of insulin sensitivity in the pancreas, liver, muscle, and adipose tissues were quantitatively compared between islet-transplanted and non-transplanted groups. Intravenous glucose tolerance test showed that whereas the non-transplanted mice failed to show notable reductions in the glucose level, the islet-transplanted mice showed significant reductions in the serum glucose level to ~200 mg/dL at 6 weeks after islet transplantation. The islet-transplanted mice showed significantly higher Matsuda index and significantly lower HOMA-IR than did the non-transplanted mice, thus signifying improved insulin sensitivity. Islet transplantation resulted in improvements in multiple indices of insulin sensitivity in a murine model of type 2 diabetes. Islet transplantation may be utilized to improve insulin sensitivity in patients with type 2 diabetes.

Efficacy of metformin and fermentable fiber combination therapy in adolescents with severe obesity and insulin resistance: study protocol for a double-blind randomized controlled trial

BackgroundAccumulating evidence suggests that the metabolic effects of metformin and fermentable fibers are mediated, in part, through diverging or overlapping effects on the composition and metabolic functions of the gut microbiome. Pre-clinical animal models have established that the addition of fiber to metformin monotherapy improves glucose tolerance. However, possible synergistic effects of combination therapy (metformin plus fiber) have not been investigated in humans. Moreover, the underlying mechanisms of synergy have yet to be elucidated. The aim of this study is to compare in adolescents with obesity the metabolic effects of metformin and fermentable fibers in combination with those of metformin or fiber alone. We will also determine if therapeutic responses correlate with compositional and functional features of the gut microbiome.MethodsThis is a parallel three-armed, double-blinded, randomized controlled trial. Adolescents (aged 12–18 years) with obesity, insulin resistance (IR), and a family history of type 2 diabetes mellitus (T2DM) will receive either metformin (850 mg p.o. twice/day), fermentable fibers (35 g/day), or a combination of metformin plus fiber for 12 months. Participants will be seen at baseline, 3, 6, and 12 months, with a phone follow-up at 1 and 9 months. Primary and secondary outcomes will be assessed at baseline, 6, and 12 months. The primary outcome is change in IR estimated by homeostatic model assessment of IR; key secondary outcomes include changes in the Matsuda index, oral disposition index, body mass index z-score, and fat mass to fat-free mass ratio. To gain mechanistic insight, endpoints that reflect host-microbiota interactions will also be assessed: obesity-related immune, metabolic, and satiety markers; humoral metabolites; and fecal microbiota composition, short-chain fatty acids, and bile acids.DiscussionThis study will compare the potential metabolic benefits of fiber with those of metformin in adolescents with obesity, determine if metformin and fiber act synergistically to improve IR, and elucidate whether the metabolic benefits of metformin and fiber associate with changes in fecal microbiota composition and the output of health-related metabolites. This study will provide insight into the potential role of the gut microbiome as a target for enhancing the therapeutic efficacy of emerging treatments for T2DM prevention.Trial registrationClinicalTrials.gov NCT04578652. Registered on 8 October 2020.

Urinary oxidized, but not enzymatic vitamin E metabolites are inversely associated with measures of glucose homeostasis in middle-aged healthy individuals

Damage induced by lipid peroxidation has been associated with impaired glucose homeostasis. Vitamin E (α-tocopherol, α-TOH) competitively reacts with lipid peroxyl radicals to mitigate oxidative damage, and forms oxidized vitamin E metabolites. Accordingly, we aimed to investigate the associations between α-TOH metabolites (oxidized and enzymatic) in both circulation and urine and measures of glucose homeostasis in the general middle-aged population. This cross-sectional study was embedded in the population-based Netherlands Epidemiology of Obesity (NEO) Study. α-TOH metabolites in blood (α-TOH and α-CEHC-SO3) and urine [sulfate (SO3) and glucuronide (GLU) of both α-TLHQ (oxidized) and α-CEHC (enzymatic)] were quantified by liquid chromatography coupled with tandem mass spectrometry (LC/MS-MS). Measures of glucose homeostasis (HOMA-B, HOMA-IR, Insulinogenic index and Matsuda index) were obtained from fasting and postprandial blood samples. Multivariable linear regression analyses were performed to assess the associations of α-TOH metabolites and measures of glucose homeostasis. We included 498 participants (45% men) with mean (SD) age of 55.8 (6.1) years who did not use glucose-lowering medication. While blood α-TOH was not associated with measures of glucose homeostasis, urinary oxidized metabolites (α-TLHQ-SO3/GLU) were associated with HOMA-IR and Matsuda index. For example, a one-SD higher α-TLHQ-SO3 was associated with 0.92 (95% CI: 0.87, 0.97) fold lower HOMA-IR and 1.06 (1.01, 1.11) fold higher Matsuda index, respectively. Similar results were obtained for the urinary α-TLHQ to α-CEHC ratio as a measure of oxidized-over-enzymatic conversion of α-TOH. Higher urinary levels of oxidized α-TOH metabolites as well as higher oxidized-to-enzymatic α-TOH metabolite ratio, but not circulating α-TOH or enzymatic metabolites, were associated with lower insulin resistance. Rather than circulating α-TOH, estimates of the conversion of α-TOH might be informative in relation to health and disease.

Impaired Suppression of Glucagon in Obese Subjects Parallels Decline in Insulin Sensitivity and Beta-Cell Function.

To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Suppression of plasma glucagon was examined in 275 obese Hispanic Americans with varying glucose tolerance. All subjects received a 2-hour oral glucose tolerance test (OGTT) and a subset (n = 90) had euglycemic hyperinsulinemic clamp. During OGTT, we quantitated suppression of plasma glucagon concentration, Matsuda index of insulin sensitivity, and insulin secretion/insulin resistance (disposition) index. Plasma glucagon suppression was compared between quartiles of insulin sensitivity and beta-cell function. Fasting plasma glucagon levels were similar in obese subjects with normal glucose tolerance (NGT), prediabetes, and type 2 diabetes (T2D), but the fasting glucagon/insulin ratio decreased progressively from NGT to prediabetes to T2D (9.28 ± 0.66 vs 6.84 ± 0.44 vs 5.84 ± 0.43; P < 0.001). Fasting and 2-hour plasma glucagon levels during OGTT progressively increased and correlated positively with severity of insulin resistance (both Matsuda index and euglycemic hyperinsulinemic clamp). The fasting glucagon/insulin ratio declined with worsening insulin sensitivity and beta-cell function, and correlated with whole-body insulin sensitivity (Matsuda index, r = 0.81; P < 0.001) and beta-cell function (r = 0.35; P < 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = -0.47; P < 0.001 and r = -0.32; P < 0.001). Insulin-mediated suppression of glucagon secretion in obese subjects is impaired with increasing severity of glucose intolerance and parallels the severity of insulin resistance and beta-cell dysfunction.

Prevalence and Features of Impaired Glucose Tolerance in Young Underweight Japanese Women.

In Japan, while it is known that underweight women over the age of 40 years have a high risk for type 2 diabetes, there is a lack of clarity on the association between glucose tolerance and underweight in younger women. Accordingly, we investigate the prevalence and features of impaired glucose tolerance (IGT) in young underweight Japanese women. In this cross-sectional study, we recruited 56 normal weight and 98 underweight young Japanese women and evaluated their glucose tolerance levels using an oral glucose tolerance test. Then, we compared the clinical characteristics associated with normal glucose tolerance (NGT) and IGT in the underweight women. Insulin secretion, whole-body insulin sensitivity, and adipose tissue insulin resistance values were measured using the insulinogenic index, whole-body insulin sensitivity index (Matsuda index), and adipose insulin resistance index (Adipo-IR), respectively. Fitness level (peak VO2) was measured using an ergometer. The prevalence of IGT was higher in the underweight women than the normal weight women (13.3% vs 1.8%). The underweight women with IGT showed a lower insulinogenic index, lower peak VO2, and Matsuda index and a higher fasting free fatty acid level and Adipo-IR than those with NGT. The whole-body composition was comparable between the NGT and IGT groups. The prevalence of IGT was higher in young Japanese women with underweight than those with a normal weight. The underweight women with IGT showed impaired early-phase insulin secretion, low fitness levels, and reduced whole-body and adipose tissue insulin sensitivity levels.

Investigation of the progress in the women with gestational diabetes mellitus postpartum

Aims: Our aim was to evaluate the uptake of postpartum screening, the prevalence and the risk factors for glucose intolerance in women with a recent history of gestational diabetes mellitus (GDM). Methods: All women with a history of GDM are advised to undergo a 75g oral glucose tolerance test (OGTT) around 6 - 12 weeks postpartum. Indices of insulin sensitivity (the Matsuda index and the reciprocal of the homeostasis model assessment of insulin resistance, HOMA-IR) and an index of beta-cell function, the Insulin Secretion-Sensitivity Index-2 (ISSI-2) were calculated based on the OGTT postpartum. Multivariable logistic regression was used to some factors. Results: Of all women (135) who received an OGTT postpartum, 42.2% (57) had glucose intolerance (11.8% impaired fasting glucose, 24.4% impaired glucose tolerance and 6.0% both impaired fasting and impaired glucose tolerance) and 1.5% (2) had overt diabetes. Compared to women with a normal OGTT postpartum, women with glucose intolerance and diabetes were older (32.5 ± 4.3 vs. 30.8 ± 4.8 years, p = 0.049), were more often obese (34.5% vs. 17.3%, p = 0.023). In the multivariable logistic regression, an EM background [OR = 2.76 (1.15 - 6.62), p = 0.023] and the HbA1c level at the time of the OGTT in pregnancy [OR = 4.78 (1.19 - 19.20), p = 0.028] remained significant predictors for glucose intolerance postpartum. Women with glucose intolerance and diabetes postpartum had a similar insulin sensitivity [Matsuda index 0.656 (0.386 - 1.224) vs. 0.778 (0.532 - 1.067), p = 0.709; HOMA-IR 0.004 (0.002 - 0.009) vs. 0.064 (0.003 - 0.007), p = 0.384] but a lower beta-cell function compared to women with a normal OGTT postpartum, remaining significant after adjustment for confounders [ISSI-2 1.6 (1.2 - 2.1) vs. 1.9 (1.7 - 2.4), p = 0.002]. Conclusions: Glucose intolerance is very frequent in early postpartum in women with GDM these women have an impaired beta-cell function. Nearly one third of women did not attend the scheduled OGTT postpartum and these women have an adverse risk profile. More efforts are needed to engage and stimulate women with GDM to attend the postpartum OGTT.

Mifepristone Improves Adipose Tissue Insulin Sensitivity in Insulin Resistant Individuals.

Increased tissue cortisol availability has been implicated in abnormal glucose and fat metabolism in patients with obesity, metabolic syndrome, and type 2 diabetes (T2DM). Our objective was to evaluate whether blockade of glucocorticoid receptor (GR) with mifepristone ameliorates insulin resistance (IR) in overweight/obese subjects with glucose intolerance. We conducted a randomized, double-blinded, placebo-controlled, crossover study in overweight/obese individuals (n = 16, 44% female) with prediabetes or mild T2DM but not clinical hypercortisolism. Mifepristone (50 mg every 6 h) or placebo was administered for 9 days, followed by crossover to the other treatment arm after a washout period of 6 to 8weeks. At baseline and following each treatment, oral glucose tolerance test (OGTT) and frequently sampled intravenous glucose tolerance test (FSIVGTT) were performed. Insulin sensitivity was measured using FSIVGTT [primary outcome: insulin sensitivity index (SI)] and OGTT [Matsuda index (MI) and oral glucose insulin sensitivity index (OGIS)]. Hepatic and adipose insulin resistance were assessed using hepatic insulin resistance index (HIRI), and adipose tissue insulin sensitivity index (Adipo-SI) and adipo-IR, derived from the FSIVGTT. Mifepristone administration did not alter whole-body glucose disposal indices of insulin sensitivity (SI, MI, and OGIS). GR blockade significantly improved Adipo-SI (61.7 ± 32.9 vs 42.8 ± 23.9; P = 0.002) and reduced adipo-IR (49.9 ± 45.9 vs 65.5 ± 43.8; P = 0.004), and HIRI (50.2 ± 38.7 vs 70.0 ± 44.3; P = 0.08). Mifepristone increased insulin clearance but did not affect insulin secretion or β-cell glucose sensitivity. Short-term mifepristone administration improves adipose and hepatic insulin sensitivity among obese individuals with hyperglycemia without hypercortisolism.

A prospective study of maternal adiposity and glycemic traits across pregnancy and mid-childhood metabolomic profiles.

Fetal exposure to maternal excess adiposity and hyperglycemia is risk factors for childhood adverse metabolic outcomes. Using data from a prospective pre-birth cohort, we aimed to further understand the prenatal determinants of fetal metabolic programming based on analyses of maternal adiposity and glycemic traits across pregnancy with childhood metabolomic profiles. This study included 330 mother-child pairs from the Gen3G cohort with information on maternal adiposity and glycemic markers at 5-16 (visit 1) and 24-30 (visit 2) weeks of pregnancy. At mid-childhood (4.8-7.2 years old), we collected fasting plasma and measured 1116 metabolites using an untargeted approach. We constructed networks of interconnected metabolites using a weighted-correlation network analysis algorithm. We estimated Spearman's partial correlation coefficients of maternal adiposity and glycemic traits across pregnancy with metabolite networks and individual metabolites, adjusting for maternal age, gravidity, race/ethnicity, history of smoking, and child's sex and age at blood collection for metabolite measurement. We identified a network of 16 metabolites, primarily glycero-3-phosphoethanolamines (GPE) at mid-childhood that showed consistent negative correlations with maternal body mass index, waist circumference, and body-fat percentage at visits 1 and 2 (ρadjusted = -0.14 to -0.21) and post-challenge glucose levels at visit 2 (ρadjusted = -0.10 to -0.13), while positive correlations with Matsuda index (ρadjusted = 0.13). Within this identified network, 1-palmitoyl-2-decosahexaenoyl-GPE and 1-stearoyl-2-decosahexaenoyl-GPE appeared to be driving the associations. In addition, a network of 89 metabolites, primarily phosphatidylcholines, plasmalogens, sphingomyelins, and ceramides showed consistent negative correlations with insulin at visit 1 and post-challenge glucose at visit 2, while positive correlation with adiponectin at visit 2. Prenatal exposure to maternal higher adiposity and hyperglycemic traits and lower insulin sensitivity markers were associated with a unique metabolomic pattern characterized by low serum phospho- and sphingolipids in mid-childhood.

Insulin sensitivity and pancreatic β-cell function in patients with primary aldosteronism.

Primary aldosteronism (PA) is associated with an increased risk for dysglycemia. However, the effects of hyperaldosteronism on insulin sensitivity and β-cell function are unclear. Using a cross-sectional study design, we assessed insulin sensitivity and pancreatic β-cell function from an oral glucose tolerance test (OGTT) in patients from two cohorts: subjects with PA (n = 21) and essential hypertension control (EHC) subjects (n = 22). Age, sex, BMI, and mean arterial pressure adjusted measures of insulin sensitivity and β-cell function were compared between the groups. PA individuals were less insulin sensitive compared to EHC subjects (Quantitative insulin sensitivity check index [QUICKI]: 0.340 ± 0.006 vs. 0.374 ± 0.013, p < 0.001; Matsuda index: 4.14 ± 0.49 vs. 7.87 ± 1.42, p < 0.001; SI: 11.45 ± 4.85 vs. 21.23 ± 6.11 dL/kg/min per μU/mL, p = 0.02). The hepatic insulin resistance index (HIRI) was higher in PA subjects (PA: 5.61 ± 1.01 vs. EHC: 4.13 ± 0.61, p = 0.002). The insulinogenic index (IGI), an index of β-cell function was higher in the PA cohort (PA: 1.49 ± 0.27 vs. 1.11 ± 0.21 μU/mL/mg/dL, p = 0.03). However, the oral disposition index (DI) was similar between the groups (PA: 4.77 ± 0.73 vs. EHC: 5.46 ± 0.85, p = 0.42), which likely accounts for the similar glucose tolerance between the two cohorts, despite lower sensitivity. In summary, insulin sensitivity is significantly lower in PA with an appropriately compensated β-cell function. These results suggest that excess aldosterone and/or other steroids in the context of PA may negatively affect insulin action without adversely impacting β-cell function.