Body Insulin Sensitivity Index Research Articles

Revisiting the Effect of Leptin on Alzheimer Disease and Parkinson Disease: The Role of Insulin Sensitivity.

Studies have indicated a link between leptin, Alzheimer disease (AD), and Parkinson disease (PD). However, the causal relationship among them remains not well established due to confounders and reverse causation. This Mendelian randomization (MR) study was performed to evaluate the impact and potential mechanism of leptin and its soluble receptor on AD and PD. Utilizing genome-wide association studies summary-level data, a comprehensive MR was conducted to assess the causal effect of leptin and soluble leptin receptor (sLEPR) on AD and PD. Additionally, we also explored the role of body mass index (BMI) and insulin sensitivity index (ISI) in using the multivariable MR. The primary analysis was performed using the inverse variance-weighted method. Pooled estimates showed that genetically proxied higher leptin levels was significantly associated with a decreased risk of AD (OR 0.838, 95% CI 0.741-0.948, P = .005), but not PD. In contrast, no significant associations were observed between sLEPR levels, AD, and PD. Moreover, the effect of leptin on AD was attenuated to null after adjustment of ISI (OR 0.879, 95% CI 0.758-1.018, P = .086), but not BMI. There was no causal impact of AD and PD on circulating levels of leptin and sLEPR, indicating the absence of reverse causation. Sensitivity analyses confirmed the robustness of these associations, with no obvious pleiotropy and heterogeneity. The study offers evidence supporting a potential protective effect of leptin in AD, but not PD, via the enhancement of insulin sensitivity. Our findings underscore the distinct roles of leptin in AD and PD.

1093-P: Incretins and Cardiac Autonomic Function in Youth with Obesity across the Glycemia Spectrum

Incretins, glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) have been related to vascular function with variable effects depending on obesity status in adults. The relationship of incretins to vascular function in youth is unclear. We hypothesized that endothelial and cardiac autonomic dysfunction (CAD) are related to lower GLP-1 and GIP in response to glucose ingestion in youth with dysglycemia compared with those with overweight (OW) or normal weight (NW) and normal glucose tolerance (NGT). Adolescents [50 male/52 female; 15.6±1.8 yrs; 24 NW-NGT, 22 OW-NGT, 27 prediabetes and 29 with type 2 diabetes (T2D)] underwent assessment of body composition (DXA scan), 2-hour oral glucose tolerance test (OGTT) with calculation of whole body insulin sensitivity index (WBISI), area under the curve (AUC) of glucose (BG), GLP-1 and GIP. Reactive hyperemia index (RHI), and heart rate variability (HRV), were measured by peripheral arterial tonometry. For HRV, a higher LF/HF (low frequency to high frequency ratio) is indicative of CAD with loss of parasympathetic tone and decreased HRV. The ratios of AUC-GLP-1 and AUC-GIP to AUC-BG were lower in the groups with dysglycemia compared NGT groups (p=0.016 and 0.001, respectively). GLP-1 and GIP were not related to RHI. Fasting and AUC-GLP-1, but not GIP, negatively related to LF/HF (r=-0.37, p=0.002 and r=-0.43, p<0.001 respectively). In a linear regression model with LnLF/HF as the dependent variable, AUC-BG (β=0.31, p=0.04) and AUC-GLP-1 (β=-0.44, p=0.002) contributed to the variance in LnLF/HF independent of %body fat, hs-CRP, WBISI, age, sex, race-ethnicity and Tanner stage (R2= 0.27, p=0.04). Youth with obesity and dysglycemia have impaired incretin response. Glycemia is negatively, whereas GLP-1 is positively associated with HRV after accounting for adiposity, WBIS and inflammation. GLP-1 may be an important determinant of CA function in youth with obesity across the glycemia spectrum. Disclosure H.El ayash: None. F.Bacha: Other Relationship; Takeda Pharmaceutical Co., Ltd., AstraZeneca. Funding U.S. Department of Agriculture-Agricultural Research Service

Discordance In Fasting And Postprandial Indices Of Glycemic Dysregulation In Individuals With Spinal Cord Injury

Fasting levels of glucose and insulin are routine clinical measures used to diagnose type-2 diabetes. However, individuals with spinal cord injury (SCI) often present with clinically normal fasting glucose but have impaired postprandial responses to a meal challenge. PURPOSE: We aimed to characterize the postprandial glycemic responses and assess the prevalence of glycemic dysregulation using fasting and postprandial indices in individuals with SCI. METHODS: Sixteen men with chronic SCI reported to the laboratory after an overnight fast to undergo either a 2-hour: oral glucose tolerance test (OGTT) using a 75-g (~300 kcal) glucose load (n = 8) or; a mixed meal tolerance test (MMTT, (1037 ± 148 kcal: 45% CHO, 37% fat, 18% PRO) (n = 8). Serial measurements of systemic glucose and insulin concentrations at baseline and in response to the OGTT/MMTT were converted into summary statistics: Insulin Resistance was estimated by the Homeostasis Model Assessment of Insulin Resistance (HOMA2-IR); whole body Insulin Sensitivity Index was estimated using methods described by Matsuda (ISIMatsuda). RESULTS: There were no differences between groups in age (p = 1.0), body mass index (p = 0.87), cardiorespiratory fitness (p = 0.26), fasting glucose (p = 0.53) or insulin (p = 0.19). In the MMTT group, 3 (38%) individuals were identified as prediabetic (fasting plasma glucose (FPG), 7.3 ± 0.9 mmol/L) and 0 individuals had impaired insulin resistance (HOMA2-IR, 1.05 ± 0.6). However, 5 (63%) individuals had impaired postprandial insulin sensitivity (ISIMatsuida, 2.2 ± 0.4). In the OGTT group, 2 (25%) individuals were prediabetic (FPG, 6.2 ± 0.2 mmol/L), 2 (25%) different individuals had impaired insulin resistance (HOMA2-IR, 3.2 ± 0.9), but 7 (88%) individuals had impaired postprandial insulin sensitivity (ISIMatsuida, 2.3 ± 0.9). CONCLUSIONS: In this small study, an OGTT identified more SCI participants with glucose dysregulation than MMTT. Postprandial measures of insulin sensitivity identified a greater proportion of SCI participants with impaired glycemic control and may have preferred utility in identifying individuals at high risk of diabetes. Future studies should compare and contrast the specificity and sensitivity of fasting and postprandial methods in this high-risk population.

Dysglycemia screening with oral glucose tolerance test in adolescents with polycystic ovary syndrome and relationship with obesity

BackgroundAdolescents with polycystic ovary syndrome (PCOS) are at increased risk of impaired glucose tolerance (IGT) and type 2 diabetes mellitus. The aim of this study is to evaluate dysglycemia and biochemical differences based on BMI status and assess the prognostic ability of elevated hemoglobin A1c (HbA1c) in predicting an abnormal 2 hour oral glucose tolerance test (OGTT).MethodsRetrospective cohort of female patients aged 11-18 years who underwent 75-g OGTT and were evaluated for PCOS at an urban tertiary care hospital between January 2002 to December 2017.ResultsIn 106 adolescents with PCOS who had OGTT results available, IGT was markedly pronounced in the ≥95th percentile BMI group (17 out of 72; 23.6%) compared with <95th percentile BMI group (4 out of 34; 11.7%). One patient with obesity met the criteria for type 2 diabetes. Patients with obesity had significantly higher homeostasis model assessment (HOMA-IR) and lower whole body insulin sensitivity index (WBISI) (p < 0.001) compared to patients without obesity. Free testosterone levels were also higher in patients with obesity (p< 0.03) and were significantly associated with HOMA-IR when controlling for body mass index (BMI). HbA1c did not demonstrate a strong ability to predict abnormal OGTT on receiver operating characteristic (ROC) curve analysis [Area under the curve (AUC) = 0.572, 95% CI: 0.428, 0.939]).ConclusionsIn a study to assess glucose abnormalities in adolescents with PCOS, IGT was found to be markedly increased in patients with obesity, with abnormal glucose metabolism identified in over one-fifth of the patients. HbA1c alone may be a poor test to assess IGT and we recommend that adolescents diagnosed with PCOS and obesity undergo formal oral glucose tolerance testing.

Time to the Peak, Shape of the Curve and Combination of These Glucose Response Characteristics During Oral Glucose Tolerance Test as Indicators of Early Beta-cell Dysfunction in Obese Adolescents

Objective:Characteristics of the glucose response during oral glucose tolerance test (OGTT) may reflect differences in insulin secretion and action. The aim was to examine whether timing of the glucose peak, shape of the glucose curve and their combination could be indicators of beta-cell dysfunction in obese/severely obese adolescents with normal glucose tolerance (NGT).Methods:Data from 246 obese/severely obese adolescents who completed OGTT were reviewed. Out of 184 adolescents with NGT, 174 could be further classified into groups based on timing of the glucose peak (early/30 minutes vs late/≥60 minutes) and shape of the glucose curve (monophasic vs biphasic). Groups were compared with respect to insulin sensitivity (whole body insulin sensitivity index - WBISI), early-phase insulin secretion (insulinogenic index - IGI) and beta-cell function relative to insulin sensitivity (oral disposition index - oDI).Results:Late glucose peak (p=0.004) and monophasic glucose curve (p=0.001) were both associated with lower oDI after adjustment for age, sex, puberty stage and body mass index z-score. Among obese/severely obese adolescents with NGT, those with coexistent late glucose peak and monophasic glucose curve had lower oDI than those with early glucose peak and biphasic glucose curve (p=0.002). Moreover, a combination of late glucose peak and monophasic glucose curve was the most powerful predictor of the lowest oDI quartile [odds ratio (OR): 11.68, 95% confidence interval: 3.048-44.755, p<0.001].Conclusion:Late timing of the glucose peak, monophasic shape of the glucose curve and, in particular, a combination of those characteristics during OGTT may indicate early beta-cell dysfunction in obese/severely obese adolescents with NGT.

Effects Of 12-weeks Of Post-meal Walking On Glycemic Control And Body Composition In Older Adults

There is strong evidence that short bouts of light-intensity post-meal exercise are effective at lowering post-prandial and 24-h glucose concentrations in older people with impaired glucose tolerance (IGT). It is unknown, however, whether these transient benefits result in more enduring improvements in glycemic control after training. PURPOSE: To determine the effects of a home-based, 12-week post-meal walking program on improvements in glucose metabolism, as well as on changes in body composition in overweight (BMI=30±1.8 kg/m2) older adults (N=6; 72±5.3 years) with IGT. METHODS: Participants performed three 15-minute bouts of low-intensity (3 METs) walking beginning 30 minutes after each meal on five days per week for 12 weeks. Glucose and insulin responses to an oral glucose tolerance test were determined 48 h after the last exercise bout before and after training. Changes in body composition were determined using iDXA. RESULTS: Overall adherence to the total training program (180 post-meal walking bouts) was 65%; however, participants reported completing an average of 82% of the post-dinner walks across the 12 weeks. Total areas under the curve for both glucose [29.5±9.3 vs. 29.5±8.9 (mg·dL-1)·3h·103] and insulin [9.2±5.4 vs. 9.0±4.4 (mg·dL-1)·3h·103] responses did not change between baseline and follow-up; however, HbA1c levels (6.45% vs.5.86%) and the Whole Body Insulin Sensitivity Index (4.5± 3.6 vs. 5.8 ± 8.7) showed promising improvements following training. There were no changes to body weight, body fat, or lean mass; however, visceral fat volume decreased (688.7±311.4 vs. 584.3±306.0 cm3), and four of the six participants reduced their visceral fat mass by over 37g. CONCLUSIONS: Data from this pilot study suggest that the benefits of regular, low-intensity post-meal walking on glycemic control may not last beyond 24h in older adults with IGT. On the other hand, if performed consistently over time, the transient benefits may result in more enduring improvements in HbA1c and particularly in visceral fat mass. Supported by NIH/NIA R56 AG050661

1254-P: Trauma and Loss-of-Control (LOC) Eating Relate to Elevated Type 2 Diabetes (T2D) Risk in Adolescents

Objective: Traumatic events, including abuse, neglect, and other dangerous/shocking experiences, are commonly observed in adolescents with T2D. Research has shown there is a link between trauma and poorer health outcomes, yet, the extent to which trauma increases risk for developing T2D is not well understood. Trauma may heighten T2D risk through LOC eating, which can arise to cope with negative emotions. Our aim was to evaluate the links of trauma and LOC eating with T2D risk in adolescent girls with obesity. Methods: Participants (n=65, mean±SD 15.2±1.6y) were girls at-risk for T2D based on BMI ≥85%ile, ≥1 family member with T2D, and elevated depression (Center for Epidemiologic Studies Depression [CES-D] score ≥21). Trauma history (presence vs. absence) was assessed with the Schedule for Affective Disorders and Schizophrenia for School-Aged Children, and LOC eating (presence vs. absence) with the Eating Disorder Examination. T2D risk was assessed as HbA1c and Matsuda Whole Body Insulin Sensitivity Index (WBISI), derived from a 7-sample 2-hr OGTT. ANCOVA tested differences in HbA1c and WBISI by trauma and LOC, controlling for age, BMIz, race/ethnicity, and depression. Results: Trauma history was endorsed in 40.6% and LOC eating in 36.4% of girls. Girls with and without a trauma history reported similar rates of LOC (36.4% vs. 37.5%, p=.93). Girls with trauma had higher HbA1c (5.7±0.06%) vs. those with no trauma (5.5±0.05%, p=0.04), with no difference in WBISI (p=0.32). Girls with LOC had worse WBISI vs. those with no LOC (3.0±0.53 vs. 4.8±0.40, p&amp;lt;0.01), with no difference in HbA1c (p=0.21). Conclusions: Trauma history and LOC eating were unrelated to each other, but each related to different aspects of elevated T2D risk. Attention to both factors may warrant consideration in intervening to lessen T2D risk in teens with obesity and elevated depression. Disclosure V. Jimenez: None. A.M. Hilkin: None. M.M. Verros: None. E.L. Clark: None. M. Casamassima: None. R.L. Miller: None. L. Pyle: None. M.M. Kelsey: Other Relationship; Self; Boehringer Ingelheim Pharmaceuticals, Inc., Daiichi Sankyo, Janssen Pharmaceuticals, Inc., Merck Sharp &amp; Dohme Corp. L.B. Shomaker: None.

Depressive symptoms in adolescent girls at-risk for type 2 diabetes and their parents

ABSTRACTFew studies have characterized the relation between parent’s depression symptoms and adolescent’s depression symptoms in adolescents at-risk for type 2 diabetes (T2D). We evaluated the associations of parental depression symptoms with the depression symptoms and metabolic functioning of adolescent offspring at-risk for T2D. One-hundred sixteen parents and adolescent girls with a family history of diabetes completed surveys of depression symptoms. Adolescents’ degree of metabolic risk for T2D was estimated from body mass index (BMI; kg/m2) standard score, percent adiposity from dual-energy x-ray absorptiometry scan, and whole body insulin sensitivity index determined from glucose/insulin concentrations during a two-hour oral glucose tolerance test. Parents’ and adolescents’ depression symptoms were significantly associated, even after accounting for race/ethnicity, age, puberty, body composition, and parental diabetes/BMI. Adjusting for similar covariates, parent depression symptoms also were positively related to adolescents’ BMI standard score and had a trend-level association with adiposity. There was an inverse relation between parental depression symptoms and adolescent insulin sensitivity, which was entirely accounted for by adolescent body composition. The associations of parental depression symptoms with more elevated depression symptoms and higher BMI in adolescents at-risk for T2D has potential implications for interventions addressing these co-morbid health conditions.

Insulin Resistance in Nonobese Renal Allograft Recipients on Maintenance Doses of Cyclosporine or Tacrolimus

PurposeIn comparison to cyclosporine (CsA), tacrolimus (Tac) seems to be more diabetogenic in renal transplant recipients, and post-transplant diabetes mellitus is more common in patients using Tac, especially during the first year after transplantation. However, at maintenance doses, there are no comparative data of insulin resistance (IR) in patients using Tac or CsA. The purpose of this study was to investigate the IR indexes in patients on maintenance doses of CsA or Tac. MethodsForty-five nondiabetic and nonobese renal transplant recipients participated in the study (M:F, 30:15; age, 36 ± 9 years); 27 patients were on CsA, and 18 were on Tac. All had stable graft function, were transplanted at least 6 months previously, and were receiving maintenance doses of steroids (5.0 mg/d), azathioprine or mycophenolate mofetil, and calcineurin inhibitors (CsA [2.14 ± 0.46 mg/kg/d] or Tac [0.06 ± 0.03 mg/kg/d]). IR was evaluated by the homeostasis model assessment (HOMA) index and composite body insulin sensitivity index. ResultsWe did not determine any significant difference in the HOMA and composite body insulin sensitivity index levels among patients using CsA or Tac (1.5 ± 1.3 vs 1.5 ± 1.1, P > .05, and 9.9 ± 5.8 vs 14.6 ± 11.7, P > .05, respectively). There was a significant correlation between creatinine and HOMA values. ConclusionThere was no difference in IR indexes in renal transplant recipients receiving maintenance doses of either CsA or Tac.

Parental obesity is associated with the severity of childhood obesity and its comorbidities

IntroductionThe influence of parental obesity on their obese offsprings is acknowledged but insufficiently characterised. Patients and methodsRetrospective study of 800 obese patients (45.2% girls; age: 10.35±3.40 years, body mass index [BMI]: +4.22±1.68 standard deviation score [SDS]). Group comparison according to the presence of obesity in none (n=347) or any of the parents (n=453), and then whether the obese parent was the father (n=185), the mother (n=151), or both parents (n=117) were performed. The parameters analysed were: Age at the onset of the obesity and at their first visit, birth weight (BW), BMI-SDS, blood glucose, insulin level, homeostatic model assessment (HOMA) index, total cholesterol (TC), HDL, LDL, triglycerides, 25-OH-vitamin-D, area under the curve (AUC) for insulin in the oral glucose tolerance test (OGTT), whole body insulin sensitivity index (WBISI), LDL/HDL and TC/HDL ratios, and weight loss after 12 month follow-up. ResultsNo differences were observed between groups as regarding gender, ethnic background, or pubertal stage. Patients with one obese parent showed higher BW-SDS and BMI-SDS (P<.01), more severe impairment of carbohydrate metabolism (blood insulin, insulin-AUC, HOMA, HbA1c [P<.01] and lower WBISI [P<.05]) than those with no obese parent. Among those patients with a single obese parent, higher BW-SDS, insulin, HOMA, and lower 25-OH-vitamin D (P<.05) was observed when obesity was present in the mother. There was a higher prevalence of metabolic syndrome when both parents were obese (χ2=5.96, P<.05). A total of 132 patients reduced their BMI by ≥1.5 SDS, or their weight by ≥10%, with no influence of the background of parental obesity. ConclusionsObesity in any parent determines a higher severity of their offspring obesity and metabolic comorbidities, more importantly when obesity is present in the mother or in both parents, but without interference in the options of therapeutic success.

Parental obesity is associated with the severity of childhood obesity and its comorbidities

The influence of parental obesity on their obese offsprings is acknowledged but insufficiently characterised. Retrospective study of 800 obese patients (45.2% girls; age: 10.35±3.40 years, body mass index [BMI]:+4.22±1.68 standard deviation score [SDS]). Group comparison according to the presence of obesity in none (n=347) or any of the parents (n=453), and then whether the obese parent was the father (n=185), the mother (n=151), or both parents (n=117) were performed. The parameters analysed were: Age at the onset of the obesity and at their first visit, birth weight (BW), BMI-SDS, blood glucose, insulin level, homeostatic model assessment (HOMA) index, total cholesterol (TC), HDL, LDL, triglycerides, 25-OH-vitamin-D, area under the curve (AUC) for insulin in the oral glucose tolerance test (OGTT), whole body insulin sensitivity index (WBISI), LDL/HDL and TC/HDL ratios, and weight loss after 12 month follow-up. No differences were observed between groups as regarding gender, ethnic background, or pubertal stage. Patients with one obese parent showed higher BW-SDS and BMI-SDS (P<.01), more severe impairment of carbohydrate metabolism (blood insulin, insulin-AUC, HOMA, HbA1c [P<.01] and lower WBISI [P<.05]) than those with no obese parent. Among those patients with a single obese parent, higher BW-SDS, insulin, HOMA, and lower 25-OH-vitamin D (P<.05) was observed when obesity was present in the mother. There was a higher prevalence of metabolic syndrome when both parents were obese (χ2=5.96, P<.05). A total of 132 patients reduced their BMI by ≥1.5SDS, or their weight by ≥10%, with no influence of the background of parental obesity. Obesity in any parent determines a higher severity of their offspring obesity and metabolic comorbidities, more importantly when obesity is present in the mother or in both parents, but without interference in the options of therapeutic success.

Acute Effects of Blood Transfusion on Insulin Sensitivity and Pancreatic β-Cell Function in Children with β-Thalassemia/Hemoglobin E Disease

Objective:To assess the acute effects of blood transfusion on insulin sensitivity and pancreatic β-cell function in thalassemia patients.Methods:Fifty children and adolescents with β-thalassemia/HbE disease were enrolled in a prospective cohort study. Hemoglobin, serum ferritin and oral glucose tolerance test (OGTT) were performed prior to, and one week after blood transfusion. Insulin sensitivity indices [homeostatic model assessment (HOMA) of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and β-cell function indices [HOMA of β-cell function (HOMA-β), insulinogenic index (IGI), and disposition index (DI)] were calculated from glucose and insulin levels obtained during the OGTT.Results:Following blood transfusion, hemoglobin and serum ferritin increased significantly; 8.5 to 10.1 g/dL (p<0.001) and 1764 to 2160 ng/mL (p<0.001), respectively. β-Cell function indices also increased significantly [median HOMA-β: 74.3 vs. 82.7 (p=0.033); median IGI: 59.6 vs. 79.3 (p=0.003); median DI: 658 vs. 794 (p=0.01)]. However, the insulin sensitivity index (WBISI) tended to decrease and the insulin resistance index (HOMA-IR) tended to increase although this did not reach significance. Multivariate analysis showed that pre-transfusion serum ferritin was the major factor negatively associated with WBISI and positively associated with HOMA-IR, but pre-transfusion hemoglobin had no significant association with insulin sensitivity indices post-transfusion.Conclusion:This study demonstrated that acute increases in serum ferritin and hemoglobin following blood transfusion in patients with thalassemia might contribute to an increase in insulin secretion and to a trend towards increased insulin resistance.

Assessment of disturbed glucose metabolism and surrogate measures of insulin sensitivity in obese children and adolescents

BackgroundWith the rising prevalence of obesity and type 2 diabetes (T2D) in obese children, it is becoming imperative to detect disturbed glucose metabolism as early as possible in order to prevent T2D development.Subjects/MethodsCross-sectional study of 92 obese children (median age 11.7 years, 51% female) and 7 lean children (median age 11.4 years, 57% female) who underwent an oral glucose tolerance test (OGTT) in a tertiary pediatric care center. Glucose tolerance was assessed and different indices for β-cell function, insulin sensitivity and insulin secretion were calculated.ResultsNineteen obese children were identified with prediabetes (PD, 12 impaired glucose tolerance, 4 increased fasting glucose and 3 combined). Compared with the 73 obese children with normal glucose tolerance (nGT), subjects with PD had higher insulin resistance, but lower insulin sensitivity and β-cell function, although their glycated hemoglobin (HbA1c) levels were comparable. The Whole Body Insulin Sensitivity Index (WBISI) and β-cell function by Insulin Secretion-Sensitivity Index-2 (ISSI-2) strongly correlated with the OGTT glucose area under the curve 0–120 min (r = 0.392, p < 0.0002; r = 0.547, p < 0.0001, respectively). When testing the relation between early insulin response during OGTT by insulinogenic index and insulin sensitivity assessed by WBISI, a hyperbolic relationship between insulin secretion and insulin sensitivity was found. The calculated disposition index was lower in subjects with PD vs. nGT (median 459 vs. 792, p = 0.004). We identified the OGTT 30-min/120-min insulin ratio as a simple marker, which is significantly lower in obese children with vs. without PD (median 0.87 vs. 1.29, p = 0.021) and which has a better sensitivity and specificity for detecting PD than HbA1c among obese children.ConclusionsChildren with identified PD had changes of several markers for β-cell function, insulin sensitivity and resistance before changes in HbA1c occurred. The lower disposition index indicates that these children have already inadequate β-cell compensation for the degree of insulin resistance.

Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Growth hormone receptor antagonism with pegvisomant in insulin resistant non-diabetic men: A phase II pilot study.

Background: Growth hormone (GH) is known to affect insulin and glucose metabolism. Blocking its effects in acromegalic patients improves diabetes and glucose metabolism. We aimed to determine the effect of pegvisomant, a GH receptor antagonist, on insulin resistance, endogenous glucose production (EGP) and lipolysis in insulin resistant non-diabetic men. Methods: Four men between the ages of 18-62 with a BMI of 18-35kg/m 2, with insulin resistance as defined by a HOMA-IR > 2.77, were treated for four weeks with pegvisomant 20 mg daily. Inpatient metabolic assessments were performed before and after treatment. The main outcome measurements were: change after pegvisomant therapy in insulin sensitivity as measured by hyperinsulinemic euglycemic clamp; and EGP and lipolysis assessed by stable isotope tracer techniques. Results: Insulin like growth factor-1 (IGF-1) concentrations decreased from 134.0 ± 41.5 (mean ± SD) to 72.0 ± 11.7 ng/mL (p = 0.04) after 4 weeks of therapy. Whole body insulin sensitivity index (M/I 3.2 ± 1.3 vs. 3.4 ± 2.4; P = 0.82), as well as suppression of EGP (89.7 ± 26.9 vs. 83.5 ± 21.6%; p = 0.10) and Ra glycerol (59.4 ± 22.1% vs. 61.2 ± 14.4%; p = 0.67) during the clamp were not changed significantly with pegvisomant treatment. Conclusions: Blockade of the GH receptor with pegvisomant for four weeks had no significant effect on insulin/glucose metabolism in a small phase II pilot study of non-diabetic insulin resistant participants without acromegaly.

Excessive Free Fatty Acid Oxidation in Non‐obese Healthy Asian Men with Insulin Resistance is Associated with Impaired Branched‐chain Amino Acid Oxidation

BackgroundBranched‐chain Amino Acids (BCAA) are elevated in insulin resistant (IR) states and may be involved in the pathogenesis of IR in non‐obese individuals. It remains unclear whether this could be secondary to impairment in clearance from oxidation or increased rate of appearance (Ra) because of IR.ObjectivesOur study compared leucine and palmitate kinetics between 14 insulin sensitive (IS) and 12 IR non‐obese healthy Asian men. We hypothesized that greater free fatty acid (FFA) availability for oxidation in IR impairs BCAA oxidation leading to higher blood BCAA concentration.MethodsSubjects underwent oral glucose tolerance testing for measurement of their whole body insulin sensitivity index (WBISI) and body composition measured using the 2H2O method. [U‐13C16] palmitate and [U‐13C6] leucine were infused at least 1‐week apart for quantification of their rates of oxidation and Ra. Kinetic data are expressed as μmol/kgFFM/h.ResultsCompared to IS subjects, IR subject had significantly lower WBISI (3.30 ± 0.26 vs. 8.03 ± 0.92), higher body mass index (24.4 ± 0.6 vs. 23.0 ± 0.3 kg/m2), body fat % (29.8 ± 2.4 vs. 23.7 ± 1.3) and total blood BCAA (438.1 ± 21.7 vs. 385.0 ± 14.5 umol/L, p = 0.048). Palmitate Ra was much higher in IR subjects (189.0 ± 13.5 vs. 151.8 ± 8.5, p = 0.027) indicating greater exposure of skeletal tissue to circulatory FFA. This was accompanied by greater palmitate oxidation (60.6 ± 4.3 vs. 46.2 ± 3.5, p = 0.016) such that plasma concentration was not significantly different between the comparator groups (124.7 ± 5.7 vs. 108.9 ± 13.1, p = 0.295). Leucine Ra (152.8 ± 5.5 vs. 144.6 ± 3.2, p = 0.067) and oxidation (19.2 ± 0.4 vs. 16.3 ± 0.7, p = 0.028) were also higher in IR but leucine oxidative capacity, defined as percentage leucine flux oxidized, was significantly lower (11.9 ± 0.4 vs. 10.6 ± 0.4, p = 0.028).ConclusionsElevated blood BCAA in healthy non‐obese but IR men is a consequence of both greater Ra and impaired BCAA oxidative capacity and this is associated with excessive FFA oxidation.Support or Funding InformationSupported by SingHealth Medicine Academic Clinical Program (03/FY2014/P1/06‐A16)

Insulin resistance in drug naive patients with multiple sclerosis

Background/Aim. Due to the fact that there is a relatively small number of data related to systemic insulin abnormalities in the multiple sclerosis (MS), the main objective of our study was to determine whether a dysbalance of glucose and insulin metabolism exist in patients with natural course of MS. Our hypothesis was that the metabolic disorder that characterizes state of the insulin resistance (IR) and reduced insulin sensitivity (IS) in untreated patients with MS could play a role in disease progression and degree of functional disability. Methods. The study included 31 patients with relapsing-remitting (RR) MS and 14 healthy controls from the same geographic area matched by age, ethnicity and number of smokers. The glucose tolerance, IS, and IR were examined using an oral glucose tolerance test (OGTT) and using basal plasma glucose and insulin levels. The functional disability and disease progression were evaluated by the Expanded Disability Status Scale (EDSS) and Multiple Sclerosis Severity Score (MSSS). Results. The MS patients tolerated glucose equally well as the healthy controls. Basal concentrations of insulin were significantly higher in the MS group (p &lt; 0.05), as well as insulin plasma level 30 min after oral glucose load (p &lt; 0.01). The patients with MS had significantly higher values of homeostasis model assessment indexes of IR (HOMA-IR) (p = 0.027; p = 0.028). The percentage of IS (HOMA2 %S) and whole body IS index (ISI Matsuda) showed significantly lower values in the MS patients than in the controls (p = 0.005; p = 0.001). The insulinogenic index in the first 30 min of OGTT was significantly higher in MS patients (p = 0.005). The measures of functional disability and MS progression did not correlate significantly with the investigated parameters of IR and IS indexes. Conclusion. This study demonstrates for the first time the existence of hyperinsulinemia, reduced insulin sensitivity and normal glucose tolerance that indicate the initial phase of IR in the natural course of MS. Additional research is necessary in order to define the mechanisms of occurrence and the impact of IR on the complex pathophysiological processes in MS.

A modified oral sugar test for evaluation of insulin and glucose dynamics in horses.

BackgroundAn oral sugar test (OST) using Karo® Light Corn Syrup has been developed in the USA as a field test for the assessment of insulin dysregulation in horses but the syrup is not available in Scandinavian grocery stores. The aim of the study was to compare the results of a modified OST between horses with equine metabolic syndrome (EMS) and healthy horses using a Scandinavian commercially available glucose syrup (Dansukker glykossirap). In addition, the effect of breed and the repeatability of the test were evaluated. In the present study, clinically healthy horses (7 Shetland ponies, 8 Icelandic horses, 8 Standardbred horses) and 20 horses of various breeds with EMS underwent the modified OST test. The Icelandic horses and Shetland ponies underwent the OST twice. Insulin and glucose data from the OST were used to calculate peak insulin concentration (PeakINS), time to peak insulin concentration (T-peakINS), area under the curve for insulin (AUCINS) and glucose (AUCGLU) as well as whole body insulin sensitivity index (ISICOMP).ResultsCompared to the healthy group, the EMS group had 6–7 times higher geometric mean for PeakINS and AUCINS and 8 times lower geometric mean for ISICOMP. The EMS group had a delayed T-peakINS compared to the healthy group. There was no effect of breed in the group of healthy horses on PeakINS, T-peakINS, AUCINS, AUCGLU and ISICOMP. Coefficient of variation for repeated tests was 19.8, 19.0 and 17.6 % for PeakINS, AUCINS and ISICOMP respectively.ConclusionsThe results of the present study demonstrate that the modified OST appears to be a practical and useful diagnostic tool for assessment of insulin dysregulation in the horse. However, to make it possible to establish the most appropriate sampling interval and to evaluate the accuracy of the modified OST, further studies in horses with a variable degree of insulin resistance are needed, where results from the modified OST are compared with quantitative measurements for IS.

Elevated serum levels of betatrophin in patients with polycystic ovary syndrome and the influential factors

To determine serum levels of betatrophin in patients with polycystic ovary syndrome (PCOS) and the influential factors. A total of 100 PCOS patients were enrolled randomly as a PCOS group, and 40 age-matched healthy women were recruited as a normal control (NC) group. Primary clinical or biochemical parameters of the subjects were detected. The results were analyzed by SPSS 19.0. Serum betatrophin levels were elevated in the PCOS group compared with the NC group. Serum betatrophin levels were positively correlated with age and Whole Body Insulin Sensitivity Index (WBISI),and negatively correlated with body mass index, fasting insulin(FINS), homeostatic model assessment insulin resistance (HOMA-IR) and homeostatic model assessment β cell function (HOMA-β). Multiple linear stepwise regression analysis showed that age and waist hip ratio (WHR) were independent influential factors for the level of betatrophin. PCOS was more likely to occur in women with higher betatrophin levels. Serum betatrophin levels increase in women with PCOS and they are independently associated with age and WHR. There is no significant correlation between betatrophin and insulin resistance or insulin levels.

Increased GLP-1 response to oral glucose in pre-pubertal obese children

Gastrointestinal hormones, such as glucagon-like peptide (GLP-1), have been hypothesized to play a role in the pathogenesis of obesity-related complications. However, few data are available in youth. The objective of this study was to investigate the GLP-1 response to oral glucose load in obese pre-pubertal children and its relationship with insulin secretion. Ten pre-pubertal obese children [five boys; 10.5±1.6 years; body mass index-standard deviation score (BMI-SDS): 2.2±0.5] and 10 controls (eight boys; 9.9±1.2 years; BMI-SDS: -0.7±0.5) underwent a modified oral glucose tolerance test (OGTT) to evaluate post-load glucose, insulin and GLP-1 responses. Insulin sensitivity [homeostasis model assessment of insulin resistance (HOMA-IR), whole body insulin sensitivity index (WBISI)] and secretion [HOMA-beta, insulinogenic index (IGI)] indexes, area under the curve (AUC) for glucose, insulin and GLP-1 were calculated. In obese children GLP-1 AUC values were higher and correlated with BMI-SDS (r=0.45; p=0.04), HOMA-IR (r=0.53; p=0.01) and fasting glucose (r=0.68; p=0.001). Obese children showed an increased GLP-1 response to oral glucose. These changes might likely represent a compensatory mechanism to avoid post-prandial hyperglycemia and allow a normal glucose tolerance.