Adequately adapted insulin secretion and decreased hepatic insulin extraction cause elevated insulin concentrations in insulin resistant non-diabetic adrenal incidentaloma patients.

BACKGROUND:Insulin-resistance is commonly found in adrenal incidentaloma (AI) patients. However, little is known about beta-cell secretion in AI, because comparisons are difficult, since beta-cell-function varies with altered insulin-sensitivity. OBJECTIVES:To retrospectively analyze beta-cell function in non-diabetic AI, compared to healthy controls (CON). METHODS:AI (n=217, 34%males, 57 ± 1 years, body-mass-index:27.7 ± 0.3 kg/m(2)) and CON [n = 25, 32%males, 56 ± 1 years, 26.7 ± 0.8 kg/m(2)] with comparable anthropometry (p ≥ 0.31) underwent oral-glucose-tolerance-tests (OGTTs) with glucose, insulin, and C-peptide measurements. 1mg-dexamethasone-suppression-tests were performed in AI. AI were divided according to post-dexamethasone-suppression-test cortisol-thresholds of 1.8 and 5 µg/dL into 3 subgroups: pDexa<1.8 µg/dL, pDexa1.8-5 µg/dL and pDexa>5 µg/dL. Using mathematical modeling, whole-body insulin-sensitivity [Clamp-like-Index (CLIX)], insulinogenic Index, Disposition Index, Adaptation Index, and hepatic insulin extraction were calculated. RESULTS:CLIX was lower in AI combined (4.9 ± 0.2 mg · kg(-1) · min(-1)), pDexa<1.8 µg/dL (4.9 ± 0.3) and pDexa1.8-5 µg/dL (4.7 ± 0.3, p<0.04 vs.CON:6.7 ± 0.4). Insulinogenic and Disposition Indexes were 35%-97% higher in AI and each subgroup (p<0.008 vs.CON), whereas C-peptide-derived Adaptation Index, compensating for insulin-resistance, was comparable between AI, subgroups, and CON. Mathematical estimation of insulin-derived (insulinogenic and Disposition) Indexes from associations to insulin-sensitivity in CON revealed that AI-subgroups had ~19%-32% higher insulin-secretion than expectable. These insulin-secretion-index differences negatively (r=-0.45, p<0.001) correlated with hepatic insulin extraction, which was 13-16% lower in AI and subgroups (p<0.003 vs.CON). CONCLUSIONS:AI-patients show insulin-resistance, but adequately adapted insulin secretion with higher insulin concentrations during an OGTT, because of decreased hepatic insulin extraction; this finding affects all AI-patients, regardless of dexamethasone-suppression-test outcome

Whole-body insulin sensitivity rather than body-mass-index determines fasting and post-glucose-load growth hormone concentrations.

Obese, non-acromegalic persons show lower growth hormone (GH) concentrations at fasting and reduced GH nadir during an oral glucose tolerance test (OGTT). However, this finding has never been studied with regard to whole-body insulin-sensitivity as a possible regulator.In this retrospective analysis, non-acromegalic (NonACRO, n = 161) and acromegalic (ACRO, n = 35), non-diabetic subjects were subdivided into insulin-sensitive (IS) and -resistant (IR) groups according to the Clamp-like Index (CLIX)-threshold of 5 mg · kg(-1) · min(-1) from the OGTT.Non-acromegalic IS (CLIX: 8.8 ± 0.4 mg · kg(-1) · min(-1)) persons with similar age and sex distribution, but lower (p < 0.001) body-mass-index (BMI = 25 ± 0 kg/m2, 84% females, 56 ± 1 years) had 59% and 70%, respectively, higher (p < 0.03) fasting GH and OGTT GH area under the curve concentrations than IR (CLIX: 3.5 ± 0.1 mg · kg(-1) · min(-1), p < 0.001) subjects (BMI = 29 ± 1 kg/m2, 73% females, 58 ± 1 years). When comparing on average overweight non-acromegalic IS and IR with similar anthropometry (IS: BMI: 27 ± 0 kg/m2, 82% females, 58 ± 2 years; IR: BMI: 27 ± 0 kg/m2, 71% females, 60 ± 1 years), but different CLIX (IS: 8.7 ± 0.9 vs. IR: 3.8 ± 0.1 mg · kg(-1) · min(-1), p < 0.001), the results remained almost the same. In addition, when adjusted for OGTT-mediated glucose rise, GH fall was less pronounced in IR. In contrast, in acromegalic subjects, no difference was found between IS and IR patients with regard to fasting and post-glucose-load GH concentrations.Circulating GH concentrations at fasting and during the OGTT are lower in non-acromegalic insulin-resistant subjects. This study seems the first to demonstrate that insulin sensitivity rather than body-mass modulates fasting and post-glucose-load GH concentrations in non-diabetic non-acromegalic subjects

Pericardial- Rather than Intramyocardial Fat Is Independently Associated with Left Ventricular Systolic Heart Function in Metabolically Healthy Humans.

BACKGROUND:Obesity is a major risk factor to develop heart failure, in part due to possible lipotoxic effects of increased intramyocardial (MYCL) and/or local or paracrine effects of pericardial (PERI) lipid accumulation. Recent evidence suggests that MYCL is highly dynamic and might rather be a surrogate marker for disturbed energy metabolism than the underlying cause of cardiac dysfunction. On the other hand, PERI might contribute directly by mechanic and paracrine effects. Therefore, we hypothesized that PERI rather than MYCL is associated with myocardial function. METHODS:To avoid potential confounding of metabolic disease 31 metabolically healthy subjects (age: 29±10yrs; BMI: 23±3kg/m2) were investigated using 1H-magnetic resonance spectroscopy and imaging. MYCL and PERI, as well as systolic and diastolic left ventricular heart function were assessed. Additionally, anthropometric data and parameters of glucose and lipid metabolism were analyzed. Correlation analysis was performed using Pearson's correlation coefficient. Linear regression model was used to show individual effects of PERI and MYCL on myocardial functional parameters. RESULTS:Correlation analysis with parameters of systolic heart function revealed significant associations for PERI (Stroke Volume (SV): R = -0.513 p = 0.001; CardiacIndex (CI): R = -0.442 p = 0.014), but not for MYCL (SV: R = -0.233; p = 0.207; CI: R = -0.130; p = 0.484). No significant correlations were found for E/A ratio as a parameter of diastolic heart function. In multiple regression analysis CI was negatively predicted by PERI, whereas no impact of MYCL was observed in direct comparison. CONCLUSIONS:Cardiac fat depots impact left ventricular heart function in a metabolically healthy population. Direct comparison of different lipid stores revealed that PERI is a more important predictor than MYCL for altered myocardial function

Circulating concentrations of glucose (A), insulin (B), and C–peptide (C), as well as whole–body insulin–sensitivity by the Clamp-like Index (D), as well as <i>Pearson</i>’s product moment correlations between Clamp-like Index and Insulinogenic Index (IGI, 0–60minutes; E) and the Disposition Index (F), as well as correlations between hepatic insulin extraction and Δ observed-calculated values of Insulinogenic Index (0–60minutes; G), Disposition Index (H) and Clamp-like Index (i) in the three AI subgroups [pDexa<1.8µg/dL (□, n=145), pDexa1.8-5µg/dL (▲, n=56), pDexa>5µg/dL (■, n=16)] and controls [CON, o, n=25).

<p>Symbols in panels <b>E</b> and <b>F</b> are given in black or in gray, if the values were obtained by measurement or calculation, respectively; arrows display the shift between expectable (i.e. calculated) and measured values. ANOVA with LSD <i>post </i><i>hoc</i> test; <i>post </i><i>hoc</i> differences with <b>p<0.05</b> among the groups are indicated by lowercase letters as follows: <b>a</b>, pDexa<1.8µg/dL vs. CON; <b>b</b>, pDexa<1.8µg/dL vs. pDexa1.8-5µg/dL; <b>c</b>, pDexa<1.8µg/dL vs. pDexa>5µg/dL; <b>d</b>, pDexa1.8-5µg/dL vs. CON; <b>e</b>, pDexa1.8-5µg/dL vs. pDexa>5µg/dL; <b>f</b>, pDexa>5µg/dL vs. CON.</p

Circulating concentrations of glucose (A), insulin (B), C–peptide (C), and whole–body insulin–sensitivity by the Clamp-like Index (D), as well as <i>Pearson</i>’s product moment correlations between the Clamp-like Index on X–axis and on Y-axis body mass index (E), Insulinogenic Index (IGI, 0–60min; F), Insulinogenic Index (0–120min; G) and Disposition Index (H) in controls (CON, n=25, o) and adrenal incidentaloma patients (AI, n=217, ●).

<p>Differences were statistically analyzed by using <i>Student</i>'s t–test: *, p<0.05.</p

Multiple linear regression analyses with total area under the curve (AUC) of oral glucose tolerance test (OGTT) growth hormone and baseline ( = 0 min) growth hormone as dependent variables, and systolic blood pressure, sex, age, body mass index (BMI) and insulin sensitivity, determined by the Clamp–like Index (CLIX) as predictors, in all participants, all insulin resistant (IR) combined, all insulin sensitive (IS) combined, and non- acromegalic (NonACRO) subjects combined, with IR and IS subgroups, and all acromegalic (ACRO) combined, again with subgroups.

<p>The regression coefficient (<i>r</i>) with B± standard error of the mean (SE) and p-value is given for each outcome; in case the model did not yield satisfactory results, an <i>r</i>–value of 0 is listed.</p><p>Multiple linear regression analyses with total area under the curve (AUC) of oral glucose tolerance test (OGTT) growth hormone and baseline ( = 0 min) growth hormone as dependent variables, and systolic blood pressure, sex, age, body mass index (BMI) and insulin sensitivity, determined by the Clamp–like Index (CLIX) as predictors, in all participants, all insulin resistant (IR) combined, all insulin sensitive (IS) combined, and non- acromegalic (NonACRO) subjects combined, with IR and IS subgroups, and all acromegalic (ACRO) combined, again with subgroups.</p

Alterations in gastrointestinal, endocrine, and metabolic processes after bariatric Roux-en-Y gastric bypass surgery

OBJECTIVE: Obesity leads to severe long-term complications and reduced life expectancy. Roux-en-Y gastric bypass (RYGB) surgery induces excessive and continuous weight loss in (morbid) obesity, although it causes several abnormal anatomical and physiological conditions. RESEARCH DESIGN AND METHODS: To distinctively unveil effects of RYGB surgery on β-cell function and glucose turnover in skeletal muscle, liver, and gut, nondiabetic, morbidly obese patients were studied before (pre-OP, five female/one male, BMI: 49 ± 3 kg/m(2), 43 ± 2 years of age) and 7 ± 1 months after (post-OP, BMI: 37 ± 3 kg/m(2)) RYGB surgery, compared with matching obese (CON(ob), five female/one male, BMI: 34 ± 1 kg/m(2), 48 ± 3 years of age) and lean controls (CON(lean), five female/one male, BMI: 22 ± 0 kg/m(2), 42 ± 2 years of age). Oral glucose tolerance tests (OGTTs), hyperinsulinemic-isoglycemic clamp tests, and mechanistic mathematical modeling allowed determination of whole-body insulin sensitivity (M/I), OGTT and clamp test β-cell function, and gastrointestinal glucose absorption. RESULTS: Post-OP lost (P < 0.0001) 35 ± 3 kg body weight. M/I increased after RYGB, becoming comparable to CON(ob), but remaining markedly lower than CON(lean) (P < 0.05). M/I tightly correlated (τ = −0.611, P < 0.0001) with fat mass. During OGTT, post-OP showed ≥15% reduced plasma glucose from 120 to 180 min (≤4.5 mmol/L), and 29-fold elevated active glucagon-like peptide-1 (GLP-1) dynamic areas under the curve, which tightly correlated (r = 0.837, P < 0.001) with 84% increased β-cell secretion. Insulinogenic index (0–30 min) in post-OP was ≥29% greater (P < 0.04). At fasting, post-OP showed approximately halved insulin secretion (P < 0.05 vs. pre-OP). Insulin-stimulated insulin secretion in post-OP was 52% higher than before surgery, but 1–2 pmol/min(2) lower than in CON(ob)/CON(lean) (P < 0.05). Gastrointestinal glucose absorption was comparable in pre-OP and post-OP, but 9–26% lower from 40 to 90 min in post-OP than in CON(ob)/CON(lean) (P < 0.04). CONCLUSIONS: RYGB surgery leads to decreased plasma glucose concentrations in the third OGTT hour and exaggerated β-cell function, for which increased GLP-1 release seems responsible, whereas gastrointestinal glucose absorption remains unchanged but lower than in matching controls

Single Point Insulin Sensitivity Estimator (SPISE) As a Prognostic Marker for Emerging Dysglycemia in Children with Overweight or Obesity

The single point insulin sensitivity estimator (SPISE) is a recently developed fasting index for insulin sensitivity based on triglycerides, high density lipoprotein cholesterol, and body mass index. SPISE has been validated in juveniles and adults; still, its role during childhood remains unclear. To evaluate the age- and sex-specific distribution of SPISE, its correlation with established fasting indexes and its application as a prognostic marker for future dysglycemia during childhood and adolescence were assessed. We performed linear modeling and correlation analyses on a cross-sectional cohort of 2107 children and adolescents (age 5 to 18.4 years) with overweight or obesity. Furthermore, survival analyses were conducted upon a longitudinal cohort of 591 children with overweight/obesity (1712 observations) with a maximum follow-up time of nearly 20 years, targeting prediabetes/dysglycemia as the end point. The SPISE index decreased significantly with age (−0.34 units per year, p p p < 0.05). The SPISE index is a surrogate marker for insulin resistance predicting emerging dysglycemia in children with overweight or obesity, and could, therefore, be applied to pediatric cohorts that lack direct insulin assessment

Hepatic rather than cardiac steatosis relates to glucose intolerance in women with prior gestational diabetes.

BACKGROUND: Increased myocardial lipid accumulation has been described in patients with pre- and overt type 2 diabetes and could underlie the development of left-ventricular dysfunction in metabolic diseases (diabetic cardiomyopathy). Since women with prior gestational diabetes (pGDM) display a generally young population at high risk of developing diabetes and associated cardiovascular complications, we aimed to assess whether myocardial lipid accumulation can be detected at early stages of glucose intolerance and relates to markers of hepatic steatosis (Fatty Liver Index), cardiac function, insulin sensitivity and secretion. METHODS: Myocardial lipid content (MYCL), left-ventricular function (1H-magnetic-resonance-spectroscopy and -imaging), insulin sensitivity/secretion (oral glucose tolerance test) and the fatty liver index (FLI) were assessed in 35 pGDM (45.6±7.0 years, 28.3±4.8 kg/m2) and 14 healthy control females (CON; 44.7±9.8 years, 26.1±2.5 kg/m2), matching for age and body-mass-index (each p>0.1). RESULTS: Of 35 pGDM, 9 displayed normal glucose tolerance (NGT), 6 impaired glucose regulation (IGR) and 20 had been already diagnosed with type 2 diabetes (T2DM). MYCL and cardiac function were comparable between pGDM and CON; in addition, no evidence of left-ventricular dysfunction was observed. MYCL was inversely correlated with the ejection fraction in T2DM (R = -0.45, p<0.05), while the FLI was tightly correlated with metabolic parameters (such as HbA1C, fasting plasma glucose and HDL-cholesterol) and rose along GT-groups. CONCLUSIONS: There is no evidence of cardiac steatosis in middle-aged women with prior gestational diabetes, suggesting that cardiac complications might develop later in the time-course of diabetes and may be accelerated by the co-existence of further risk factors, whereas hepatic steatosis remains a valid biomarker for metabolic diseases even in this rather young female cohort