Insulin Resistance in Congenital Adrenal Hyperplasia is Compensated for by Reduced Insulin Clearance

2021 ◽  
Author(s):  
Daniel Minutti de Oliveira ◽  
Andrea Tura ◽  
Ana Carolina Junqueira Vasques ◽  
Daniella Fernandes Camilo ◽  
Marcelo Miranda Lima ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Congenital Adrenal Hyperplasia ◽  
Beta Cell Function ◽  
Cell Function ◽  
Insulin Clearance ◽  
Adrenal Hyperplasia ◽  
Hyperglycemic Clamp ◽  
Hepatic Insulin Clearance

Abstract Context Congenital adrenal hyperplasia (CAH) patients have potential normal longevity. However, a greater risk for cardiovascular disease has been reported. Insulin resistance and hyperinsulinemia have been described in CAH patients, whereas the prevalence of overt type 2 diabetes is not higher in CAH than in normal population. Objective To examine the contributions of insulin secretion and of hepatic insulin clearance to compensatory hyperinsulinemia in young insulin-resistant adults with classic CAH due to 21-hydroxylase deficiency (21-OHD). Design Cross-sectional. Setting University outpatient clinics. Methods Fifty-one participants: 21 controls, and 30 CAH (15 virilizing and 15 salt-wasting phenotypes), female/male (33/18), age (mean [SD]): 24.0 (3.6) years, body mass index: 24.6 (4.9)kg/m2 with normal glucose tolerance, were submitted to a hyperglycemic clamp study. Main Outcome Measures Insulin sensitivity, beta cell function, and hepatic insulin clearance using appropriate modeling. Results We found an increased insulin resistance in 21-OHD. The systemic hyperinsulinemia (posthepatic insulin delivery) was elevated in CAH patients. No increases were observed in insulin secretory rate (beta cell function) in the first phase or during the hyperglycemic clamp. The increase in insulin concentrations was totally due to a ~33% reduction in insulin clearance. Conclusion 21-OHD nonobese subjects have reduced insulin sensitivity and beta cell response unable to compensate for the insulin resistance, probably due to overexposure to glucocorticoids. Compensatory hyperinsulinemia is most related with reduced hepatic insulin clearance. The exclusive adaptation of the liver acts as a gating mechanism to regulate the access of insulin to insulin-sensitive tissues to maintain glucose homeostasis.

scholarly journals Biomarkers of subclinical inflammation and increases in glycaemia, insulin resistance and beta-cell function in non-diabetic individuals: the Whitehall II study

2016 ◽  
Vol 175 (5) ◽  
pp. 367-377 ◽  
Author(s):  
Christian Herder ◽  
Kristine Færch ◽  
Maren Carstensen-Kirberg ◽  
Gordon D Lowe ◽  
Rita Haapakoski ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Fasting Insulin ◽  
Subclinical Inflammation ◽  
Increased Risk

Objective Higher systemic levels of pro-inflammatory biomarkers and low adiponectin are associated with increased risk of type 2 diabetes, but their associations with changes in glycaemic deterioration before onset of diabetes are poorly understood. We aimed to study whether inflammation-related biomarkers are associated with 5-year changes in glucose and insulin, HbA1c, insulin sensitivity and beta-cell function before the diagnosis of type 2 diabetes and whether these associations may be bidirectional. Design and methods We used multiple repeat measures (17 891 person-examinations from 7683 non-diabetic participants) from the Whitehall II study to assess whether circulating high-sensitivity C-reactive protein (hsCRP), interleukin-6 (IL6), IL1 receptor antagonist (IL1Ra) and adiponectin are associated with subsequent changes in glycaemia, insulin, insulin resistance and beta-cell function (based on oral glucose tolerance tests). We examined bidirectionality by testing if parameters of glucose metabolism at baseline are associated with changes in inflammation-related biomarkers. Results Higher hsCRP and IL6 were associated with increases in fasting insulin, insulin resistance and, for IL6, with beta-cell function after adjustment for confounders. Higher adiponectin was associated with decreases in fasting glucose, HbA1c, fasting insulin, insulin resistance and beta-cell function. The reverse approach showed that 2-h glucose and insulin sensitivity were associated with changes in IL1Ra. Fasting insulin and insulin resistance showed inverse associations with changes in adiponectin. Conclusions Subclinical inflammation is associated with development of increased glycaemia, insulin resistance and beta-cell function in non-diabetic individuals. These findings are consistent with the hypothesis that inflammation-related processes may increase insulin resistance and lead to a compensatory upregulation of beta-cell function.

scholarly journals Clinical phenotyping of newly diagnosed type 2 diabetes in Yemen

2018 ◽  
Vol 6 (1) ◽  
pp. e000587 ◽  
Author(s):  
Abdallah Ahmed Gunaid ◽  
Mohammed Mohammed Al-Kebsi ◽  
Mahfouth Abdalla Bamashmus ◽  
Saleh Ahmed Al-Akily ◽  
Ahmed Nasser Al-Radaei
Keyword(s):  
Insulin Resistance ◽  
Cluster Analysis ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Clinical Variables ◽  
High Insulin ◽  
Function Group ◽  
Cluster 2

ObjectiveTo identify clinical phenotypes of type 2 diabetes (T2D) among adults presenting with a first diagnosis of diabetes.Research design and methodsA total of 500 consecutive patients were subject to clinical assessment and laboratory investigations. We used data-driven cluster analysis to identify phenotypes of T2D based on clinical variables and Homeostasis Model Assessment (HOMA2) of insulin sensitivity and beta-cell function estimated from paired fasting blood glucose and specific insulin levels.ResultsThe cluster analysis identified three statistically different clusters: cluster 1 (high insulin resistance and high beta-cell function group), which included patients with low insulin sensitivity and high beta-cell function; cluster 2 (low insulin resistance and low beta-cell function group), which included patients with high insulin sensitivity but very low beta-cell function; and cluster 3 (high insulin resistance and low beta-cell function group), which included patients with low insulin sensitivity and low beta-cell function. Insulin sensitivity, defined as median HOMA2-S, was progressively increasing from cluster 1 (35.4) to cluster 3 (40.9), to cluster 2 (76) (p<0.001). On the contrary, beta-cell function, defined as median HOMA2-β, was progressively declining from cluster 1 (78.3) to cluster 3 (30), to cluster 2 (22.3) (p<0.001). Clinical and biomarker variables associated with insulin resistance like obesity, abdominal adiposity, fatty liver, and high serum triglycerides were mainly seen in clusters 1 and 3. The highest median hemoglobin A1c value was noted in cluster 2 (88 mmol/mol) and the lowest in cluster 1.ConclusionCluster analysis of newly diagnosed T2D in adults has identified three phenotypes based on clinical variables central to the development of diabetes and on specific clinical variables of each phenotype.

scholarly journals Neighborhood walkability and risk of gestational diabetes

2020 ◽  
Vol 8 (1) ◽  
pp. e000938
Author(s):  
Simone Kew ◽  
Chang Ye ◽  
Sadia Mehmood ◽  
Anthony J Hanley ◽  
Mathew Sermer ◽  
...  
Keyword(s):  
Physical Activity ◽  
Diabetes Mellitus ◽  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Maternal Risk ◽  
Neighborhood Walkability ◽  
Walk Score

ObjectiveHigher neighborhood walkability has been associated with a lower risk of type 2 diabetes mellitus (T2DM) by promoting greater physical activity (thereby reducing weight and lowering insulin resistance). However, it is not known if walkability may similarly reduce maternal risk of gestational diabetes mellitus (GDM), which arises in the setting of the severe physiologic insulin resistance of pregnancy. Indeed, the insulin resistance of pregnancy is primarily driven by placental hormones and not maternal weight gain. Thus, we sought to evaluate the impact of neighborhood walkability on maternal risk of GDM and the pathophysiologic determinants thereof (insulin sensitivity and pancreatic beta-cell function).MethodsIn this study, 1318 women reported their pregravid physical activity (Baecke questionnaire) while undergoing an oral glucose tolerance test (OGTT) at mean 29.3 weeks’ gestation. The OGTT identified 290 women with GDM and enabled assessment of insulin sensitivity and beta-cell function. Based on their residential Walk Score, the women were stratified into the following four established categories of neighborhood walkability: car dependent (n=328), somewhat walkable (n=315), very walkable (n=406), and walker’s paradise (n=269).ResultsThere was a progressive increase in pregravid total physical activity (p=0.002), non-sport leisure-time activity (p=0.009) and sport activity (p=0.01) across the walkability groups (from car dependent to somewhat walkable to very walkable to walker’s paradise), coupled with a concomitant decline in pre-pregnancy body mass index (p=0.007). However, in pregnancy, the groups did not differ in gestational weight gain (p=0.80). Moreover, the walkability groups also did not differ in mean adjusted insulin sensitivity, beta-cell function, or glycemia on the antepartum OGTT. On logistic regression analysis, Walk Score did not predict GDM (OR=1.001, 95% CI 0.995 to 1.007).ConclusionNeighborhood walkability is not a significant determinant of maternal risk of GDM. Thus, in contrast to T2DM, the effect of neighborhood design on incidence of GDM will be comparatively modest.

scholarly journals Maternal Rat Diabetes Mellitus Deleteriously Affects Insulin Sensitivity and Beta-Cell Function in the Offspring

2013 ◽  
Vol 2013 ◽  
pp. 1-10 ◽  
Author(s):  
Abdel-Baset M. Aref ◽  
Osama M. Ahmed ◽  
Lobna A. Ali ◽  
Margit Semmler
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Maternal Diabetes ◽  
Serum Glucose ◽  
Time Intervals ◽  
Rat Offspring ◽  
Normal Rat

This study was designed to assess the effect of maternal diabetes in rats on serum glucose and insulin concentrations, insulin resistance, histological architecture of pancreas and glycogen content in liver of offspring. The pregnant rat females were allocated into two main groups: normal control group and streptozotocin-induced diabetic group. After birth, the surviving offspring were subjected to biochemical and histological examination immediately after delivery and at the end of the 1st and 2nd postnatal weeks. In comparison with the offspring of normal control dams, the fasting serum glucose level of offspring of diabetic mothers was significantly increased at the end of the 1st and 2nd postnatal weeks. Serum insulin level of offspring of diabetic dams was significantly higher at birth and decreased significantly during the following 2 postnatal weeks, while in normal rat offspring, it was significantly increased with progress of time. HOMA Insulin Resistance (HOMA-IR) was significantly increased in the offspring of diabetic dams at birth and after 1 week than in normal rat offspring, while HOMA insulin sensitivity (HOMA-IS) was significantly decreased. HOMA beta-cell function was significantly decreased at all-time intervals in offspring of diabetic dams. At birth, islets of Langerhans as well as beta cells in offspring of diabetic dams were hypertrophied. The cells constituting islets seemed to have a high division rate. However, beta-cells were degenerated during the following 2 post-natal weeks and smaller insulin secreting cells predominated. Vacuolation and necrosis of the islets of Langerhans were also observed throughout the experimental period. The carbohydrate content in liver of offspring of diabetic dams was at all-time intervals lower than that in control. The granule distribution was more random. Overall, the preexisting maternal diabetes leads to glucose intolerance, insulin resistance, and impaired insulin sensitivity andβ-cell function in the offspring at different postnatal periods.

scholarly journals Importance of quantifying insulin secretion in relation to insulin sensitivity to accurately assess beta cell function in clinical studies

2004 ◽  
pp. 97-104 ◽  
Author(s):  
B Ahren ◽  
G Pacini
Keyword(s):  
Insulin Resistance ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Glucose Tolerance Test ◽  
Cell Function ◽  
Tolerance Test ◽  
Hyperbolic Function

Insulin sensitivity and insulin secretion are mutually related such that insulin resistance is compensated by increased insulin secretion. A correct judgement of insulin secretion therefore requires validation in relation to the insulin sensitivity in the same subject. Mathematical analyses of the relationship between insulin sensitivity and insulin secretion has revealed a hyperbolic function, such that the product of the two variables is constant. This product is usually called the disposition index. Several techniques may be used for its estimation such as data derived from the frequently sampled i.v. glucose tolerance test, the oral glucose tolerance test or the glucose-dependent arginine stimulation test or the euglycemic hyperinsulinemic clamp technique in combination with a test on insulin secretion. Using these techniques the compensatory increase in beta cell function in insulin resistance has been verified in obesity, in pregnancy and after glucocorticoid administration as has the defective beta cell function as the underlying cause of impaired glucose tolerance and type 2 diabetes. Similarly, combined analysis of insulin sensitivity and insulin secretion has shown a down-regulation of beta cell function in increased insulin sensitivity accompanying weight reduction in obesity and following exercise. Acknowledging this inverse relationship between insulin secretion and insulin sensitivity therefore requires estimation of both variables for correct assessment in any individual.

scholarly journals The Effect of Sodium-Glucose Cotransporter 2 Inhibitor Ipragliflozin on Insulin Resistance, Hepatic Insulin Clearance, Beta-Cell Function in the Japanese Patients with type 2 Diabetes

2021 ◽  
Author(s):  
Tsuyoshi Okura ◽  
Yohei Fujioka ◽  
Risa Nakamura ◽  
Sonoko Kitao ◽  
Yuichi Ito ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Type 2 Diabetes ◽  
Body Composition ◽  
Beta Cell Function ◽  
Cell Function ◽  
Insulin Clearance ◽  
C Peptide ◽  
Sodium Glucose Cotransporter ◽  
Hepatic Insulin Clearance

Abstract Introduction: Sodium-glucose cotransporter 2 inhibitor (SGLT2i) is a medication for type 2 diabetes mellitus (T2DM). Some reports showed SGLT2i improved insulin resistance, however, the effect on insulin resistance is not well established. Hepatic insulin clearance (HIC) is new pathophysiology of T2DM. The effect of SGLT2i on hepatic insulin clearance and insulin resistance is not well known. We investigated the effect of SGLT2i on insulin resistance, insulin secretion, incretins, body composition, and hepatic insulin clearance. Materials and Methods: We conducted a meal tolerance test (MTT), and the hyperinsulinemic-euglycemic clamp in 9 T2DM patients. 50 mg/day ipragliflozin was admitted, MTT and clamp were performed after 4 months. We calculated the postprandial C-peptide AUC to insulin AUC ratio as the HIC. We also measured GLP1, GIP, and glucagon levels during MTT. Results: Body weight, HbA1c, and body composition were not significantly changed after 4 months of treatment. Postprandial glucose, fasting, and postprandial insulin were significantly decreased. The insulin resistance of the glucose clamp was not changed, but HOMA-IR and insulin sensitivity index (ISI) were significantly improved. Incretins and glucagon were not changed. Hepatic insulin clearance was significantly increased, but whole-body insulin clearance was not changed. Fib 4 index and fatty liver index were significantly reduced. HOMA-beta and insulinogenic index was not changed but the C-peptide index was significantly increased. Conclusions: Although patients’ number was small, these results suggest that SGLT2i treatment decreased hepatic insulin resistance, increased hepatic insulin clearance, and decreased hyperinsulinemia, it might protect beta-cell function.

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

2021 ◽  
Author(s):  
Xi Chen ◽  
Enrique Maldonado ◽  
Ralph A DeFronzo ◽  
Devjit Tripathy
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Plasma Glucagon ◽  
Euglycemic Hyperinsulinemic Clamp ◽  
Matsuda Index ◽  
Obese Subjects

Abstract Aim To examine the relationship between plasma glucagon levels and insulin sensitivity and insulin secretion in obese subjects. Methods 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. Results 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 &lt; 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 &lt; 0.001) and beta-cell function (r = 0.35; P &lt; 0.001). The glucagon/insulin ratio also correlated and with beta-cell function during OGTT at 60 and 120 minutes (r = −0.47; P &lt; 0.001 and r = −0.32; P &lt; 0.001). Conclusion 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.

scholarly journals Changes Over Time in Uric Acid in Relation to Changes in Insulin Sensitivity, Beta-Cell Function, and Glycemia

2019 ◽  
Vol 105 (3) ◽  
pp. e651-e659
Author(s):  
Alessandro Volpe ◽  
Chang Ye ◽  
Anthony J Hanley ◽  
Philip W Connelly ◽  
Bernard Zinman ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Uric Acid ◽  
Insulin Sensitivity ◽  
Beta Cell ◽  
Serum Uric Acid ◽  
Beta Cell Function ◽  
Cell Function ◽  
Matsuda Index ◽  
Changes Over Time ◽  
Over Time

Abstract Context Serum uric acid has been linked to risk of type 2 diabetes (T2DM), but debate persists as to whether it plays a causal role. Indeed, it is unclear if changes in uric acid relate to the pathophysiologic determinants of T2DM (insulin resistance, beta-cell dysfunction), as would be expected if causal. Objective To evaluate the impact of changes in uric acid over 2 years on changes in insulin sensitivity, beta-cell function, and glycemia in women with and without recent gestational diabetes (GDM), a model of the early natural history of T2DM. Design/Setting/Participants At both 1 and 3 years postpartum, 299 women (96 with recent GDM) underwent uric acid measurement and oral glucose tolerance tests that enabled assessment of insulin sensitivity/resistance (Matsuda index, homeostasis model assessment of insulin resistance [HOMA-IR]), beta-cell function (insulin secretion-sensitivity index-2 [ISSI-2], insulinogenic index/HOMA-IR [IGI/HOMA-IR]), and glucose tolerance. Results Women with recent GDM had higher serum uric acid than their peers at both 1 year (281 ± 69 vs 262 ± 58 µmol/L, P = 0.01) and 3 years postpartum (271 ± 59 vs 256 ± 55 µmol/L, P = 0.03), coupled with lower insulin sensitivity, poorer beta-cell function, and greater glycemia (all P &lt; 0.05). However, on fully adjusted analyses, neither uric acid at 1 year nor its change from 1 to 3 years was independently associated with any of the following metabolic outcomes at 3 years postpartum: Matsuda index, HOMA-IR, ISSI-2, IGI/HOMA-IR, fasting glucose, 2-hour glucose, or glucose intolerance. Conclusion Serum uric acid does not track with changes over time in insulin sensitivity, beta-cell function, or glycemia in women with recent GDM, providing evidence against causality in its association with diabetes.

Glucose tolerance stages in Cystic Fibrosis are idenfied by a unique pattern of defects of Beta-cell function

2020 ◽  
Author(s):  
Claudia Piona ◽  
Sonia Volpi ◽  
Chiara Zusi ◽  
Enza Mozzillo ◽  
Antonella Tosco ◽  
...  
Keyword(s):  
Cystic Fibrosis ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Beta Cell ◽  
Beta Cell Function ◽  
Cell Function ◽  
Insulin Clearance ◽  
Glucose Regulation ◽  
Unique Pattern ◽  
Glucose Tolerance Status

Abstract Aim To assess the order of severity of the defects of three direct determinants of glucose regulation, i.e., beta-cell function, insulin clearance and insulin sensitivity, in patients with CF categorized according their glucose tolerance status, including early elevation of mid-OGTT glucose values (&gt;140 and &lt; 200 mg/dL), named AGT140. Methods Two hundred and thirty-two CF patients aged 10-25 underwent OGTT. Beta-cell function and insulin clearance were estimated by OGTT mathematical modelling and OGTT-derived biomarkers of insulin secretion and sensitivity were calculated. The association between five glucose tolerance stages [NGT, AGT140, Indeterminate glucose Tolerance (INDET), impaired glucose tolerance (IGT), Cystic fibrosis related diabetes (CFRD)] and glucometabolic variables was assessed with general linear model. Results Beta-cell function and insulin sensitivity progressively worsened across glucose tolerance stages (p&lt;0.001) with AGT140 patients significantly differing from NGT (all p&lt;0.01). AGT140 and INDET showed a degree of beta-cell dysfunction similar to IGT and CFRD, respectively (all p&lt;0.01). Insulin clearance was not significantly associated with glucose tolerance stages (p=0.162). Each class of glucose tolerance was uniquely identified by a specific combination of defects of the direct determinants of glucose regulation. Conclusions In CF patients each of the five glucose tolerance stages shows a unique pattern of defects of the direct determinants of glucose regulation, with AGT140 patients significantly differing from NGT and being similar to IGT. These findings suggest to recognize AGT 140 as a distinct glucose tolerance class and to reconsider the grade of glucometabolic deterioration across glucose tolerance stages in CF.

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