Effects of pioglitazone and metformin on β-cell function in nondiabetic subjects at high risk for type 2 diabetes

2007 ◽  
Vol 292 (1) ◽  
pp. E359-E365 ◽  
Author(s):  
Neda Rasouli ◽  
Philip A Kern ◽  
E. Albert Reece ◽  
Steven C. Elbein
Keyword(s):  
At Risk ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Glucose Disposal ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Glucose Levels ◽  
Β Cell Function

Thiazolidinediones (TZDs) and metformin decreased the incidence of diabetes in subjects at risk for developing diabetes and improved peripheral or hepatic insulin sensitivity, respectively. Whether they also directly improved β-cell function is not clear. In vitro studies showed improved β-cell function in response to TZDs and metformin; however, the effects of TZDs or metformin on β-cell function in humans are still uncertain. We hypothesized that both TZDs and metformin directly affect β-cell function. We evaluated β-cell function and insulin sensitivity (SI) in subjects with impaired glucose tolerance or a history of gestational diabetes using oral and intravenous glucose tolerance tests in addition to the glucose-potentiated arginine stimulation test. In contrast to metformin, pioglitazone improved SI, glucose tolerance, and insulin-independent glucose disposal [glucose effectiveness (SG)]. Neither pioglitazone nor metformin significantly improved β-cell compensation for insulin resistance [disposition index (DI)], but the change in DI significantly correlated with baseline SI. Insulin secretion in response to arginine at maximally potentiating glucose levels (AIRmax) tended to increase after metformin and to decrease after pioglitazone; however, when adjusted for SI, the changes were not significant. Our results demonstrate that, in nondiabetic subjects at risk for diabetes, pioglitazone, but not metformin, significantly improved glucose tolerance by improving SI and SG. We did not find any evidence that either pioglitazone or metformin improved β-cell function. Improved β-cell compensation was observed primarily in the subgroup of subjects that had the lowest SI at baseline.

Identifying glucose thresholds for incident diabetes by physiological analysis: a mathematical solution

2015 ◽  
Vol 308 (7) ◽  
pp. R590-R596 ◽  
Author(s):  
Ele Ferrannini ◽  
Maria Laura Manca
Keyword(s):  
Insulin Sensitivity ◽  
Confidence Interval ◽  
Glucose Tolerance ◽  
Odds Ratio ◽  
Cell Function ◽  
Oral Glucose ◽  
Oral Glucose Tolerance ◽  
Β Cell ◽  
Glucose Levels ◽  
Β Cell Function

Plasma glucose thresholds for diagnosis of type 2 diabetes are currently based on outcome data (risk of retinopathy), an inherently ill-conditioned approach. A radically different approach is to consider the mechanisms that control plasma glucose, rather than its relation to an outcome. We developed a constraint optimization algorithm to find the minimal glucose levels associated with the maximized combination of insulin sensitivity and β-cell function, the two main mechanisms of glucose homeostasis. We used a training cohort of 1,474 subjects (22% prediabetic, 7.7% diabetic) in whom insulin sensitivity was measured by the clamp technique and β-cell function was determined by mathematical modeling of an oral glucose tolerance test. Optimized fasting glucose levels were ≤87 and ≤89 mg/dl in ≤45-yr-old women and men, respectively, and ≤92 and ≤95 mg/dl in >45-yr-old women and men, respectively; the corresponding optimized 2-h glucose levels were ≤96, ≤98, ≤103, and ≤105 mg/dl. These thresholds were validated in three prospective cohorts of nondiabetic subjects (Relationship Between Insulin Sensitivity and Cardiovascular Disease Study, Botnia Study, and Mexico City Diabetes Study) with baseline and follow-up oral glucose tolerance tests. Of 5,593 participants, 452 progressed to diabetes. Similarly, in the three cohorts, subjects with glucose levels above the estimated thresholds had an odds ratio of 3.74 (95% confidence interval = 2.64–5.48) of progressing, substantially higher than the risk carried by baseline conventionally defined prediabetes [odds ratio = 2.32 (95% confidence interval = 1.91–2.81)]. The concept that optimization of glucose concentrations by direct measures of insulin sensitivity and β-cell function identifies gender- and age-specific thresholds that bear on disease progression is proven in a physiologically sound, quantifiable manner.

Reduced β-cell function contributes to impaired glucose tolerance in dogs made obese by high-fat feeding

1999 ◽  
Vol 277 (4) ◽  
pp. E659-E667 ◽  
Author(s):  
Karl J. Kaiyala ◽  
Ronald L. Prigeon ◽  
Steven E. Kahn ◽  
Stephen C. Woods ◽  
Daniel Porte ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Chow Diet ◽  
High Fat ◽  
Β Cell ◽  
Intravenous Glucose ◽  
Β Cell Function ◽  
Fat Feeding

The ability to increase β-cell function in the face of reduced insulin sensitivity is essential for normal glucose tolerance. Because high-fat feeding reduces both insulin sensitivity and glucose tolerance, we hypothesized that it also reduces β-cell compensation. To test this hypothesis, we used intravenous glucose tolerance testing with minimal model analysis to measure glucose tolerance ( K g), insulin sensitivity (SI), and the acute insulin response to glucose (AIRg) in nine dogs fed a chow diet and again after 7 wk of high-fat feeding. Additionally, we measured the effect of consuming each diet on 24-h profiles of insulin and glucose. After high-fat feeding, SI decreased by 57% ( P = 0.003) but AIRg was unchanged. This absence of β-cell compensation to insulin resistance contributed to a 41% reduction of K g( P = 0.003) and abolished the normal hyperbolic relationship between AIRg and SI observed at baseline. High-fat feeding also elicited a 44% lower 24-h insulin level ( P = 0.004) in association with an 8% reduction of glucose ( P = 0.0003). We conclude that high-fat feeding causes insulin resistance that is not compensated for by increased insulin secretion and that this contributes to the development of glucose intolerance. These effects of high-fat feeding may be especially deleterious to individuals predisposed to type 2 diabetes mellitus.

scholarly journals The effect of vitamin D supplementation on the glycemic control of pre-diabetic Qatari patients in a randomized control trial

BMC Nutrition ◽  
2019 ◽  
Vol 5 (1) ◽  
Author(s):  
Mohammed Al Thani ◽  
Eman Sadoun ◽  
Angeliki Sofroniou ◽  
Amin Jayyousi ◽  
Khaled Ahmed Mohamed Baagar ◽  
...  
Keyword(s):  
Vitamin D ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Plasma Glucose ◽  
Cell Function ◽  
Vitamin D Supplementation ◽  
Β Cell ◽  
Baseline Serum ◽  
Link Type ◽  
Β Cell Function

Abstract Background Vitamin D deficiency is associated with indicators of pre-diabetes including, insulin resistance, β-cell dysfunction and elevated plasma glucose with controversial findings from current trials. This study aims to investigate the long-term effect of vitamin D on glucose metabolism and insulin sensitivity in pre-diabetic and highly vitamin-deficient subjects. Methods One hundred thirty-two participants were randomized to 30,000 IU vitamin D weekly for 6 months. Participants underwent oral glucose tolerance test (OGTT) at 3-month intervals to determine the change in plasma glucose concentration at 2 h after 75 g OGTT (2hPCG). Secondary measurements included glycated hemoglobin, fasting plasma glucose and insulin, post-prandial insulin, indices of insulin sensitivity (HOMA-IR, Matsuda Index), β-cell function (HOMA-β, glucose and insulin area under the curve (AUC), disposition and insulinogenic indices), and lipid profile. Results A total of 57 (vitamin D) and 75 (placebo) subjects completed the study. Mean baseline serum 25(OH) D levels were 17.0 ng/ml and 14.9 ng/ml for placebo and vitamin D group, respectively. No significant differences were observed for 2hPC glucose or insulin sensitivity indices between groups. HOMA-β significantly decreased in the vitamin D group, while area under curve for glucose and insulin showed a significant reduction in β-cell function in both groups. Additionally, HOMA-β was found to be significantly different between control and treatment group and significance persisted after adjusting for confounding factors. Conclusion Vitamin D supplementation in a pre-diabetic and severely vitamin-deficient population had no effect on glucose tolerance or insulin sensitivity. The observed reduction in β-cell function in both placebo and vitamin D groups could be attributed to factors other than supplementation. Trial registration NCT02098980, 28/03/2014 (www.clinicaltrials.gov).

Association between Genetic Polymorphisms of β-Cell Differentiation Genes and Insulin Resistance (β-Cell Dysfunction) in Childhood Acute Lymphoblastic Leukemia (ALL) Survivors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4281-4281
Author(s):  
Pacharapan Surapolchai ◽  
Suradej Hongeng ◽  
Samart Pakakasama ◽  
Pat Mahachoklertwattana ◽  
Angkana Winaichatsak ◽  
...  
Keyword(s):  
Insulin Resistance ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Sensitivity Index ◽  
Insulin Sensitivity Index ◽  
Β Cell ◽  
Childhood All ◽  
Cell Dysfunction ◽  
Β Cell Function

Abstract Background: The purposes of the study were to determine β-cell function and insulin sensitivity after ALL therapy cessation and the association between genetic polymorphisms of β-cell differentiation genes, TCF7L2 and PAX4, with insulin resistance (β-cell dysfunction) in childhood ALL survivors. Methods: Childhood ALL patients diagnosed during 1997–2004 finished the treatment for at least 6 months. The oral glucose tolerance test and lipid screening were performed. Impaired glucose tolerance and diabetes mellitus (DM) were defined according to WHO criteria. β-cell function was estimated by homeostasis model assessment β-cell (HOMA β-cell) and insulinogenic index (IGI) and insulin sensitivity was estimated by whole body insulin sensitivity index (WBISI). The polymorphisms of TCF7L2 (rs12255372 and rs7903146) and PAX4 (A1186C) were genotyped and assessed for the association between these polymorphisms and the β-cell function and the insulin sensitivity. Results: 126 patients were studied (52 females, 74 males and age at the time of study; 4–20 yrs). 116 patients (92%) had normal glucose tolerance (NGT) while the others 10 patients (8%) had impaired glucose tolerance (IGT). Comparing between IGT and NGT groups respectively, we found statistically significant differences in age at the diagnosis (7.5 and 5.2 yrs, p=0.041), age at the study (14 and 10.3 yrs, p=0.001), the duration of post ALL therapy cessation (43 and 26 months, p=0.015), and insulin sensitivity index (WBISI) (5.75 and 9.52, p<0.001). HOMA β-cell and IGI were not different between NGT and IGT group (190.8 and 139.5, p=0.332; 23.6 and 15.8, p=0.310, respectively). Moreover, 32 of 126 patients (25%) had insulin resistance (modified from the criteria of WBISI in obese children and adolescents). These 32 patients who had insulin resistance demonstrated significant pictures of metabolic syndrome i.e. hypertriglyceridemia (116.6 and 85.4 mg/dL, p=0.036), low HDL-C (43.0 and 48.3 mg/dL, p=0.015), obesity (BMI SDS 1.03 and 0.38, p=0.044) and were also older age at the study (12.8 and 9.9 yrs, p<0.001). The genotype frequencies and allele frequencies of polymorphisms of TCF7L2 and PAX4 genes between IGT and NGT groups and between insulin resistance and nonresistance were not difference (p>0.05). Conclusion: The childhood ALL survivors who had IGT were associated with the longer duration of ALL therapy cessation, the older age at diagnosis and at the time of study, and insulin resistance while β-cell function was still relatively preserved. Long-term childhood ALL survivors have potential risks of IGT, insulin resistance and metabolic syndrome. Our findings with such small representatives are not yet applicable to associate TCF7L2 and PAX4 polymorphisms with the insulin resistance (β-cell dysfunction) in the childhood ALL survivors.

Estimation of β-cell function from the data of the oral glucose tolerance test

2007 ◽  
Vol 292 (6) ◽  
pp. E1575-E1580 ◽  
Author(s):  
Shinji Sakaue ◽  
Shinji Ishimaru ◽  
Daisuke Ikeda ◽  
Yoshinori Ohtsuka ◽  
Toshiro Honda ◽  
...  
Keyword(s):  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Glucose Tolerance Test ◽  
Cell Function ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Sensitivity Index ◽  
Β Cell ◽  
Β Cell Function ◽  
The Relationship

Although a hyperbolic relationship between insulin secretion and insulin sensitivity has been shown, the relationship has been often questioned. We examined the relationship using oral glucose tolerance test (OGTT)-derived indexes. A total of 374 Japanese subjects who had never been given a diagnosis of diabetes underwent a 75-g OGTT. In subjects with normal glucose tolerance (NGT), the ln [insulinogenic index (IGI)] was described by a linear function of ln ( x) ( x, insulin sensitivity index) in regression analysis when the reciprocal of the insulin resistance index in homeostasis model assessment, Matsuda's index, and oral glucose insulin sensitivity index were used as x. Because the 95% confidence interval of the slope of the regression line did not necessarily include −1, the relationships between IGI and x were not always hyperbolic, but power functions IGI × xα = a constant. We thought that IGI × xα was an appropriate β-cell function estimate adjusted by insulin sensitivity and referred to it as β-cell function index (BI). When Matsuda's index was employed as x, the BI values were decreased in subjects without NGT. Log BI had a better correlation with fasting plasma glucose (PG; FPG) and 2-h PG in non-NGT subjects than in NGT subjects. In subjects with any glucose tolerance, log BI was linearly correlated with 1-h PG and glucose spike (the difference between maximum PG and FPG). In conclusion, the relationship between insulin secretion and insulin sensitivity was not always hyperbolic. The BI is a useful tool in the estimation of β-cell function with a mathematical basis.

Dynamics of insulin sensitivity, β-cell function, and β-cell mass during the development of diabetes in fa/fa rats

2007 ◽  
Vol 293 (6) ◽  
pp. E1730-E1735 ◽  
Author(s):  
Brian G. Topp ◽  
Laura L. Atkinson ◽  
Diane T. Finegood
Keyword(s):  
Insulin Sensitivity ◽  
Cell Function ◽  
Cell Mass ◽  
Primary Role ◽  
High Fat ◽  
Β Cell ◽  
Glucose Levels ◽  
Β Cell Function ◽  
Zdf Rats ◽  
Secretory Capacity

Both male Zucker Fatty (mZF) and lower-fat-fed female Zucker diabetic fatty (LF-fZDF) rats are obese but remain normoglycemic. Male ZDF (mZDF) and high-fat-fed female ZDF rats (HF-fZDF) are also obese but develop diabetes between 7 and 10 wk of age. Although these models have been well studied, the mechanisms governing the adaptations to obesity in the normoglycemic animals, and the failure of adaptation in the animals that develop diabetes, remain unclear. Here we use quantitative morphometry and our recently developed coupled β-cell mass (βm), insulin, and glucose model to elucidate the dynamics of insulin sensitivity (SI), β-cell secretory capacity (βsc), and βm in these four animal models. Both groups that remained normoglycemic with increasing obesity (mZF, LF-fZDF) exhibited increased βm and constant βsc in response to a falling SI. In rats that developed hyperglycemia (mZDF, HF-fZDF), there was a greater reduction in SI and slower expansion of βm, with constant βsc. βsc decreased after glucose levels rose above 20 mM. Taken together, these data suggest that excessive insulin resistance and insufficient β m adaptation play a primary role in the pathogenesis of diabetes.

Immediate enhancement of first-phase insulin secretion and unchanged glucose effectiveness in patients with type 2 diabetes after Roux-en-Y gastric bypass

2015 ◽  
Vol 308 (6) ◽  
pp. E535-E544 ◽  
Author(s):  
Christoffer Martinussen ◽  
Kirstine N. Bojsen-Møller ◽  
Carsten Dirksen ◽  
Siv H. Jacobsen ◽  
Nils B. Jørgensen ◽  
...  
Keyword(s):  
Type 2 Diabetes ◽  
Insulin Secretion ◽  
Insulin Sensitivity ◽  
Glucose Tolerance ◽  
Cell Function ◽  
Β Cell ◽  
Glucose Effectiveness ◽  
Β Cell Function ◽  
First Phase Insulin Secretion

Roux-en-Y gastric bypass surgery (RYGB) in patients with type 2 diabetes often leads to early disease remission, and it is unknown to what extent this involves improved pancreatic β-cell function per se and/or enhanced insulin- and non-insulin-mediated glucose disposal (glucose effectiveness). We studied 30 obese patients, including 10 with type 2 diabetes, 8 with impaired glucose tolerance, and 12 with normal glucose tolerance before, 1 wk, and 3 mo after RYGB, using an intravenous glucose tolerance test (IVGTT) to estimate first-phase insulin response, insulin sensitivity (Si), and glucose effectiveness with Bergman's minimal model. In the fasting state, insulin sensitivity was estimated by HOMA-S and β-cell function by HOMA-β. Moreover, mixed-meal tests and oral GTTs were performed. In patients with type 2 diabetes, glucose levels normalized after RYGB, first-phase insulin secretion in response to iv glucose increased twofold, and HOMA-β already improved 1 wk postoperatively, with further enhancements at 3 mo. Insulin sensitivity increased in the liver (HOMA-S) at 1 wk and at 3 mo in peripheral tissues (Si), whereas glucose effectiveness did not improve significantly. During oral testing, GLP-1 responses and insulin secretion increased regardless of glucose tolerance. Therefore, in addition to increased insulin sensitivity and exaggerated postprandial GLP-1 levels, diabetes remission after RYGB involves early improvement of pancreatic β-cell function per se, reflected in enhanced first-phase insulin secretion to iv glucose and increased HOMA-β. A major role for improved glucose effectiveness after RYGB was not supported by this study.

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