Pancreatic beta-cell dysfunction REStorEd by Rosiglitazone and Valsartan Effects: a 52-week randomised controlled factorial study in subjects with impaired fasting glucose and/or impaired glucose tolerance

ObjectiveImpaired fasting glucose (IFG) and impaired glucose tolerance (IGT) may convey disparate risks of metabolic consequences. Fasting plasma glucose (FPG), while an expedient screening procedure, may not adequately assess metabolic risk, particularly among youths. In order to inform a strategy for screening Chinese youth for pre-diabetes, we examined the relative value of IFG versus IGT to define metabolic risk by assessing their association with insulin resistance, beta-cell dysfunction, adverse adipokine profiles and other cardiometabolic risk factors.Research design and methodsWe recruited 542 subjects (age 14–28 years) from the Beijing Child and Adolescent Metabolic Syndrome study for an in-depth assessment of cardiometabolic risk factors, including a 2-hour oral glucose tolerance test, liver ultrasound and serum levels of four adipokines.ResultsFPG failed to identify nearly all (32/33) youths with IGT, whereas 2-hour plasma glucose (2 h PG) missed 80.8% (21/26) of subjects with IFG. Impaired beta-cell function was evident from decreased oral disposition indices in those with isolated impaired fasting glucose (iIFG) or isolated impaired glucose tolerance (iIGT) versus normal glucose tolerance (NGT) (all p<0.001), whereas reduced insulin sensitivity (Matsuda) index was most pronounced in the iIGT group (p<0.01). Moreover, alterations in adipokine levels (fibroblast growth factor 21, adiponectin and leptin/adiponectin ratio) were associated with iIGT (p<0.05) but not iIFG. Youths with iIGT had a 2-fold to 32-fold increased incidence of hypertriglyceridemia, hypertension and metabolic syndrome (MetS) compared with those with NGT. In addition, subgroup analyses of participants with normal FPG revealed that the odds of having IGT increased 3-fold to 18-fold among those with elevated TGs, hypertension, moderate-to-severe non-alcoholic fatty liver disease or MetS.ConclusionsChinese youth with iIGT exhibit a higher cardiometabolic risk profile than those with iIFG. Thus, 2 h PG is preferred over FPG to identify the pre-diabetes phenotype at greatest risk of subsequent development of cardiovascular disease.Trial registration numberNCT03421444.

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Impaired fasting glucose with or without impaired glucose tolerance: progressive or parallel states of prediabetes?

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.90354.2008 ◽

2008 ◽

Vol 295 (2) ◽

pp. E428-E435 ◽

Cited By ~ 26

Author(s):

Leigh Perreault ◽

Bryan C. Bergman ◽

Mary C. Playdon ◽

Chiara Dalla Man ◽

Claudio Cobelli ◽

...

Keyword(s):

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Impaired Fasting Glucose ◽

Insulin Action ◽

Low Dose ◽

Fasting Glucose ◽

Normal Glucose Tolerance ◽

Β Cell ◽

Cell Dysfunction ◽

Normal Glucose

Our objective was to determine whether defects underlying impaired fasting glucose (IFG) are maintained and additive when combined with impaired glucose tolerance (IGT) (representing a progressive form of prediabetes) or are distinct in IFG/IGT (reflecting a parallel form of prediabetes). Volunteers with IFG ( n = 10), IFG/IGT ( n = 14), or normal glucose tolerance (NGT; n = 15) were matched for demographics and anthropometry. Insulin secretion was assessed using the glucose step-up protocol and insulin action through the use of a two-stage hyperinsulinemic euglycemic clamp with infusion of [6,6-2H2]glucose. Modeling of insulin secretory parameters revealed similar basal (Φb) but diminished dynamic (Φd) components in both IFG and IFG/IGT ( P = 0.05 vs. NGT for both). Basal glucose rate of appearance (Ra) was higher in IFG compared with NGT ( P < 0.01) and also, surprisingly, with IFG/IGT ( P < 0.04). Moreover, glucose Ra suppressed more during the low-dose insulin clamp in IFG ( P < 0.01 vs. NGT, P = 0.08 vs. IFG/IGT). Insulin-stimulated glucose uptake [glucose rate of disappearance (Rd)] was similar in IFG, IFG/IGT, and NGT throughout the clamp. We conclude that nuances of β-cell dysfunction observed in IFG were also noted in IFG/IGT. A trend for additional insulin secretory defects was observed in IFG/IGT, possibly suggesting progression in β-cell failure in this group. In contrast, basal glucose Ra and its suppressability with insulin were higher in IFG, but not IFG/IGT, compared with NGT. Together, these data indicate that IFG/IGT may be a distinct prediabetic syndrome rather than progression from IFG.

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Effect of rosiglitazone on the frequency of diabetes in patients with impaired glucose tolerance or impaired fasting glucose: a randomised controlled trial

The Lancet ◽

10.1016/s0140-6736(06)69420-8 ◽

2006 ◽

Vol 368 (9541) ◽

pp. 1096-1105 ◽

Cited By ~ 988

Keyword(s):

Randomised Controlled Trial ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Impaired Fasting Glucose ◽

Fasting Glucose ◽

Controlled Trial ◽

Randomised Controlled

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Contributions of -Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose

Diabetes Care ◽

10.2337/dc05-2179 ◽

2006 ◽

Vol 29 (5) ◽

pp. 1130-1139 ◽

Cited By ~ 466

Author(s):

M. A. Abdul-Ghani ◽

D. Tripathy ◽

R. A. DeFronzo

Keyword(s):

Insulin Resistance ◽

Glucose Tolerance ◽

Impaired Glucose Tolerance ◽

Impaired Fasting Glucose ◽

Fasting Glucose ◽

Cell Dysfunction

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433 NEW TRANSGENIC PIG DIABETES MODEL EXPRESSING THE MUTANT Insulinc93S FOR THE STUDY OF THE PANCREATIC BETA CELL DYSFUNCTION

Reproduction Fertility and Development ◽

10.1071/rdv22n1ab433 ◽

2010 ◽

Vol 22 (1) ◽

pp. 373

Author(s):

S. Renner ◽

N. Klymiuk ◽

A. Wuensch ◽

B. Kessler ◽

M. Kurome ◽

...

Keyword(s):

Diabetes Mellitus ◽

Glucose Tolerance ◽

Beta Cell ◽

Point Mutation ◽

Genetic Background ◽

Mutant Mouse ◽

Pancreatic Beta Cell ◽

Beta Cell Dysfunction ◽

Transgenic Pig ◽

Cell Dysfunction

We previously established a mutant mouse line showing diabetes which was caused by a point mutation in the Insulin 2 (Ins2) gene. The point mutation leads to the amino acid exchange C95S and the loss of the A6-A11 intrachain disulfide bond of insulin. Male heterozygous Ins2C95S mutant mice develop progressive diabetes mellitus with strong reduction of the total pancreatic islet volume and the total beta cell volume together with severe alterations of the beta cell structure. As pigs share many anatomical and physiological characteristics with humans, we aimed to establish a transgenic pig model expressing the mutant insulin by additive gene transfer for the subsequent study of beta cell dysfunction in diabetes mellitus. The transgene consisted of German Landrace insulin sequences including 1.3 kb of the insulin promoter and 1 kb insulin gene sequences with the 3 exons and the T to A (C93S) point mutation in exon 3 analogous to the mutant mouse insulin. A floxed neomycin resistance gene at the 3′ end of the transgene was used as a selection marker. After successful transfection of male fetal fibroblasts of both the German Landrace and the Schwaebisch- Haellisch pig breeds, pooled transgenic fibroblasts were used for somatic cell nuclear transfer (SCNT). Five hundred three reconstructed pig embryos were generated and endoscopically transferred to 5 synchronized recipients. One pregnancy with German Landrace genetic background and one pregnancy with Schwaebisch-Haellisch genetic background of the cloned embryos developed to term, which gave rise to 3 living offspring from each of the 2 pregnancies; 5 of the 6 piglets were transgenic. Southern blot analysis showed different transgene signal patterns in all animals examined. Transgenic pigs of both litters revealed unaltered fasting blood glucose levels up to an age of 8 months. However, disturbed intravenous glucose tolerance and reduced insulin secretion were detected in 1 transgenic pig of the first litter at 8 months of age. The area under the glucose curve of this transgenic pig was 75% larger (22 136 v. 12617) and the area under the insulin curve 53% smaller (1250 v. 2670) compared with the control. Ongoing analyses comprise glucose tolerance tests in the second litter as well as pathohistologic analysis of the pancreata of both litters. Cells from suitable transgenic founders will be used for recloning to establish a new transgenic pig model expressing the mutant InsulinC93S for an in-depth study of pancreatic beta cell dysfunction in diabetes mellitus. Supported by the Deutsche Forschungsgemeinschaft (GRK1029).

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