Decreased insulin secretion and dyslipidemia coexist in subjects with impaired fasting glucose

Ozaki, Kayo; Okubo, Masamichi; Mori, Hiroshi; Mito, Kazuyo; Hara, Hitoshi; Kohno, Nobuoki

doi:10.1016/s0168-8227(01)00315-1

Cited by 6 publications

(8 citation statements)

References 17 publications

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“…Subsequently, however, studies of the pathogenesis of Type 2 diabetes have focussed on reduced insulin sensitivity, interpreting the hyperinsulinaemia primarily in terms of a compensatory response to insulin resistance [39]. Our analysis re-emphasises the importance of loss of the first-phase insulin response, independent of any decline in insulin sensitivity, and is consistent with the original observations, albeit in smaller numbers, of a previous study [19] and with a recent large cross-sectional study of Japanese volunteers, in whom the early insulin response during an OGTT was evaluated [40]. However, pancreatic insulin secretion, insulin sensitivity and insulin elimination were not measured in these studies, nor was the onset of the decline in secretion analysed.…”

Section: Discussionsupporting

confidence: 82%

Loss of beta cell function as fasting glucose increases in the non-diabetic range

2004

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Aims/hypothesis. Our aim was to define the level of glycaemia at which pancreatic insulin secretion, particularly first-phase insulin release, begins to decline. Methods. Plasma glucose and insulin concentrations were measured during an IVGTT in 553 men with non-diabetic fasting plasma glucose concentrations. In 466 of the men C-peptide was also estimated. IVGTT insulin secretion in first and late phases was assessed by: (i) the circulating insulin response; (ii) population parameter deconvolution analysis of plasma C-peptide concentrations; and (iii) a combined model utilising both insulin and C-peptide concentrations. Measurements of insulin sensitivity and elimination were also derived by modelling analysis.Results. As fasting plasma glucose (FPG) increased, IVGTT first-phase insulin secretion declined by 73%, 71% and 68% for the three methods respectively. The FPG values at which this decline began, determined by change point regression, were 4.97, 5.16 and 5.42 mmol/l respectively. The sensitivity of late-phase insulin secretion to glucose declined at FPG concentrations above 6.0 mmol/l. Insulin elimination, but not insulin sensitivity, varied with FPG. IntroductionThe respective roles of insulin deficiency and insulin resistance in the development of Type 2 diabetes mellitus remain controversial [1,2]. In response to a glucose stimulus, two phases of insulin secretion may be distinguished [3]. The first occurs as an immediate response to a rise in blood glucose concentrations. Low first-phase insulin release is an early abnormality in deteriorating glucose homeostasis and predicts the subsequent development of Type 2 diabetes [4,5,6,7]. Late-phase insulin release is more prolonged, but of lesser amplitude. It includes the progressively increasing second phase of insulin secretion seen in response to sustained hyperglycaemia [3], and also the compensatory insulin secretion that is the feedback response to a continued increase in circulating glucose. This late-phase insulin secretion may seem to be preserved even when glucose metabolism is defective,In the course of this work, our colleague and co-author James Jeffs died unexpectedly after a short illness. His contribution will be greatly missed.

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Section: Discussionsupporting

confidence: 82%

Loss of beta cell function as fasting glucose increases in the non-diabetic range

2004

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“…We agree with Abdul-Ghani and DeFronzo that the decline in IVGTT first-phase insulin secretion that accompanies the rise in FPG does not necessarily indicate a causal relationship [2]. It is also noteworthy that in the study of Ozaki et al of 8,923 men and women in Japan, in which OGTT insulin concentrations at 30 and 120 min provided indices of early-and late-phase insulin secretion, relationships were noted between plasma insulin concentrations and FPG levels in the range 4.4-8.3 mmol/l that were similar to those we distinguished between pancreatic insulin secretion and FPG [8].With regard to the apparent lack of association between insulin sensitivity and FPG in our study, the critical point to note is that, as stated in the table legend, the data we reported in Table 2 was standardised for age and BMI. As Abdul-Ghani and DeFronzo affirm, the important aspect of this decline was that it occurred within ranges of glucose concentrations hitherto considered normal.…”

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Reply to comment on: Godsland IF, Jeffs JA, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

Godsland

Johnston

2005

Diabetologia

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To the Editor: As we stated in our original paper [1], our intention was to define the level of glycaemia at which pancreatic insulin secretion begins to decline. We were careful throughout to emphasise that we were concerned not with causal relationships but with identifying the principal accompaniments of deteriorating fasting plasma glucose (FPG) levels in the sub-diabetic range. We agree with Abdul-Ghani and DeFronzo that the decline in IVGTT first-phase insulin secretion that accompanies the rise in FPG does not necessarily indicate a causal relationship [2]. Nevertheless, in our study, the decline in first-phase pancreatic insulin secretion was by far the most striking feature that accompanied increasing glucose levels. As Abdul-Ghani and DeFronzo affirm, the important aspect of this decline was that it occurred within ranges of glucose concentrations hitherto considered normal.In drawing attention to glucotoxicity and the sensitivity of pancreatic insulin secretion to rising glucose levels, Abdul-Ghani and DeFronzo raise an important mechanistic possibility. This does, however, pose a potential 'chicken and egg' problem, since glucose concentrations would have to rise for there to be deficient pancreatic insulin secretion, but there might have to be deficient insulin secretion for glucose concentrations to rise. Which comes first? One possibility, which they allude to, is that it is not decreasing insulin secretion that sets glucose levels rising but decreasing insulin sensitivity. Our finding that there was little change in insulin sensitivity with increasing FPG appears contrary to the weight of evidence in this respect.Abdul-Ghani and DeFronzo raise the possibility that our IVGTT protocol was not sensitive enough to detect impaired insulin sensitivity [2]. That this is not the case is illustrated by our previous publications, which attest to the ability of our protocol to detect diminished insulin sensitivity in a variety of circumstances and to detect significant associations with metabolic correlates of insulin sensitivity at a strength equivalent to that seen with other protocols and methodologies (see [3][4][5][6] for examples). Abdul-Ghani and DeFronzo also question the relevance of conclusions regarding pancreatic insulin secretion based on the non-physiological intravenous route of administration. However, they point out that, consistent with our results [1], in their own studies using the OGTT [7] there was a decline in the OGTT plasma insulin response with increasing FPG at levels >5.6 mmol/l. It is also noteworthy that in the study of Ozaki et al. of 8,923 men and women in Japan, in which OGTT insulin concentrations at 30 and 120 min provided indices of early-and late-phase insulin secretion, relationships were noted between plasma insulin concentrations and FPG levels in the range 4.4-8.3 mmol/l that were similar to those we distinguished between pancreatic insulin secretion and FPG [8].With regard to the apparent lack of association between insulin sensitivity and FPG in our study, the crit...

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“…After an overnight fast, fasting blood samples were obtained and a 75-g oral glucose tolerance test (OGTT) was performed as described previously (19). Subjects with either a fasting plasma glucose (FPG) Ն7.0 mmol/l or a 2-h postchallenge glucose (PG) level Ն11.1 mmol/l (n ϭ 434) were defined as having diabetes and excluded from analysis.…”

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Elevated White Blood Cell Count in Subjects With Impaired Glucose Tolerance

et al. 2004

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OBJECTIVE -Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) differ in their risk of all-cause and cardiovascular mortality, but previous cross-sectional studies have suggested little difference in their levels of lipids or blood pressure. We compared the white blood cell (WBC) count between subjects with IFG and IGT.RESEARCH DESIGN AND METHODS -The subjects were 4,720 nondiabetic Japanese men aged 24 -84 years. Based on the 75-g oral glucose tolerance test, the subjects were classified into the following four groups: normal fasting glucose/normal glucose tolerance (n ϭ 3,753), isolated IFG (n ϭ 290), isolated IGT (n ϭ 476), and IFG/IGT (n ϭ 201). We compared the WBC count among the four groups and investigated variables that showed a significant association with the WBC count.RESULTS -The isolated IGT group had a significantly higher WBC count than the isolated IFG group (6,530 vs. 6,210/mm 3 , P Ͻ 0.05). By stepwise analyses, age, triglycerides, HDL cholesterol, fasting insulin, and 2-h postchallenge plasma glucose (PG) showed an independent association with the WBC count (adjusted R 2 ϭ 0.057). In the analysis stratified by smoking status, the WBC count was independently associated with 2-h PG and triglycerides, irrespective of smoking status.CONCLUSIONS -Individuals with isolated IGT had a significantly higher WBC count than those with isolated IFG. The WBC count was associated with 2-h PG and various components of the metabolic syndrome.

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Decreased insulin secretion and dyslipidemia coexist in subjects with impaired fasting glucose

Cited by 6 publications

References 17 publications

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Loss of beta cell function as fasting glucose increases in the non-diabetic range

Reply to comment on: Godsland IF, Jeffs JA, Johnston DG (2004) Loss of beta cell function as fasting glucose increases in the non-diabetic range. Diabetologia 47:1157–1166

Elevated White Blood Cell Count in Subjects With Impaired Glucose Tolerance

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