Adipokine pattern in subjects with impaired fasting glucose and impaired glucose tolerance in comparison to normal glucose tolerance and diabetes

Aim

Altered adipokine serum concentrations early reflect impaired adipose tissue function in obese patients with type 2 diabetes (T2D). It is not entirely clear whether these adipokine alterations are already present in prediabetic states and so far there is no comprehensive adipokine panel available. Therefore, the aim of this study was to assess distinct adipokine profiles in patients with normal glucose tolerance (NGT), impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or T2D.

Methods

Based on 75 g oral glucose tolerance tests, 124 individuals were divided into groups of IFG (n = 35), IGT (n = 45), or NGT (n = 43). Furthermore, 56 subjects with T2D were included. Serum concentrations of adiponectin, chemerin, fetuin-A, leptin, interleukin (IL)-6, retinol-binding protein 4 (RBP4), monocyte chemoattractant protein (MCP)-1, vaspin, progranulin, and soluble leptin receptor (sOBR) were measured by ELISAs.

Results

Chemerin, progranulin, fetuin-A, and RBP4, IL-6, adiponectin and leptin serum concentrations were differentially regulated among the four investigated groups but only circulating chemerin was significantly different in patients with IGT compared to those with IFG. Compared to T2D the IFG subjects had higher serum chemerin, progranulin, fetuin-A and RBP4 levels which was not detectable in the comparison of the T2D and IGT group.

Conclusion

Alterations in adipokine serum concentrations are already detectable in prediabetic states, mainly for chemerin, and may reflect adipose tissue dysfunction as an early pathogenetic event in T2D development. In addition, distinct adipokine serum patterns in individuals with IFG and IGT suggest a specific role of adipose tissue in the pathogenesis of these prediabetic states.     

Plasma interleukin 8 concentrations in obese subjects with impaired glucose tolerance.

Background

Left ventricular hypertrophy (LVH) is a powerful independent risk factor for cardiovascular morbidity and mortality among hypertensive patients. Data regarding relationships between diabetes and LVH are controversial and inconclusive, whereas possible gender differences were not specifically investigated. The goal of this work was to investigate whether gender differences in left heart structure and mass are present in hypertensive patients with type 2 diabetes.

Methods

Five hundred fifty hypertensive patients with at least one additional cardiovascular risk factor (314 men and 246 women, age 52 to 81, mean 66 ± 6 years), were enrolled in the present analysis. In 200 (36%) of them – 108 men and 92 women – type 2 diabetes mellitus was found upon enrollment. End-diastolic measurements of interventricular septal thickness (IVS), LV internal diameter, and posterior wall thickness were performed employing two-dimensionally guided M-mode echocardiograms. LVH was diagnosed when LV mass index (LVMI) was >134 g/m² in men and >110 g/m² in women.

Results

Mean LVMI was significantly higher among diabetic vs. nondiabetic women (112.5 ± 29 vs. 105.6 ± 24, p = 0.03). In addition, diabetic women presented a significantly higher prevalence of increased IVS thickness, LVMI and left atrial diameter on intra-gender comparisons. The age adjusted relative risk for increased LVMI in diabetics vs. nondiabetics was 1.47 (95% CI: 1.0–2.2) in females and only 0.8 (0.5–1.3) in males.

Conclusion

Type 2 diabetes mellitus was associated with a significantly higher prevalence of LVH and left atrial enlargement in hypertensive women.     

Effect of repaglinide on endothelial dysfunction during a glucose tolerance test in subjects with impaired glucose tolerance

Background

Secondary treatment of arteriosclerosis may be applicable for the primary prevention of atherosclerosis in diabetic patients. This prospective, 2-year follow-up study was designed to determine the efficacy and safety of antiplatelet therapy in the prevention of atherosclerosis of diabetic subjects.

Methods

Patients with type 2 diabetes and arteriosclerosis obliterans from the Eastern Asian countries were registered online and randomly assigned either to the aspirin group (81–100 mg/day) or the cilostazol group (100–200 mg/day) in this international, 2-year, prospective follow-up interventional study.

Results

The primary study endpoint was changes in right and left maximum intima-media thickness of the common carotid artery. Secondary endpoints include changes in right and left maximum intima-media thickness of the internal carotid artery; semiquantitative evaluation of cerebral infarction by magnetic resonance imaging; cardiovascular events including sudden death, stroke, transient cerebral ischemic attacks, acute myocardial infarction, angina, and progression of arteriosclerosis obliterans; overall death; withdrawal; and change in ankle-brachial pressure index.

Conclusion

This is the first study to use an online system that was developed in Asian countries for pooling data from an international clinical trial. These findings are expected to help in the prevention of diabetic atherosclerosis and subsequent cardiovascular and cerebrovascular disease.     

Effects of coffee consumption on glucose tolerance, serum glucose and insulin levels--a cross-sectional analysis.

OBJECTIVE: Coffee has several metabolic effects that could reduce the risk of type 2 diabetes. Our objective was to examine the effects of coffee consumption on glucose tolerance, glucose and insulin levels. RESEARCH DESIGN AND METHODS: A subsample of subjects aged 45 to 64 years in 1987 and in 1992 from the population-based FINRISK study (12,287 individuals) was invited to receive the standard oral glucose tolerance test at baseline. Plasma samples were taken after an overnight fast, and a two-hour oral glucose tolerance test was administered. Fasting and two-hour plasma glucose and insulin were measured in 2434 subjects with data on coffee use and potential confounders. RESULTS: After adjustment for potential confounding factors (age, body mass index, systolic blood pressure, occupational, commuting and leisure time physical activity, alcohol and tea drinking, smoking), coffee consumption was significantly and inversely associated with fasting glucose, two-hour plasma glucose, and fasting insulin in both men and women. Coffee consumption was significantly and inversely associated with impaired fasting glucose, impaired glucose regulation, and hyperinsulinemia among both men and women and with isolated impaired glucose tolerance among women. CONCLUSIONS: In this cross-sectional analysis, coffee showed positive effects on several glycemia markers.     

Relationship between serum concentrations of interleukin-6 and tumor necrosis factor alpha in female Turkish subjects with normal and impaired glucose tolerance.

Serum interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNFalpha) concentrations were measured in subjects during two-hour glucose loading in order to investigate the effects of glucose on serum IL-6 and TNFalpha concentrations. Twenty-six female subjects (mean age 60 +/- 10 years) had normal glucose tolerance (NGT) and nineteen female subjects (mean age: 63 +/- 9 years) had impaired glucose tolerance (IGT) according to WHO criteria. Serum IL-6 and TNFalpha concentrations were measured by chemiluminescent immunometric assay. Subjects with IGT have higher fasting serum TNFalpha levels than subjects with NGT (p < 0.01). Serum IL-6 and TNFalpha concentrations were elevated during glucose loading (for each comparison, p < 0.01). The increase in serum TNFalpha concentrations in IGT was greater than in NGT (p < 0.01). Serum IL-6 and TNFalpha concentration significantly correlated with insulin and glucose in IGT group (for each comparison, p < 0.01). The correlation between serum glucose and cytokines concentrations was significant in IGT (for each comparison, p < 0.01). There was also a positive correlation between serum IL-6 and TNFalpha in NGT and IGT (for each comparison, p < 0.01). In conclusion, hyperglycemia is associated with increased circulating cytokine concentrations and fasting TNFalpha concentrations seem to be more associated with IGT than IL-6.     

Association of the CD36 gene with impaired glucose tolerance, impaired fasting glucose, type-2 diabetes, and lipid metabolism in essential hypertensive patients

Essential hypertension is a common disorder that can increase the risk of type 2 diabetes (T2D). CD36 has been studied in patients with diabetes and hypertension extensively; however, few studies have focused on the relationship of the CD36 gene with impaired fasting glucose (IFG)/impaired glucose tolerance (IGT) or T2D in essential hypertension patients. To identify rs1049673 and rs1527483 in the CD36 gene conferring susceptibility to IFG/IGT and T2D, we conducted a case-control study in 1257 essential hypertension patients among the Han Chinese population (control: 676; IGT/IFG: 468; T2D: 113). We also evaluated the impact of two loci on insulin sensitivity, glucose tolerance and serum lipid. The major findings of this study were that rs1049673 was found associated with IFG/IGT and T2D in essential hypertension patients (Pco = 0.028; Pdom = 0.015). The rs1049673 G carriers showed significant higher Glu0 (βdom = 0.08 (0.01~0.16), Pdom = 0.045) and Lp(a) (βco = 0.04 (0.002~0.07), Pco = 0.041; βdom = 0.06 (0.01~0.12), Pdom = 0.032), and lower HDL by the linear regression with the adjustment for gender, age, BMI, and mean blood pressures. These findings provided evidence that the CD36 gene may play some role in the pathogenesis of IFG/IGT and T2D in essential hypertension patients.     

High body weight associated with impaired nonshivering thermogenesis but improved glucose tolerance in Mongolian gerbils (Meriones unguiculatus)

Overweight and obesity correspond with metabolic syndromes, such as glucose intolerance and type 2 diabetes. The objective of this study was to determine whether decreased thermogenesis mass and glucose intolerance are directly related to changes in body mass in Mongolian gerbils. High body weight gerbils displayed increase in total body fat mass especially epididymal fat pad, and decrease in nonshivering thermogenesis, as indicated by depressed mitochondrial protein content and uncoupling protein-1 content in brown adipose tissue. No variations of sirtuin 1 and subunit IV of cytochrome oxidase expression were found in brown adipose tissue and skeletal muscle between the two groups. High body weight gerbils showed increased serum leptin and insulin concentrations but surprisingly increased glucose tolerance, suggesting a difference from other obese species in the regulation of glucose metabolism. Serum leptin levels were negatively correlated with UCP1 content in BAT and positively correlated with energy intake and insulin concentration. Our data suggest that leptin may be involved in thermogenesis regulation, insulin secretion and glucose metabolism in HBW gerbils.     

Factors responsible for glucose intolerance in Japanese subjects with impaired fasting glucose.

Impaired fasting glucose (IFG) represents risk of development of diabetes (DM) and its complications. We investigated insulin secretion and insulin sensitivity in 403 IFG subjects divided into three levels of 2-hour postchallenge glucose (2-h PG) to clarify the factors responsible in the development of glucose intolerance in Japanese IFG. Nearly 60% of the subjects at annual medical check-up with FPG of 6.1-7.0 mmol/l at the first screening were diagnosed by 75 g oral glucose tolerance test (OGTT) to have impaired glucose tolerance (IGT; FPG <7.0 mmol/l and 7.8 mmol/l <2-h PG <11.1 mmol/l) or DM (isolated postchallenge hyperglycemia (IPH); FPG <7.0 mmol/l and 11.1 mmol/l <2-h PG level). The primary factor in the decreased glucose tolerance was a decrease in early-phase insulin, with some contribution of increasing insulin resistance. In addition, IFG/IGT and IFG/IPH subjects showed a compensatory increase in basal insulin secretion sufficient to keep FPG levels within the non-diabetic range. IFG is composed of three different categories in basal, early-phase insulin secretion, and insulin sensitivity.     

Impact of incretin hormones on beta-cell function in subjects with normal or impaired glucose tolerance

The mechanisms by which the enteroinsular axis influences beta-cell function have not been investigated in detail. We performed oral and isoglycemic intravenous (IV) glucose administration in subjects with normal (NGT; n = 11) or impaired glucose tolerance (IGT; n = 10), using C-peptide deconvolution to calculate insulin secretion rates and mathematical modeling to quantitate beta-cell function. The incretin effect was taken to be the ratio of oral to IV responses. In NGT, incretin-mediated insulin release [oral glucose tolerance test (OGTT)/IV ratio = 1.59 +/- 0.18, P = 0.004] amounted to 18 +/- 2 nmol/m(2) (32 +/- 4% of oral response), and its time course matched that of total insulin secretion. The beta-cell glucose sensitivity (OGTT/IV ratio = 1.52 +/- 0.26, P = 0.02), rate sensitivity (response to glucose rate of change, OGTT/IV ratio = 2.22 +/- 0.37, P = 0.06), and glucose-independent potentiation were markedly higher with oral than IV glucose. In IGT, beta-cell glucose sensitivity (75 +/- 14 vs. 156 +/- 28 pmol.min(-1).m(-2).mM(-1) of NGT, P = 0.01) and potentiation were impaired on the OGTT. The incretin effect was not significantly different from NGT in terms of plasma glucagon-like peptide 1 and glucose-dependent insulinotropic polypeptide responses, total insulin secretion, and enhancement of beta-cell glucose sensitivity (OGTT/IV ratio = 1.73 +/- 0.24, P = NS vs. NGT). However, the time courses of incretin-mediated insulin secretion and potentiation were altered, with a predominance of glucose-induced vs. incretin-mediated stimulation. We conclude that, under physiological circumstances, incretin-mediated stimulation of insulin secretion results from an enhancement of all dynamic aspects of beta-cell function, particularly beta-cell glucose sensitivity. In IGT, beta-cell function is inherently impaired, whereas the incretin effect is only partially affected.     

Genotype and diet affect resistance,survival, and fecundity but not fecundity tolerance

Insects are exposed to a variety of potential pathogens in their environment, many of which can severely impact fitness and health. Consequently, hosts have evolved resistance and tolerance strategies to suppress or cope with infections. Hosts utilizing resistance improve fitness by clearing or reducing pathogen loads, and hosts utilizing tolerance reduce harmful fitness effects per pathogen load. To understand variation in, and selective pressures on, resistance and tolerance, we asked to what degree they are shaped by host genetic background, whether plasticity in these responses depends upon dietary environment, and whether there are interactions between these two factors. Females from ten wild‐type Drosophila melanogaster genotypes were kept on high‐ or low‐protein (yeast) diets and infected with one of two opportunistic bacterial pathogens, Lactococcus lactis or Pseudomonas entomophila. We measured host resistance as the inverse of bacterial load in the early infection phase. The relationship (slope) between fly fecundity and individual‐level bacteria load provided our fecundity tolerance measure. Genotype and dietary yeast determined host fecundity and strongly affected survival after infection with pathogenic P. entomophila. There was considerable genetic variation in host resistance, a commonly found phenomenon resulting from for example varying resistance costs or frequency‐dependent selection. Despite this variation and the reproductive cost of higher P. entomophila loads, fecundity tolerance did not vary across genotypes. The absence of genetic variation in tolerance may suggest that at this early infection stage, fecundity tolerance is fixed or that any evolved tolerance mechanisms are not expressed under these infection conditions.     

The relationship between fasting hyperglycemia and insulin secretion in subjects with normal or impaired glucose tolerance

To assess the relationship between the fasting plasma glucose (FPG) concentration and insulin secretion in normal glucose tolerance (NGT) and impaired glucose tolerance (IGT) subjects, 531 nondiabetic subjects with NGT (n = 293) and IGT (n = 238; 310 Japanese and 232 Mexican Americans) received an oral glucose tolerance test (OGTT) with measurement of plasma glucose, insulin, and C-peptide every 30 min. The insulin secretion rate was determined by plasma C-peptide deconvolution. Insulin sensitivity (Matsuda index) was measured from plasma insulin and glucose concentrations. The insulin secretion/insulin resistance (IS/IR) or disposition index was calculated as DeltaISR/DeltaG / IR. As FPG increased in NGT subjects, the IS/IR index declined exponentially over the range of FPG from 70 to 125 mg/dl. The relationship between the IS/IR index and FPG was best fit with the equation: 28.8 exp(-0.036 FPG). For every 28 mg/dl increase in FPG, the IS/IR index declined by 63%. A similar relationship between IS/IR index and FPG was observed in IGT. However, the decay constant was lower than in NGT. The IS/IR index for early-phase insulin secretion (0-30 min) was correlated with the increase in FPG in both NGT and IGT (r = -0.43, P < 0.0001 and r = -0.20, P = 0.001, respectively). However, the correlation between late-phase insulin secretion (60-120 min) and FPG was not significant. In conclusion, small increments in FPG, within the "normal" range, are associated with a marked decline in glucose-stimulated insulin secretion and the decrease in insulin secretion with increasing FPG is greater in subjects with NGT than IGT and primarily is due to a decline in early-phase insulin secretion.     

Keratinocyte-specific ablation of Stat3 exhibits impaired skin remodeling, but does not affect skin morphogenesis.

To elucidate the biological role of Stat3 in the skin, conditional gene targeting using the Cre-loxP system was performed as germline Stat3 ablation leads to embryonic lethality. K5-Cre;Stat3(flox/-) transgenic mice, whose epidermal and follicular keratinocytes lack functional Stat3, were viable and the development of epidermis and hair follicles appeared normal. However, hair cycle and wound healing processes were severely compromised. Furthermore, mutant mice expressed sparse hair and developed spontaneously occurring ulcers with age. Growth factor-dependent in vitro migration of Stat3-disrupted keratinocytes was impaired despite normal proliferative responses. We therefore conclude that Stat3 plays a crucial role in transducing a signal required for migration but not for proliferation of keratinocytes, and that Stat3 is essential for skin remodeling, including hair cycle and wound healing.     

3,5-T2 stimulates oxygen consumption, but not glucose uptake in human mononuclear blood cells.

L-thyroxine (T4), L-triiodothyronine (T3) and 3,5-di-iodothyronine (T2) rapidly (within 30 min) stimulated oxygen consumption in human mononuclear blood cells, whereas the D isomers of T4 and T3 and Triac had no stimulatory effect. Oxygen consumption was stimulated by the same magnitude by equimolar concentrations (5-500 nmol/l) of L-T4, L-T3 and 3,5-T2 reaching a plateau at 100 nmol/l of 0.025 umol/mg DNA x h. The stimulatory effects of T4 and T3, but not of T2 were inhibited by PTU. Glucose uptake was stimulated only by L-T4 and L-T3, whereas 3,5-T2, Triac and the D-isomers of T4 and T3 had no effect. The dose response curve reached an apparent maximum at 100 nmol/l of 0.30 mmol/l x mg DNA x h and PTU had no effect on iodothyronine stimulated glucose uptake. We conclude that 3,5-T2 is a significant intracellular stimulator of oxygen consumption, whereas T3 and T4 stimulate glucose uptake.     

Impaired glucose tolerance (IGT) is not associated with disturbed homocysteine metabolism

Summary. Elevated plasma total homocysteine (tHcy) has been suggested to be an additional risk factor for cardiovascular disease in subjects with impaired glucose tolerance (IGT) and Type 2 diabetes (T2D). In order to investigate whether an insulin resistant/chronic hyperinsulinemic situation in male diabetic and prediabetic subjects directly influences the tHcy metabolism, fasting tHcy and post-methionine load tHcy plasma levels (PML-tHcy) were determined in 15 men with IGT, 13 men with newly dia-gnosed T2D, and 16 normoglycemic controls (NGT). Fasting tHcy (IGT, 13.1 ± 4.6; T2D, 12.8 ± 4.0; NGT, 10.7 ± 4.4 μmol/L) and PML-tHcy (IGT, 46.5 ± 17.39; T2D, 41.1 ± 6.8; NGT, 38.0 ± 9.7 μmol/L) showed no differences between the groups. Fasting tHcy and PML-tHcy correlated with fasting proinsulin (r = 0.395, p < 0.05; r = 0.386, p< 0.05) and creatinine (r = 0.489, p < 0.01; r = 0.339, p < 0.05), resp. Multiple regression analysis showed only a relationship between fasting tHcy and creatinine. No relationships have been found between fasting tHcy and PML-tHcy, resp., and indicators of an insulin resistant state, e.g., insulin and proinsulin, as well as serum cobalamin and folate concentrations. In conclusion, our data suggest that the degree of glucose intolerance has no direct impact on the metabolism of homocysteine. However, tHcy levels tend to be elevated with the development of nephropathy, indicating an association between tHcy and renal function in these subjects. Received May 11, 1999     

Pre-meal water consumption reduces meal energy intake in older but not younger subjects

Objective: To determine whether the consumption of water 30 minutes before an ad libitum meal reduces meal energy intake in young and older adults. Research Methods and Procedures: Healthy, non‐obese young (n = 29; age, 21 to 35 years) and older (n = 21; age, 60 to 80 years) individuals were provided with an ad libitum lunch meal on two occasions. Thirty minutes before the lunch meals, subjects were given either a water preload (WP: 375 mL, women; 500 mL, men) or no preload (NP). Energy intake at the two lunch meals was measured. Visual analog scales were used to assess changes in hunger, fullness, and thirst during the meal studies. Results: There was no significant difference in meal energy intake between conditions in the young subjects (892 + 51 vs. 913 ± 54 kcal for NP and WP, respectively; p = 0.65). However, meal energy intake after the WP was significantly reduced relative to the NP condition in the older subjects (682 + 53 vs. 624 ± 56 kcal for NP and WP, respectively; p = 0.02). This effect was caused primarily by the reduction in meal energy intake after water consumption in older men. Hunger ratings were lower and fullness ratings were higher in older compared with younger adults (p < 0.01). Fullness ratings were higher in the WP condition compared with the NP condition for all subjects (p = 0.01). No age differences in thirst were detected during the test meals. Discussion: Under acute test meal conditions, pre‐meal water consumption reduces meal energy intake in older but not younger adults. Because older adults are at increased risk for overweight and obesity, intervention studies are needed to determine whether pre‐meal water consumption is an effective long‐term weight management strategy for the aging population.     

Dietary fibres,fibre analogues,and glucose tolerance: importance of viscosity.

To define the type of dietary fibre of fibre analogue with the greatest potential use in diabetic treatment, groups of four to six volunteers underwent 50-g glucose tolerance tests (GTT) with and without the addition of either guar, pectin, gum tragacanth, methylcellulose, wheat bran, or cholestyramine equivalent to 12 g fibre. The addition of each substance significantly reduced blood glucose concentration at one or more points during the GTT and generally reduced serum insulin concentrations. The greatest flattening of the glucose response was seen with guar, but this effect was abolished when hydrolysed non-viscous guar was used. The reduction in the mean peak rise in blood glucose concentration for each substance correlated positively with its viscosity (r = 0.926; P less than 0.01), as did delay in mouth-to-caecum transit time (r = 0.885; P less than 0.02). Viscous types of dietary fibre are therefore most likely to be therapeutically useful in modifying postprandial hyperglycaemia.