Impairments in glucose tolerance can have a negative impact on cognitive function: a systematic research review

There is an increasing body of research investigating whether abnormal glucose tolerance is associated with cognitive impairments, the evidence from which is equivocal. A systematic search of the literature identified twenty-three studies which assessed either clinically defined impaired glucose tolerance (IGT) or variance in glucose tolerance within the clinically defined normal range (NGT). The findings suggest that poor glucose tolerance is associated with cognitive impairments, with decrements in verbal memory being most prevalent. However, the evidence for decrements in other domains was weak. The NGT studies report a stronger glucose tolerance-cognition association than the IGT studies, which is likely to be due to the greater number of glucose tolerance parameters and the more sensitive cognitive tests in the NGT studies compared to the IGT studies. It is also speculated that the negative cognitive impact of abnormalities in glucose tolerance increases with age, and that glucose consumption is most beneficial to individuals with poor glucose tolerance compared to individuals with normal glucose tolerance. The role of potential mechanisms are discussed.

Risk of cardiovascular and all-cause mortality in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose tolerance. The Australian Diabetes, Obesity and Lifestyle Study (AusDiab)

Background--Diabetes mellitus increases the risk of cardiovascular disease (CVD) and all-cause mortality. The relationship between milder elevations of blood glucose and mortality is less clear. This study investigated whether impaired fasting glucose and impaired glucose tolerance, as well as diabetes mellitus, increase the risk of all-cause and CVD mortality.

Methods and Results--In 1999 to 2000, glucose tolerance status was determined in 10 428 participants of the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). After a median follow-up of 5.2 years, 298 deaths occurred (88 CVD deaths). Compared with those with normal glucose tolerance, the adjusted all-cause mortality hazard ratios (HRs) and 95% confidence intervals (CIs) for known diabetes mellitus and newly diagnosed diabetes mellitus were 2.3 (1.6 to 3.2) and 1.3 (0.9 to 2.0), respectively. The risk of death was also increased in those with impaired fasting glucose (HR 1.6, 95% CI 1.0 to 2.4) and impaired glucose tolerance (HR 1.5, 95% CI 1.1 to 2.0). Sixty-five percent of all those who died of CVD had known diabetes mellitus, newly diagnosed diabetes mellitus, impaired fasting glucose, or impaired glucose tolerance at baseline. Known diabetes mellitus (HR 2.6, 95% CI 1.4 to 4.7) and impaired fasting glucose (HR 2.5, 95% CI 1.2 to 5.1) were independent predictors for CVD mortality after adjustment for age, sex, and other traditional CVD risk factors, but impaired glucose tolerance was not (HR 1.2, 95% CI 0.7 to 2.2).

Conclusions--This study emphasizes the strong association between abnormal glucose metabolism and mortality, and it suggests that this condition contributes to a large number of CVD deaths in the general population. CVD prevention may be warranted in people with all categories of abnormal glucose metabolism.

Demographic and metabolic characteristics of individuals with progressive glucose tolerance

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)

Abnormal retinal vascular reactivity in individuals with impaired glucose tolerance:a preliminary study

To investigate the relationship between vascular function parameters measured at the retinal and systemic level and known markers for cardiovascular risk in patients with impaired glucose tolerance (IGT). Sixty age- and gender- matched White-European adults (30 IGT and 30 normal glucose tolerance -NGT) were recruited for the study. Fasting plasma glucose, lipids and 24-hour blood pressure (BP) was measured in all subjects. Systemic vascular and endothelial function was assessed using carotid-artery intimal media thickness (cIMT) and flow mediated dilation (FMD). Retinal vascular reactivity was assessed by the Dynamic Retinal Vessel Analyser (DVA). Additionally, blood glutathione (GSH, GSSG and tGSH) and plasma von-Willebrand (vWF) factor levels were also measured. Individuals with IGT demonstrated higher BP values (p<0.001), fasting TG and TG:HDL ratios (p<0.001) than NGT subjects. Furthermore, Total:HDL-C ratios and Framingham scores were raised (p=0.010 and p<0.001 respectively). Blood glutathione levels (GSH, GSSG and tGSH) were lower (p<0.001, p=0.039 and p<0.001 respectively) while plasma vWF was increased (p=0.014) in IGT subjects compared to controls. IGT individuals also demonstrated higher IMT in right and left carotid arteries (p=0.017 and p=0.005, respectively) alongside larger brachial artery diameter (p=0.015), lower FMD% (p=0.026) and GTN induced dilation (GID) (p=0.012) than healthy controls. At the retinal arterial level, the IGT subjects showed higher baseline fluctuations (BDF) (p=0.026), longer reaction time (RT) (p=0.032) and reduced baseline-corrected flicker response (bFR) (p=0.045). In IGT subjects retinal BDF correlated with and Total:HDL (p= 0.003) and HDL-C (p= 0.004). Arterial RT also correlated with FMD (p=0.017) in IGT but not NGT subjects. In IGT individuals there is a relationship between macro- and microvascular function, as well as a direct correlation between the observed retinal microcirculatory changes and established plasma markers for CVD. Multifactorial preventive interventions to decrease vascular risk in these individuals should be considered.

Investigating the effects of physiological bile acids on GLP-1 secretion and glucose tolerance in normal and GLP-1R(-/-) mice

Physiological secretion of bile acids has previously been linked to the regulation of blood glucose. GLP-1 is an intestinal peptide hormone with important glucose-lowering actions, such as stimulation of insulin secretion and inhibition of glucagon secretion. In this investigation, we assessed the ability of several bile acid compounds to secrete GLP-1 in vitro in STC-1 cells. Bile acids stimulated GLP-1 secretion from 3.3- to 6.2-fold but some were associated with cytolytic effects. Glycocholic and taurocholic acids were selected for in vivo studies in normal and GLP-1R(-/-) mice. Oral glucose tolerance tests revealed that glycocholic acid did not affect glucose excursions. However, taurocholic acid reduced glucose excursions by 40% in normal mice and by 27% in GLP-1R(-/-) mice, and plasma GLP-1 concentrations were significantly elevated 30 min post-gavage. Additional studies used incretin receptor antagonists to probe involvement of GLP-1 and GIP in taurocholic acid-induced glucose lowering. The findings suggest that bile acids partially aid glucose regulation by physiologically enhancing nutrient-induced GLP-1 secretion. However, GLP-1 secretion appears to be only part of the glucose-lowering mechanism and our studies indicate that the other major incretin GIP is not involved.

RENAL EXCRETION OF ZINC IN NORMAL INDIVIDUALS DURING ZINC TOLERANCE-TEST AND GLUCOSE-TOLERANCE TEST

The urinary excretion, renal clearance, and tubular reabsorption of zinc were investigated in 30 adult healthy subjects under basal conditions and during the zinc and glucose tolerance tests. After a 12h overnight fast, each subject was submitted to renal clearance of zinc. The procedures were performed between 8.00 and 12.00 a.m., after emptying the bladder and ingestion of 4 ml deionized water/kg body weight at 8.00 a.m. The first urine sample was collected at 10.00 a.m., and the second at 12.00 a.m. A dose of 110 mg ZnSO4.7H(2)O was administered orally to each subject, diluted in 20 mi deionized water, at time 0 min. Blood samples were collected from an antecubital vein at times -30, 0, and 30 min and at 30 min intervals up to 240 min. Glucose was administered intravenously (0.5 ml 50%/kg body weight) during the first 3 min of the test, and blood samples were collected from an unconstricted, contralateral, antecubital vein at times -30, 0, 3, 5, 10, 20, 30, 45, 60, and 90 min. The results showed that urinary zinc excretion, and renal zinc clearance were significantly higher during the zinc and glucose tolerance tests than in the control condition. on the other hand, renal zinc clearance was more elevated during the glucose tolerance test than during the zinc tolerance test. Variations in zinc tubular reabsorption and glomerular filtration rate were not detected. The results suggest that urinary excretion and renal clearance of zinc in healthy subjects increase during acute zinc ingestion and glucose infusion. Although zinc ingestion raised urinary zinc excretion, glucose infusion was more effective in increasing renal zinc clearance. These normal parameters are important in the investigation of diabetic patients with serum and urine zinc changes.

Renal excretion of zinc in normal individuals during zinc tolerance test and glucose tolerance test

The urinary excretion, renal clearance, and tubular reabsorption of zinc were investigated in 30 adult healthy subjects under basal conditions and during the zinc and glucose tolerance tests. After a 12h overnight fast, each subject was submitted to renal clearance of zinc. The procedures were performed between 8.00 and 12.00 a.m., after emptying the bladder and ingestion of 4 ml deionized water/kg body weight at 8.00 a.m. The first urine sample was collected at 10.00 a.m., and the second at 12.00 a.m. A dose of 110 mg ZnSO47H2O was administered orally to each subject, diluted in 20 ml deionized water, at time 0 min. Blood samples were collected from an antecubital vein at times -30, 0, and 30 min and at 30 min intervals up to 240 min. Glucose was administered intravenously (0.5 ml 50%/kg body weight) during the first 3 min of the test, and blood samples were collected from an unconstricted, contralateral, antecubital vein at times -30, 0, 3, 5, 10, 20, 30, 45, 60, and 90 min. The results showed that urinary zinc excretion, and renal zinc clearance were significantly higher during the zinc and glucose tolerance tests than in the control condition. On the other hand, renal zinc clearance was more elevated during tile glucose tolerance test than during the zinc tolerance test. Variations in zinc tubular reabsorption and glomerular filtration rate were not detected. The results suggest that urinary excretion and renal clearance of zinc in healthy subjects increase during acute zinc ingestion and glucose infusion, Although zinc ingestion raised urinary zinc excretion, glucose infusion was more effective in increasing renal zinc clearance. These normal parameters are important in the investigation of diabetic patients with serum and urine zinc changes.

Acute exercise and impaired glucose tolerance in obese humans

BACKGROUND: Individuals with impaired glucose tolerance (IGT) have a greater risk of developing diabetes and cardiovascular disease compared with those with normal glycemic control. The aim of this study was to examine the effects of acute aerobic exercise on glycemia, regional arterial stiffness, and oxidative stress in obese subjects with IGT.

Intergenerational effects of birth weight on glucose tolerance and reproductive performance

Women who were themselves small-for-gestational age (SGA) are at a greater risk of adulthood diseases such as non-insulin-dependent diabetes mellitus (NIDDM), and twice at risk of having an SGA baby themselves. The aim of this study was to examine the intergenerational pig. Low (L) and normal (N) birth weight female piglets were followed throughout their first pregnancy (generation 1 (0)). After they had given birth, the growth and development of the lightest (I) and heaviest (n) female piglet from each litter were monitored until approximately 5 months of age (generation 2 (G2)). A glucose tolerance test (GTT) was conducted on G1 pig at similar to 6 months of age and again during late pregnancy; a GTT was also conducted on G2 pigs at similar to 4 months of age. G1 L offspring exhibited impaired glucose metabolism in later life compared to their G1 N sibling but in the next generation a similar scenario was only observed between I and n offspring born to G1 L mothers. Despite G1 L mothers showing greater glucose intolerance in late pregnancy and a decreased litter size, average piglet birth weight was reduced and there was also a large variation in litter weight; this suggests that they were, to some extent, prioritising their nutrient intake towards themselves rather than promoting their reproductive performance. There were numerous relationships between body shape at birth and glucose curve characteristics in later life, which can, to some extent, be used to predict neonatal outcome. In conclusion, intergenerational effects are partly seen in the pig. It is likely that some of the intergenerational influences may be masked due to the pig being a litter-bearing species.

Brazilian individuals with impaired glucose tolerance are characterized by impaired insulin secretion

Background: To better understand the pathogenesis of type 2 diabetes mellitus, insulin secretion and insulin sensitivity (IS) were evaluated in white Brazilians with impaired glucose tolerance (IGT), using the oral glucose tolerance test (OGTT) and the hyperglycemic clamp technique.Methods: Twenty-five IGT subjects were individually matched with normal glucose-tolerant (NGT) subjects for demographic characteristics, At first, they were submitted to the OGTT and plasma glucose and insulin were measured. of the 25 pairs, 20 could participate in the hyperglycemic clamp procedures, at a second visit. All participants had their plasma glucose levels equally increased to 180 mg/dl; this was maintained for three hours by variable glucose infusion. During the procedure, plasma glucose and insulin were measured at established intervals.Results: In the postabsorptive state, the IGT subjects presented higher levels of plasma glucose, blood HbA(1) and serum triglycerides, but similar plasma insulin levels. After the oral glucose load, early and total insulin release, in relation to glucose levels, were respectively, 43 and 67% lower in the IGT individuals, the index of whole-body IS was increased in the IGT individuals (4.36 +/- 1.71 vs 3.61 +/- 1.28 mg(-1).muU(-1) 100.ml(2); p < 0.05). By the hyperglycemic clamp technique first- (82 &PLUSMN; 26 vs 215 &PLUSMN; 88 μU/ml; p < 0.001) and second- (36 +/- 19 vs 73 +/- 44 muU/ml; p < 0.05) phases of insulin secretion was decreased in the IGT individuals, especially the first one. However, the groups did not differ in relation to the IS: IGT = 13.52 &PLUSMN; 7.27 and NGT = 9.96 &PLUSMN; 6.70 mg.ml/kg.μU.min(-1); p > 0.05. Functional relationship of IS (y) on first-phase insulin release (x) showed a smaller (p < 0,05) regression coefficient for the IGT group.Conclusion: Brazilians with IGT well-matched with NGT ones were characterized by impaired first- and second-phase insulin secretion (mainly the former), while defects in IS were not evident.

Effects of protein malnutrition on glucose tolerance in rats with alloxan-induced diabetes

Protein-calorie malnutrition produces glucose intolerance and reduced insulin release in response to glucose. Rats adapted to low- or high-protein diets show an increased resistance to the diabetogenic action of a single dose of streptozotocin or alloxan. To determine the effects of dietary protein level on pancreatic function, we measured serum glucose levels under basal conditions and during the oral glucose tolerance test (GTT) performed before and after a single dose of alloxan administered to rats fed a 25% or a 6% protein diet for a period of 8 weeks. The incidence of mild hyperglycemia (serum glucose > 250 mg/dl) was greater among the rats fed the 25% protein diet (81%) than among those fed the 6% protein diet (42%). During the GTT performed before alloxan administration the serum glucose levels of the rats fed the 6% protein diet were not found to be significantly different from those of rats fed the 25% protein diet. During the GTT performed after alloxan injection all rats showed intolerance to the substrate (serum glucose > 160 mg/dl 120 min after glucose administration) regardless of whether basal serum glucose was normal or high. In summary, alloxan was less effective in producing basal hyperglycemia in the rats fed the 6% protein diet than in those fed the 25% protein diet but caused glucose intolerance during the oral GTT in both groups. Thus, it seems that feeding a 6% protein diet to rats offers only partial protection against the toxic effects of alloxan.

Daytime variations in glucose tolerance in people with impaired glucose tolerance

To determine whether glucose tolerance varies throughout the day in people with impaired glucose tolerance (IGT). We studied 15 healthy IGT, and 18 matched normal glucose tolerant (NGT) individuals. Blood samples were taken every 30-120 min during a 24 h period in which all individuals had three mixed meals and nocturnal sleep. We measured glucose, free fatty acids, specific insulin, intact proinsulin, cortisol and growth hormone. Variable responses were considered as concentrations and areas under the curves. Comparison between the groups was by Student's t-test, Mann-Whitney, and analysis of variance. Higher total glucose response, inappropriate normal total insulin response, and unproportionally increased proinsulin total response were observed in the IGT group. Lower glucose tolerance occurred in IGT after dinner, as in the NGT, and after breakfast associated with increased insulin response after breakfast, and similar proinsulin response after all three meals. IGT had higher glucose response than NGT after breakfast and lunch, similar insulin responses, and increased proinsulin-insulin ratio after all three meals. Data from this study demonstrate that IGT individuals present lower glucose tolerance in the evening, as those with NGT, and in the morning, as reported in patients with type 2 diabetes. © 2006 Elsevier B.V. All rights reserved.

Influence of lower cutoff values for 100-g oral glucose tolerance test and glycemic profile for identification of pregnant women at excessive fetal growth risk

Objective: To evaluate data from patients with normal oral glucose tolerance test (OGTT) results and a normal or impaired glycemic profile (GP) to determine whether lower cutoff values for the OGTT and GP (alone or combined) could identify pregnant women at risk for excessive fetal growth. Methods: We classified 701 pregnant women with positive screening for gestational diabetes mellitus (GDM) into 2 categories - (1) normal 100-g OGTT and normal GP and (2) normal 100-g OGTT and impaired GP - to evaluate the influence of lower cutoff points in a 100-g OGTT and GP (alone or in combination) for identification of pregnant women at excessive fetal growth risk. The OGTT is considered impaired if 2 or more values are above the normal range, and the GP is impaired if the fasting glucose level or at least 1 postprandial glucose value is above the normal range. To establish the criteria for the OGTT (for fasting and 1, 2, and 3 hours after an oral glucose load, respectively), we considered the mean (75 mg/dL, 120 mg/dL, 113 mg/dL, and 97 mg/dL), mean plus 1 SD (85 mg/dL, 151 mg/dL, 133 mg/dL, and 118 mg/dL), and mean plus 2 SD (95 mg/dL, 182 mg/dL, 153 mg/dL, and 139 mg/dL); and for the GP, we considered the mean and mean plus 1 SD (78 mg/dL and 92 mg/dL for fasting glucose levels and 90 mg/dL and 130 mg/dL for 1- or 2-hour postprandial glucose levels, respectively). Results: Subsequently, the women were reclassified according to the new cutoff points for both tests (OGTT and GP). Consideration of values, in isolation or combination, yielded 6 new diagnostic criteria. Excessive fetal growth was the response variable for analysis of the new cutoff points. Odds ratios and their respective confidence intervals were estimated, as were the sensitivity and specificity related to diagnosis of excessive fetal growth for each criterion. The new cutoff points for the tests, when used independently rather than collectively, did not help to predict excessive fetal growth in the presence of mild hyperglycemia. Conclusion: Decreasing the cutoff point for the 100-g OGTT (for fasting and 1, 2, and 3 hours) to the mean (75 mg/dL, 120 mg/dL, 113 mg/dL, and 97 mg/dL) in association with the GP (mean or mean plus 1 SD-78 mg/dL and 92 mg/dL for the fasting state and 90 mg/dL and 130 mg/dL for 1- or 2-hour postprandial values-increased the sensitivity and specificity, and both criteria had statistically significant predictive power for detection of excessive fetal growth. © 2008 AACE.