Significant Deterioration Of Glucose Tolerance Research Articles

Effects of ketogenic amino acid replacement diet on insulin resistance in mice fed with high fat diet

Objective To investigate the effects of ketogenic amino acid (KAA)replacement diet on insulin resistance in mice fed with high fat diet(HFD) and to analyze the possible mechanism. Methods C57BL mice were fed with a control diet, HFD, and KAA-fortified HFD(HFDKAAR)from the age of 8 weeks, and 8 weeks after HFD initiation, the HFD-fed mice were divided into two groups: one group of mice were fed the same HFD, the other group were fed HFDKAAR (HFD→HFDKAAR). The metabolic evaluations were performed at the end of 16 weeks. Blood glucose levels were measured at 0, 15, 30, 60, 90, and 120 min after the injection of glucose(1 g/kg BW intraperitoneal glucose tolerance test, ipGTT). The insulin, β-hydroxybutyrate, and acetoacetate levels in the plasma were measured via ELISA. The insulin resistance index (IRI)and area under curve (AUC)were calculated. The expression of hepatic LKB1(liver kinase B1), AMP-activated protein kinase(AMPK), and mTOR (Mammalian target of rapamycin)protein, and mcp-1 mRNA were measured by western blot and real-time PCR respectively. Results HFD-fed group of mice displayed significantly heavier body weight, heavier intra-abdominal fat weight, and significant deterioration of glucose tolerance at the end of 16 weeks in addition to higher insulin levels( all P<0.05), HFDKAAR-fed mice exhibited significantly ameliorated high fat diet-induced obesity and glucose intolerance compared to the HFD-fed mice, which was associated with decreased insulin levels, IRI, AUC, and mcp-1 mRNA expression(all P<0.05). HFD suppressed hepatic LKB1 and AMPK phosphorylation expression, and increased mTOR phosphorylation levels compared to the control diet-fed mice(all P<0.05). In contrast, treatment with the HFDKAAR diet increased LKB1and p-AMPK expression, which was associated with suppressed p-mTOR levels compared to the HFD-fed mice(all P<0.05). Conclusion KAA may ameliorate high fat diet-induced obesity, glucose intolerance, via normalizing the hepatic LKB1-AMPK-mTOR nutritional signal passageway. KAA replacement diet seems to be a potential nutritional intervention for the treatment for patients with metabolic defects, such as obesity, glucose intolerance, as well as metabolic syndrome. (Chin J Endocrinol Metab, 2016, 32: 399-404) Key words: Amino acid; Insulin resistance; Metabolic syndrome

Age-dependent impairment of glucose tolerance in the 3xTg-AD mouse model of Alzheimer's disease.

Alzheimer's disease (AD) has been associated with type II diabetes (T2D) and obesity in several epidemiologic studies. To determine whether AD neuropathology can cause peripheral metabolic impairments, we investigated metabolic parameters in the triple-transgenic (3xTg)-AD mouse model of AD, compared with those in nontransgenic (non-Tg) controls, at 6, 8, and 14 mo of age. We found a more pronounced cortical Aβ accumulation (2- and 3.5-fold increase in Aβ42 in the soluble and insoluble protein fractions, respectively) in female 3xTg-AD mice than in the males. Furthermore, female 3xTg-AD mice displayed a significant deterioration in glucose tolerance (AUC, +118% vs. non-Tg mice at 14 mo). Fasting plasma insulin levels rose 2.5-fold from 6 to 14 mo of age in female 3xTg-AD mice. Glucose intolerance and cortical amyloid pathology worsened with age, and both were more pronounced in the females. Pancreatic amyloidopathy was revealed and could underlie the observed deficit in glycemic response in 3xTg-AD mice. The present results suggest that AD-like neuropathology extends to the pancreas in the 3xTg-AD mouse, leading to glucose intolerance and contributing to a pathologic self-amplifying loop between AD and T2D.

Systemic inhibition of nitric oxide synthesis in non-diabetic individuals produces a significant deterioration in glucose tolerance by increasing insulin clearance and inhibiting insulin secretion

Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester (L-NAME, at rates of 2.5, 5, 10 and 20 μg min⁻¹ kg⁻¹) infusion. Another five volunteers underwent an OGTT with either saline or L-NAME (20 μg min⁻¹ kg⁻¹) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. Compared with saline, L-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (-12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity (M/I index) was unchanged. During the OGTT, L-NAME raised 2 h plasma glucose by 1.8 mmol/l (p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity.

Morning cortisol levels and glucose effectiveness

Anabolic corticosteroids have been reported to enhance glucose effectiveness (SG). In experimental models of long-term cortisol infusion in diabetic dogs, the maintenance of normal SG during chronic hypercortisolemia prevented a significant deterioration of glucose tolerance. We hypothesized that in analogy with exogenous corticosteroids, endogenous cortisol might influence SG. We aimed to study the influence of serum cortisol on SG prior to a frequently sampled intravenous glucose tolerance test (FSIVGTT) in 18 otherwise healthy men. The serum cortisol level or free cortisol index (ratio of cortisol to cortisol-binding globulin [CBG]) were not associated with the body mass index (BMI), waist to hip ratio (WHR), fasting insulin, or insulin sensitivity ([SI] all r < .20, P = NS). Conversely, SG correlated with serum cortisol levels measured prior to the FSIVGTT (r = .60, P = .008) and with the free cortisol index (r = .48, P = .03). The association was stronger in lean subjects (BMI < 25 kg/m2, r = .90, P = .002, n = 8). Men with a pre-FSIVGTT serum cortisol level above the median (431 nmol/L) were similar by age, BMI, WHR, and SI to the subjects with cortisol levels below the median, but the latter presented a significantly decreased SG (0.0014 +/- 0.006 v 0.022 +/- 0.007 min(-1), P = .03). In multiple linear regression analysis, fasting glucose (P = .02) and serum cortisol (P = .027) independently predicted SG, contributing to 26% of its variance. In summary, our findings suggest that the prevailing cortisol level appears to be associated with SG. The lower cortisol levels usually found in abdominally obese men could contribute to their altered glucose tolerance, perhaps via decreased SG.

Effect of the fat/carbohydrate ratio in the diet on obesity and oral glucose tolerance in C57BL/6J mice.

To study whether consumed dietary fat has a linear relationship or a threshold with glycemic controls, female C57BL/6J mice were fed different levels of a safflower oil (10, 20, 30, 40, 50, and 60% of total energy) diet ad libitum for 15 wk. Food intake, body weight, parametrial white adipose tissue (WAT) and liver weight were measured, and oral glucose tolerance tests were conducted. Although there was no significant difference in average energy intake, graded increments of safflower oil resulted in graded deterioration of glucose tolerance during 5 and 12-wk feeding, and deterioration of glucose tolerance was more manifested after 12-wk feeding as compared to 5-wk feeding. After 12-wk feeding, a significant deterioration of glucose tolerance was observed in diets of more than 40% fat. Graded increments of body weight and WAT weight were observed, and their weight increases were manifested in diets of more than 30% fat. These data indicated that the amount of dietary fat had an almost linear relationship with glucose tolerance, and significant differences were observed in mice fed diets more of than 40% fat.

Effects of aging and a high fat diet on body weight and glucose tolerance in glucagon-like peptide-1 receptor -/- mice.

Disruption of glucagon-like peptide-1 (GLP-1) receptor signaling in mice results in mild glucose intolerance, principally due to elimination of the incretin effect of GLP-1. Despite the inhibitory effects of GLP-1 on food intake, 6- to 8-week-old GLP-1 receptor -/-(GLP-1R-/-) mice were not obese and did not exhibit disturbances of feeding behavior. As both diabetes and obesity frequently become more phenotypically evident in older rodents, we studied the consequences of aging and a high fat diet on glucose control and body weight in GLP-1R-/- mice. No evidence of obesity or deterioration in glucose control was detected in 11- and 16-month-old GLP-1R-/- mice (mean weight, 34.7 +/- 2.0, 30.5 +/- 1.5, and 34.6 +/- 2.8 g in male and 25.3 +/-1.6, 28.4 +/-1.2, and 31.9 +/- 2.9 g in female GLP-1R+/+, GLP-1R+/-, and GLP-1R-/- mice, respectively; P = NS). After 18 weeks of high fat feeding, GLP-1R-/- mice gained similar (males) or less (females) weight than age- and sex-matched CD1 controls. No significant deterioration in glucose tolerance was observed after high fat feeding in GLP-1R-/- mice. These observations demonstrate that long term disruption of GLP-1 signaling in the central nervous system and peripheral tissues of older mice is not associated with the development of obesity or deterioration in glucose homeostasis.

Hepatic glucose production and insulin sensitivity preceding diabetes in monkeys.

The purpose of this study was to identify the relationship between basal hepatic glucose production (HGP) and peripheral insulin sensitivity as assessed by the hyperinsulinemic euglycemic clamp prior to and during the development of non-insulin-dependent (type 2) diabetes mellitus in rhesus monkeys. Twenty-six male monkeys (Macaca mulatta), including normal animals and monkeys in various phases of the development of spontaneous obesity-associated type 2 diabetes were studied. Fasting plasma glucose (FPG) and insulin (FIRI), basal HGP using a [3H]glucose infusion, and peripheral insulin sensitivity (as determined by the euglycemic clamp technique) were examined. The earliest change that could be detected was a significant reduction in peripheral insulin sensitivity accompanied by increased FIRI. These changes preceded a significant deterioration of glucose tolerance. Basal HGP changed in parallel with FPG (r = 0.90, P less than 0.001), becoming significantly elevated only when FPG rose to levels diagnostic of diabetes (greater than 140 mg/dl). Thus basal HGP and fasting glucose levels showed no significant changes early in the development of type 2 diabetes. We conclude that the early serial decreases in insulin sensitivity and progressive increases in FIRI, with or without decreased glucose tolerance, are prognostic of the future development of diabetes in obese monkeys, a longitudinal process that is also likely to be observed in most if not all obese humans progressing to diabetes.

Effects of Oral Contraceptives on Clinical Chemistry Parameters in Malnourished Women from India and Thailand

WHO undertook a study to examine the effects of combination type oral contraceptives containing 30 or 50μg ethinyl estradiol and 150μg d-norgestrel on undernourished women from India and Thailand. As compared with a middle-income population of women in each of these centers, women recruited for the study were undernourished. To discriminate hormone effects from other time-related changes, the baseline data on the cross-section of the study population were analyzed for effects of duration of lactation, anthropometry, and season. Both oral pills brought about a similar small but significant deterioration in glucose tolerance. The change tended to be progressive in some women, but the overall trend was not significant. Effects on other parameters were absent or inconsistent. Maternal nutritional status (as assessed by body weight) and lactational status did not modify the metabolic effects of the oral contraceptives.

The effect of E. Coli L-asparaginase on oral glucose tolerance and insulin release in man

To study the effect of E. Coli L-asparaginase on glucose tolerance and insulin release, 6 patients with neoplastic disease were subjected to 3 hour oral glucose tolerance tests with simultaneous measurement of serum immunoreactive insulin (IRI) levels before and following the intravenous administration of 5000 I. U. L-asparaginase/day for 4 days. Five of the patients exhibited a significant deterioration in glucose tolerance; however, no change was noted in their fasting glucose and IRI levels. The deterioration in glucose tolerance was associated with a decrease in the amount of insulin secreted in the first 30 minutes after the oral glucose load. The total amount of insulin released during the 3 hour test remained unchanged. These studies suggest that L-asparaginase can cause a deterioration of glucose tolerance without accompanying fasting hyperglycaemia. This may be due, in part, to a decrease in glucose-induced insulin release during the first thirty minutes following oral glucose.

Acute effects of exogenous growth hormone in man: time- and dose-bound modification of glucose tolerance and glucose-induced insulin release.

The time and dose dependency of the effects of a 30-min long iv infusion of human growth hormone (GH) on glucose tolerance and glucose-stimulated insulin release was investigated in 19 healthy subjects. Glucose tolerance deteriorated immediately following GH, and the k-value continued to decrease up to 300 min later. A small but significant reduction of glucose tolerance persisted 24 h after GH administration. Significant deterioration of glucose tolerance was observed with the smallest GH dose used (5 mug per kg body weight), increasing the amount of the hormone having no further major influence. Glucose-stimulated insulin release was significantly inhibited 1 h after administration of a relatively high GH dose (40 mug per kg), both if expressed as mean plasma insulin levels, or as insulin release per magnitude of glucose stimulation (insulinogenic index). In the majority of subjects, insulin release was inhibited also by lower GH doses (5-20 mug GH per kg). However, the mean change with these doses was not statistically significant. The inhibitory effect of GH on insulin secretion seemed to have a duration of several hours. Five hours, but not 24 h, after GH administration (10 mug GH per kg) insulin release was still significantly suppressed. It is suggested that the initial effect of GH on pancreatic beta cells may be inhibition of insulin release, in contrast with the enhancement of insulin secretion observed during chronic administration of GH.

Effects of carbohydrate restriction on glucose tolerance of normal men and reactive hypoglycemic patients

Normal individuals ingesting a low carbohydrate diet frequently develop an impairment of glucose tolerance as measured by the oral glucose tolerance test; most of these diets, however, have been high in fat content. Our present studies demonstrate that a low carbohydrate diet (57 g/day) did not impair the glucose tolerance of normal men if the fat content was similar to values on a standard (301 g/day) carbohydrate diet. However, a low carbohydrate diet did lead to impaired glucose tolerance when the fat content was 16 per cent higher than on the control diet. Thus our present and previous studies demonstrate that normal men maintain normal glucose tolerance on low carbohydrate diets and suggest that the deterioration of the glucose tolerance observed on high fat diets is related to the increased fat content rather than to the reduced carbohydrate content of these diets. Seven patients with reactive hypoglycemia were exquisitely sensitive to carbohydrate deprivation. Whereas the glucose tolerance tests of normal men were not altered by a low carbohydrate, high protein diet, a significant deterioration of glucose tolerance occurred when reactive hypoglycemic patients were changed from control diets to low carbohydrate, high protein diets. These hypoglycemic patients also showed an exaggerated deterioration of the glucose tolerance after a 48-hour fast when compared tothe response of normal men. Our observations suggest that a low carbohydrate, high protein diet is not the best therapeutic diet for certain patients with reactive hypoglycemia because this diet does not provide symptomatic improvement and, in addition, leads to impaired glucose tolerance.