Altered Fasting Plasma Glucose Research Articles

The impact of ethnicity and intra-pancreatic fat on the postprandial metabolome response to whey protein in overweight Asian Chinese and European Caucasian women with prediabetes.

The "Thin on the Outside Fat on the Inside" TOFI_Asia study found Asian Chinese to be more susceptible to Type 2 Diabetes (T2D) compared to European Caucasians matched for gender and body mass index (BMI). This was influenced by degree of visceral adipose deposition and ectopic fat accumulation in key organs, including liver and pancreas, leading to altered fasting plasma glucose, insulin resistance, and differences in plasma lipid and metabolite profiles. It remains unclear how intra-pancreatic fat deposition (IPFD) impacts TOFI phenotype-related T2D risk factors associated with Asian Chinese. Cow's milk whey protein isolate (WPI) is an insulin secretagogue which can suppress hyperglycemia in prediabetes. In this dietary intervention, we used untargeted metabolomics to characterize the postprandial WPI response in 24 overweight women with prediabetes. Participants were classified by ethnicity (Asian Chinese, n=12; European Caucasian, n=12) and IPFD (low IPFD < 4.66%, n=10; high IPFD ≥ 4.66%, n=10). Using a cross-over design participants were randomized to consume three WPI beverages on separate occasions; 0g (water control), 12.5g (low protein, LP) and 50g (high protein, HP), consumed when fasted. An exclusion pipeline for isolating metabolites with temporal (T0-240mins) WPI responses was implemented, and a support vector machine-recursive feature elimination (SVM-RFE) algorithm was used to model relevant metabolites by ethnicity and IPFD classes. Metabolic network analysis identified glycine as a central hub in both ethnicity and IPFD WPI response networks. A depletion of glycine relative to WPI concentration was detected in Chinese and high IPFD participants independent of BMI. Urea cycle metabolites were highly represented among the ethnicity WPI metabolome model, implicating a dysregulation in ammonia and nitrogen metabolism among Chinese participants. Uric acid and purine synthesis pathways were enriched within the high IPFD cohort's WPI metabolome response, implicating adipogenesis and insulin resistance pathways. In conclusion, the discrimination of ethnicity from WPI metabolome profiles was a stronger prediction model than IPFD in overweight women with prediabetes. Each models' discriminatory metabolites enriched different metabolic pathways that help to further characterize prediabetes in Asian Chinese women and women with increased IPFD, independently.

Different Gestational Diabetes Phenotypes: Which Insulin Regimen Fits Better?

ObjectiveMaternal characteristics and OGTT values of pregnancies complicated by gestational diabetes mellitus (GDM) were evaluated according to treatment strategies. The goal was to identify different maternal phenotypes in order to predict the appropriate treatment strategy.MethodsWe conducted a retrospective study among 1,974 pregnant women followed up for GDM in a tertiary referral hospital for high-risk pregnancies (Careggi University Hospital, Florence, Italy) from 2013 to 2018. We compared nutritional therapy (NT) alone (n = 962) versus NT and insulin analogues (n = 1,012) group. Then, we focused on different insulin analogues groups: long acting (D), rapid acting (R), both D and R. We compared maternal characteristics of the three groups, detecting which factors may predict the use of rapid or long-acting insulin analogue alone versus combined therapy.ResultsAmong women included in the analysis, 51.3% of them needed insulin therapy for glycemic control: 61.8% D, 28.3% combined D and R, and 9.9% R alone. Age >35 years, pre-pregnancy BMI >30, family history of diabetes, previous GDM, altered fasting plasma glucose (FPG), hypothyroidism, and assisted reproductive technologies (ART) were identified as maternal variables significantly associated with the need of insulin therapy. Altered 1-h and 2-h glucose plasma glucose level at OGTT, age >35 years, and previous GDM were found as independent predicting factors for the use of combined therapy with rapid and long acting analogues for glycemic control. On the contrary, pre-pregnancy BMI <25 and normal fasting plasma glucose values at OGTT were found to be significantly associated to the use of rapid insulin analogue only.ConclusionA number of maternal and metabolic variables may be identified at the diagnosis of GDM, in order to identify different GDM phenotypes requiring a personalized treatment for glycemic control.

Supplementation with Korean Red Ginseng Improves Current Perception Threshold in Korean Type 2 Diabetes Patients: A Randomized, Double-Blind, Placebo-Controlled Trial.

Background Many Type 2 diabetes (T2DM) patients in Korea take Korean Red Ginseng (KRG) for various reasons. In this study, we investigated the effects of KRG administration on diabetic peripheral neuropathy in T2DM patients. Methods This study was a randomized, double-blind, placebo-controlled trial. Participants were randomly allocated to either the placebo or KRG group and took corresponding tablets for 24 weeks. The primary outcomes were changes in current perception threshold (CPT) at week 24. Secondary outcomes were altered fasting plasma glucose, HbA1c, and various metabolic and inflammatory markers at week 24. Results Sixty-one patients completed the study. The CPT of the lower extremities at various frequencies exhibited significant improvements at week 24 in the KRG group. Other metabolic parameters were not altered after 24 weeks in both groups. In the subgroup analysis, CPT levels were improved in those with a longer diabetes duration or who already had neuropathy at the beginning of the study, and insulin resistance was improved in patients with a shorter diabetes duration. Conclusion Twenty-four week administration of KRG in T2DM patients resulted in a significant improvement in neuropathy, especially in those with a longer diabetes duration. A further, larger population study with a longer follow-up period is warranted to verify the effects of KRG on diabetic neuropathy.

Prematurity blunts the feeding-induced stimulation of translation initiation signaling and protein synthesis in muscle of neonatal piglets.

Postnatal growth of lean mass is commonly blunted in preterm infants and may contribute to short- and long-term morbidities. To determine whether preterm birth alters the protein anabolic response to feeding, piglets were delivered at term or preterm, and fractional protein synthesis rates (Ks) were measured at 3 days of age while fasted or after an enteral meal. Activation of signaling pathways that regulate protein synthesis and degradation were determined. Relative body weight gain was lower in preterm than in term. Gestational age at birth (GAB) did not alter fasting plasma glucose or insulin, but when fed, plasma insulin and glucose rose more slowly, and reached peak value later, in preterm than in term. Feeding increased Ks in longissimus dorsi (LD) and gastrocnemius muscles, heart, pancreas, and kidney in both GAB groups, but the response was blunted in preterm. In diaphragm, lung, jejunum, and brain, feeding increased Ks regardless of GAB. Liver Ks was greater in preterm than term and increased with feeding regardless of GAB. In all tissues, changes in 4EBP1, S6K1, and PKB phosphorylation paralleled changes in Ks. In LD, eIF4E·eIF4G complex formation, phosphorylation of TSC2, mTOR, and rpS6, and association of mammalian target of rapamycin (mTOR1) complex with RagA, RagC, and Rheb were increased by feeding and blunted by prematurity. There were no differences among groups in LD protein degradation markers. Our results demonstrate that preterm birth reduces weight gain and the protein synthetic response to feeding in muscle, pancreas, and kidney, and this is associated with blunted insulin- and/or amino acid-induced translation initiation signaling.

Association of General and Abdominal Obesity With Hypertension, Dyslipidemia and Prediabetes in the PREDAPS Study

Introduction and objectivesSome anthropometric measurements show a greater capacity than others to identify the presence of cardiovascular risk factors. This study estimated the magnitude of the association of different anthropometric indicators of obesity with hypertension, dyslipidemia, and prediabetes (altered fasting plasma glucose and/or glycosylated hemoglobin). MethodsCross-sectional analysis of information collected from 2022 participants in the PREDAPS study (baseline phase). General obesity was defined as body mass index ≥ 30kg/m2 and abdominal obesity was defined with 2 criteria: a) waist circumference (WC) ≥ 102cm in men/WC ≥ 88cm in women, and b) waist-height ratio (WHtR) ≥ 0.55. The magnitude of the association was estimated by logistic regression. ResultsHypertension showed the strongest association with general obesity in women (OR, 3.01; 95%CI, 2.24-4.04) and with abdominal obesity based on the WHtR criterion in men (OR, 3.65; 95%CI, 2.66-5.01). Hypertriglyceridemia and low levels of high-density lipoprotein cholesterol showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.49; 95%CI, 1.68-3.67 and OR, 2.70; 95%CI, 1.89-3.86) and with general obesity in men (OR, 2.06; 95%CI, 1.56-2.73 and OR, 1.68; 95%CI, 1.21-2.33). Prediabetes showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.48; 95%CI, 1.85-3.33) and with abdominal obesity based on the WC criterion in men (OR, 2.33; 95%CI, 1.75-3.08). ConclusionsAbdominal obesity indicators showed the strongest association with the presence of prediabetes. The association of anthropometric indicators with hypertension and dyslipidemia showed heterogeneous results.

Asociación de obesidad general y abdominal con hipertensión, dislipemia y presencia de prediabetes en el estudio PREDAPS

Introduction and objectivesSome anthropometric measurements show a greater capacity than others to identify the presence of cardiovascular risk factors. This study estimated the magnitude of the association of different anthropometric indicators of obesity with hypertension, dyslipidemia, and prediabetes (altered fasting plasma glucose and/or glycosylated hemoglobin). MethodsCross-sectional analysis of information collected from 2022 participants in the PREDAPS study (baseline phase). General obesity was defined as body mass index ≥ 30kg/m2 and abdominal obesity was defined with 2 criteria: a) waist circumference (WC) ≥ 102cm in men/WC ≥ 88cm in women, and b) waist-height ratio (WHtR) ≥ 0.55. The magnitude of the association was estimated by logistic regression. ResultsHypertension showed the strongest association with general obesity in women (OR, 3.01; 95%CI, 2.24-4.04) and with abdominal obesity based on the WHtR criterion in men (OR, 3.65; 95%CI, 2.66-5.01). Hypertriglyceridemia and low levels of high-density lipoprotein cholesterol showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.49; 95%CI, 1.68-3.67 and OR, 2.70; 95%CI, 1.89-3.86) and with general obesity in men (OR, 2.06; 95%CI, 1.56-2.73 and OR, 1.68; 95%CI, 1.21-2.33). Prediabetes showed the strongest association with abdominal obesity based on the WHtR criterion in women (OR, 2.48; 95%CI, 1.85-3.33) and with abdominal obesity based on the WC criterion in men (OR, 2.33; 95%CI, 1.75-3.08). ConclusionsAbdominal obesity indicators showed the strongest association with the presence of prediabetes. The association of anthropometric indicators with hypertension and dyslipidemia showed heterogeneous results.Full English text available from:www.revespcardiol.org/en

Moringa oleifera from Cambodia Ameliorates Oxidative Stress, Hyperglycemia, and Kidney Dysfunction in Type 2 Diabetic Mice.

Recent reports have shown the antidiabetic effect of Moringa oleifera from various parts of the world. However, M. oleifera from Cambodia has never determined. Therefore, the aim of this study was to assess the antidiabetic effect of M. oleifera extract from Cambodia. The leaf ethanolic extract contained flavonoids (31.90 mg/mL), polyphenols (53.03 mg/mL), lycopene (0.042 mg/mL), and ß-carotene (0.170 mg/mL), and possessed 2,2-diphenyl-1-picrylhydrazyl, hydrogen peroxide, and hydroxyl radical scavenging activities of 92.40, 99.25, and 83.57 TE/μM at 1 mg/mL, respectively. Db/db mice were orally administered the leaf extract (150 mg/kg/day) for 5 weeks. M. oleifera treatment significantly ameliorated the altered fasting plasma glucose (from 483 to 312 mg/dL), triglyceride (from 42.12 to 23.00 mg/dL), and low-density lipoprotein cholesterol (from 107.21 to 64.25 mg/dL) compared to control group, and increased the insulin levels from 946 ± 92 to 1678 ± 268 pg/mL. The histopathological damage and expression levels of tumor necrosis factor-alpha, interleukin (IL)-1β, IL-6, cyclooxygenase-2, and inducible nitric oxide synthase in renal tissue decreased. These results indicate the potential antidiabetic benefits of M. oleifera ethanolic leaf extract.

Ghrelin Impairs Prandial Glucose Tolerance and Insulin Secretion in Healthy Humans Despite Increasing GLP-1.

Administration of ghrelin inhibits the acute insulin response to glucose and worsens IV glucose tolerance in healthy subjects. Evidence from preclinical studies suggests that ghrelin may have differential effects on glucose metabolism during fasting and feeding. Our objective was to test the effects of ghrelin on glucose and insulin responses during a meal tolerance test. Acyl ghrelin (0.26 and 2.0 μg/kg/h) or saline was infused in 13 healthy subjects on three separate occasions in randomized order. Ghrelin was infused for 45 minutes to achieve steady-state levels and continued for 240 minutes after ingestion of a liquid test meal. Primary outcomes were area under the curve for glucose and insulin secretion. We found that ghrelin infusions of 0.26 and 2.0 μg/kg/h raised steady-state plasma total ghrelin levels to 1.7- and 4.8-fold above fasting concentrations, but did not alter fasting plasma glucose or insulin levels. During the meal tolerance test, ghrelin decreased insulin sensitivity, impaired β-cell function, and induced glucose intolerance. The high-dose ghrelin infusion also raised postprandial glucagon like peptide 1 secretion without affecting glucose dependent insulinotropic polypeptide, glucagon, or peptide YY concentrations. We conclude that both physiologic and pharmacologic doses of ghrelin worsen the glucose and β-cell responses to meal ingestion in healthy humans. The increase in postprandial glucagon like peptide 1 secretion by ghrelin suggests a novel enteroendocrine connection, but does not mitigate the glucose intolerance.

3,5 Diiodo-L-Thyronine (T2) Does Not Prevent Hepatic Steatosis or Insulin Resistance in Fat-Fed Sprague Dawley Rats.

Thyroid hormone mimetics are alluring potential therapies for diseases like dyslipidemia, nonalcoholic fatty liver disease (NAFLD), and insulin resistance. Though diiodothyronines are thought inactive, pharmacologic treatment with 3,5- Diiodo-L-Thyronine (T2) reportedly reduces hepatic lipid content and improves glucose tolerance in fat-fed male rats. To test this, male Sprague Dawley rats fed a safflower-oil based high-fat diet were treated with T2 (0.25 mg/kg-d) or vehicle. Neither 10 nor 30 days of T2 treatment had an effect on weight, adiposity, plasma fatty acids, or hepatic steatosis. Insulin action was quantified in vivo by a hyperinsulinemic-euglycemic clamp. T2 did not alter fasting plasma glucose or insulin concentration. Basal endogenous glucose production (EGP) rate was unchanged. During the clamp, there was no difference in insulin stimulated whole body glucose disposal. Insulin suppressed EGP by 60% ± 10 in T2-treated rats as compared with 47% ± 4 suppression in the vehicle group (p = 0.32). This was associated with an improvement in hepatic insulin signaling; insulin stimulated Akt phosphorylation was ~2.5 fold greater in the T2-treated group as compared with the vehicle-treated group (p = 0.003). There was no change in expression of genes thought to mediate the effect of T2 on hepatic metabolism, including genes that regulate hepatic lipid oxidation (ppara, carnitine palmitoyltransferase 1a), genes that regulate hepatic fatty acid synthesis (srebp1c, acetyl coa carboxylase, fatty acid synthase), and genes involved in glycolysis and gluconeogenesis (L-pyruvate kinase, glucose 6 phosphatase). Therefore, in contrast with previous reports, in Sprague Dawley rats fed an unsaturated fat diet, T2 administration failed to improve NAFLD or whole body insulin sensitivity. Though there was a modest improvement in hepatic insulin signaling, this was not associated with significant differences in hepatic insulin action. Further study will be necessary before diiodothyronines can be considered an effective treatment for NAFLD and dyslipidemia.

Effects of metformin, buformin, and phenformin on the post-initiation stage of chemically induced mammary carcinogenesis in the rat.

Metformin is a widely prescribed drug for the treatment of type II diabetes. Although epidemiologic data have provided a strong rationale for investigating the potential of this biguanide for use in cancer prevention and control, uncertainty exists whether metformin should be expected to have an impact in nondiabetic patients. Furthermore, little attention has been given to the possibility that other biguanides may have anticancer activity. In this study, the effects of clinically relevant doses of metformin (9.3 mmol/kg diet), buformin (7.6 mmol/kg diet), and phenformin (5.0 mmol/kg diet) were compared with rats fed control diet (AIN93-G) during the post-initiation stage of 1-methyl-1-nitrosourea-induced (50 mg/kg body weight) mammary carcinogenesis (n = 30/group). Plasma, liver, skeletal muscle, visceral fat, mammary gland, and mammary carcinoma concentrations of the biguanides were determined. In comparison with the control group, buformin decreased cancer incidence, multiplicity, and burden, whereas metformin and phenformin had no statistically significant effect on the carcinogenic process relative to the control group. Buformin did not alter fasting plasma glucose or insulin. Within mammary carcinomas, evidence was obtained that buformin treatment perturbed signaling pathways related to energy sensing. However, further investigation is needed to determine the relative contributions of host systemic and cell autonomous mechanisms to the anticancer activity of biguanides such as buformin.

Association of urinary metal profiles with altered glucose levels and diabetes risk: a population-based study in China.

BackgroundElevated heavy metals and fasting plasma glucose (FPG) levels were both associated with increased risk of cardiovascular diseases. However, studies on the associations of heavy metals and essential elements with altered FPG and diabetes risk were limited or conflicting. The objective of this study was to evaluate the potential associations of heavy metals and essential trace elements with FPG and diabetes risk among general Chinese population.MethodsWe conducted a cross-sectional study to investigate the associations of urinary concentrations of 23 metals with FPG, impaired fasting glucose (IFG) and diabetes among 2242 community-based Chinese adults in Wuhan. We used the false discovery rate (FDR) method to correct for multiple hypothesis tests.ResultsAfter adjusting for potential confounders, urinary aluminum, titanium, cobalt, nickel, copper, zinc, selenium, rubidium, strontium, molybdenum, cadmium, antimony, barium, tungsten and lead were associated with altered FPG, IFG or diabetes risk (all P< 0.05); arsenic was only dose-dependently related to diabetes (P< 0.05). After additional adjustment for multiple testing, titanium, copper, zinc, selenium, rubidium, tungsten and lead were still significantly associated with one or more outcomes (all FDR-adjusted P< 0.05).ConclusionsOur results suggest that multiple metals in urine are associated with FPG, IFG or diabetes risk. Because the cross-sectional design precludes inferences about causality, further prospective studies are warranted to validate our findings.

Impacto da função retardada do enxerto pancreático no transplante simultâneo pâncreas-rim

Simultaneous pancreas-kidney transplantation is an effective treatment for patients with type 1 diabetes mellitus and end-stage chronic kidney disease. Delayed pancreatic graft function is a common and multifactor condition with significant impact in short-term outcome of simultaneous pancreas-kidney transplantations. The aim of this study was to analyze the impact of pancreatic delayed pancreatic graft function on simultaneous pancreas-kidney transplantation. Donor and recipient's demographic data, percentage of panel reactivity, acute rejection incidence, and patient and grafts survivals were retrospectively analyzed in 180 SPKT performed between 2002 and 2007. The incidence of pancreatic delayed pancreatic graft function was 11%. Donors older than 45 years had significant risk of pancreatic delayed pancreatic graft function (OR 2.26; p < 0,05). Patients with pancreatic delayed pancreatic graft function had higher rates of acute renal rejection (47 versus 24%; p < 0.05), altered fasting plasma glucose (25 versus 5%; p < 0.05) and mean glycated hemoglobin (5.8 versus 5.4%; p < 0.05), than patients without pancreatic delayed pancreatic graft function at the end of the first year of follow up. There were no significant differences between patients with and without pancreatic delayed pancreatic graft function regarding patient survival (95 versus 88.7%; p = 0.38), pancreatic graft survival (90 versus 85.6%; p = 0.59) and renal graft survival (90 versus 87.2%; p = 0.70), respectively at the sample period of time. Pancreatic delayed pancreatic graft function had no significant impact in the short-term outcome of simultaneous pancreas-kidney transplantations. Although delayed pancreatic graft function had no impact on 1-year pancreas graft survival, it contributed to early pancreas graft dysfunction, as assessed by enhanced insulin and oral anti-diabetic drugs requirements.

Supplementation with EPA or fish oil for 11 months lowers circulating lipids, but does not delay the onset of diabetes in UC Davis-type 2 diabetes mellitus rats

EPA or fish oil supplementation has been suggested as treatments for the prevention of type 2 diabetes mellitus (T2DM) due to their lipid-lowering and potential insulin-sensitising effects. We investigated the effects of supplementation with EPA (1 g/kg body weight per d) or fish oil (3 g/kg body weight per d) on the age of onset of T2DM and circulating glucose, insulin, lipids, leptin and adiponectin in UC Davis (UCD)-T2DM rats. Animals were divided into three groups starting at 1 month of age: control, EPA and fish oil. All the animals were followed until diabetes onset or for up to 12 months of age. Monthly fasting blood samples were collected for the measurement of glucose, lipids, hormones and C-reactive protein (CRP). Neither EPA nor fish oil delayed the onset of T2DM or altered fasting plasma glucose, insulin, CRP, adiponectin or leptin concentrations. The groups did not differ in energy intake or body weight. Fish oil treatment lowered fasting plasma TAG concentrations by 39 (sd 7) % (P < 0.001) and EPA lowered fasting plasma NEFA concentrations by 23 (sd 5) % (P < 0.05) at 4 months of age compared with the control group. EPA and fish oil lowered fasting plasma cholesterol concentrations at 4 months of age by 19 (sd 4) and 22 (sd 4) % compared with the control group, respectively (both P < 0.01). In conclusion, EPA and fish oil supplementation lowers circulating lipid concentrations, but does not delay the onset of T2DM in UCD-T2DM rats.

DHEA in Elderly Women and DHEA or Testosterone in Elderly Men

One common approach to preventing or delaying age-related disorders is to supplement falling hormone levels. Animal studies give some evidence that dehydroepiandrosterone (DHEA) lessens age-related changes in body composition and has beneficial effects on diabetes and cardiovascular disease, but rodents—unlike humans—have very low DHEA levels. Whether or not to give supplemental testosterone to elderly men also is unsettled. This randomized 2-year placebo-controlled, double-blind study enrolled 87 men aged 60 years and older having low levels of sulfated DHEA and bioavailable testosterone, and 57 elderly women with low levels of sulfated DHEA. The men received 75 mg of DHEA daily in tablet form, 5 mg of testosterone daily via transdermal patch, or an appropriate placebo for 2 years. The women received either a 50-mg DHEA tablet daily or a placebo tablet. There were no major group differences at baseline. DHEA recipients had significant increases in levels of sulfated DHEA and estradiol, and treated women had increased total testosterone levels. Both bioavailable and total testosterone increased significantly in testosterone-treated men compared with placebo recipients. DHEA did not significantly alter gonadotropin levels in men or women, but lower levels were found in testosterone-treated men. Neither treatment significantly altered fasting plasma glucose levels or insulin sensitivity. Both men and women given DHEA had significant reductions in levels of high-density lipoprotein cholesterol. In men and women combined, those given DHEA had a slight but significant rise in fat-free mass and a reduction in proportion of body fat. Fat-free mass also increased in men given testosterone. Measures of muscle strength remained unchanged. Small increases in bone mineral density were noted at some but not all sites with both active treatments. Neither treatment significantly altered quality of life as reflected by scores on the Physical Component and Mental Component scales of the Health Status Questionnaire. Neither treatment altered prostate volume, liver function, or levels of electrolytes or hemoglobin. In this study, neither DHEA nor low-dose testosterone had physiologically meaningful beneficial effects on body composition, physical performance, or quality of life in elderly men or women. The investigators strongly recommend that these treatments not be used as anti-aging measures.

Individual differences in glucose homeostasis: Do our early life interactions with bacteria matter?

Exposure to endotoxin during the neonatal period in the rat has been shown to alter the development of the hypothalamic–pituitary–adrenal axis, inducing hyper-responsivity and increased glucocorticoid production in later-life. Glucocorticoids are known to have major metabolic effects, therefore, early life endotoxin exposure may have potentially serious consequences for metabolic homeostasis in the exposed animal. The aims of this study were therefore to assess the effect of neonatal bacterial endotoxin exposure on subsequent glucose homeostasis, insulin action and corticosterone production from puberty through to senescence. Male Fischer-344 rat pups were treated with bacterial endotoxin (0.05 mg/kg Salmonella enteritidis i.p.) or vehicle (sterile pyrogen free saline) on days 3 and 5 postnatally. Insulin and glucose levels were assessed before and during and intraperitoneal glucose tolerance test (IPGTT) together with body mass on postnatal days 40, 80, and 400. In addition, circulating levels of corticosterone were measured at 0, 30, and 90 min following a 30-min restraint challenge at these ages. Neonatal endotoxin challenge did not alter fasting plasma glucose or insulin, but impaired glucose tolerance at puberty ( p < .05), improved glucose tolerance in adulthood ( p < .05) and had no effect at senescence. During the IPGTT insulin was reduced at all ages ( p < .05) following neonatal endotoxin challenge, but insulin sensitivity was unaltered, except for an increase in adulthood ( p < .05), which is consistent with the observed improvement in glucose tolerance at this age. Neonatal endotoxin challenge reduced body mass during puberty and senescence ( p < .05) but did not alter basal or stressed plasma corticosterone levels at any of the three developmental time points examined. These findings suggest that variations in an individual’s early life bacterial environment may contribute to differences in glucose homeostasis, insulin action and disease susceptibility later in life.

Studies of variations of the cyclin-dependent kinase inhibitor 1C and the cyclin-dependent kinase 4 genes in relation to type 2 diabetes mellitus and related quantitative traits

CDK4 is involved in the regulation of body weight, pancreatic beta-cell proliferation, insulin responsiveness, and diabetes pathogenesis. CDK4 activity is inhibited by CDKN1C, which is regulated by insulin. In addition, CDKN1C plays an important role in beta-cell proliferation and is involved in the pathogenesis of the Beckwith-Wiedemann syndrome, a disorder characterized by neonatal hyperinsulinaemic hypoglycaemia and pre- and post-natal overgrowth. The aim of this study was to investigate if variations in the proximal promoter and the coding region of the CDKN1C and CDK4 genes are associated with type 2 diabetes or changes in related quantitative phenotypes among glucose-tolerant subjects. Mutation analyses of the two genes in 62 type 2 diabetic patients resulted in the discovery of seven variants of CDKN1C and two variants of CDK4. In a case-control study comprising 717 type 2 diabetic patients and 518 glucose-tolerant subjects the most frequent variants did not show any difference in allele frequencies between the type 2 diabetic patients and the control subjects. However, in two genotype-quantitative trait correlation studies involving 206 glucose-tolerant offspring of type 2 diabetic patients and 359 young, healthy subjects the CDKN1C del171APVA variant associated with increased birth weight (P=0.05 and P=0.05). Furthermore, the same variant tended to be associated with decreased basal glucose oxidation among 16 genotypically discordant dizygotic twins (P=0.03). In a genotype-quantitative trait study involving 500 middle-aged glucose-tolerant subjects the CDK4 IVS2-31G-->A variant was associated with an increased waist circumference (P=0.03) and waist-to-hip ratio (P=0.02) and altered fasting plasma glucose (P=0.03). However, these later findings could not be replicated in additional studies. In conclusion, variants in CDKN1C may contribute to the inter-individual variation in birth weight.

Growth hormone-induced insulin resistance: role of the insulin receptor, IRS-1, GLUT-1, and GLUT-4.

Treatment of rats with growth hormone (GH; 1 mg/kg sc) twice daily over 2.5 days did not alter fasting plasma glucose or glucose tolerance but increased fasting plasma insulin levels 65% and peak insulin response to a glucose load 35% over controls, indicating the development of insulin resistance. Studies on partially purified insulin receptors from soleus muscles showed that GH increased the abundance of insulin receptor beta-subunits by 48% as measured by immunoblotting. Despite this increase, GH abolished the increase in autophosphorylation of the insulin receptor beta-subunit in response to physiological hyperinsulinemia and diminished by 28% the response to supraphysiological hyperinsulinemia. Similarly, insulin-stimulated phosphorylation of insulin receptor substrate-1 (IRS-1) was decreased 25% by GH, but the abundance of IRS-1 was not affected. Studies on rats pretreated with streptozotocin suggested that the effects of GH are direct and not secondary to GH-induced hyperinsulinemia. GH decreased basal GLUT-1 abundance in the low-density microsome and plasma membrane fractions of epididymal adipocytes by 50 and 42%, respectively, but decreased basal GLUT-4 abundance only in the low-density microsome fraction by 24%. Despite these alterations, the abundance of both transporters in the plasma membrane fraction of adipocytes incubated with 0.1 U insulin/ml was not diminished by GH.

Long-term effects of dietary fructose on carbohydrate metabolism in non-insulin-dependent diabetes mellitus

The effect of dietary fructose on glycemic control in subjects with diabetes mellitus is controversial. Therefore our aim was to conduct a long-term study to examine the effects of dietary fructose on glucose tolerance and insulin sensitivity and to delineate the mechanisms for the effects observed. Six subjects with non-insulin-dependent diabetes mellitus (NIDDM) who were being treated by diet alone consumed 13% of their calories as fructose incorporated into mixed meals in place of sucrose for 3 months as inpatients on a metabolic ward. The following parameters were measured: (1) weekly fasting plasma-glucose concentrations, (2) postprandial serum glucose and insulin levels after four sugar tolerance tests, (3) basal hepatic glucose production, and (4) hepatic and whole-body insulin sensitivity determined during a hyperinsulinemic, euglycemic clamp. When modest amounts of fructose were substituted for sucrose in the diet for 3 months, basal hepatic glucose output remained unchanged (12.84 ± 1.83 nmol/kg/min v 12.51 ± 2.00 nmol/kg/min) as did hepatic insulin sensitivity (92% ± 4% v 93% ± 4% suppression) and peripheral glucose disposal (22.52 ± 4.56 nmol/kg/min v 25.80 ± 9.45 nmol/kg/min) to a 860 pmol/m 2/min insulin infusion at euglycemia (4.8 mmol/L). Fructose feeding also did not alter fasting plasma-glucose concentrations or postprandial plasma glucose and insulin responses to oral glucose or fructose loads or to mixed meals containing either sucrose or fructose. In conclusion, substitution of physiologic amounts of sucrose by fructose for prolonged periods is unlikely to have adverse effects on glucose metabolism in diabetic subjects who are being treated with diet alone.