Lower Plasma Glucose Concentrations Research Articles

Hypoglycaemic Status in Low Birth Weight Neonates During First 48 Hours of Life

Introduction: In developing countries more than 90% infants are born with low birth weight (LBW). In Bangladesh the incidence is about 30%. Newborn baby has got a definite difference in metabolic profile from the adult; this difference is much more pronounced in case of LBW newborn. Infants born prematurely or following intrauterine malnutrition may develop abnormally low plasma glucose concentration for a prolonged period as a result of the failure to adapt a metabolic and endocrine response.Glucose is an essential nutrient for the brain. Abnormally low levels (hypoglycaemia) can cause encephalopathy and have the potential to produce long-term neurological injury. Adequate knowledge about neonatal physiology is important in the management of LBW neonates in the neonatal nursery specially in the first 48 hours of life as most of the neonatal deaths occur in this critical period of time. Objectives: To evaluate the clinical features of hypoglycaemic low birth weight (LBW) neonates in the first 48 hours of life. Methods: This cross-sectional study was conducted on 56 LBW neonates in the inpatient departments of Paediatrics and Obstetrics of Combined Military Hospital (CMH), Dhaka between 15th September 2010 to 14th March 2011. LBW (Weight <2500gm) neonates, both term and preterm, from birth to 48 hours of age and who were well at the time of blood collection were included in this study. After enrollment of the newborn, with all aseptic precaution blood samples were taken from cord (as basal) at birth, from venous blood at 2 hours and then from capillary blood at 4 hours, in between 12-24 hours and in between 24-48 hours by heel prick from each case . Cord and capillary blood glucose were measured by using “Accu-Check-Active”- glucometer. Blood glucose concentrations less than 2.6 mmol/L irrespective of weight and gestational age were considered as low for the purpose of analysis. Results: It was revealed from the study that the mean birth weight was 1.77 gm mean gestational age was 36.09 weeks. 30 ( 53.57% ) were intrauterine growth retarded (IUGR) and 26 (46.43% ) were appropriate for gestational age (AGA). Out of thirty IUGR, 24 (51.79%) infants had low blood glucose (<2.6 mmol/L) levels. Twenty-two (75.86%) of 29 low birth weight infants showed low blood glucose at one of the five time points, 07 (17.07%) had low values on two hypoglycemia at 12-24 hours of age.The mean blood glucose concentration in LBW infants were 4.03 mmol/L at birth (cord), 2.33mmol/L at 2 hours, 2.96mmol/L, at 4 hours 3.14mmol/L, at 12—24hours and 3.43mmol/ L at 24—48hours of age. In the first 48 hours, the lowest blood glucose (mean) concentrations were found at 2 hours after delivery.Hypoglycaemia was most common among the preterm intrauterine growth retarded (IUGR) neonates at 2 hours after delivery. Most 23 (79.31%) of the hypoglycaemic infants were asymptomatic and 6 (20.69%) had symptoms.Early feeding prevents hypoglycaemia and appears to influence subsequent glucose values. Among the manifestations jitteriness, hyperalert, tachypnoea, high pitched cry, lethargy, apnoea and poor feeding were observed. Conclusion: The study findings may be helpful in the management of LBW neonates with hypoglycaemia and will encourage the mother in initiation of feeding immediately after delivery. DOI: http://dx.doi.org/10.3329/jafmc.v9i1.18726 Journal of Armed Forces Medical College Bangladesh Vol.9(1) 2013: 49-56

Effects of gestation and lactation on forage intake, digestion, and passage rates of primiparous beef heifers and multiparous beef cows1

Angus-cross cows (n = 13; 8 pregnant, BW 610 ± 24 kg, and 5 nonpregnant, BW 571 ± 23 kg) and heifers (n = 13; 8 pregnant, BW 511 ± 40 kg, and 5 nonpregnant, BW 451 ± 60 kg) were individually fed chopped warm-season grass hay (5.5% CP, 67% NDF) for ad libitum intake and soybean meal (46% CP) at 450 g/d. Intake was measured daily, and DM digestibility, digesta passage rate, and plasma glucose and β-hydroxybutyrate (BHBA) concentrations were measured every 14 d from 49 d prepartum to 49 d postpartum. Prepartum DMI (% of BW) increased over time for pregnant heifers through 2 wk prepartum before declining but did not change over time for pregnant cows. Dry matter digestibility decreased with advancing gestation (P < 0.001); pregnant animals had greater digestibility than nonpregnant cows and heifers (P = 0.02). Digestibility was not influenced by age (P = 0.99). Pregnant cows and heifers had faster digesta passage rates than their nonpregnant counterparts (P = 0.02). Pregnant animals had lower plasma glucose (P < 0.001). Plasma BHBA concentrations were greater in pregnant animals than in nonpregnant animals (P < 0.001) but were not influenced by age (P = 0.27) or time prepartum (P = 0.98). Postpartum DMI (% of BW) was greater for lactating heifers than other groups (age × lactation status; P = 0.05) and increased over time (P < 0.001). Diet digestibility increased with time postpartum (P < 0.001), and heifers had greater digestibility than cows from 3 to 7 wk postpartum but not at 1 wk postpartum (age × time; P = 0.02). Postpartum passage rate was not influenced by age or lactation status (P > 0.23). Lactating animals had lower plasma glucose and greater plasma BHBA concentrations postpartum than nonlactating animals (P < 0.001). Calves from mature cows grew faster than calves from heifers (age × time; P < 0.001). These data show that although primiparous beef heifers have similar DM digestibility, passage rates, and plasma glucose and BHBA concentrations, intake patterns differ between heifers and cows. Although DMI (% of BW) and digestibility did not differ between pregnant beef heifers and pregnant mature cows, the DMI (% of BW) was greater for lactating primiparous cows (heifers) than for lactating multiparous cows. Even with their postpartum increase in DMI, primiparous beef heifers were not able to consume adequate amounts of the warm-season forage to support their requirements for maintenance, growth, and lactation.

Exenatide dosing in alpacas

In order to investigate whether exenatide could be used to stimulate glucose clearance and insulin secretion in alpacas without causing colic signs, six healthy adult alpacas were injected once a day with increasing subcutaneous doses. A follow-up intravenous glucose injection was given to induce hyperglycemia, and serial blood samples were collected to measure plasma concentrations of glucose, insulin, triglycerides, beta-hydroxybutyrate, and nonesterified fatty acids. The exenatide doses used were saline control (no drug), and 0.02, 0.05, or 0.1 mcg/kg injected subcutaneously. Alpacas had significantly lower plasma glucose concentrations and higher insulin concentrations on all treatment days compared with the control day, but the increase in insulin was significantly greater and lasted significantly longer when the alpacas received the two higher dosages. Two of the alpacas developed mild colic signs at the 0.05 mcg/kg dose and were not evaluated at the highest dose. Based on these findings, the 0.05 mcg/kg dose appears to offer the greatest stimulation of insulin secretion and glucose clearance without excessive risk or severity of complications.

Acute effects of an oral supplement of (−)-epicatechin on postprandial fat and carbohydrate metabolism in normal and overweight subjects

Postprandial hyperglycemia, in particular when accompanied by excessive hypertriglyceridemia, is associated with increased cardiovascular risk, mainly in overweight or obese subjects, as it favors oxidative stress, systemic inflammation and endothelial dysfunction. Thus, treatments that favorably modulate metabolism by reducing steep increases in postprandial serum glucose and triglycerides, are of considerable interest. Evidence suggests that (-)-epicatechin (EPI) is responsible for reductions in cardiometabolic risk associated with chocolate consumption; these effects may be associated with favorable effects of EPI on postprandial metabolism. The aims of this study were to assess the effects of EPI on postprandial metabolism in normal-weight and overweight/obese subjects. Twenty adult volunteers (normal and overweight) underwent oral metabolic tolerance tests in the absence and presence of oral EPI (1 mg kg(-1)). Metabolic responses were examined using indirect calorimetry and determining blood glucose and triglycerides at 0, 2 and 4 hours after metabolic load ingestion. Results show that EPI increased postprandial lipid catabolism, as evidenced by a significant decrease in the respiratory quotient, which implies an increase in fat oxidation. The effect was associated with significantly lower postprandial plasma glucose and triglycerides concentrations. The effects were more prominent in overweight subjects. In conclusion, EPI modulates postprandial metabolism by enhancing lipid oxidation accompanied by reductions in glycemia and triglyceridemia.

Jejunal Leptin-PI3K Signaling Lowers Glucose Production

The fat-derived hormone leptin binds to its hypothalamic receptors to regulate glucose homeostasis. Leptin is also synthesized in the stomach and subsequently binds to its receptors expressed in the intestine, although the functional relevance of such activation remains largely unknown. We report here that intrajejunal leptin administration activates jejunal leptin receptors and signals through a phosphatidylinositol 3-kinase (PI3K)-dependent and signal transducer and activator of transcription 3 (STAT3)-independent signaling pathway to lower glucose production in healthy rodents. Jejunal leptin action is sufficient to lower glucose production in uncontrolled diabetic and high-fat-fed rodents and contributes to the early antidiabetic effect of duodenal-jejunal bypass surgery. These data unveil a glucoregulatory site of leptin action and suggest that enhancing leptin-PI3K signaling in the jejunum lowers plasma glucose concentrations in diabetes.

Treating fatty liver and insulin resistance

Treating fatty liver and insulin resistance

Experimental and Clinical Pharmacology: Sodium-glucose co-transporter inhibitors: Mechanisms of action

SUMMARY Sodium-glucose co-transporter 2 inhibitors are a new class of drug for the treatment of type 2 diabetes. They lower plasma glucose concentrations by increasing renal excretion of glucose. This class of drugs reduces glucose reabsorption in the kidney and lowers plasma glucose independent of changes in insulin concentrations or peripheral insulin resistance. They have a low risk of hypoglycaemia when used as monotherapy. The known adverse effects of the sodiumglucose co-transporter 2 inhibitors are related to their mechanism of action. They include an increased risk of dehydration and genital and urinary tract infections because of the increase in urinary glucose.

Fat Mass Localization Alters Fuel Oxidation during Exercise in Normal Weight Women

Abdominal and lower body fat mass tissues exhibit particular metabolic profiles at rest and during exercise. However, data are missing in normal weight women during exercise. The purpose of this study was to investigate the effect of low (LA/LB) and high (HA/LB) abdominal to lower body (A/LB) fat mass ratio on metabolic and hormonal responses during exercise in premenopausal normal weight women. After preliminary testing (V˙O2max and body composition assessment), substrate oxidation (RER, lipid, and carbohydrate oxidation rates), metabolic response (glycerol, free fatty acids, and glucose), and hormonal response (insulin, growth hormone, atrial natriuretic peptide, adrenaline, and noradrenaline) were determined during exercise (45 min at 65% of V˙O2max) in 21 premenopausal normal weight women (10 HA/LB women vs 11 LA/LB women). Waist circumference was significantly higher in HA/LB women compared with LA/LB women (P < 0.01). No difference in other anthropometric characteristics, V˙O2max, and resting blood values was observed between the two groups. LA/LB subjects exhibited greater lipid oxidation rates compared with HA/LB women during exercise (P < 0.01). This occurred with lower plasma insulin (P < 0.05) and glucose (P < 0.05) concentrations and higher plasma free fatty acids (P < 0.05), glycerol (P < 0.05), growth hormone (P < 0.05), and atrial natriuretic peptide levels (P < 0.01) during exercise in the LA/LB group compared with the HA/LB group. The present study demonstrated that LA/LB women exhibited an increase in whole-body lipid mobilization and use during exercise compared with HA/LB counterparts. This greater reliance on lipid as fuel metabolism during exercise could be explained by substrate availability and metabolic and hormonal responses. It appeared that LA/LB women exhibited greater metabolic flexibility during an exercise bout of 45 min at 65% of V˙O2max on cycle ergometer.

Response of the hypothalamic-pituitary-adrenal axis to stimulation tests before and after exercise training in old and young Standardbred mares1

This study tested the hypotheses that age-induced alteration in cortisol, ACTH, and glucose concentrations are due to differences in the response of the hypothalamic-pituitary-adrenal axis and that exercise training would attenuate these differences. Six old (22.0±0.7 yr; mean±SE) and 6 young (7.3±0.6 yr) unfit Standardbred mares ran 3 graded exercise tests (GXT): before (GXT1), after 8 wk of training (GXT2), and at study end at 15 wk (GXT3). Mares trained 3 d/wk at 60% maximum heart rate. Each mare underwent 5 endocrine stimulation tests pre- and posttraining: 1) control (CON), 2) adrenocorticotropin hormone (ACTHtest), 3) combined dexamethasone suppression/ACTH (DEX/ACTH), 4) dexamethasone suppression (DEX), and 5) combined DEX/corticotropin releasing factor (DEX/CRF). For CON, there was no difference in plasma cortisol between age groups pretraining (P=0.19), but young mares had a 102% higher mean (P=0.02) plasma cortisol concentration than old mares posttraining. The pretraining ACTHtest showed young mares had a 72% higher (P=0.05) overall plasma cortisol concentration compared to old. There was no overall age difference in cortisol in the posttraining ACTHtest, but old mares still had lower cortisol concentrations at 30 min during the test, suggesting decreased adrenal response to ACTH stimulation. There was no difference in cortisol response between old and young mares in DEX, DEX/ACTH, or DEX/CRF tests. Young mares had higher (P=0.02) overall plasma cortisol concentration posttraining in response to DEX/ACTH, but old mares showed no change. In CON and DEX/CRF, there were no age differences in plasma ACTH concentration, pre- or posttraining. Pretraining, there was no age difference in glucose response to DEX, but posttraining old mares had a 4% (P=0.04) lower overall plasma glucose concentration compared to young. Posttraining, old mares had lower mean plasma glucose concentrations during DEX compared to pretraining (P=0.02), but there was no change pre- vs. posttraining in young mares (P=0.19). Old and young mares had lower plasma glucose concentrations posttraining during DEX/ACTH (P<0.001 and P=0.05, respectively) and DEX/CRF (P<0.001 and P=0.003, respectively) compared to pretraining. Both the pituitary and adrenal glands experience a decline in function with age although the exact mechanisms behind such changes remain unknown. Exercise training facilitates the counteraction of these deficits.

Hydroxychloroquine Associated Hyperinsulinemic Hypoglycemia

Introduction Hypoglycemia in the patient without diabetes mellitus is uncommon. 1 An initial evaluation of hypoglycemia begins with confirming Whipple’s triad which includes: the presence of sympathoadrenal and neuroglycopenic symptoms, documented low plasma glucose concentration, and resolution of symptoms when plasma glucose is raised. 2 Hypoglycemia secondary to hydroxychloroquine previously has been documented in humans. 3,4 We describe a case of severe hyperinsulinemic hypoglycemia in a patient initiated on hydroxychloroquine therapy.

Acute Diabetes Management

In acute diabetes conditions, management of the following 3 potential complications is required: diabetic ketoacidosis, hyperosmolar hyperglycemic state, and iatrogenic hypoglycemia. The hyperglycemic crises diabetic ketoacidosis and hyperosmolar hyperglycemic state are the 2 most serious metabolic complications of diabetes. Hypoglycemia, specifically iatrogenic hypoglycemia, results from treatments that raise circulating insulin levels and thus lower plasma glucose concentrations to an abnormally low level, which exposes the patient to potential harm. This article reviews the pathogenesis, precipitating or risk factors, diagnosis or identification, and treatment of these critical complications of diabetes. In addition, a case study on diabetic ketoacidosis is provided.

Oral Green Tea Catechins Transiently Lower Plasma Glucose Concentrations in Female db/db Mice

Polyphenols, including green tea catechins, are secondary plant compounds often discussed in the context of health-promoting potential. Evidence for such effects is mainly derived from epidemiological and cell culture studies. The aim of the present study was to investigate antidiabetic, antiadipogenic, and anti-inflammatory effects at nonpharmacological doses in an obese diabetic mouse model that exerts early relevant clinical signs of non-insulin-dependent diabetes mellitus. Female db/db mice received a flavonoid-poor diet either without additive, with rosiglitazone (RSG, 0.02 g/kg diet), or with green tea extract (low-dose green tea extract [LGTE] and high-dose green tea extract [HGTE], 0.1 and 1 g/kg diet). Food and water were freely available. The body weight was monitored weekly. Blood was sampled (12-h fasted) from the tail vein on day 28 and analyzed for glucose, cholesterol, triacylglycerol, nonesterified fatty acids, insulin, adiponectin, and soluble intercellular adhesion molecule-1 (sICAM-1). Blood glucose was also analyzed on day 14. Furthermore, sICAM-1 release was investigated in tumor necrosis factor alpha-stimulated EAhy926 cells. After 14 days, fasting glycemia was improved by RSG or HGTE supplementation compared to controls. However, at the end of the study (day 28), only RSG exhibited glucose-lowering effects and induced plasma adiponectin concentrations, paralleled by higher body weight gain and reduced periuterine fat pads compared to controls. However, only GTE treatment reduced sICAM-1 release in vitro and in vivo. Nonpharmacological HGTE supplementation in db/db mice caused (1) no adiponectin-inducing or antiadipogenic effects, (2) reduced sICAM-1 release, thereby potentially exerting anti-inflammatory effects in the progressive diabetic state, and (3) a transient improvement in glycemia.

New Therapies for Diabetes Management

New Therapies for Diabetes Management

Associations Between Polymorphisms in the Glucocorticoid-Receptor Gene and Cardiovascular Risk Factors in a Chinese Population

BackgroundGlucocorticoid is an important regulator of energy homeostasis. Glucocorticoid receptor (GR) gene polymorphisms that contribute to variability in glucocorticoid sensitivity have been identified. We explored the associations of single-nucleotide polymorphisms (SNPs) of the GR gene with traditional cardiovascular risk factors in the Chinese Han population.MethodsWe recruited 762 consecutive adults who underwent a regular physical examination at Beijing Xuanwu Hospital. Blood pressure, glucose, lipid levels (total cholesterol, high-density lipoprotein cholesterol, low-density lipoprotein [LDL] cholesterol and triglycerides), body mass index (BMI), and waist-to-hip ratio were measured. Fourteen tag SNPs and 5 functional SNPs were selected and genotyped using the high-throughput Sequenom genotyping platform. Differences between genotypes/alleles for each SNP were adjusted for sex and age and tested using a general linear model procedure. Various models of inheritance, including additive, dominant, and recessive, were tested.ResultsAmong the 19 SNPs examined, 5 markers were associated with cardiovascular risk factors. The rs41423247 GG genotype and the rs7701443 AA genotype were associated with higher BMI and systolic blood pressure (P < 0.0004), and the rs17209251 GG genotype was associated with higher systolic blood pressure (P < 0.0004). Lower systolic blood pressure, total cholesterol, and LDL cholesterol were observed among rs10052957 A allele carriers (P < 0.0004), and lower plasma glucose and LDL-cholesterol concentrations were observed among rs2963156 TT carriers (P < 0.0004).ConclusionsPolymorphism of the GR gene was associated with cardiovascular risk factors and may contribute to susceptibility to cardiovascular disease.

Acute Diabetes Management

In acute diabetes conditions, management of the following 3 potential complications is required: diabetic ketoacidosis, hyperosmolar hyperglycemic state, and iatrogenic hypoglycemia. The hyperglycemic crises diabetic ketoacidosis and hyperosmolar hyperglycemic state are the 2 most serious metabolic complications of diabetes. Hypoglycemia, specifically iatrogenic hypoglycemia, results from treatments that raise circulating insulin levels and thus lower plasma glucose concentrations to an abnormally low level, which exposes the patient to potential harm. This article reviews the pathogenesis, precipitating or risk factors, diagnosis or identification, and treatment of these critical complications of diabetes. In addition, a case study on diabetic ketoacidosis is provided.

(Val8)GLP‐1‐Glu‐PAL: a GLP‐1 Agonist That Improves Hippocampal Neurogenesis, Glucose Homeostasis, and β‐Cell Function in High‐Fat‐Fed Mice

This study examined the biological properties of a novel GLP-1 peptide, (Val(8))GLP-1-Glu-PAL, engineered with an Ala(8)→Val(8) substitution and additional incorporation of a C(16) fatty acid moiety at Lys(26) via a glutamic acid linker. GLP-1 underwent 75 % degradation by DPP-IV over 8 h, whereas (Val(8))GLP-1 and (Val(8))GLP-1-Glu-PAL remained intact. All GLP-1 peptides significantly stimulated insulin secretion at 5.6 mM (1.3- to 4.9-fold, p<0.01 to p<0.001) and 16.7 mM glucose (1.5- to 2.3-fold, p<0.001). At higher concentrations (Val(8))GLP-1-Glu-PAL was significantly more potent at stimulating insulin secretion (1.2- to 1.3-fold, p<0.05). In high-fat-fed mice, all GLP-1 peptides significantly lowered plasma glucose concentrations (41-66 % decrease, p<0.05 to p<0.001), with (Val(8))GLP-1-Glu-PAL eliciting protracted glucose-lowering actions (32-59 % decrease, p<0.05 to p<0.01) when administered 8 h prior to a glucose load. Twice-daily administration of (Val(8))GLP-1-Glu-PAL in high-fat-fed mice for 21 days had no effect on bodyweight or food intake, but significantly lowered non-fasting plasma glucose (43-46 % decrease, p<0.05). (Val(8))GLP-1-Glu-PAL markedly decreased glycemic excursion following intraperitoneal glucose (32-48 % decrease, p<0.05), enhanced insulin response to glucose (2- to 2.3-fold, p<0.05 to p<0.01), and improved insulin sensitivity (25-38 % decrease in plasma glucose, p<0.05). O(2) consumption, CO(2) production, RER, and energy expenditure were not altered by (Val(8))GLP-1-Glu-PAL therapy. Treatment with (Val(8))GLP-1-Glu-PAL resulted in a significant increase in BrdU-positive cells (1.3-fold, p<0.05) in the granule cell layer of the dentate gyrus. These data demonstrate that (Val(8))GLP-1-Glu-PAL is a long-acting GLP-1 peptide that significantly improves hippocampal neurogenesis, glucose homeostasis, and insulin secretion in high-fat-fed mice.

Motivation to obtain a food reward of pregnant ewes in negative energy balance: Behavioural, metabolic and endocrine considerations

Low food availability often coincides with pregnancy in grazing animals. This study investigated how chronic reductions in food intake affected feeding motivation, and metabolic and endocrine parameters in pregnant sheep, which might be indicative of compromised welfare. Ewes with an initial Body Condition Score of 2.7±0.3 (BCS; 0 indicates emaciation and 5 obesity) were fed to attain low (LBC 2.0±0.0,), medium (MBC 2.9±0.1) or high BCS (HBC 3.7±0.1) in the first trimester of pregnancy. A feeding motivation test in which sheep were required to walk a set distance for a palatable food reward was conducted in the second trimester. LBC and MBC ewes consumed more rewards (P=0.001) and displayed a higher expenditure (P=0.02) than HBC ewes, LBC ewes also tended to consume more rewards than MBC ewes (P=0.09). Plasma leptin and glucose concentrations were inversely correlated to expenditure (both P<0.05) and appear to be associated with hunger in sheep. LBC ewes were in negative energy balance, with lower muscle dimensions, plasma glucose, leptin, insulin, cortisol, and insulin-like growth factor-1 concentrations and higher free fatty acids concentrations compared to HBC ewes; metabolic and endocrine parameters of the MBC ewes were intermediate. The high feeding motivation and negative energy balance of low BCS ewes suggested an increased risk of compromised welfare. Imposing even a small cost on a food reward reduced motivation substantially in high BCS ewes (despite high intake when food was freely available). Assessment of a willingness to work for rewards, combined with measures of key metabolic and endocrine parameters, may provide sensitive barometers of welfare in energetically-taxed animals.

Increased insulin secretion and decreased glucose concentrations, but not allostatic load, are associated with stress-related exhaustion in a clinical patient population

Allostatic load (AL) has been shown to be a useful marker of physiological strain during chronic stress and burnout in non-clinical working populations. The usability of the AL index for a clinical population with severe stress-related exhaustion was tested in this study. Thirteen biomarkers assembled as an AL index were analysed using blood samples from 90 patients with stress-related exhaustion (43 men and 47 women, age 31–61 years) and 90 healthy controls (46 men and 44 women, age 25–56 years). The AL scores did not differ between patients and controls. For men, some indication of higher cardiovascular risk was seen in the patient group: male patients had higher body mass index and waist–hip ratio and a poorer blood lipid status than male controls. We found lower plasma glucose concentrations in both female and male patients than those in controls. The male patients also showed increased fasting serum insulin concentrations. Further analysis using homeostasis model assessment for insulin resistance and β-cell function showed indications of insulin resistance in the patient group, particularly in the males, and an increased insulin secretion in both male and female patients. In conclusion, AL index does not seem to capture plausible physiological strain in patients diagnosed with stress-related exhaustion. The finding of lower plasma glucose concentrations, probably due to higher insulin secretion, in patients with severe stress-related exhaustion, needs to be further investigated, including mechanisms and the clinical relevance.

&lt;i&gt;Bhlhe40&lt;/i&gt;, a potential diabetic modifier gene on &lt;i&gt;Dbm1&lt;/i&gt; locus, negatively controls myocyte fatty acid oxidation

We have previously identified significant quantitative trait loci (QTL) Dbm1 (diabetic modifier QTL 1) on chromosome 6, affecting plasma glucose and insulin concentrations and body weight on F(2) progeny of hypoinsulinemic diabetic Akita mice, with the heterozygous Ins2 gene Cys96Tyr mutation, and non-diabetic A/J mice. To discover diabetic modifier genes on Dbm1, we constructed congenic strain for Dbm1 using the Akita allele as donor in A/J allele genetic background, and compared diabetes-related phenotypes to control mice. The homozygote for Akita allele of Dbm1 was associated with lower plasma glucose concentrations in glucose tolerance test (GTT) in the hypoinsulinemic condition derived from the Ins2 mutation and lower plasma insulin concentrations and body weight in the normoinsulinemic condition without the Ins2 mutation than the homozygote for A/J allele, as we performed QTL analysis on F(2) intercross mice. The Akita allele also decreased the epididymal white adipose tissue (EWAT) weight. According to the analysis of sub-congenic strains, we narrowed down the responsible diabetic modifier region to 9 Mb. As fourteen candidate genes exist in this region, we analyzed genomic variants of these genes and gene expression in the muscle, liver, and EWAT and identified that Bhlhe40 gene expression in muscle is decreased in congenic mice. According to the in vitro functional analyses, Bhlhe40 was shown to negatively control fatty acid oxidation in cultured myocyte. Based on these, we conclude that Bhlhe40 is a possible candidate diabetic modifier gene responsible for Dbm1 locus affecting diabetes and/or obesity through negatively controlling fatty acid oxidation in muscle.

Role of renal proximal tubule transport in thiazolidinedioneinduced volume expansion

Thiazolidinediones (TZDs), pharmacological activators of peroxisome-proliferator-activated receptors γ (PPARγ), significantly improve insulin resistance and lower plasma glucose concentrations. However, the use of TZDs is associated with plasma volume expansion, the mechanism of which has been a matter of controversy. Originally, PPARγ-mediated enhanced transcription of the epithelial Na channel (ENaC) γ subunit was thought to play a central role in TZD-induced volume expansion. However, later studies suggested that the activation of ENaC alone could not explain TZD-induced volume expansion. We have recently shown that TZDs rapidly stimulate sodium-coupled bicarbonate absorption from renal proximal tubule (PT) in vitro and in vivo. TZD-induced transport stimulation was dependent on PPARγ/Src/EGFR/ERK, and observed in rat, rabbit and human. However, this stimulation was not observed in mouse PTs where Src/EGFR is constitutively activated. Analysis in mouse embryonic fibroblast cells confirmed the existence of PPARγ/Src-dependent non-genomic signaling, which requires the ligand binding ability but not the transcriptional activity of PPARγ. The TZD-induced enhancement of association between PPARγ and Src supports an obligatory role for Src in this signaling. These results support the view that TZD-induced volume expansion is multifactorial. In addition to the PPARγ-dependent enhanced expression of the sodium transport system(s) in distal nephrons, the PPARγ-dependent non-genomic stimulation of renal proximal transport may be also involved in TZD-induced volume expansion.