Glucose Tolerance Response Research Articles

The Ablation of Sensory Neurons Expressing the Nav1.8 Sodium Channel Improves Glucose Homeostasis and Amplifies the GLP-1 Signaling in Obese Female Mice.

Sensory neurons expressing the sodium channel Nav1.8 contain a repertoire of receptors for nutrient, hormonal, and inflammatory ligands. However, their function in key regulators of energy homeostasis control is not well understood and is completely unexplored in females. Mice lacking neurons expressing the sodium channel Nav1.8 were generated using an ablation strategy based on cre recombinase-mediated expression of diphtheria toxin fragment A (DTA) (Nav1.8-cre/DTA mice) to investigate whether these neurons modulate body weight, food intake, gut hormone secretion, gastrointestinal transit, and glucose tolerance in response to nutrient challenges in a sex-dependent manner. Male Nav1.8-cre/DTA mice show resistance to gain weight in response to high-fat high-sugar diet (HFHSD), whereas females lacking Nav1.8+ neurons have improved oral glucose tolerance accompanied by higher insulin levels and attenuated glucagon secretion after an oral glucose load. Female Nav1.8-cre/DTA mice also show higher fasting and postprandial glucagon like peptide-1 (GLP-1) levels with an increased number of GLP-1-positive cells. Finally, ablation of Nav1.8-expressing neurons accelerates the gastrointestinal transit in female mice under HFHSD. This data demonstrates sex-dependent differences in the Nav1.8-mediated regulation of energy metabolism, and provides new insights that may help in the design of sex-specific neuromodulation therapies for metabolic disorders induced by diets rich in fats and simple sugars.

A homeostatic metabolic role for estrogen receptor α in the subfornical organ

Approximately 70% of American adults are considered overweight or obese putting them at increased risk for metabolic syndrome, which includes a constellation of abnormalities that can result in cardiovascular disease, type II diabetes, and fatty liver. Sexual dimorphism in metabolic syndrome is clearly established. Adult men display increased prevalence of metabolic syndrome comorbidities when compared to fertile women. However, post-menopause, the incidence of metabolic syndrome in women significantly increases. It is widely proposed that the increased post-menopausal incidence of metabolic syndrome is due, in part, to estrogen deficiency. Within the brain, estrogen regulates metabolism primarily through actions on estrogen receptor alpha (ERα). While a major emphasis has been placed on hypothalamic nuclei, whether there is a distributed neural network of ERα that works through autonomic and endocrine actions to influence metabolism remains incompletely defined. We have recently shown a critical role for the subfornical organ (SFO), a circumventricular region that lies outside the blood barrier, in the regulation of peripheral metabolism in males. However, whether this brain nucleus and further estrogen signaling within this region is involved the control of metabolism in females is unknown. Taken together, we hypothesized that ERα in the SFO may regulate peripheral metabolism in female mice during obesity. To investigate this, 6 wk old female ESRα flox mice received targeted SFO microinjections of AAV-Cre-GFP and titer matched control AAV-LacZ-GFP. Following 2 wks of viral incorporation, mice were fed a high fat diet (HFD; 60% kcal from fat) for 10 weeks. Indirect calorimetry measurements indicated that SFO ERα removal resulted inhyperphagic behavior during HFD feeding (Cumulative food intake: 27.4±2.7 g vs 37.5±3.3 g, GFP vs. Cre, n=7-8, p<0.05) that was counterbalanced by increased energy expenditure (0.46±0.02 vs. 0.51±0.02 kcal/hr, GFP vs. Cre, n=7-8, p<0.05) resulting in no influence on body weight (ΔBody weight: 18.9±3.2 vs. 20.3±1.6 g, GFP vs. Cre, n=4, p>0.05) or adiposity. Interestingly, SFO ERα knockdown exacerbated hepatic steatosis during diet-induced obesity (Oil Red staining, 8.8±1.9 vs 18.8±2.8 au x 107, GFP vs. Cre, n=7-8, p<0.05), although this was in contrast to improved whole-body glucose tolerance in response to an i.p. glucose load (6.1±0.2 vs 4.7±0.5 AUC x 104, GFP vs. Cre, n=5-6, p<0.05) and upregulation of skeletal muscle long-chain fatty acid b-oxidation genes (e.g. Cpt1: 2.3±0.7 Cre fold GFP, n=4-5, p<0.05). Finally, deletion of SFO ERα was associated with a reduction in circulating estrogen during obesity (80.0±4.3 vs 45.2±12.5 pg/mL, GFP vs. Cre, n=3-4, p=0.06). Collectively, these findings indicate that SFO ERα may differentially regulate target organs during obesity and points to a complex set of interactions whereby SFO estrogen signaling can both positively and negatively regulate peripheral metabolism. R01DK117007, R01HL141393, F31 NIDDK12829388 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Improved Aerobic Capacity and Adipokine Profile Together with Weight Loss Improve Glycemic Control without Changes in Skeletal Muscle GLUT-4 Gene Expression in Middle-Aged Subjects with Impaired Glucose Tolerance.

(1) Objective: The aim of this study was to clarify the role of adipokines in the regulation of glucose metabolism in middle-aged obese subjects with impaired glucose tolerance in response to a long-term exercise and dietary intervention. (2) Methods: Skeletal muscle, plasma and serum samples were examined in 22 subjects from an exercise–diet intervention study aiming to prevent type 2 diabetes. The subjects were further divided into two subgroups (non-responders n = 9 and responders n = 13) based on their achievement in losing at least 3 kg. (3) Results: The two-year exercise–diet intervention reduced leptin levels and increased adiponectin levels in responders; the changes in leptin levels were significantly associated with changes in their weights (r = 0.662, p < 0.01). In responders, insulin sensitivity (Bennett and McAuley index) increased and was associated with changes in maximal oxygen uptake (VO2peak) (r = 0.831, p < 0.010 and r = 0.890, p < 0.01). In addition, the VO2peak and oxidative capacity of skeletal muscle improved in responders, but not in non-responders. However, there were no changes between the two groups in expressions of the glucose transporter protein-4 (GLUT-4) gene or of AMP-activated protein kinase (AMPK)-α1 or AMPK-α2 proteins. (4) Conclusions: The exercise–diet intervention decreased serum leptin and increased serum adiponectin concentrations, improved glucose control without affecting GLUT-4 gene expression in the skeletal muscle in responders.

Weight Loss With a Novel Peptide YY Analogue for Obesity: A Randomised, Placebo-Controlled Phase I Trial

Abstract Background: Obesity and its co-morbidities remain a prime driver of global morbidity and mortality. Current therapies for obesity are limited in efficacy and durability, have serious adverse effects or are not scalable to the numbers required to treat this widespread disease. Gut hormones such as peptide YY (PYY) have emerged as candidate therapies for obesity which activate natural satiety pathways, reduce food intake and therefore body weight. We report the results from a Phase I trial of a PYY analogue, Y14, in overweight volunteers. Methods: In a first time in human Phase I randomized placebo-controlled trial, an extended-release formulation of Y14 with zinc chloride for subcutaneous injection, utilizing various Zn:peptide molar ratios, was tested. Part A of the trial was a partially blinded single ascending dose study. Part B was double-blinded and tested multiple ascending doses given at 7–14 day intervals over the course of 28 days with up to 5 doses given per subject. The primary outcome was the safety and tolerability of extended-release Y14; the secondary outcome was to assess its pharmacokinetics. Exploratory outcomes included the assessment of food consumption, body weight and glucose tolerance in response to 75g oral glucose load after multiple doses of Y14. [ClinicalTrials.gov NCT03673111]. Findings: Between Apr 11, 2017, and Dec 24, 2018 44 participants were enrolled into Part A of the trial and 24 into Part B and were included in the full analysis and safety datasets. The multiple doses of Y14 given in Part B led to significant mean placebo-subtracted reductions in body weight of 2.76 to 3.59 kg at 31 days after the first dose, in association with profound reductions in food intake and no evidence of tachyphylaxis. No significant changes in glucose tolerance were detected. The most common adverse events were nausea, vomiting and injection site reactions. No serious adverse events occurred. The pharmacokinetic characteristics of extended-release Y14 were compatible with administration every 7–14 days. Interpretation: Our results support the continued development of Y14 as a novel treatment for obesity. Funding: UK Medical Research Council Developmental Pathway Funding Scheme.

Myostatin dysfunction is associated with lower physical activity and reduced improvements in glucose tolerance in response to caloric restriction in Berlin high mice.

Myostatin is an inhibitor of skeletal muscle growth and might be involved in adaptations to caloric restriction (CR). We compared responses to 12-week 30% CR in male mice of Berlin high strain with myostatin dysfunction (BEH) and wild-type myostatin (BEH+/+). BEH mice were heavier than BEH+/+ mice (58.8 ± 2.0 versus 53.1 ± 2.7 g, p < 0.001), had 1.8-fold greater hind limb muscle mass and were less (p < 0.05) physically active when fed ad libitum. After CR, BEH and BEH+/+ strains experienced similar weight loss (24.7 ± 5.7 versus 20.6 ± 6.5%, p > 0.05, respectively) and decreases (p < 0.001) in plasma IGF-1 and total cholesterol, but loss of hind limb muscle mass was greater (p < 0.001) in BEH mice than BEH+/+ mice. BEH mice had better (p < 0.001) glucose tolerance and showed smaller (p < 0.05) improvements of it than BEH+/+ mice after CR (1038.2 ± 174.7 versus 744.4 ± 95.8 glucose mM× 120 min, p < 0.01 for BEH; 1365.8 ± 218.5 versus 831.5 ± 134.4 glucose mM ×120 min, p < 0.001, for BEH+/+, respectively). In summary, myostatin dysfunction is associated with muscle hypertrophy and high glucose tolerance, but greater muscle wasting and smaller improvements in glucose tolerance in response to CR.

Abstract 037: Role of Pro-opiomelanocortin (POMC) Specific PTP1B in Differential Regulation of Blood Pressure, Liver Lipid Accumulation and Glucose Tolerance in Response to a High Fat Diet

Obese subjects are often resistant to leptin’s metabolic effects although blood pressure (BP) and sympathetic nervous system responses appear to be preserved. Protein tyrosine phosphatase 1B (PTP1B), a negative regulator of leptin signaling, may play a role in promoting this selective leptin resistance and causing metabolic dysfunction in obesity. Our previous studies suggest that the chronic BP responses to leptin are mediated via activation of pro-opiomelanocortin (POMC) neurons. The goal of this study was to determine if PTP1B in POMC neurons differentially controls metabolic functions and BP in mice fed a high fat diet (HFD). Male mice with POMC specific PTP1B deletion (POMC/PTP1B -/- ) and littermate controls (PTP1B flox/flox ) were fed a HFD from 6 to 22 wks of age. Baseline BP after 16 weeks of a HFD (95±2 vs. 95±3 mmHg) and BP responses to acute stress (Δ32±0 vs. Δ32±6 mmHg), measured by telemetry, were not different in POMC/PTP1B -/- compared to control mice, respectively. Heart rate (HR) was not different in POMC/PTP1B -/- and control mice during acute stress (699±4 vs. 697±15 bpm, respectively). Total body weight (TBW) and fat mass were reduced at 20 weeks of age in POMC/PTP1B -/- compared to controls (36.7±0.1 vs. 42.0±1 g TBW and 12.7±0.4 vs. 16.1±1.0 g fat mass, respectively). Liver weight of POMC/PTP1B -/- mice was less than in controls, and this was evident even when liver weight was normalized as % of TBW (4.5±0.2 vs. 5.0±0.2 %). POMC/PTP1B -/- males had reduced liver lipid accumulation compared to controls as measured by EchoMRI (0.08±0.03 vs. 0.15±0.03 g/g liver weight). Glucose tolerance was also improved by 46% in POMC/PTP1B -/- compared to controls as measured by AUC, 25856±1683 vs. 47267±5616 mg/dLx120min, respectively. These findings indicate that PTP1B signaling in POMC neurons plays a crucial role in regulating liver lipid accumulation and glucose tolerance but does not appear to mediate changes in BP or BP responses to acute stress in mice fed a high HFD (supported by NHLBI-PO1HL51971 and NIGMS P20GM104357)

High-fat diet-induced metabolic disorders impairs 5-HT function and anxiety-like behavior in mice.

The link between type 2 diabetes mellitus (T2DM) and depression is bidirectional. However, the possibility that metabolic disorders may elicit anxiogenic-like/depressive-like symptoms or alter the efficacy of antidepressant drugs remains poorly documented. This study explored the influence of T2DM on emotionality and proposed a therapeutic strategy that might be used in depressed diabetic patients. Mice were fed a high-fat diet (HFD) and subjected to a full comprehensive metabolic and behavioural analysis to establish correlations between metabolic and psychiatric disorders. In vivo intra-hippocampal microdialysis was also applied to propose a mechanism underpinning the phenotype of mice fed the HFD. Finally, we tested whether chronic administration of the selective 5-HT reuptake inhibitor escitalopram or HFD withdrawal could reverse HFD-induced metabolic and behavioural anomalies. The increased body weight, hyperglycaemia and impaired glucose tolerance in response to HFD were correlated with anxiogenic-like/depressive-like symptoms. Moreover, this phenotype was associated with decreased extracellular 5-HT levels in the hippocampus which may result from increased sensitivity of the dorsal raphe 5-HT1A autoreceptor. Interestingly, the beneficial effect of prolonged administration of escitalopram was abolished in HFD-fed mice. On the contrary, HFD withdrawal completely reversed metabolic impairments and positively changed symptoms of anxiety, although some behavioural anomalies persisted. Our data provide clear-cut evidence that both pathologies are finely correlated and associated with impaired 5-HT mediated neurotransmission in the hippocampus. Further experiments are warranted to define the most adequate strategy for the treatment of such co-morbidity. This article is part of a themed section on Updating Neuropathology and Neuropharmacology of Monoaminergic Systems. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v173.13/issuetoc.

Pappa2 deletion alters IGFBPs but has little effect on glucose disposal or adiposity

ObjectiveInsulin-like growth factor binding proteins (IGFBPs) are involved in glucose and lipid metabolism, and their actions are modulated by proteases. The aim of this study was to examine the effects of an IGFBP-5 protease, pregnancy associated plasma protein-A2 (PAPP-A2), on glucose metabolism and susceptibility to diet-induced obesity. DesignPostnatal growth, circulating IGF-I, IGFBP-3 and IGFBP-5 levels, and glucose tolerance were measured in Pappa2 deletion mice and littermate controls on a chow diet. Males were subsequently fed a high-fat diet for 8weeks to measure weight gain and adiposity, as well as glucose tolerance in response to a metabolic challenge. ResultsCirculating IGFBP-5 levels were ~2-fold higher in mice with no functional PAPP-A2 than in littermate controls, as expected. In contrast, circulating IGFBP-3 levels were reduced by ~15-fold, and total IGF-I levels were ~60% higher in Pappa2 deletion mice. There was no effect of Pappa2 deletion on fasting blood glucose levels or glucose clearance after intraperitoneal injection of 2g glucose/kg body weight in mice on a chow diet. In males on a high-fat diet, there was no difference between genotypes in weight gain or adiposity, adjusting for differences in initial body weight, or in fasting blood glucose or insulin levels, or in glucose clearance. ConclusionsDespite a dramatic disruption of the balance between circulating IGF-I, IGFBP-3 and -5, we found no effects of Pappa2 deletion on glucose metabolism, weight gain or adiposity on a high-fat diet.

Reduction of AMPK activity and altered MAPKs signalling in peripheral blood mononuclear cells in response to acute glucose ingestion following a short-term high fat diet in young healthy men

BackgroundPeripheral blood mononuclear cells (PBMCs) are known to respond to systematic changes in nutrient availability. The impact of a short-term high fat diet (HFD), with and without acute glucose ingestion, on the energy-sensing enzyme 5’ AMP-activated protein kinase (AMPK) as well as mitochondrial oxidative phosphorylation (OXPHOS) proteins in PBMCs is currently unknown. MethodsNine healthy, lean young males participated in a 7day HFD intervention, designed to induce transient glucose intolerance. The phosphorylation status and total protein content of AMPK and inflammatory mitogen-activated protein kinases (MAPKs), and total OXPHOS protein in PBMCs, along with circulating cytokines, were assessed in the fasted state and following an oral glucose tolerance test (OGTT) before and after the HFD. ResultsOne week of HFD resulted in relative glucose intolerance. The HFD resulted in a reduction of AMPK phosphorylation under fasting basal conditions and following the OGTT (both P<0.05), while there were no differences in OXPHOS protein expression. Although the short-term HFD had no effect on basal phosphorylation of p38, JNK or ERK1/2, the activation of MAPKs signalling in response to glucose ingestion was attenuated post-HFD as compared to pre-HFD (P<0.05 for all). Circulating cytokines were not significantly affected by the HFD. ConclusionsWe conclude that impaired glucose tolerance in response to 7day HFD resulted in decreased AMPK activity and impaired glucose-stimulated MAPK activation following glucose ingestion in vivo in PBMCs from young, lean subjects. Further studies are warranted to explore how dietary manipulations impact interplay between AMPK and inflammatory signalling, along with immune function, in PBMCs.

Glucose Tolerance in Response to a High‐Fat Diet Is Improved by a High‐Protein Diet

Consumption of a high-fat (HF) diet results in insulin resistance and glucose intolerance. Weight loss is often recommended to reverse these metabolic alterations and the use of a high-protein (HP), low-carbohydrate diet is encouraged. In lean rats, consumption of a HP diet improves glycemic control. However, it is unknown whether this diet has a similar effectiveness in rodents with impaired glucose tolerance. Rats were fed a HF or a chow (CH) diet for 6 weeks and then switched to a HP diet or a CH or pair-fed (PF) to the amount of kcals consumed per day by the HP group. Following the diet switch, body weight gain was attenuated as compared to HF rats, and similar between HP, CH, and PF rats. Despite similar weight progression, HP and PF rats had a significant decrease in body fat after 2 weeks, as compared to HF rats. In contrast, CH rats did not show this effect. Glucose tolerance was attenuated more quickly in HP rats than in CH or PF rats. These results indicate that a HP diet may be more effective than a balanced diet for improving glycemic control in overweight individuals.

16,17-Dihydro-17b-hydroxy isomitraphylline alkaloid as an inhibitor of DPP-IV, and its effect on incretin hormone and β-cell proliferation in diabetic rat

Reduces levels of intact GLP-1 and inhibition of DPPIV augments levels of intact GLP-1 improves glycemic control in type 2 diabetes patients and diabetic animal model. Although, GLP-1 is known to stimulate insulin secretion, insulin biosynthesis and dose insulin gene transcription, augmented supplies of insulin for secretion. DHIM is an indole alkaloid, isolated from Mitragyna parvifolia. In the present in vitro study, we investigated the inhibitor activity of novel alkaloid on DPP IV. DHIM produced marked inhibition of DPP IV. Accordingly, we used 5, 10 and 20μg DHIM alkaloids in DPPIV assay, and then found 18%, 56%, and 68% inhibition activity.In the present in vivo study, we examined the 16,17-dihydro-17b-hydroxy (DHIM) effect on neonatal Wistar albino rats treated with streptozotocin, an established model of type 2 diabetes. Diabetic rats, 8weeks chronic administered with DHIM (100mg/kg) markedly reduced plasma glucose concentration, increased glucose tolerance in response to glucose loading. Consequently, GLP-1and IL-10 levels were also significantly increased in treated diabetic rats. Despite, body weight was not found changed significantly; the insulin content and β-cell mass at 2months were significantly increased by DHIM.Immunostaining and Confocal image of TUNEL assay showed that DHIM stimulates β-cell proliferation and reduced pancreatic cell apoptosis in diabetic treated rats. These results suggest that DHIM induces proliferation of pancreatic cells and increases the formation of β-cells.

Dietary supplementation with decaffeinated green coffee improves diet-induced insulin resistance and brain energy metabolism in mice

ObjectivesThere is accumulating evidence that coffee consumption may reduce risk for type 2 diabetes, a known risk factor for Alzheimer's and other neurological diseases. Coffee consumption is also associated with reduced risk for Alzheimer's disease and non-Alzheimer's dementias. However, preventive and therapeutic development of coffee is complicated by the cardiovascular side effects of caffeine intake. As coffee is also a rich source of chlorogenic acids and many bioactive compounds other than caffeine, we hypothesized that decaffeinated coffee drinks may exert beneficial effects on the brain.MethodsWe have investigated whether dietary supplementation with a standardized decaffeinated green coffee preparation, Svetol®, might modulate diet-induced insulin resistance and brain energy metabolism dysfunction in a high-fat diet mouse model.ResultsAs expected, dietary supplementation with Svetol® significantly attenuated the development of high-fat diet-induced deficits in glucose-tolerance response. We have also found that Svetol® treatment improved brain mitochondrial energy metabolism as determined by oxygen consumption rate. Consistent with this evidence, follow-up gene expression profiling with Agilent whole-genome microarray revealed that the decaffeinated coffee treatment modulated a number of genes in the brain that are implicated in cellular energy metabolism.DiscussionOur evidence is the first demonstration that dietary supplementation with a decaffeinated green coffee preparation may beneficially influence the brain, in particular promoting brain energy metabolic processes.

Effect of an aqueous Russian tarragon extract on glucose tolerance in response to an oral dextrose load in non-diabetic men

Effect of an aqueous Russian tarragon extract on glucose tolerance in response to an oral dextrose load in non-diabetic men Richard J Bloomer1, Robert E Canale1, Ivo Pischel21Cardiorespiratory/Metabolic Laboratory, The University of Memphis, Memphis, TN, USA; 2PhytoLab GmbH &amp; Co. KG, Vestenbergsgreuth, GermanyBackground: Russian tarragon extracts have been reported to have anti-diabetic activity in animals. This pilot study aimed to investigate the acute effects of an aqueous extract of Russian tarragon (RT) on serum glucose and insulin in response to an oral glucose tolerance test (OGTT).Methods: Using a randomized, double-blind, cross-over design, 12 non-diabetic men reported to the lab on 2 different mornings separated by 1 to 2 weeks, and ingested 75 g of dextrose in solution. Fifteen minutes before ingestion, subjects ingested either 2 g of RT or a placebo. Blood samples were collected before ingestion of the RT and placebo, and at 15, 30, 45, 60, and 75 minutes post ingestion of the dextrose load. Samples were assayed for serum glucose and insulin.Results: For serum glucose, no condition (P = 0.19) or condition &times; time (P = 0.99) effect was noted. A time effect was noted (P &lt; 0.0001), with values at 15 and 30 minutes higher than pre-ingestion (P &lt; 0.05). No area under the curve (AUC) effect (P = 0.54) was noted, although a 4.5% reduction in AUC was observed for RT (569 &plusmn; 92 mg &middot; dL&minus;1 &middot; 75 min&minus;1) vs placebo (596 &plusmn; 123 mg&nbsp;&middot; dL&minus;1&nbsp;&middot; 75 min&minus;1). Similar findings were noted for serum insulin, with no condition (P = 0.24) or condition &times; time (P = 0.98) effect noted. A time effect was noted (P &lt; 0.0001), with values at 15, 30, and 45 minutes higher than pre-ingestion (P &lt; 0.05). No AUC effect (P = 0.53) was noted, although a 17.4% reduction in AUC was observed for RT (114 &plusmn; 22 &micro;IU&nbsp;&middot; mL&minus;1&nbsp;&middot; 75 min&minus;1) vs placebo (138 &plusmn; 30 &micro;IU &middot; mL&minus;1&nbsp;&middot; 75 min&minus;1). Approximately two-thirds of subjects ingesting the RT experienced attenuation in both the glucose and insulin response to the OGTT.Conclusion: These data indicate that acute ingestion of RT results in a slight, non-statistically significant lowering of blood glucose in response to a dextrose load. This occurs in the presence of a slightly lower insulin response. These findings are specific to a small sample of healthy, non-diabetic men. Additional study is needed involving a larger sample of individuals with pre-diabetes or untreated diabetes.Keywords: Artemisia dracunculus L., glucose, insulin resistance, nutritional supplements, Russian tarragon

Prdm16 determines the thermogenic program of subcutaneous white adipose tissue in mice

The white adipose organ is composed of both subcutaneous and several intra-abdominal depots. Excess abdominal adiposity is a major risk factor for metabolic disease in rodents and humans, while expansion of subcutaneous fat does not carry the same risks. Brown adipose produces heat as a defense against hypothermia and obesity, and the appearance of brown-like adipocytes within white adipose tissue depots is associated with improved metabolic phenotypes. Thus, understanding the differences in cell biology and function of these different adipose cell types and depots may be critical to the development of new therapies for metabolic disease. Here, we found that Prdm16, a brown adipose determination factor, is selectively expressed in subcutaneous white adipocytes relative to other white fat depots in mice. Transgenic expression of Prdm16 in fat tissue robustly induced the development of brown-like adipocytes in subcutaneous, but not epididymal, adipose depots. Prdm16 transgenic mice displayed increased energy expenditure, limited weight gain, and improved glucose tolerance in response to a high-fat diet. shRNA-mediated depletion of Prdm16 in isolated subcutaneous adipocytes caused a sharp decrease in the expression of thermogenic genes and a reduction in uncoupled cellular respiration. Finally, Prdm16 haploinsufficiency reduced the brown fat phenotype in white adipose tissue stimulated by β-adrenergic agonists. These results demonstrate that Prdm16 is a cell-autonomous determinant of a brown fat-like gene program and thermogenesis in subcutaneous adipose tissues.

Daytime variability of postprandial glucose tolerance and pancreatic B‐cell function using 12‐h profiles in persons with Type 2 diabetes

To study the variation in daytime glucose tolerance and pancreatic B-cell function at different levels of glycated haemoglobin (HbA(1c)) in subjects with Type 2 diabetes (T2DM). T2DM subjects (n = 49; 34 men) had 12-h daytime plasma glucose (PG), insulin (PI), total (PTp) and intact proinsulin (PIp) profiles determined in response to three identical test meals at 4-h intervals. Subjects were divided into three groups according to HbA(1c)--group 1: < 7.3% (n = 18); group 2: 7.3-8.0% (n = 17); group 3: > 8.0% (n = 14). Fasting and preprandial (prior to meals 2 and 3) concentrations, total area under the curve (AUC), AUC above fasting (dAUC) and maximum postprandial metabolic concentrations (C(max)) were compared between the three meals and across the groups. Subjects in group 1 had significantly higher fasting plasma glucose (FPG) compared with preprandial PG concentrations (7.1 +/- 0.2 vs. 5.9 +/- 0.3 vs. 5.4 +/- 0.2; P < 0.01). Subjects in groups 2 and 3 had significantly higher FPG compared with preprandial PG levels prior to meal 3. PG.dAUC was highest in response to meal 1 and lowest following meal 2 (P < 0.05). FPI concentrations were significantly lower compared with preprandial PI concentrations. Subjects in group 1 had significantly higher PI prior to meal 2 compared with meal 3. PI.dAUC was highest in response to meal 1. Subjects in group 1 had lowest PI.dAUC following meal 2. FTp and FIp concentrations were also significantly lower compared with preprandial concentrations. PTp.dAUC and PIp.dAUC was highest in response to meal 1. There appears to be a shift in diurnal variation in glucose homeostasis and pancreatic B-cell function. Subjects had decreased glucose tolerance in response to the first and third meal of the day irrespective of glycaemic control. The variability in glucose tolerance was reflected by both quantitative and qualitative dysfunction of the pancreatic B-cell.

Promotion of beta-cell differentiation by conophylline in fetal and neonatal rat pancreas.

Conophylline is a vinca alkaloid extracted from the tropical plant Ervatamia microphylla and has been shown to induce differentiation of pancreatic AR42J cells. In the present study, we investigated the effect of conophylline on the differentiation of pancreatic precursor cells. In the rat pancreatic rudiment in organ culture, conophylline inhibited the formation of cystic structure and increased the number of insulin-positive cells. Conophylline also markedly increased the expression of mRNA for insulin and the number of pancreatic duodenal homeobox-1-positive cells. These effects of conophylline were similar to those of activin A. We also examined the effect of conophylline on neonatal rats treated with streptozotocin, a model of type 2 diabetes. Treatment with conophylline significantly reduced the plasma glucose concentration and improved glucose tolerance in response to glucose loading. The insulin content and the beta-cell mass at 2 months were significantly increased by conophylline. The number of islet-like cell clusters and pancreatic duodenal homeobox-1-positive ductal cells was greater in conophylline-treated rats. These results suggest that conophylline induces differentiation of pancreatic precursor cells and increases the formation of beta-cells.

Modest lifestyle intervention and glucose tolerance in obese African Americans.

Previous studies have demonstrated the benefit of short-term diets on glucose tolerance in obese individuals. The purpose of this study was to evaluate the effectiveness of modest lifestyle changes in maintaining improvements in glucose tolerance induced by short-term energy restriction in obese African Americans with impaired glucose tolerance or type 2 diabetes mellitus. An intervention group (n = 45; 47 +/- 1 year [mean +/- SE]), 105 +/- 4 kg; body mass index: 39 +/- 1 kg/m(2)) received an energy-restricted diet (943 +/- 26 kcal/d) for 1 week, followed by a lifestyle program of reduced dietary fat (-125 kcal/d) and increased physical activity (+125 kcal/d) for 1 year. Body weight and plasma concentrations of glucose, insulin, and C-peptide during an oral glucose tolerance test were measured at baseline, 1-week, and 4-month intervals. A control group (n = 24; 48 +/- 1 year; 110 +/- 5 kg; body mass index: 41 +/- 2 kg/m(2)) underwent these measurements at 4-month intervals. No changes in weight or glucose tolerance were observed in the control group. The intervention group had significant (p < 0.05) improvements in body weight and glucose tolerance in response to the 1-week diet, which persisted for 4 months (p < 0.001 vs. control for change in weight). A total of 19 subjects (42%) continued the intervention program for 1 year, with sustained improvements (weight: -4.6 +/- 1.0 kg; p < 0.001 vs. control; oral glucose tolerance test glucose area: -103 +/- 44 mM. min; p < 0.05 vs. control). A modest lifestyle program facilitates weight loss and enables improvements in glucose tolerance to be maintained in obese individuals with abnormal glucose tolerance. However, attrition was high, despite the mild nature of the program.

Effects of parathyroid hormone infusion on glucose tolerance and glucose-stimulated insulin secretion in normal and uremic rats

We used thyroparathyroidectomized (TPTX) rats with hypocalcemia to evaluate the effects of parathyroid hormone (PTH) infusion on glucose tolerance and glucose-stimulated insulin secretion in normal and uremic rats. Animals were subjected to oral glucose tolerance test (OGTT) and glucose-stimulated insulin secretion before and after TPTX or after their plasma calcium level was normalized by PTH infusion, vitamin D injection or calcium load. In both normal and uremic groups, TPTX produced a significant increase in area under the cure (AUC) of plasma glucose from 0 to 6 h in response to an oral glucose challenge and decrease plasma insulin level in response to glucose-stimulated insulin secretion. Before TPTX, uremic animals have a normal basal plasma insulin level (29±3 versus 31±2 μU/ml) and a normal glucose-stimulated insulin secretion, but significantly increase plasma glucose AUC in response to OGTT as compared with normal rats. TPTX worsen the response of glucose intolerance in uremic rats. After PTH infusion, vitamin D injection or calcium load, all rats in the response of OGTT and glucose-stimulated insulin secretion are recovered to the level before TPTX including normal and uremic rats, but uremic rats still have an abnormal glucose tolerance in response to OGTT. Uremic rats have a low basal plasma glucose level as compared with normal rats. TPTX significantly increase basal plasma glucose level in normal and uremic rats, but the uremic rats with TPTX have been found to elevate basal plasma glucose level to the range of normal rats. The basal plasma glucose level of normal rats with TPTX was recovered to the range before TPTX by PTH infusion, vitamin D injection or calcium load, but PTH infusion, vitamin D injection or calcium load did not decrease the level of basal plasma glucose in uremic rats with TPTX. All TPTX rats, including intact kidney or five-sixths Nx rats, were treated three times weekly by subcutaneous injection of 8 μg/kg l-thyroxin. These results indicate that uremia may produce thyroid dysfunction and PTH infusion did not affect the glucose tolerance in OGTT and glucose-stimulated insulin secretion in normal and uremic rats. In addition to PTH, other uremic toxins may be responsible for the glucose intolerance of uremia.

Biotin administration improves the impaired glucose tolerance of streptozotocin-induced diabetic Wistar rats.

The effect of biotin administration on the glucose tolerance of streptozotocin (STZ)-induced diabetic Wistar rats was investigated. STZ-induced diabetes was induced by intraperitoneal injection of streptozotocin (45 mg/kg body weight as a single dose). The impaired glucose tolerance in response to an oral glucose load (1.8g per kg body weight) in STZ-induced diabetic rats (STZ-rat) was partially improved by intraperitoneal administration of biotin for 15 days (100 micrograms/rat/day). However, a recovery in the STZ-rat's insulin secretion was not found after biotin administration. To help clarify the mechanism underlying the improvement in glucose tolerance seen with biotin treatment, glucokinase and hexokinase activities were determined in the liver and pancreas. In STZ-rats that had received biotin (STZ-biotin rats), glucokinase activity was higher by 3.4-fold in liver and by 2.4-fold in pancreas than in the STZ-rats. The biotin level of STZ-rats was significantly lower in the liver and pancreas than that of the control rats (no STZ administration); but in STZ-biotin rats, the level in these organs recovered to the control level. These results demonstrate that injected biotin can improve glucose handling without increasing insulin secretion in STZ-rats.

Acute effects of a zinc supplement taken before a glucose load.

Observations from animal studies suggest that individuals who consume oral zinc supplements may show elevations in blood glucose. To examine whether this effect occurs in humans, we conducted glucose and zinc tolerance tests on eight adult women volunteers. All eight volunteers were subjected to two test conditions: (a) ingestion of 50 g D-glucose and (b) ingestion of 110 mg ZnSO4.7H2O followed 60 minutes later by ingestion of 50 g D-glucose. Two subjects also ingested 110 mg ZnSO4.7H20 without glucose. Blood samples were drawn before and 15, 30, 45, 60, 90 and 120 minutes following consumption of the glucose solutions, and were analyzed for glucose and zinc content. Our results did not indicate significantly altered glucose tolerance in response to the acute elevation of plasma zinc. These preliminary data suggest that increasing plasma zinc prior to elevating blood glucose does not alter the rate of glucose removal from circulation or the area under the glucose curve in normal individuals.