Insulin Sensitivity Of Glucose Metabolism Research Articles

Insulin Similar to Activator of KCNQ1 Channel Recovers the Prolonged Repolarization of Ventricular Cardiomyocytes from Insulin Resistant Aged Rats

Both cardiac dysfunction and systemic insulin resistance mostly observed together with advancing aging or metabolic syndrome (MetS), while the exact underlying mechanisms of heart‐specific insulin resistance and cardiac dysfunction still remain unclear. There also are relations between delayed ventricular repolarization, increased risk in arrhythmia and QT‐prolongation in ECG with diabetes, aging and MetS. They also showed that the mutations/functional alterations in QT‐prolongation related K+‐channels such as KCNQ1‐channels might be responsible for these changes. In addition, most of recent observations that insulin sensitivity of glucose metabolism are affected by a new molecule KCNQ1, which brings up a thought on possible relation of development of insulin resistance, changes in this channel and QT‐prolongations in senescent mammalian cardiomyocytes. Therefore, we aimed to clarify a possible association between prolonged action potential duration and alterations in KCNQ1‐channel function as well as insulin application in ventricular cardiomyocytes from either insulin resistant aged or MetS rats. Our data showed that there is a significant prolongation in action potential repolarization phase in isolated cardiomyocytes from insulin‐resistant aged or MetS rats, while those animals have a significant prolonged‐QT in ECG and can respond to insulin application. Besides, application of KCNQ1‐channel activator reduced the prolonged action potential repolarizations and this indicates the contribution of KCNQ1‐currents and possible benefits of insulin on action potential prolongation of both aged and MetS cardiomyocytes. Our present study also showed that the protein expression level of KCNQ1 and KCNE1 remained unchanged. Overall, our present results can reveal important information on the contributions of these parameters on the aging‐related or metabolic syndrome‐related cardiac dysfunction and the effect of insulin on these alterations. Therefore, our findings will contribute to the literature and the clinical applications with a new therapeutic approach by revealing the molecular mechanisms of insulin treatment on insulin resistant aged or MetS mammalian cardiac dysfunction.Support or Funding InformationSupported through TUBITAK SBAG‐119S661

Sex-specific programming of adult insulin resistance in guinea pigs by variable perinatal growth induced by spontaneous variation in litter size.

Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in programming of insulin resistance later in life. Spontaneous IUGR in the guinea pig, due to natural variation in litter size, produces offspring with asymmetric IUGR and neonatal catch-up growth. We hypothesized that spontaneous IUGR and/or accelerated neonatal growth would impair insulin sensitivity in adult guinea pigs. Insulin sensitivity of glucose metabolism was determined by hyperinsulinemic-euglycemic clamp (HEC) in 38 (21 male, 17 female) young adult guinea pigs from litters of two-to-four pups. A subset (10 male, 8 female) were infused with d-[3-3H]glucose before and during the HEC to determine rates of basal and insulin-stimulated glucose utilization, storage, glycolysis, and endogenous glucose production. n males, the insulin sensitivity of whole body glucose uptake ( r = 0.657, P = 0.002) and glucose utilization ( r = 0.884, P = 0.004) correlated positively and independently with birth weight, but not with neonatal fractional growth rate (FGR10-28). In females, the insulin sensitivity of whole body and partitioned glucose metabolism was not related to birth weight, but that of endogenous glucose production correlated negatively and independently with FGR10-28 ( r = -0.815, P = 0.025). Thus, perinatal growth programs insulin sensitivity of glucose metabolism in the young adult guinea pig and in a sex-specific manner; impaired insulin sensitivity, including glucose utilization, occurs after IUGR in males and impaired hepatic insulin sensitivity after rapid neonatal growth in females.

Validation of different measures of insulin sensitivity of glucose metabolism in dairy cows using the hyperinsulinemic euglycemic clamp test as the gold standard

The aim of the present research was to compare different measures of insulin sensitivity in dairy cows at the end of the dry period. To do so, 10 clinically healthy dairy cows with a varying body condition score were selected. By performing hyperinsulinemic euglycemic clamp (HEC) tests, we previously demonstrated a negative association between the insulin sensitivity and insulin responsiveness of glucose metabolism and the body condition score of these animals. In the same animals, other measures of insulin sensitivity were determined and the correlation with the HEC test, which is considered as the gold standard, was calculated. Measures derived from the intravenous glucose tolerance test (IVGTT) are based on the disappearance of glucose after an intravenous glucose bolus. Glucose concentrations during the IVGTT were used to calculate the area under the curve of glucose and the clearance rate of glucose. In addition, glucose and insulin data from the IVGTT were fitted in the minimal model to derive the insulin sensitivity parameter, Si. Based on blood samples taken before the start of the IVGTT, basal concentrations of glucose, insulin, NEFA, and β-hydroxybutyrate were determined and used to calculate surrogate indices for insulin sensitivity, such as the homeostasis model of insulin resistance, the quantitative insulin sensitivity check index, the revised quantitative insulin sensitivity check index and the revised quantitative insulin sensitivity check index including β-hydroxybutyrate. Correlation analysis revealed no association between the results obtained by the HEC test and any of the surrogate indices for insulin sensitivity. For the measures derived from the IVGTT, the area under the curve for the first 60 min of the test and the Si derived from the minimal model demonstrated good correlation with the gold standard.

Effects of acute exposure to increased plasma branched-chain amino acid concentrations on insulin-mediated plasma glucose turnover in healthy young subjects.

BackgroundPlasma branched-chain amino acids (BCAA) are inversely related to insulin sensitivity of glucose metabolism in humans. However, currently, it is not known whether there is a cause-and-effect relationship between increased plasma BCAA concentrations and decreased insulin sensitivity.ObjectiveTo determine the effects of acute exposure to increased plasma BCAA concentrations on insulin-mediated plasma glucose turnover in humans.MethodsTen healthy subjects were randomly assigned to an experiment where insulin was infused at 40 mU/m2/min (40U) during the second half of a 6-hour intravenous infusion of a BCAA mixture (i.e., BCAA; N = 5) to stimulate plasma glucose turnover or under the same conditions without BCAA infusion (Control; N = 5). In a separate experiment, seven healthy subjects were randomly assigned to receive insulin infusion at 80 mU/m2/min (80U) in association with the above BCAA infusion (N = 4) or under the same conditions without BCAA infusion (N = 3). Plasma glucose turnover was measured prior to and during insulin infusion.ResultsInsulin infusion completely suppressed the endogenous glucose production (EGP) across all groups. The percent suppression of EGP was not different between Control and BCAA in either the 40U or 80U experiments (P > 0.05). Insulin infusion stimulated whole-body glucose disposal rate (GDR) across all groups. However, the increase (%) in GDR was not different [median (1st quartile – 3rd quartile)] between Control and BCAA in either the 40U ([199 (167–278) vs. 186 (94–308)] or 80 U ([491 (414–548) vs. 478 (409–857)] experiments (P > 0.05). Likewise, insulin stimulated the glucose metabolic clearance in all experiments (P < 0.05) with no differences between Control and BCAA in either of the experiments (P > 0.05).ConclusionShort-term exposure of young healthy subjects to increased plasma BCAA concentrations does not alter the insulin sensitivity of glucose metabolism.

Diurnal variation in insulin sensitivity of glucose metabolism is associated with diurnal variations in whole-body and cellular fatty acid metabolism in metabolically normal women.

The mechanism(s) responsible for diurnal variations in insulin sensitivity of glucose metabolism in healthy people are unclear. The objective of the study was to evaluate whether diurnal variations in whole-body and cellular fatty acid metabolism could contribute to evening insulin resistance in metabolically normal people. We measured plasma the free fatty acid (FFA) concentration, palmitate kinetics, and skeletal muscle expression of genes involved in fatty acid metabolism at breakfast (7:00 am) and dinner (7:00 pm) in 13 overweight (body mass index 27.8 ± 1.2 kg/m(2)) but metabolically normal, women. Plasma FFA concentration was approximately 30% greater just before consuming dinner than breakfast (P < .05) and remained greater after dinner than breakfast (FFA areas under the curve: 0.88 ± 0.33 and 0.51 ± 0.09 μmol/mL × 4 h, P = .001). However, adipose tissue lipolytic activity was not different in the evening and in the morning. Skeletal muscle expression of genes that regulate fatty acid oxidation were 38-82% lower, whereas genes involved in de novo lipogenesis were 51%-87 % higher before dinner than before breakfast (all P < .05), and these changes were associated with diurnal variation in the muscle expression of core clock genes that regulate fatty acid metabolism. Metabolically normal women demonstrate diurnal variations in fatty acid metabolism, manifested by an increase in circulating FFAs, presumably derived from previous meal consumption rather than lipolysis of adipose tissue triglycerides, and a shift in muscle fatty acid metabolism from oxidation to lipogenesis. These metabolic alterations could be responsible for the known evening decline in insulin sensitivity.

Prolonged Rapamycin treatment led to beneficial metabolic switch

Prolonged Rapamycin treatment led to beneficial metabolic switch

Genetic variation in PNPLA3 (adiponutrin) confers sensitivity to weight loss–induced decrease in liver fat in humans

The rs738409 C→G single nucleotide polymorphism in the patatin-like phospholipase domain-containing 3 (PNPLA3; adiponutrin) leads to a missense mutation (I148M), which is associated with increased liver fat but not insulin resistance. The I148M mutation impedes triglyceride hydrolysis in vitro, and its carriers have an increased risk of developing severe liver disease. We explored whether the rs738409 PNPLA3 G allele influences the ability of weight loss to decrease liver fat or change insulin sensitivity. We recruited 8 subjects who were homozygous for the rs738409 PNPLA3 G allele (PNPLA3-148MM) and 10 who were homozygous for the rs738409 PNPLA3 C allele (PNPLA3-148II). To allow comparison of changes in liver fat, the groups were matched with respect to baseline age, sex, body mass index, and liver fat. The subjects were placed on a hypocaloric low-carbohydrate diet for 6 d. Liver fat content (proton magnetic resonance spectroscopy), whole-body insulin sensitivity of glucose metabolism (euglycemic clamp technique), and lipolysis ([(2)H(5)]glycerol infusion) were measured before and after the diet. At baseline, fasting serum insulin and C-peptide concentrations were significantly lower in the PNPLA3-148MM group than in the PNPLA3-148II group, as predicted by study design. Weight loss was not significantly different between groups (PNPLA3-148MM: -3.1 ± 0.5 kg; PNPLA3-148II: -3.1 ± 0.4 kg). Liver fat decreased by 45% in the PNPLA3-148MM group (P < 0.001) and by 18% in the PNPLA3-148II group (P < 0.01). Weight loss is effective in decreasing liver fat in subjects who are homozygous for the rs738409 PNPLA3 G or C allele. This trial was registered at www.hus.fi as 233775.

Protein Anabolic Responses to a Fed Steady State in Healthy Aging

Protein anabolism in response to feeding may be impaired with aging. To determine if this could contribute to muscle loss, we studied fed-state metabolic responses in healthy, non-sarcopenic elderly women. Whole-body [(3)H]glucose and protein ([(13)C]leucine) kinetics were measured, and muscle protein fractional synthesis rate ([(2)H(5)]phenylalanine) and signaling events were assessed from vastus lateralis biopsies in eight elderly (73 ± 3 years) and eight young women (24 ± 1 years), using a simulated fed steady-state clamp. Both groups had similar muscle and lean body mass indices and activity level. During insulin, glucose (8 mmol/L), and amino acid (AA; 2× fasting) infusions, serum insulin was lower in the elderly women and C-peptide increased less. Glucose uptake was stimulated, and production suppressed similarly. Suppression of whole-body protein breakdown was less in the elderly women, leading to lower AA infusion rates, oxidation, and net positive protein balance, but differences were not present when adjusted for serum insulin. Whole-body protein synthesis and muscle protein fractional synthesis rate increased similarly. Similar increases in phosphorylated Akt(Ser473), PRAS40(Thr246), FoxO3a(Thr32), and rpS6(Ser240/244) indicated no alterations in insulin/nutrient signaling with aging. Both whole-body and muscle fed-state protein anabolic responses were preserved, as was insulin sensitivity of glucose metabolism, in active, healthy elderly women. This is consistent with other factors such as sedentarity, low protein intake, and concurrent diseases, being responsible for the sarcopenia of aging.

Differential effects of various fish proteins in altering body weight, adiposity, inflammatory status, and insulin sensitivity in high-fat–fed rats

Mounting evidence suggests that the benefits of fish consumption are not limited to the well-appreciated effects of omega-3 fatty acids. We previously demonstrated that cod protein protects against the development of diet-induced insulin resistance. The goal of this study was to determine whether other fish protein sources present similar beneficial effects. Rats were fed a high-fat, high-sucrose diet containing protein from casein or fish proteins from bonito, herring, mackerel, or salmon. After 28 days, oral glucose tolerance tests or hyperinsulinemic-euglycemic clamps were performed; and tissues and plasma were harvested for biochemical analyses. Despite equal energy intake among all groups, the salmon-protein–fed group presented significantly lower weight gain that was associated with reduced fat accrual in epididymal white adipose tissue. Although this reduction in visceral adiposity was not associated with improved glucose tolerance, we found that whole-body insulin sensitivity for glucose metabolism was improved using the very sensitive hyperinsulinemic-euglycemic clamp technique. Importantly, expression of both tumor necrosis factor–α and interleukin-6 was reduced in visceral adipose tissue of all fish-protein–fed groups when compared with the casein-fed control group, suggesting that fish proteins carry anti-inflammatory properties that may protect against obesity-linked metabolic complications. Interestingly, consumption of the salmon protein diet was also found to raise circulating salmon calcitonin levels, which may underlie the reduction of weight gain in these rats. These data suggest that not all fish protein sources exert the same beneficial properties on the metabolic syndrome, although anti-inflammatory actions appear to be common.

Enhanced insulin sensitivity of gene-targeted mice lacking functional KCNQ1

The pore-forming K+-channel alpha-subunit KCNQ1 is expressed in a wide variety of tissues including heart, skeletal muscle, liver, and epithelia. Most recent evidence revealed an association of the KCNQ1 gene with the susceptibility to type 2 diabetes. KCNQ1 participates in the regulation of cell volume, which is, in turn, critically important for the regulation of metabolism by insulin. The present study explored the influence of KCNQ1 on insulin-induced cellular K+ uptake and glucose metabolism. Insulin (100 nM)-induced K+ uptake was determined in isolated perfused livers from KCNQ1-deficient mice (kcnq1(-/-)) and their wild-type littermates (kcnq1(+/+)). Moreover, plasma glucose and insulin levels, intraperitoneal glucose (3 g/kg) tolerance, insulin (0.15 U/kg)-induced hypoglycemia, and peripheral uptake of radiolabeled 3H-deoxy-glucose were determined in both genotypes. Insulin-stimulated hepatocellular K+ uptake was significantly more sustained in isolated perfused livers from kcnq1(-/-) mice than from kcnq1(+/+)mice. The decline of plasma glucose concentration following an intraperitoneal injection of insulin was again significantly more sustained in kcnq1(-/-) than in kcnq1(+/+) mice. Both fasted and nonfasted plasma glucose and insulin concentrations were significantly lower in kcnq1(-/-) than in kcnq1(+/+)mice. Following an intraperitoneal glucose injection, the peak plasma glucose concentration was significantly lower in kcnq1(-/-) than in kcnq1(+/+)mice. Uptake of 3H-deoxy-glucose into skeletal muscle, liver, kidney and lung tissue was significantly higher in kcnq1(-/-) than in kcnq1(+/+)mice. In conclusion, KCNQ1 counteracts the stimulation of cellular K+ uptake by insulin and thereby influences K+-dependent insulin signaling on glucose metabolism. The observations indicate that KCNQ1 is a novel molecule affecting insulin sensitivity of glucose metabolism.

Protein Feeding Promotes Redistribution of Endogenous Glucose Production to the Kidney and Potentiates Its Suppression by Insulin

The aim of this study was to assess in rats the effect of protein feeding on the: 1) distribution of endogenous glucose production (EGP) among gluconeogenic organs, and 2) repercussion on the insulin sensitivity of glucose metabolism. We used gene expression analyses, a combination of glucose tracer dilution and arteriovenous balance to quantify specific organ release, and hyperinsulinemic euglycemic clamps to assess EGP and glucose uptake. Protein feeding promoted a dramatic induction of the main regulatory gluconeogenic genes (glucose-6 phosphatase and phosphoenolpyruvate carboxykinase) in the kidney, but not in the liver. As a consequence, the kidney glucose release was markedly increased, compared with rats fed a normal starch diet. Protein feeding ameliorated the suppression of EGP by insulin and the sparing of glycogen storage in the liver but had no effect on glucose uptake. Combined with the previously reported induction of gluconeogenesis in the small intestine, the present work strongly suggests that a redistribution of glucose production among gluconeogenic organs might occur upon protein feeding. This phenomenon is in keeping with the improvement of insulin sensitivity of EGP, most likely involving the hepatic site. These data shed a new light on the improvement of glucose tolerance, previously observed upon increasing the amount of protein in the diet, in type 2 diabetic patients.

Age-related insulin resistance in hypothalamus and peripheral tissues of orexin knockout mice

Orexin/hypocretin is a hypothalamic neuropeptide that regulates motivated behaviours, such as feeding and arousal, and, importantly, is also involved in energy homeostasis. The aim of this study was to reveal the role of orexin in the regulation of insulin sensitivity for glucose metabolism. Orexin knockout mice fasted overnight underwent oral glucose tolerance testing and insulin tolerance testing. The impact of orexin deficiency on insulin signalling was studied by Western blotting to measure levels of Akt phosphorylation and its upstream and downstream molecules in the hypothalamus, muscle and liver in orexin knockout mice. We found that orexin deficiency caused the age-related development of impaired glucose tolerance and insulin resistance in both male mice without obesity and female mice with mild obesity, fed a normal chow diet. When maintained on a high-fat diet, these abnormalities became more pronounced exclusively in female orexin knockout mice that developed severe obesity. Insulin signalling through Akt was disrupted in peripheral tissues of middle-aged (9-month-old) but not young adult (2-to-3-month-old) orexin knockout mice fed a normal chow diet. Moreover, basal levels of hypothalamic Akt phosphorylation were abnormally elevated in orexin knockout mice at every age studied, and insulin stimulation failed to increase the level of phosphorylation. Similar abnormalities were observed with respect to GSK3beta phosphorylation in the hypothalamus and peripheral tissues of middle-aged orexin knockout mice. Our results demonstrate a novel role for orexin in hypothalamic insulin signalling, which is likely to be responsible for preventing the development of peripheral insulin resistance with age.

Sex-specific effects of placental restriction on components of the metabolic syndrome in young adult sheep

Prenatal and early postnatal life experiences, reflected by size at birth and postnatal catch-up growth, contribute to the risk of developing the metabolic syndrome in adulthood, but their relative importance is unclear. Therefore, we determined the effects of restricted placental and fetal growth on components of the metabolic syndrome in young adult sheep and the relationships of the latter to size at birth and early postnatal growth. Fasting plasma metabolites, glucose tolerance (by intravenous glucose tolerance test, IVGTT), insulin secretion and sensitivity, and resting blood pressure were measured in 22 control and 20 placentally restricted (PR) 1-yr-old sheep. In male sheep, PR increased the initial rise in glucose during an IVGTT and reduced diastolic blood pressure, and small size at birth independently predicted reduced adult size, glucose tolerance, and fasting plasma insulin and insulin disposition of glucose metabolism but increased insulin disposition of circulating FFAs. Also in males, high fractional growth rates in early postnatal life independently predicted impaired early glucose clearance during an IVGTT. In female animals, PR increased insulin sensitivity of glucose metabolism and reduced fasting plasma FFAs, and thinness at birth predicted increased adult size, fasting blood glucose, and pulse pressure. In conclusion, PR and small size at birth are associated with more components of the metabolic syndrome in adult male than in adult female sheep, with few independent effects of early postnatal growth. These sex differences in the onset and extent of adverse metabolic consequences after prenatal restraint in the sheep are consistent with observations in humans.

Exercise training reduces fatty acid availability and improves the insulin sensitivity of glucose metabolism

It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. We randomised 17 sedentary overweight male subjects (age 50 +/- 2.6 years, BMI 27.6 +/- 0.5 kg/m(2)) to a 6-week exercise programme (n = 10) or control group (n = 7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg(-1) min(-1)]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. After 6 weeks, fasting glycerol, palmitic acid Ra (p = 0.003, p = 0.042) and NEFA concentration (p = 0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p = 0.026; p = 0.007 and p = 0.04). There was no change in muscle triacylglycerol and liver fat in either group. Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

Gut–Brain Axis: Regulation of Glucose Metabolism

Obesity and type II diabetes mellitus have reached epidemic proportions. From this perspective, knowledge about the regulation of satiety and food intake is more important than ever. The gut releases several peptides upon feeding, which affect hypothalamic pathways involved in the regulation of satiety and metabolism. Within the hypothalamus, there are complex interactions between many nuclei of which the arcuate nucleus is considered as one of the most important hypothalamic centres that regulates food intake. The neuropeptides, which are present in the hypothalamus and are involved in regulating food intake, also play a key role in regulating glucose metabolism and energy expenditure. In synchrony with the effects of those neuropeptides, gastrointestinal hormones also affect glucose metabolism and energy expenditure. In this review, the effects of the gastrointestinal hormones ghrelin, cholecystokinin, peptide YY, glucagon-like peptide, oxyntomodulin and gastric inhibitory polypeptide on glucose and energy metabolism are reviewed. These gut hormones affect glucose metabolism at different levels: by altering food intake and body weight, and thereby insulin sensitivity; by affecting gastric delay and gut motility, and thereby meal-related fluctuations in glucose levels; by affecting insulin secretion, and thereby plasma glucose levels, and by affecting tissue specific insulin sensitivity of glucose metabolism. These observations point to the notion of a major role of the gut-brain axis in the integrative physiology of whole body fuel metabolism.

Effects of Non-protein Energy Intake on the Concentrations of Plasma Metabolites and Insulin, and Tissue Responsiveness and Sensitivity to Insulin in Goats

A glucose clamp technique was used to investigate the effects of non-protein energy intake on tissue responsiveness and sensitivity to insulin for glucose metabolism in intact adults male goats. Three goats were fed diets at 1.0, 1.5 and 2.0 times of ME for maintenance, each for 21 d. Crude protein intake was 1.5 times of maintenance requirement in each treatment. Tissue responsiveness and sensitivity to insulin were evaluated using a hyperinsulinemic euglycemic clamp technique with four levels of insulin infusion, beginning at 13 h after feeding. Concentrations of plasma metabolites and insulin were also measured at 3, 6 and 13 h after feeding, for evaluating effects of non-protein energy intake on the metabolic status of the animals. Increasing non-protein energy intake prevented an increase in plasma NEFA concentration at 13 h after feeding (p = 0.03). Plasma urea-nitrogen and total amino-nitrogen concentrations decreased (p<0.01) and increased (p = 0.03), respectively, with increasing non-protein energy intake across time relating to feeding. Plasma insulin concentration was unaffected (p = 0.43) by non-protein energy intake regardless of time relating to feeding. In the glucose clamp experiment, increasing non-protein energy intake decreased numerically (p = 0.12) the plasma insulin concentration at half-maximal glucose infusion rate (insulin-sensitivity), but did not affect (p = 0.60) maximal glucose infusion rate (tissue responsiveness to insulin). The present results suggest that an increase in non-protein energy intake may enhance insulin sensitivity for glucose metabolism, unlike responsiveness to insulin, in adult male goats. The possible enhancement in insulin sensitivity may play a role in establishing anabolic status in the body, when excess energy is supplied to the body.

The influence of sex on the protein anabolic response to insulin

We hypothesize that sex influences whole-body protein anabolism in the postabsorptive state and in response to hyperinsulinemia. Kinetics of 3- 3H-glucose and 13C-leucine were studied in 16 men and 15 women after energy- and protein-controlled diets, before and during a hyperinsulinemic, euglycemic, isoaminoacidemic clamp. In the postabsorptive state, women had 20% higher rates of leucine Ra (protein breakdown) and nonoxidative Rd (synthesis) adjusted for fat-free mass than men but net leucine balance was as negative. In response to hyperinsulinemia, leucine oxidation rates increased only in women and the change in net leucine balance was less than in men. Net leucine balance during the clamp correlated with rates of glucose disposal. Thus, women showed greater protein turnover rates when adjusted for fat free mass in the postabsorptive state, and lesser insulin sensitivity of protein anabolism and net protein accretion. A relationship exists between the protein anabolic response to insulin and the insulin sensitivity of glucose metabolism.

Thiazolidinediones: Pleiotropic drugs with potent anti-inflammatory properties for tissue protection

Peroxisome proliferator-activated receptor-gamma (PPARgamma) is a nuclear transcription factor that comprises the primary molecular target for thiazolidinedione (TZD) insulin-sensitizing drugs. Whilst expressed in many tissues in humans, its abundant expression in adipose tissue is believed to be the focal point through which TZDs regulate genes involved in glucose and lipid metabolism and via which these agents ultimately improve the hyperglycemia of type 2 diabetes. However, TZDs exhibit many additional properties, not least an array of effects which suggest a broad attack on the inflammatory process. Thus, TZDs have been shown to reduce plasma levels of the chemokine, monocyte chemotactic protein-1 (MCP-1), the anti-fibrinolytic protein, plasminogen activator inhibitor-1 (PAI-1), the endothelial cell adhesion molecules, e-selectin and inter-cellular adhesion molecule-1 (ICAM-1), the leucocyte-activating molecule, CD40L, and the tissue-remodeling enzyme, matrix metalloproteinase-9 (MMP-9). Further tangible evidence of a reduction by TZDs of systemic inflammation in patients with the classical metabolic syndrome stems from falls in the white blood cell count, P-selectin-positive platelets and in the acute-phase inflammatory proteins, C-reactive protein, serum amyloid A and fibrinogen. At the tissue level, TZDs improve vascular endothelial function, and reduce the rate of progression of intimal-medial thickening of the carotid artery and the microalbuminuria of type 2 diabetes. Further, TZDs have been shown to be efficacious in inflammatory diseases as wide-ranging as psoriasis, ulcerative colitis and non-alcoholic steatohepatitis (NASH). In the case of the latter, a broad spectrum of TZD-related properties is visible. Here, these drugs improve insulin sensitivity for glucose metabolism, reduce hyperinsulinemia, hepatic steatosis, inflammation and fibrosis, and lower the circulating levels of liver transaminases (ALT, AST), alkaline phosphatase and gamma glutamyl transferase. These effects in humans are also well-supported by investigative animal and in vitro studies. The ameliorative effects on liver fibrosis are of particular interest since they suggest that TZDs are able to activate a program of corrective tissue-remodeling. The basis for this action may be partly an ability to inhibit matrix protein secretion by hepatic stellate cells. An analogous action has also been seen in kidney mesangial cells. In conclusion, TZDs are important new drugs, presently indicated for the treatment of type 2 diabetes but with a spectrum of properties which suggests their potential for treating a number of degenerative inflammatory diseases, including NASH. However, full-scale, long-term clinical trials are needed with TZDs to test their potential to treat NASH, not least because of the (hepatotoxic) legacy of the prototype TZD, troglitazone, but also in view of the escalating burden of liver disease which is accompanying the increasing global prevalence of clinical obesity and type 2 diabetes.

Insulin sensitivity of protein and glucose metabolism in overweight female adolescents with type 1 diabetes mellitus: positive modulation by physical exercise

Impairment of insulin sensitivity of glucose metabolism, a prominent feature of type 1 diabetes (DM), is also well documented in adolescence and obesity. Overweight is frequently present during adolescence in females. Spurt in growth is significantly reduced during puberty in females with type 1 DM, while it is normal in males. In this study we assessed the effect of the coexistence of type 1 DM, adolescence, overweight, and their possible interference with growth. Moreover, we evaluated whether dietetic control associated with physical exercise improved insulin sensitivity in adolescence. The study enrolled 11 female adolescents and young adults (aged 18.5±0.6 years), affected by type 1 DM for 8.3±0.9 years, who were overweight (BMI, 27.3±0.8 kg/m2) and receiving conventional insulin therapy (0.78±0.10 U/kg day). We used the euglycemic hyperinsulinemic clamp technique coupled to [2H2]glucose and [13C]leucine infusion. The results show a striking increase in insulin resistance of glucose metabolism: the suppression of endogenous glucose production (EGP) was 59% in comparison to 90%–100% recorded by others at similar insulin levels in subjects at different periods of life. Insulin resistance in type 1 DM overweight adolescents was also present on protein metabolism: the postabsorptive plasma leucine (146.9±10.1 μM) and the endogenous leucine flux (ELF, 88.8±4.5 µmol/kg min) were higher than in healthy controls. The suppression of ELF during hyperinsulinemia was defective in diabetic adolescents (27%, p<0.001) with respect to controls (36%). Only three of the 11 overweight diabetic subjects completed the 6-month physical exercise and diet program, and showed improvement of insulin sensitivity at the final evaluation. The EGP suppression by insulin shifted from 41% to 79%; ELF suppression increased from 26% to 34%. All the parameters of glucose metabolism correlated with the weight loss (BMI reduction from 27.8±1.9 to 25.6±1.2 kg/m2). In conclusion, overweight female adolescents with type 1 DM have an impaired insulin action on glucose and protein metabolism. Physical exercise and correct dietary regimen positively influence insulin sensitivity. The present preliminary data are relevant for an improved control of glucose homeostasis and a normal growth in adolescence.

A Low-Carbohydrate/High-Fat Diet Improves Glucoregulation in Type 2 Diabetes Mellitus by Reducing Postabsorptive Glycogenolysis

The aim of this study was to examine the mechanisms by which dietary carbohydrate and fat modulate fasting glycemia. We compared the effects of an eucaloric high-carbohydrate (89% carbohydrate) and high-fat (89% fat) diet on fasting glucose metabolism and insulin sensitivity in seven obese patients with type 2 diabetes using stable isotopes and euglycemic hyperinsulinemic clamps. At basal insulin levels glucose concentrations were 148 +/- 11 and 123 +/- 11 mg/dl (8.2 +/- 0.6 and 6.8 +/- 0.6 mmol/liter) on the high-carbohydrate and high-fat diet, respectively (P < 0.001), with insulin concentrations of 12 +/- 2 and 10 +/- 1 microIU/ml (82 +/- 11 and 66 +/- 10 pmol/liter) (P = 0.08). Glucose production was higher on the high-carbohydrate diet (1.88 +/- 0.06 vs. 1.55 +/- 0.05 mg/kg.min (10.44 +/- 0.33 vs. 8.61 +/- 0.28 micromol/kg.min) (P < 0.001) because of higher glycogenolysis. Gluconeogenic rates were not different between the diets. During the use of hyperinsulinemic euglycemic clamps, insulin-mediated suppression of glucose production and stimulation of glucose disposal were not different between the diets. Free fatty concentrations were suppressed by 89 and 62% (P < 0.0001) on the high-carbohydrate and high-fat diet, respectively. We conclude that short-term variations in dietary carbohydrate to fat ratios affect basal glucose metabolism in people with type 2 diabetes merely through modulation of the rate of glycogenolysis, without affecting insulin sensitivity of glucose metabolism.