Long-term consumption of fermented soybean-derived Chungkookjang attenuates hepatic insulin resistance in 90% pancreatectomized diabetic rats.

Soy protein and isoflavonoids in soybeans exhibit the improvement of insulin resistance. Our previous IN VITRO study showed that Chungkookjang (CKJ), fermented unsalted soybeans, had better antidiabetic actions than cooked unfermented soybeans (CSB) by increasing isoflavones aglycones and small peptides. We investigated whether 40% fat diets with different protein sources such as CSB, CKJ, and casein modulated peripheral insulin resistance in 90% pancreatectomized (Px) diabetic rats. The Px rats weighing 209+/-14 g were freely provided casein, CSB, or CKJ diets for 8 weeks. Both CKJ and CSB increased whole body glucose disposal rates and glucose uptake into skeletal muscles of Px rats as much as rosiglitazone plus casein treated rats during euglycemic hyperinsulinemic clamp. In addition, CKJ and CSB decreased hepatic glucose output at hyperinsulinemic clamped states, compared to the Casein group. The reduction of hepatic glucose output was greater in CKJ than CSB. This reduction was associated with enhanced tyrosine phosphorylation of IRS2 and serine (473) phosphporylation of Akt, indicating improved hepatic insulin signaling. This improved signaling led to decreased phosphoenolpyruvate carboxykinase expression to reduce hepatic glucose output. In conclusion, fermented soybeans mainly with BACILLUS SUBTILIS improved hepatic insulin sensitivity better than unfermented soybeans by enhancing hepatic insulin signaling cascade in diabetic rats.     

Capsiate improves glucose metabolism by improving insulin sensitivity better than capsaicin in diabetic rats

Red peppers and red pepper paste are reported to have anti-obesity, analgesic and anti-inflammatory effects in animals and humans due to the capsaicin in red pepper. We investigated whether consuming capsaicin and capsiate, a nonpungent capsaicin analogue, modifies glucose-stimulated insulin secretion, pancreatic β-cell survival and insulin sensitivity in 90% pancreatectomized (Px) diabetic rats, a moderate and non-obese type 2 diabetic animal model. Px diabetic rats were divided into 3 treatment groups: 1) capsaicin (Px-CPA), 2) capsiate (Px-CPI) or 3) dextrose (Px-CON) and provided high fat diets (40 energy % fat) containing assigned components (0.025% capsaicin, capsiate, or dextrose) for 8 weeks. Both capsaicin and capsiate reduced body weight gain, visceral fat accumulation, serum leptin levels and improved glucose tolerance without modulating energy intake in diabetic rats. In comparison to the control, both capsaicin and capsiate potentiated first and second and phase insulin secretion during hyperglycemic clamp. Both also increased β-cell mass by increasing proliferation and decreasing apoptosis of β-cells by potentiating insulin/IGF-1 signaling. However, only capsiate enhanced hepatic insulin sensitivity during euglycemic hyperinuslinemic clamp. Capsiate reduced hepatic glucose output and increased triglyceride accumulation in the hyperinsulinemic state and capsiate alone significantly increased glycogen storage. This was related to enhanced pAkt→PEPCK and pAMPK signaling. Capsaicin and capsiate reduced triglyceride storage through activating pAMPK. In conclusion, capsaicin and capsiate improve glucose homeostasis but they differently enhance insulin sensitivity in the liver, insulin secretion patterns, and islet morphometry in diabetic rats. Capsiate has better anti-diabetic actions than capsaicin.     

Effect of leptin on insulin sensitivity in the Otsuka Long-Evans Tokushima Fatty rat

Leptin has been proposed to be a sensor of energy storage in adipose tissues, and is capable of mediating a feedback signal to the hypothalamus, which is involved in the regulation of energy homeostasis and body weight. In order to investigate the issue of whether resistance to the activity of leptin on insulin sensitivity is observed in young Otsuka Long-Evans Tokushima Fatty (OLETF) rats at 8 weeks of age, leptin (50 nmol/kg/h) was administered intravenously for 16 h to OLETF and Long-Evans Tokushima Otsuka (LETO) (lean controls) rats, followed by a measurement of insulin-stimulated glucose uptake in hindlimb muscles during hyperinsulinemic euglycemic clamp technique. In the case of LETO rats, the administration of leptin significantly decreased plasma insulin levels prior to the clamp test, but did not change plasma glucose levels. Furthermore, leptin led to an increase in insulin-stimulated glucose uptake in hindlimb muscles. However, in the case of OLETF rats, leptin administration changed neither plasma insulin levels nor insulin-stimulated glucose uptake. These data demonstrate that OLETF rats at 8 weeks of age have already become resistant to high concentration of peripheral leptin.     

A steroidal glycoside from Polygonatum odoratum (Mill.) Druce. improves insulin resistance but does not alter insulin secretion in 90% pancreatectomized rats

The aim of this study was to investigate the effects of three steroidal glycosides (SG-100, SG-280, and SG-460) obtained from Polygonatum odoratum (Mill.) Druce. on insulin secretion, insulin action, and relative glucose uptake in various tissues of 90% pancreatectomized male Sprague-Dawley rats. One of the compounds (30 mg/kg body weight daily) with a 40%-fat diet was orally administered to a group of such rats for 13 weeks. On the day after a hyperglycemic clamp, euglycemic hyperinsulinemic clamp with 1 microCi of [1-(14)C]2-deoxyglucose per 100 g body weight was used. Serum glucose levels were lowest in the rats receiving SG-100. Insulin secretion from pancreatic beta-cells did not change with SG administration. Whole-body glucose disposal rates increased with SG-100 administration by 39%. SG-100 increased the glycogen contents and glycogen synthase activity in the soleus muscle of pancreatectomized rats. Uptake of [1-(14)C]2-deoxyglucose into the soleus muscle was higher in such rats receiving SG-100 than in rats receiving other compounds. In conclusion, SG-100 has an antihyperglycemic effect by promoting peripheral insulin sensitivity without changing insulin secretion.     

Chlorpromazine exacerbates hepatic insulin sensitivity via attenuating insulin and leptin signaling pathway, while exercise partially reverses the adverse effects

Investigated in this study are the effects and mechanisms of exercise and chlorpromazine (CPZ), a widely used conventional antipsychotic drug, on the hepatic insulin sensitivity of 90% pancreatectomized (Px) male Sprague–Dawley rats. The Px diabetic rats were provided with 0, 5, or 50 mg CPZ per kg of body weight (No-CPZ, LCPZ, or HCPZ) for 8 weeks, and half of each group had regular exercise. LCPZ did not exacerbate hepatic insulin sensitivity through insulin and leptin signaling in diabetic rats. However, HCPZ decreased whole-body glucose infusion rates in hyperinsulinemic clamped states, but not whole-body glucose uptake. This was due to the elevated hepatic glucose output in hyperinsulinemic states. The decreased hepatic insulin sensitivity was associated with insulin receptor substrate-2 (IRS2) protein levels in the liver. Decreased IRS2 levels attenuated hepatic insulin and leptin signaling pathways in hyperinsulinemic states, which elevated glucose production by inducing phosphoenolpyruvate carboxykinase expression. Long-term exercise recovered hepatic insulin sensitivity attenuated by HCPZ to reduce the hepatic glucose output in hyperinsulinemic clamped states. This recovery was related to enhanced insulin and leptin signaling via increased IRS2 gene and protein levels by activating the cAMP responding element-binding protein, but exercise improved only insulin signaling. In conclusion, HCPZ exacerbates hepatic insulin action by attenuating insulin and leptin signaling in type 2 diabetic rats, while regular exercise partially reverses the attenuation of hepatic insulin sensitivity by improving insulin signaling. Enhancement of insulin and leptin signaling through an induction of IRS2 may play an important role in improving hepatic glucose homeostasis.     

Effect of short-term low-intensity exercise on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in non-obese Japanese type 2 diabetic patients.

The aim of the present study was to investigate the effects of short-term physical exercise that did not change body mass on insulin sensitivity, insulin secretion, and glucose and lipid metabolism in 39 non-obese Japanese type 2 diabetic patients. Insulin sensitivity and insulin secretion were estimated with homeostasis model assessment insulin resistance (HOMA-IR) and HOMA-B-cell function proposed by Matthews et al., respectively. All patients were hospitalized and were engaged in low-intensity exercise that consisted of walking and dumbbell exercise for successive 7 days. There were no changes in hospital diet and the dose of any medications used throughout the study. Fasting glucose, insulin, and lipids were measured before and after exercise.After exercise, serum triglyceride levels significantly decreased, but no significant changes were observed in total and HDL cholesterol concentrations. Fasting glucose, insulin, and HOMA-IR levels significantly decreased after exercise, but HOMA-B-cell function did not change during the study. There was no significant difference between BMI levels before and after exercise.From these results, it can be concluded that short-term (7 days) low-intensity physical exercise combined with hospital diet reduces serum triglycerides, insulin resistance, and fasting glucose levels without affecting BMI in non-obese Japanese type 2 diabetic patients.     

Lactate induces insulin resistance in skeletal muscle by suppressing glycolysis and impairing insulin signaling

Elevation of plasma lactate levels induces peripheral insulin resistance, but the underlying mechanisms are unclear. We examined whether lactate infusion in rats suppresses glycolysis preceding insulin resistance and whether lactate-induced insulin resistance is accompanied by altered insulin signaling and/or insulin-stimulated glucose transport in skeletal muscle. Hyperinsulinemic euglycemic clamps were conducted for 6 h in conscious, overnight-fasted rats with or without lactate infusion (120 micromol x kg(-1) x min(-1)) during the final 3.5 h. Lactate infusion increased plasma lactate levels about fourfold. The elevation of plasma lactate had rapid effects to suppress insulin-stimulated glycolysis, which clearly preceded its effect to decrease insulin-stimulated glucose uptake. Both submaximal and maximal insulin-stimulated glucose transport decreased 25-30% (P < 0.05) in soleus but not in epitrochlearis muscles of lactate-infused rats. Lactate infusion did not alter insulin's ability to phosphorylate the insulin receptor, the insulin receptor substrate (IRS)-1, or IRS-2 but decreased insulin's ability to stimulate IRS-1- and IRS-2-associated phosphatidylinositol 3-kinase activities and Akt/protein kinase B activity by 47, 75, and 55%, respectively (P < 0.05 for all). In conclusion, elevation of plasma lactate suppressed glycolysis before its effect on insulin-stimulated glucose uptake, consistent with the hypothesis that suppression of glucose metabolism could precede and cause insulin resistance. In addition, lactate-induced insulin resistance was associated with impaired insulin signaling and decreased insulin-stimulated glucose transport in skeletal muscle.     

Sensory nerve inactivation by resiniferatoxin improves insulin sensitivity in male obese Zucker rats

Recent studies have suggested that sensory nerves may influence insulin secretion and action. The present study investigated the effects of resiniferatoxin (RTX) inactivation of sensory nerves (desensitization) on oral glucose tolerance, insulin secretion and whole body insulin sensitivity in the glucose intolerant, hyperinsulinemic, and insulin-resistant obese Zucker rat. After RTX treatment (0.05 mg/kg RTX sc given at ages 8, 10, and 12 wk), fasting plasma insulin was reduced (P < 0.0005), and oral glucose tolerance was improved (P < 0.005). Pancreas perfusion showed that baseline insulin secretion (7 mM glucose) was lower in RTX-treated rats (P = 0.01). Insulin secretory responsiveness to 20 mM glucose was enhanced in the perfused pancreas of RTX-treated rats (P < 0.005) but unaffected in stimulated, isolated pancreatic islets. At the peak of spontaneous insulin resistance in the obese Zucker rat, insulin sensitivity was substantially improved after RTX treatment, as evidenced by higher glucose infusion rates (GIR) required to maintain euglycemia during a hyperinsulinemic euglycemic (5 mU.kg(-1).min(-1)) clamp (GIR(60-120min): 5.97 +/- 0.62 vs. 11.65 +/- 0.83 mg.kg(-1).min(-1) in RTX-treated rats, P = 0.003). In conclusion, RTX treatment and, hence, sensory nerve desensitization of adult male obese Zucker rats improved oral glucose tolerance by enhancing insulin secretion, and, in particular, by improving insulin sensitivity.     

Assessment of insulin resistance in vivo: application to the study of type 2 diabetes.

Besides insulin secretion, insulin sensitivity plays a key role in the feedback glucose-insulin closed loop. It can be altered in numerous physiological, pathological and pharmacological conditions. It can be estimated in vivo using methods that open the feedback loop (insulin suppression test, glucose clamp) or that analyze the closed loop by employing mathematical models of glucose kinetics. The most popular method is the euglycemic hyperinsulinemic glucose clamp. This test should be ideally coupled with a priming-constant infusion of a glucose tracer together with indirect calorimetry. This combination allows to study the glucose kinetics (Ra and Rd, and thus endogenous-mainly hepatic-glucose production) and its metabolism (oxidation or storage as glycogen), respectively. One alternative approach is the frequently sampled intravenous glucose tolerance test where the dynamic changes in plasma insulin and glucose levels are analyzed using the so-called 'minimal model' method. Noninsulin-dependent or type 2 diabetes is characterized by a significant defect in both insulin secretion and action. The insulin resistance is located at the liver site (increased glucose production) and at the peripheral tissues (decreased oxidation and, even more, defective storage of glucose in the muscles). This insulin resistance, which predominates at the postreceptor level, seems to be genetically determined but is worsened by weight excess and by hyperglycemia itself. This contributes to a vicious circle which aggravates progressively the severity of the disease.     

Effects of insulin secretagogues on the secretion of insulin during thiamine deficiency

The mechanism by which glucose and other nutrient secretagogues induce the insulin secretion, is still controversial. Thiamine deficient rats, having a block in the glucose and branched chain amino acid metabolism at pyruvate and branched chain keto acids dehydrogenases respectively, were used to study the effects of insulin secretagogues. The levels of fasting blood glucose and serum insulin were estimated. Also, the serum insulin was assayed after intravenous administration of leucine, arginine and tolbutamide. The fasting blood glucose was increased and the serum insulin was decreased in thiamine deficiency. Leucine and arginine did not enhance insulin secretion in thiamine deficient animals. Tolbutamide induces the insulin secretion minimally in thiamine deficient rats. These results suggest that the nutrient secretagogues require an unimpaired glucose metabolism to induce insulin secretion.     

Effects of clenbuterol on insulin resistance in conscious obese Zucker rats

The present study was conducted to determine the effect of chronic administration of the long-acting beta(2)-adrenergic agonist clenbuterol on rats that are genetically prone to insulin resistance and impaired glucose tolerance. Obese Zucker rats (fa/fa) were given 1 mg/kg of clenbuterol by oral intubation daily for 5 wk. Controls received an equivalent volume of water according to the same schedule. At the end of the treatment, rats were catheterized for euglycemic-hyperinsulinemic (15 mU insulin. kg(-1). min(-1)) clamping. Clenbuterol did not change body weight compared with the control group but caused a redistribution of body weight: leg muscle weights increased, and abdominal fat weight decreased. The glucose infusion rate needed to maintain euglycemia and the rate of glucose disappearance were greater in the clenbuterol-treated rats. Furthermore, plasma insulin levels were decreased, and the rate of glucose uptake into hindlimb muscles and abdominal fat was increased in the clenbuterol-treated rats. This increased rate of glucose uptake was accompanied by a parallel increase in the rate of glycogen synthesis. The increase in muscle glucose uptake could not be ascribed to an increase in the glucose transport protein GLUT-4 in clenbuterol-treated rats. We conclude that chronic clenbuterol treatment reduces the insulin resistance of the obese Zucker rat by increasing insulin-stimulated muscle and adipose tissue glucose uptake. The improvements noted may be related to the repartitioning of body weight between tissues.     

Chronic reduction of insulin receptors in the ventromedial hypothalamus produces glucose intolerance and islet dysfunction in the absence of weight gain

Insulin is believed to regulate glucose homeostasis mainly via direct effects on the liver, muscle, and adipose tissues. The contribution of insulin's central nervous system effects to disorders of glucose metabolism has received less attention. To evaluate whether postnatal reduction of insulin receptors (IRs) within the ventromedial hypothalamus (VMH), a brain region critical for glucose sensing, contributes to disorders of peripheral glucose metabolism, we microinjected a lentiviral vector expressing an antisense sequence to knockdown IRs or a control lentiviral vector into the VMH of nonobese nondiabetic rats. After 3-4 mo, we assessed 1) glucose tolerance, 2) hepatic insulin sensitivity, and 3) insulin and glucagon secretion, using the glucose clamp technique. Knockdown of IRs locally in the VMH caused glucose intolerance without altering body weight. Increments of plasma insulin during a euglycemic clamp study failed to suppress endogenous glucose production and produced a paradoxical rise in plasma glucagon in the VMH-IR knockdown rats. Unexpectedly, these animals also displayed a 40% reduction (P < 0.05) in insulin secretion in response to an identical hyperglycemic stimulus (～220 mg/dl). Our data demonstrate that chronic suppression of VMH-IR gene expression is sufficient to impair glucose metabolism as well as α-cell and β-cell function in nondiabetic, nonobese rats. These data suggest that insulin resistance within the VMH may be a significant contributor to the development of type 2 diabetes.     

beta-cell adaptation in 60% pancreatectomy rats that preserves normoinsulinemia and normoglycemia

Islet beta-cells are the regulatory element of the glucose homeostasis system. When functioning normally, they precisely counterbalance changes in insulin sensitivity or beta-cell mass to preserve normoglycemia. This understanding seems counter to the dogma that beta-cells are regulated by glycemia. We studied 60% pancreatectomy rats (Px) 4 wk postsurgery to elucidate the beta-cell adaptive mechanisms. Nonfasting glycemia and insulinemia were identical in Px and sham-operated controls. There was partial regeneration of the excised beta-cells in the Px rats, but it was limited in scope, with the pancreas beta-cell mass reaching 55% of the shams (40% increase from the time of surgery). More consequential was a heightened glucose responsiveness of Px islets so that glucose utilization and insulin secretion per milligram of islet protein were both 80% augmented at normal levels of glycemia. Investigation of the biochemical basis showed a doubled glucokinase maximal velocity in Px islets, with no change in the glucokinase protein concentration after adjustment for the different beta-cell mass in Px and sham islets. Hexokinase activity measured in islet extracts was also minimally increased, but the glucose 6-phosphate concentration and basal glucose usage of Px islets were not different from those in islets from sham-operated rats. The dominant beta-cell adaptive response in the 60% Px rats was an increased catalytic activity of glucokinase. The remaining beta-cells thus sense, and respond to, perceived hyperglycemia despite glycemia actually being normal. beta-Cell mass and insulin secretion are both augmented so that whole pancreas insulin output, and consequently glycemia, are maintained at normal levels.     

Endothelial and vascular dysfunctions and insulin resistance in rats fed a high-fat, high-sucrose diet

This study was designed to examine the effects of a high-fat, high-sucrose (HFHS) diet on vascular and metabolic actions of insulin. Male rats were randomized to receive an HFHS or regular chow diet for 4 wk. In a first series of experiments, the rats had pulsed Doppler flow probes and intravascular catheters implanted to measure blood pressure, heart rate, and regional blood flows. Insulin sensitivity and vascular responses to insulin were assessed during a euglycemic hyperinsulinemic clamp performed in conscious rats. In a second series of experiments, new groups of rats were used to examine skeletal muscle glucose transport activity and to determine in vitro vascular reactivity, endothelial nitric oxide synthase (eNOS) protein expression in muscle and vascular tissues and endothelin content, nitrotyrosine formation, and NAD(P)H oxidase protein expression in vascular tissues. The HFHS-fed rats displayed insulin resistance, hyperinsulinemia, hypertriglyceridemia, hyperlipidemia, elevated blood pressure, and impaired insulin-mediated renal and skeletal muscle vasodilator responses. A reduction in endothelium-dependent vasorelaxation, accompanied by a decreased eNOS protein expression in muscles and blood vessel endothelium, and increased vascular endothelin-1 protein content were also noted in HFHS-fed rats compared with control rats. Furthermore, the HFHS diet induced a reduced insulin-stimulated glucose transport activity in muscles and increased levels of NAD(P)H oxidase protein and nitrotyrosine formation in vascular tissues. These findings support the importance of eNOS protein in linking metabolic and vascular disease and indicate the ability of a Westernized diet to induce endothelial dysfunction and to alter metabolic and vascular homeostasis.     

Nitric oxide decreases insulin resistance induced by high-fructose feeding.

The effect of nitric oxide (NO) on insulin resistance was studied in high-fructose-fed rats. A sequential hyperinsulinemic euglycemic clamp procedure was employed (insulin infusion rates: 3 and 30 mU/kg BW/min) in 12 high-fructose-fed rats and 12 chow-fed rats while awake. Half of the high-fructose-fed and the chow-fed rats, respectively, were continuously given sodium nitroprusside (SNP, 3 ng/kg BW/min) during the clamp study. Blood glucose was clamped at the fasting level in each rat. Plasma insulin levels during the 3 and 30 mU/kg BW/min insulin infusions were 30 and 400 microU/ml, respectively. Metabolic clearance rate of glucose (MCR) was regarded as an index of whole body insulin action. At both 3 and 30 mU/kg BW/min insulin infusions, high-fructose feeding showed a significant decrease in MCR compared with the chow-fed rats. However, decreased MCRs were stimulated by SNP administration and reached similar levels as the chow-fed rats. SNP infusion did not influence MCRs in the chow-fed rats. Therefore it could be concluded that NO can improve insulin resistance induced by high-fructose feeding.     

Effect of adenosine on the serum levels of glucose, insulin and glucagon in vivo

The in vivo effect of adenosine on the serum levels of glucose, insulin and glucagon in rats fasted for twenty four hours or after an oral glucose load were studied. Under fasting conditions adenosine produced an hyperglycaemia without change in the insulin or glucagon serum levels. After a glucose load adenosine induced a marked hyperglycaemia concomitant to a decrease in insulin serum levels and an increase in glucagon serum levels. Adenosine did not alter the relationship between insulin and glucagon. In vivo adenosine administration altered the secretion of hormones by the islets of Langerhans (increased the release of glucagon and decreased the secretion of insulin) but this was only clearly observable under stimulated conditions. Adenosine did not alter the regulatory mechanism(s) that modulate the relationship between insulin and glucagon.     

Normal insulin sensitivity and IMCL content in overweight humans are associated with higher fasting lipid oxidation

Intramyocellular lipid (IMCL) storage is considered a local marker of whole body insulin resistance; because increments of body weight are supposed to impair insulin sensitivity, this study was designed to assess IMCL content, lipid oxidation, and insulin action in individuals with a moderate increment of body fat mass and no family history of diabetes. We studied 14 young, nonobese women with body fat <30% (n = 7) or >30% (n = 7) and 14 young, nonobese men with body fat <25% (n = 7) or >25% (n = 7) by means of the euglycemic-insulin clamp to assess whole body glucose metabolism, with indirect calorimetry to assess lipid oxidation, by localized (1)H NMR spectroscopy of the calf muscles to assess IMCL content, and with dual-energy X-ray absorptiometry to assess body composition. Subjects with higher body fat had normal insulin-stimulated glucose disposal (P = 0.80), IMCL content in both soleus (P = 0.22) and tibialis anterior (P = 0.75) muscles, and plasma free fatty acid levels (P = 0.075) compared with leaner subjects in association with increased lipid oxidation (P < 0.05), resting energy expenditure (P = 0.046), resting oxygen consumption (P = 0.049), and plasma leptin levels (P < 0.01) in the postabsorptive condition. In conclusion, in overweight subjects, preservation of insulin sensitivity was combined with increased lipid oxidation and maintenance of normal IMCL content, suggesting that abnormalities of these factors may mutually determine the development of insulin resistance associated with weight gain.     

Co-administration of etomoxir and RU-486 mitigates insulin resistance in hepatic and muscular tissues of STZ-induced diabetic rats.

Insulin resistance is a condition of central importance in a cluster of clinical disorders including diabetes mellitus, hypertension, dyslipidemia, central obesity and coronary heart disease. Despite its association with numerous health problems, the mechanism responsible for the development of this phenomenon remains to be established. A novel theory has proposed that insulin resistance in diabetes stems, at least in part, from enhanced free fatty acid (FFA) oxidation and/or excessive production of glucocorticoids (GCs). Several key predictions of this premise were subjected to experimental testing using streptozotocin (STZ)-treated rats as a model for insulin-dependent diabetes mellitus and euglycemic-hyperinsulinemic clamp technique for the in vivo measurement of insulin actions. Euglycemic clamp studies with an insulin infusion index of 5 mU/kg/min were used to measure endogenous glucose production (EGP), glucose infusion rate (GIR), glucose disposal rate (GDR) and skeletal muscle glucose utilization index (GUI). Post-absorptive basal EGP and plasma levels of glucose and free fatty acids (FFA) were elevated in the STZ diabetic rats compared to their corresponding control values. In contrast, hypoinsulinemia was evident in these animals. Steady-state GIR and GDR during euglycemic-hyperinsulinemic clamp were markedly decreased in the STZ diabetic rats. Similarly, insulin-mediated suppression of EGP and plasma FFA concentration was also impaired in these animals. GUI, a measure of 2-deoxyglucose (2-DG) uptake, was increased in response to insulin in the order of white gastrocnemus (WG), red gastrocnemus (RG), extensor digitorum longus and soleus muscles. This parallels the percentage of red fibers in these muscles. Diabetes interferes with insulin's ability to increase 2-DG uptake in all of the above muscles with the exception of WG. Nullification of the associated hyperlipidemic and hypercortisolemic states of diabetes with etomoxir (hyperlipidemic) and the glucocorticoid receptor blocker RU-486 (hypercortisolemic) ameliorated the diabetes-related impairment of the in vivo insulin action. Overall these results together with those garnered from the literature support the notion that hypercortisolemia and the enhancement of FFA oxidation are involved, at least in part, in the development of hepatic and skeletal muscle insulin resistance in poorly controlled type I diabetes.     

Neutralization of tumor necrosis factor-alpha reverses insulin resistance in skeletal muscle but not adipose tissue

We examined the possible role of tumor necrosis factor-alpha (TNF-alpha) as a mediator of insulin resistance in maturing male Sprague-Dawley rats. Rats were treated either with goat anti-murine TNF-alpha IgG (anti-TNF-alpha) or goat nonimmune IgG (NI) for 7 days. Vascular catheters were implanted, and rats were fasted overnight before hyperinsulinemic euglycemic clamp (HUC) studies were performed. TNF-alpha neutralization increased the rate of glucose infusion required to maintain euglycemia by 68%. Insulin-stimulated glucose transport into individual tissues was measured after bolus administration of 2-deoxy-[(14)C]glucose during HUC. Anti-TNF-alpha administration increased glucose transport in muscles composed predominantly of fast-twitch fibers: white gastrocnemius muscle (68% increase) and tibialis anterior muscle (64% increase). There were nonsignificant trends for increased glucose transport in the slow-twitch soleus muscle and in the mixed-fiber red gastrocnemius muscle. Glucose transport was unchanged in visceral and subcutaneous fat. Anti-TNF treatment did not alter body weight, muscle mass, or fat mass. Anti-TNF-alpha did not alter the distribution of the 17-kDa and 26-kDa forms of TNF-alpha in either muscle or fat. However, anti-TNF-alpha treatment caused an approximately 50% reduction in the secretion of TNF-alpha bioactivity in vitro by explants of visceral and subcutaneous fat. We conclude that TNF-alpha neutralization reversed insulin resistance substantially in fast-twitch muscle and may have done so in other muscles, while having little effect in fat. TNF-alpha neutralization was accompanied by reduced TNF-alpha bioactivity without tissue depletion of TNF-alpha protein.     

Follow-up of GK rats during prediabetes highlights increased insulin action and fat deposition despite low insulin secretion

The adult Goto-Kakizaki (GK) rat is characterized by impaired glucose-induced insulin secretion in vivo and in vitro, decreased beta-cell mass, decreased insulin sensitivity in the liver, and moderate insulin resistance in muscles and adipose tissue. GK rats do not exhibit basal hyperglycemia during the first 3 wk after birth and therefore could be considered prediabetic during this period. Our aim was to identify the initial pathophysiological changes occurring during the prediabetes period in this model of type 2 diabetes (T2DM). To address this, we investigated beta-cell function, insulin sensitivity, and body composition in normoglycemic prediabetic GK rats. Our results revealed that the in vivo secretory response of GK beta-cells to glucose is markedly reduced and the whole body insulin sensitivity is increased in the prediabetic GK rats in vivo. Moreover, the body composition of suckling GK rats is altered compared with age-matched Wistar rats, with an increase of the number of adipocytes before weaning despite a decreased body weight and lean mass in the GK rats. None of these changes appeared to be due to the postnatal nutritional environment of GK pups as demonstrated by cross-fostering GK pups with nondiabetic Wistar dams. In conclusion, in the GK model of T2DM, beta-cell dysfunction associated with increased insulin sensitivity and the alteration of body composition are proximal events that might contribute to the establishment of overt diabetes in adult GK rats.