Insulin Sensitivity In Peripheral Tissues Research Articles

Programming of hepatic and peripheral tissue insulin sensitivity by maternal protein restriction.

In recent years a great deal of research effort has been directed towards understanding the molecular basis of the relationship between markers of fetal and early growth retardation and the subsequent development of Type 2 diabetes. A lot of this work has focused on the maternal low protein rat model. Like many animal models, it does not perfectly represent the human situation and frank diabetes has not yet been produced. However, this model has yielded much information on potential mechanisms by which changes in insulin sensitivity can occur and has helped in understanding the role of the molecular machinery involved in the signalling of the metabolic actions of insulin.

Pharmacological profiles of a novel oral antidiabetic agent, JTT-501, an isoxazolidinedione derivative

JTT-501, 4-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]benzyl]-3,5-isoxazolidinedione, is an isoxazolidinedione derivative which is structurally distinct from thiazolidinediones such as pioglitazone and troglitazone. We investigated the effects of JTT-501 on insulin-sensitizing activity and in rodent diabetic models. JTT-501 enhanced insulin-stimulated cell differentiation of 3T3-L1 fibroblasts with an EC 50 value of 110 nM. Furthermore, JTT-501 activated peroxisome proliferator-activated (PPA) γ and α receptors with the EC 5-fold values of 0.28 and 5.4 μM, respectively. In the non-insulin-dependent diabetes mellitus model KK-A y mice, JTT-501 improved hyperglycemia, hyperinsulinemia and hypertriglyceridemia, and enhanced insulin-stimulated glucose oxidation in adipose tissues. JTT-501 was also effective in the non-insulin-dependent diabetes mellitus model Zucker diabetic fatty (ZDF) rats but not in the insulin-dependent diabetes mellitus model streptozotocin-induced diabetic mice. These observations suggest that JTT-501 enhances insulin sensitivity in peripheral tissues and improves hyperglycemia, hyperinsulinemia, and hypertriglyceridemia in non-insulin dependent diabetes mellitus models. In particular, the triglyceride-lowering activity of JTT-501 is a unique characteristic compared to the thiazolidinediones. Therefore, JTT-501 may be a promising antidiabetic agent for treating non-insulin-dependent diabetes mellitus patients with insulin resistance.

Changes in the liver protein pattern of female wistar rats treated with the hypoglycemic agent SDZ PGU 693

SDZ PGU 693 acts as a hypoglycemie agent by stimulating glucose utilisation in insulin-sensitive peripheral tissues, such as skeletal muscle and fat. In a 28 day toxicity study the compound was found to induce hepatocellular hypertrophy in Wistar rats treated with 300 mg/kg day . To gain insights into the pathomechanism of these alterations, aliquots of liver samples from control and treated female Wistar rats were separated by two-dimensional protein gel electrophoresis and the digitized images of the protein patterns were searched for protein abundance changes. Significant treatment-related quantitative changes (P < 0.001) were found in 29 liver proteins. Major increases were observed in several microsomal proteins, including NADPH cytochrome P-450 reductase, cytochrome b5 and serine protease inhibitor. The changes in the cytochrome related enzymes, both known co-factors of the P-450 enzyme system, strongly suggest that SDZ PGU 693 induces microsomal proliferation and induction of the P-450 enzyme system. Decreases were observed in a series of mitochondrial proteins, such as F 1ATPase-δ subunit and ornithine aminotransferase precursor as well as in several cytosolic proteins such as the liver fatty acid binding protein, arylsulfotransferase and the senescence marker protein-30. The changes in F 1ATPase-δ subunit and liver fatty acid binding protein together suggest a down-regulation of the mitochondrial liver fatty acid metabolism, likely reflecting the pharmacological action of the compound. These results show that SDZ PGU 693 produces a complex pattern of gene expression changes which give insights into the molecular mechanisms of both its pharmacological action and a toxic response.

Insulin stimulation of glucose uptake in skeletal muscles and adipose tissues in vivo is NO dependent.

The purpose of this study was to investigate whether in vivo nitric oxide synthase (NOS) inhibition influences insulin-mediated glucose disposal in rat peripheral tissues. The NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME) or saline was infused constantly during a hyperinsulinemic-euglycemic clamp in normal rats. Glucose utilization rates of insulin-sensitive tissues (individual muscles, heart, and adipose tissues) were simultaneously determined using tracer infusion of 2-deoxy-D-[3H]glucose (2-[3H]DG). NOS blockade with L-NAME resulted in significant (P < 0.05) reduction in both whole body glucose disposal (-16%, P < 0.01) and plasma 2-[3H]DG disappearance rate (-30%, P < 0.05) during hyper-insulinemic-euglycemic clamp. L-NAME significantly decreased insulin-stimulated glucose uptake in heart (-62%, P = 0.01), soleus (-42%, P = 0.05), red (-53%, P < 0.001) and white (-62%, P < 0.001) gastrocnemius, tibialis (-57%, P < 0.01), and quadriceps (-33%, P < 0.05) muscles. The NOS inhibitor also decreased insulin action in brown interscapular (-47%, P < 0.01), retroperitoneal (-52%, P = 0.07), and gonadal (-66%, P = 0.06) adipose tissues. In contrast to in vivo NOS blockade, L-NAME failed to affect basal or insulin-stimulated 2-[3H]DG transport in isolated soleus or extensor digitorum longus muscles in vitro. These results support the hypothesis that the action of insulin to augment glucose uptake by skeletal muscles and other peripheral insulin-sensitive tissues in vivo is NO dependent.

Therapy of Hypertension and Metabolic Syndrome: Today's Standard and Tomorrow's Perspectives

Treatment of arterial hypertension is known to reduce cardiovascular morbidity and mortality and has apositive effect against stroke, where benefit is strongly linked to reduction in blood pressure per se. Theprotective effects against coronary heart disease (CHD) have also been significant but numerically lessimpressive than the effect against stroke. It is conceivable that this due to the fact that not just bloodpressure, but also a number of metabolic variables need to be considered in this context. The insight thathypertension is often just one of the components of the so-called metabolic syndrome suggests that amodern antihypertensive drug should not only lower blood pressure; to exert optimal cardioprotectiveproperties it should also have a neutral or even positive metabolic profile as regards its effects on lipids,glucose and insulin in order to achieve a better protection against CHD. Against this background thecentrally acting selective imidazoline receptor (I1) agonist moxonidine is of considerable interest.Moxonidine has been shown to improve glucose tolerance in man, probably by two different mechanisms,i.e. by augmenting insulin sensitivity in peripheral tissues and by enhancing glucose-stimulated insulinrelease from the pancreas. By employing a therapeutic intervention against hypertension that not onlylowers elevated arterial pressure but also positively affects some of the frequently occurring concomitantmetabolic disturbances, it appears that today's standard of antihypertensive therapy may be surpassed intomorows perspective.

Therapy of Hypertension and Metabolic Syndrome: Today's Standard and Tomorrow's Perspectives

Treatment of arterial hypertension is known to reduce cardiovascular morbidity and mortality and has a positive effect against stroke, where benefit is strongly linked to reduction in blood pressure per se. The protective effects against coronary heart disease (CHD) have also been significant but numerically less impressive than the effect against stroke. It is conceivable that this due to the fact that not just blood pressure, but also a number of metabolic variables need to be considered in this context. The insight that hypertension is often just one of the components of the so-called metabolic syndrome suggests that a modern antihypertensive drug should not only lower blood pressure; to exert optimal cardioprotective properties it should also have a neutral or even positive metabolic profile as regards its effects on lipids, glucose and insulin in order to achieve a better protection against CHD. Against this background the centrally acting selective imidazoline receptor (I1) agonist moxonidine is of considerable interest. Moxonidine has been shown to improve glucose tolerance in man, probably by two different mechanisms, i.e. by augmenting insulin sensitivity in peripheral tissues and by enhancing glucose-stimulated insulin release from the pancreas. By employing a therapeutic intervention against hypertension that not only lowers elevated arterial pressure but also positively affects some of the frequently occurring concomitant metabolic disturbances, it appears that today's standard of antihypertensive therapy may be surpassed in tomorow's perspective.

Role of exercise training in the prevention and treatment of insulin resistance and non-insulin-dependent diabetes mellitus.

Recent epidemiological studies indicate that individuals who maintain a physically active lifestyle are much less likely to develop impaired glucose tolerance and non-insulin-dependent diabetes mellitus (NIDDM). Moreover, it was found that the protective effect of physical activity was strongest for individuals at highest risk of developing NIDDM. Reducing the risk of insulin resistance and NIDDM by regularly performed exercise is also supported by several aging studies. It has been found that older individuals who vigorously train on a regular basis exhibit a greater glucose tolerance and a lower insulin response to a glucose challenge than sedentary individuals of similar age and weight. While the evidence is substantial that aerobic exercise training can reduce the risk of impaired glucose tolerance and NIDDM, the evidence that exercise training is beneficial in the treatment of NIDDM is not particularly strong. Many of the early studies investigating the effects of exercise training on NIDDM could not demonstrate improvements in fasting plasma glucose and insulin levels, or glucose tolerance. The adequacy of the training programmes in many of these studies, however, is questionable. More recent studies using prolonged, vigorous exercise-training protocols have produced more favourable results. There are several important adaptations to exercise training that may be beneficial in the prevention and treatment of insulin resistance, impaired glucose tolerance and NIDDM. An increase in abdominal fat accumulation and loss of muscle mass are highly associated with the development of insulin resistance. Exercise training results in preferential loss of fat from the central regions of the body and should therefore contribute significantly in preventing or alleviating insulin resistance due to its development. Likewise, exercise training can prevent muscle atrophy and stimulate muscle development. Several months of weight training has been found to significantly lower the insulin response to a glucose challenge without affecting glucose tolerance, and to increase the rate of glucose clearance during a euglycaemic clamp. Muscle glucose uptake is equal to the product of the arteriovenous glucose difference and the rate of glucose delivery or muscle blood flow. While it has been known for many years that insulin will accelerate blood glucose extraction by insulin-sensitive peripheral tissues, recent evidence suggests that it can also acutely vasodilate skeletal muscle and increase muscle blood flow in a dose-dependent manner. A reduced ability of insulin to stimulate muscle blood flow is a characteristic of insulin-resistant obese individuals and individuals with NIDDM. Exercise training, however, has been found to help alleviate this problem, and substantially improve the control of insulin over blood glucose. Improvements in insulin resistance and glucose tolerance with exercise training are highly related to an increased skeletal muscle insulin action. This increased insulin action is associated with an increase in the insulin-regulatable glucose transporters, GLUT4, and enzymes responsible for the phosphorylation, storage and oxidation of glucose. Changes in muscle morphology may also be important following training. With exercise training there is an increase in the conversion of fast twitch glycolytic IIb fibres to fast twitch oxidative IIa fibres, as well as an increase in capillary density. IIa fibres have a greater capillary density and are more insulin-sensitive and -responsive than IIb fibres. Evidence has been provided that morphological changes in muscle, particularly the capillary density of the muscle, are associated with changes in fasting insulin levels and glucose tolerance. Furthermore, significant correlations between glucose clearance, muscle capillary density and fibre type have been found in humans during a euglycaemic clamp. Exercise training may also improve control over hepatic glucose production by increasin

Arsenic: a paradoxical human carcinogen.

Chronic exposure to high concentrations of arsenic in drinking water is associated with an increased risk for developing type 2 diabetes. The present revision focuses on the effect of arsenic on tissues that participate directly in glucose homeostasis, integrating the most important published information about the impairment of the expression of genes related to type 2 diabetes by arsenic as one of the possible mechanisms by which it leads to the disease.Many factors are involved in the manner in which arsenic contributes to the occurrence of diabetes. The reviewed studies suggest that arsenic might increase the risk for type 2 diabetes via multiple mechanisms, affecting a cluster of regulated events, which in conjunction trigger the disease.Arsenic affects insulin sensitivity in peripheral tissue by modifying the expression of genes involved in insulin resistance and shifting away cells from differentiation to the proliferation pathway. In the liver arsenic disturbs glucose production, whereas in pancreatic beta-cells arsenic decreases insulin synthesis and secretion and reduces the expression of antioxidant enzymes. The consequences of these changes in gene expression include the reduction of insulin secretion, induction of oxidative stress in the pancreas, alteration of gluconeogenesis, abnormal proliferation and differentiation pattern of muscle and adipocytes as well as peripheral insulin resistance.

Pubertal changes in insulin secretion and peripheral insulin sensitivity.

Using a simple and standardized method we estimated both insulin secretion and insulin sensitivity in peripheral tissues in relation to Tanner pubertal stages. Early insulin response, mean blood glucose (MBG), mean serum insulin (MSI), glucose uptake rate in peripheral tissues and insulin sensitivity index (SI) in response to the standard oral glucose tolerance test were evaluated in 73 normal girls. Study subjects were divided into 4 groups: group 1 (Tanner stage I, n = 20); group 2 (Tanner stage II, n = 14); group 3 (Tanner stages III and IV, n = 15), and group 4 (Tanner stage V, n = 24). Steroid levels and insulin-like growth factors were determined to characterize clinical pubertal development. MBG was similar in all groups but MSI increased at stage II and retained similar values throughout puberty, with those of group I being statistically lower than in the other groups (p < 0.001). When MSI values were adjusted per kilogram of body weight, a significant increase was observed in group II (p < 0.05). The MSI adjusted values were: group 1, 1.0 +/- 0.4; group 2, 1.4 +/- 0.4; group 3, 1.0 +/- 0.3, and group 4, 1.0 +/- 0.4 mU/l/kg. SI values were similar in groups 1 and 2 and significantly lower than in groups 3 and 4 (p < 0.001). Our results confirm both that insulin secretion is related to age and that an insulin-resistant state occurs during puberty. Thus, the insulin-resistant state coincides with Tanner stage II. In conclusion, this mathematical approach is considered to be a simple and reliable method for analyzing the possible alterations in insulin secretion and action in children and adolescents in whom more sophisticated procedures must be limited in this early period of life for ethical reasons.

A study of caloric restriction and cardiovascular aging in cynomolgus monkeys (Macaca fascicularis): a potential model for aging research.

Caloric restriction has been demonstrated to retard aging processes and extend maximal life span in rodents, and is currently being evaluated in several nonhuman primate trials. We initiated a study in 32 adult cynomolgus monkeys to evaluate the effect of caloric restriction on parameters contributing to atherosclerosis extent. Following pretrial determinations, at which time a baseline measure of ad libitum (ad lib) dietary intake was assessed, animals were randomized to an ad lib fed group (control) or a caloric restriction group (30% reduction from baseline intake). The animals are being evaluated for glycated proteins, insulin, glucose, insulin sensitivity measures, and specific measures of body fat composition by CT scans (e.g., intra-abdominal fat) over specified intervals. The results from the first year of observation demonstrate a significant diet effect on body weight, and specifically intra-abdominal fat. Further, insulin sensitivity has been significantly increased after 1 year of caloric restriction compared to the ad lib fed group. These studies indicate that caloric restriction has a marked effect on a pathologic fat depot, and this change is associated significantly with an improvement in peripheral tissue insulin sensitivity.

Insulin resistance seen in non-insulin dependent diabetes mellitus and hypertension.

The characteristics of NIDDM seen in Japanese is coexistence of diminished insulin secretion and the impaired sensitivity to insulin in the target tissues. Thus, insulin resistance does not mean hyperinsulinemia. To investigate the organ-specific insulin action on glucose homeostasis, we developed an innovative non-invasive method, using an euglycemic hyperinsulinemic clamp combined with oral glucose load. With this procedure, we could reveal muscle glucose uptake and hepatic glucose uptake following oral glucose load, quantitatively, separately and simultaneously. The effect of strict glycemic control in non-obese NIDDM who were secondary failure to sulfonylurea with 3 times prandial regular insulin injections, on glucose disposals are investigated. Glucose disposal by peripheral tissues was not altered (clamped blood glucose and insulin concentration are, 90 mg/dl and 200 microU/ml, respectively). The ratio of splanchnic glucose disposal to the amount of ingested glucose, on the other hand, significantly increased to 33.1% from 14.5%. Therefore, short-term strict glycemic control appears to improve glucose handling by splanchnic tissues without affecting insulin sensitivity of peripheral tissues in NIDDM. This method would be feasible to investigate whether insulin resistance seen in hypertensive patients, is located only in peripheral tissues or is also in the liver. To find patients with asymptomatic atherosclerosis, we routinely apply a noninvasive maneuver using high resolution B-mode imaging of the carotid artery, to determine atherosclerosis quantitatively. Impaired glucose tolerance (IGT) male subjects showed significantly greater thickness of the intimal plus medial complex (IMT) than age-matched healthy males and showed no significant differences compared to age-matched NIDDM patients. Among IGT, those with exaggerated insulin secretion (average serum insulin concentration was 100 microU/ml at 1 and 2 h after), in other words, insulin resistant, showed thicker IMT. The characteristics of IGT groups with high insulin level were, BMI more than 25, diastolic blood pressure more than 83 mmHg, serum triglyceride more than 215 mg/dl. Thus, among mildly obese, mild hypertensive, mild glucose intolerant, slightly hypertriglyceridemic Japanese male subjects, there exist advanced atherosclerotic subjects.

本態性高血圧症におけるインスリン感受性と代謝異常(特に, 糖, 脂質代謝異常)との関連

Objective:We studied the relationship between glucose and lipid metabolism abnormalities, to clarify the reduced insulin sensitivity and hypersinsulinemia in patients with arteriosclerosis associated with essential hypertension.Method:In 25 patients with essential hypertension and normal glucose tolerance and in eight normal individuals with no family history of hypertension or diabetes mellitus, we measured the insulin sensitivity in peripheral tissue by oral glucose tolerance testing and the euglycemic glucose clamp method using an artifical pancreas. Since the glucose infusion rate in the normal individuals was 8.27±0.95mg/kg/min, 6.37mg/kg/min (-2SD), or higher level were regarded as normal insulin sensitivity, and a lower level as reduced insulin sensitivity. The relationship between the glucose tolerance test, and glucose, serum triglyceride, serum total cholesterol, serum HDL-cholesterol, and urinary noradrenaline, were studied.Results:The glucose infusion rate was reduced in 64% of the patients with essential hypertension, who also showed an excessively delayed insulin secretion in the oral glucose tolerance test, and high accumulation of insulin (p<0.01), at 91.2±32.6μu/ml·hr. Lipid metabolism dosorders were found in 52% patients with essntial hypertension, and hypertriglyceridemia was seen in 44% of these patients. Serum triglyceride in patients with essential hypertension asociated with reduced insulin sensitivity showed a negative correlation with the glucose infusion rate (r=-0.77, p<0.01), and a positive correlation with the accumulated amount of insulin (r=-0.62, p<0.05). Hypercholesterolemia was found in 32% of the patients with essential hypertension, and total cholesterol showed a negative correlation with the glucose infusion rate (r=-0.51, p<0.05). Hyper LDLcholesterolemia was observed in 32% of the patients with essential hypertension, and LDL-cholesterol showed a negative correlation with the glucose infusion rate (r=-0.49, p<0.05). Hypo HDL-cholesterolemia was found in 36% of the patients with essential hypertension, and HDL-cholesterol showed a positive correlation with the glucose infusion rate (r=-0.54, p<0.05).Conclusion:Reduced insulin sensitivity is often associated with essential hypertension, but a relationship between increased blood pressure and reduced insulin sensitivity can be ruled out. The reduced insluin sensitivity in related with glucose and insulin metablolism abnormalities and lipid metabolism abnormalities, mainly increases in serum triglyceride. In the prevention of the onset of arteriosclerosis as a fatal complication of essential hypertension, we recommend examination of insulin resistance by the euglycemic glucose clamp method using an artificial pancreas.

A study of effect of CS-045, a new antidiabetic drug, on hypertension in spontaneously hypertensive rat.

Several lines of evidence have suggested that insulin resistance may play an important role in the pathogenesis of hypertension. CS-045 is a new hypoglycemic drug by which improves insulin sensitivity in peripheral tissues. We assessed the effect of CS-045 on hypertension in spontaneously hypertensive rats (SHR) and Wistar-Kyoto rats (WKY) as a control. At 20 weeks of age, the treatment with CS-045 was started by being mixed with chow pellets in the proportion of 0.2% (w/w) and continued for 6 weeks. Nonfasting plasma glucose levels were not changed in either strain of rats treated with CS-045, but plasma insulin levels decreased in SHR 4 and 5 weeks after the start of CS-045 therapy. Blood pressure increased with age in SHR without treatment, but CS-045 decreased blood pressure only 4 and 6 weeks after the treatment. These findings suggest that insulin resistance is not strongly associated with the pathogenesis of hypertension in SHR.

Insulin receptor substrate-1 (IRS-1) expression in rat brain.

IRS-1 is phosphorylated on tyrosine residues after insulin stimulation and participates in the early events of signal transduction in peripheral insulin-sensitive tissues. This study determined whether neuronal populations in the rat olfactory bulb and hippocampus (brain regions which have very high concentrations of insulin receptors) also express IRS-1 and contain phosphotyrosine, using in situ hybridization, receptor binding, and immunocytochemistry. IRS-1 mRNA was colocalized with insulin receptor mRNA in neuron cell bodies of hippocampus and olfactory bulb. Similarly, IRS-1 immunoreactivity in hippocampus and olfactory bulb was concentrated in layers that contain synapses of these neurons and have both high insulin binding and phosphotyrosine levels. Thus, IRS-1 and insulin receptors are coexpressed in discrete populations of neurons, suggesting a signal transduction mechanism by which insulin may influence metabolism and gene expression in the brain.

Insulin receptor substrate-1 (IRS-1) expression in rat brain

IRS-1 is phosphorylated on tyrosine residues after insulin stimulation and participates in the early events of signal transduction in peripheral insulin-sensitive tissues. This study determined whether neuronal populations in the rat olfactory bulb and hippocampus (brain regions which have very high concentrations of insulin receptors) also express IRS-1 and contain phosphotyrosine, using in situ hybridization, receptor binding, and immunocytochemistry. IRS-1 mRNA was colocalized with insulin receptor mRNA in neuron cell bodies of hippocampus and olfactory bulb. Similarly, IRS-1 immunoreactivity in hippocampus and olfactory bulb was concentrated in layers that contain synapses of these neurons and have both high insulin binding and phosphotyrosine levels. Thus, IRS-1 and insulin receptors are coexpressed in discrete populations of neurons, suggesting a signal transduction mechanism by which insulin may influence metabolism and gene expression in the brain.

Immunocytochemical detection of insulin receptor substrate-1 (IRS-1) in rat brain: colocalization with phosphotyrosine.

In peripheral insulin-sensitive tissues, insulin receptor substrate (IRS-1) undergoes tyrosine phosphorylation immediately after cells are stimulated by insulin or insulin-like growth factor-1 (IGF-1), and may function as a molecular link between insulin/IGF-1 receptor tyrosine kinases and enzymes regulating cell growth and metabolism. A fundamental question pertaining to insulin/IGF-1 action in the brain is whether IRS-1 is expressed by neurons. In this study, the distribution of cells containing immunoreactivity to IRS-1 in the brain was determined by immunocytochemistry with polyclonal IRS-1 antiserum, and compared to the localization of immunostaining for phosphotyrosine using polyclonal phosphotyrosine antiserum. The immunostaining results with ABC-peroxidase method and cryostat sections showed the presence of IRS-1 immunoreactivity in many neuron cell bodies throughout the rat forebrain, particularly in the habenula, cerebral cortex and piriform cortex. In the hypothalamus, IRS-1 immunostaining was present in neurons of the paraventricular nucleus, supraoptic nucleus, and arcuate nucleus. The choroid plexus stained intensely for IRS-1. The populations of cells that stained for IRS-1 also showed strong immunostaining for phosphotyrosine. Studies at the cellular level are needed to verify coexpression of IRS-1 and receptors for insulin or IGF-1 by the same neurons, as well as in cells of the choroid plexus. The present results are the first demonstration of IRS-1 expression by neurons in adult mammalian brain. These findings are consistent with the hypothesis that insulin and IGF-1 actions in the brain involve signal transduction mechanisms common to those found in peripheral tissues.

Pregnancy and Undernutrition Alter Glucose Metabolic Responses to Insulin in Sheep

Nonpregnant and late-pregnant ditocous ewes were fed either to maintain zero energy balance in maternal tissues (fed) or at 50% of this level (underfed) for several weeks. Whole-body kinetics of glucose metabolism were measured under basal conditions, and the hyperinsulinemic, euglycemic clamp technique was used to define insulin-dose response profiles for several indices of whole-body glucose utilization, and for endogenous glucose production. Pregnancy increased and undernutrition decreased basal glucose entry rate (GER), glucose metabolic clearance rate (GMCR) and insulin-independent glucose utilization (IIGU). The consistent increment in IIGU of pregnant over nonpregnant ewes was comparable to previous estimates of uterine glucose uptake. Pregnancy resulted in higher plasma concentration for 50% maximal responses (ED50) to insulin of GER, GMCR, steady-state glucose infusion rate (SSGIR) to maintain euglycemia and insulin-dependent glucose utilization (IDGU). These changes were especially large in underfed pregnant ewes. Effects on the maximal response to insulin of these variables (Rmax) were relatively small (GMCR, IDGU) or nonsignificant (GER, SSGIR). Maximum insulin-induced suppression of endogenous glucose production was significantly lower due to undernutrition; neither Rmax nor ED50 for this response was affected by pregnancy. Insulin resistance in late-pregnant ewes is primarily due to decreased insulin sensitivity in (presumably) peripheral tissues, implying an alteration of receptor function or of early postreceptor signal transduction.

The effects of the intestinal glucosidase inhibitor BAY M 1099 (miglitol) on glycemic status of obese-diabetic rats

1. Groups of lean and obese-diabetic (NIDDM) congenic male SHR/Ntul//- cp rats were fed a nutritionally adequate, high carbohydrate diet ad libitum with or without the a-glucosidase inhibitor miglitol (150 mg/kg diet) from 8 until 15 weeks of age, and key glycemic parameters were monitored throughout the study. 2. Miglitol treatment resulted in clinical improvements toward normal in percent glycosylated hemoglobin, glycemic and insulinogenic responses to an oral glucose tolerance, and in liver glucokinase activity, in concert with modest decreases in weight gain in obese rats. 3. These observations are consistent with improved insulin sensitivity in peripheral tissues following miglitol treatment, and indicate that this drug may be a useful adjunct to diet in the treatment of obesity, NIDDM, and possibly other disorders of carbohydrate metabolism.

Impact of Obesity on Insulin Action in NIDDM

Although a strong clinical association exists between obesity and NIDDM, previous studies have failed to confirm a significant relationship between the degree of obesity and the insulin resistance of NIDDM. We examined the impact of obesity on insulin-mediated glucose metabolism in 25 patients with NIDDM, whose BMI ranged from 20.8 to 36.9 kg/m2, during insulin infusions of 0.4, 1.0, and 10 microU/kg min using the glucose clamp technique. Rates of glucose disposal and HGP were compared in 14 of the diabetic patients with 19 nondiabetic control subjects of similar sex, age, and weight distribution. We found an inverse correlation between BMI and the glucose infusion rate necessary to maintain euglycemia during the first two of three insulin infusions (r = -0.63, P < 0.001, r = -0.57, P < 0.01, and r = -0.36, P = 0.08). Glucose disposal was correlated with BMI during the 1.0 mU/kg min insulin infusion (r = -0.57, P < 0.05), and glucose production was correlated at the 0.4 mU/kg min infusion (r = 0.69, P < 0.01). We concluded that obesity diminishes the insulin sensitivity of both hepatic and peripheral tissues in patients with NIDDM. The exacerbation of the insulin resistance of NIDDM by obesity indicates why weight reduction is an effective treatment for the obese NIDDM patient.

Dose-response relationship between lymph insulin and glucose uptake reveals enhanced insulin sensitivity of peripheral tissues

To examine the role of transcapillary insulin transport to peripheral insulin sensitivity in vivo, we performed dose-response experiments in which both plasma and thoracic duct lymph insulin and glucose utilization (Rd) were measured in conscious dogs. Euglycemic clamps (n = 22) consisted of a 3-h activation period in which insulin was infused (rates: "physiological" 3.6, 5.4, 7.2 pmol.min-1.kg-1; "pharmacological" 108 pmol.min-1.kg-1), followed by a 3-h deactivation period. [14C]inulin was also infused as a diffusionary marker. Insulin sensitivity was estimated as the ED50. When based on plasma insulin, ED50 was 480 pM. However, when calculated from lymph (i.e., interstitial) insulin measurements, ED50 was 240 pM. Thus, interstitial insulin measurements reveal that insulin sensitivity of peripheral tissues is approximately twice that estimated from plasma insulin and is similar to sensitivity reported for suppression of hepatic glucose production. Furthermore, although [14C]inulin achieved equilibrium between plasma and lymph within 180 min, within the physiological range, steady state plasma insulin was higher than insulin in lymph (306 +/- 18, 474 +/- 42, and 780 +/- 60 pM vs. 180 +/- 18, 318 +/- 12, and 504 +/- 36 pM; P less than 0.0001); plasma insulin achieved steady state faster than lymph insulin (6 +/- 1, 6 +/- 2, and 11 +/- 3 min vs. 29 +/- 4, 16 +/- 6, and 44 +/- 8 min; P less than 0.01) and disappeared faster (5 +/- 2, 7 +/- 2, and 15 +/- 6 min vs. 37 +/- 8, 32 +/- 4, and 43 +/- 9 min; P less than 0.01). The time course of lymph insulin at each dose was similar to that of Rd, and at each dose, unlike plasma insulin, lymph insulin was strongly correlated with Rd (r = 0.93 or better). At pharmacological hyperinsulinemia (plasma 35232 +/- 5250 pM, lymph 27366 +/- 4380 pM), Rd rose faster than lymph insulin and disappeared more slowly than insulin. Thus, lymph insulin data indicate that the periphery is more sensitive to insulin than previously realized from estimates based solely on plasma hormone. Furthermore, lymph insulin is proportional to Rd within the physiological but not pharmacological range of insulin, indicating that transcapillary insulin transport is rate limiting for insulin action in this range. Finally, based on in vivo lymph (i.e., interstitial) insulin measurements, peripheral tissue is almost twice as sensitive to insulin than previously realized.