Showing papers on "Insulin published in 1994"
1,696 citations
TL;DR: The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation.
Abstract: Nutrition is one of the main regulators of circulating IGF-I. In humans, serum IGF-I concentrations are markedly lowered by energy and/or protein deprivation. Both energy and proteins are critical in the regulation of serum IGF-I concentrations. Indeed, after fasting, optimal intake of both energy and protein is necessary for the rapid restoration of circulating IGF-I. We believe, however, that in adult humans energy may be somewhat more important than protein in this regard. While the lowest protein intake is able to increase IGF-I in the presence of adequate energy, there is a threshold energy requirement below which optimal protein intake fails to raise IGF-I after fasting. When energy intake is severely reduced, the carbohydrate content of the diet is a major determinant of responsiveness of IGF-I to GH. The essential amino acid content of the diet is also critical for the optimal restoration of IGF-I after fasting, when protein intake is reduced. The exquisite sensitivity of circulating IGF-I to nutrients, the nycthemeral stability of its concentrations and its relative short half-life constitute the basis for its use as a marker of both nutritional status and adequacy of nutritional rehabilitation. For these indications, IGF-I measurement is more sensitive and more specific than measurement of the other nutrient-related serum proteins (albumin, prealbumin, transferrin, retinol-binding protein). Animal models have been developed to investigate the mechanisms responsible for the nutritional regulation of IGF-I. There is no doubt that many mechanisms are involved (Fig. 12). Decline of serum IGF-I in dietary restriction is independent of the diet-induced alterations in pituitary GH secretion. The role of the liver GH receptors is dependent on the severity of the nutritional insult. In severe dietary restriction (fasting), a marked decrease of the number of somatogenic receptors supports the role of a receptor defect in the decline of circulating IGF-I. In contrast, in less severe forms of dietary restriction (protein restriction), the decline of IGF-I results from a postreceptor defect in the GH action at the hepatic level. Nutritional deprivation decreases hepatic IGF-I production by diminishing IGF-I gene expression. Decline in IGF-I gene expression is mainly caused by nutrient deficiency and less importantly by the nutritionally induced hormonal changes (insulin and T3). Diet restriction also increases the clearance and degradation of serum IGF-I through changes in the levels of circulating IGFBPs.(ABSTRACT TRUNCATED AT 400 WORDS)
1,577 citations
TL;DR: It is concluded that intensive therapy effectively delays the onset and slows the progression of diabetic retinopathy and nephropathy when initiated in adolescent subjects; the benefits outweigh the increased risk of hypoglycemia that accompanies such treatment.
1,454 citations
TL;DR: The results strongly suggest that TNF-α may play a crucial role in the systemic insulin resistance of NIDDM, and may allow for new treatments of disorders involving resistance to insulin.
Abstract: Recent data have suggested a key role for tumor necrosis factor (TNF)-alpha in the insulin resistance of obesity and non-insulin-dependent diabetes mellitus (NIDDM). TNF-alpha expression is elevated in the adipose tissue of multiple experimental models of obesity. Neutralization of TNF-alpha in one of these models improves insulin sensitivity by increasing the activity of the insulin receptor tyrosine kinase, specifically in muscle and fat tissues. On a cellular level, TNF-alpha is a potent inhibitor of the insulin-stimulated tyrosine phosphorylations on the beta-chain of the insulin receptor and insulin receptor substrate-1, suggesting a defect at or near the tyrosine kinase activity of the insulin receptor. Given the clear link between obesity, insulin resistance, and diabetes, these results strongly suggest that TNF-alpha may play a crucial role in the systemic insulin resistance of NIDDM. This may allow for new treatments of disorders involving resistance to insulin.
1,321 citations
TL;DR: Evidence is provided for IRS- 1-dependent and IRS-1-indepen-dent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.
Abstract: The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3'-OH kinase (PI(3)K) and several other proteins containing SH2 (Src-homology 2) domains. To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. These mice had no IRS-1 and showed no evidence of IRS-1 phosphorylation or IRS-1-associated PI(3)K activity. They also had a 50 per cent reduction in intrauterine growth, impaired glucose tolerance, and a decrease in insulin/IGF-1-stimulated glucose uptake in vivo and in vitro. The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.
1,240 citations
TL;DR: Results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.
Abstract: Insulin resistance is a common problem associated with infections and cancer and, most importantly, is the central component of non-insulin-dependent diabetes mellitus. We have recently shown that tumor necrosis factor (TNF) alpha is a key mediator of insulin resistance in animal models of non-insulin-dependent diabetes mellitus. Here, we investigate how TNF-alpha interferes with insulin action. Chronic exposure of adipocytes to low concentrations of TNF-alpha strongly inhibits insulin-stimulated glucose uptake. Concurrently, TNF-alpha treatment causes a moderate decrease in the insulin-stimulated autophosphorylation of the insulin receptor (IR) and a dramatic decrease in the phosphorylation of IR substrate 1, the major substrate of the IR in vivo. The IR isolated from TNF-alpha-treated cells is also defective in the ability to autophosphorylate and phosphorylate IR substrate 1 in vitro. These results show that TNF-alpha directly interferes with the signaling of insulin through its receptor and consequently blocks biological actions of insulin.
1,185 citations
TL;DR: The data suggest that mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth and the exis-tence of both IRS- 1-dependent and IRS-2-independent pathways for signal transduction of insulin and IGFs is suggested.
Abstract: INSULIN receptor substrate-1 (IRS-1) is the major substrate of insulin receptor and IGF-1 receptor tyrosine kinases; it has an apparent relative molecular mass of 160–190,000 (Mr, 160–190K) on SDS polyacrylamide gel1–3. Tyrosine-phosphorylated IRS-1 binds the 85K subunit of phosphatidylinositol 3-kinase4,5 which may be involved in the translocation of glucose transporters6,7 and the abundant src homology protein (ASH)/Grb28,9 which may be involved in activation of p2lras and MAP kinase cascade10. IRS-1 also has binding sites for Syp11 and Nck12 and other src homology 2 (SH2) signalling molecules10. To clarify the physiological roles of IRS-1 in vivo, we made mice with a targeted disruption of the IRS-1 gene locus. Mice homozygous for targeted disruption of the IRS-1 gene were born alive but were retarded in embryonal and postnatal growth. They also had resistance to the glucose-lowering effects of insulin, IGF-1 and IGF-2. These data suggest the exis-tence of both IRS-1-dependent and IRS-1-independent pathways for signal transduction of insulin and IGFs.
1,050 citations
TL;DR: The ability of troglitazone to reduce insulin resistance and improves glucose tolerance in obese subjects with either impaired or normal glucose tolerance could be useful in preventing NIDDM.
Abstract: Background Troglitazone decreases insulin resistance and hyperglycemia in patients with non-insulin-dependent diabetes mellitus (NIDDM), but its effects on subjects without diabetes are not known. Methods We performed oral and intravenous glucose-tolerance tests, studies with the euglycemic-hyperinsulinemic clamp, meal-tolerance tests, and 24-hour blood-pressure measurements at base line and after the administration of troglitazone, 200 mg orally twice daily, or placebo for 12 weeks in 18 nondiabetic obese subjects, 9 of whom had impaired glucose tolerance. Results The mean (±SD) rates of glucose disposal increased from 4.7 ±1.7 to 6.0 ±1.7 mg per kilogram of body weight per minute (P = 0.004) and from 9.0 ±1.8 to 9.9 ±1.3 mg per kilogram per minute (P = 0.02) during insulin infusions of 40 and 300 mU per square meter of body-surface area per minute, respectively, in the troglitazone group. The insulin-sensitivity index, calculated from the results of intravenous glucose-tolerance tests, increased from 0....
954 citations
TL;DR: It is concluded that activation of wortmannin-sensitive PI 3-kinase plays a pivotal role in the intracellular signaling pathways arising from the insulin receptor autophosphorylation and leading to certain metabolic responses.
937 citations
TL;DR: It is demonstrated that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
Abstract: Insulin resistance is an important metabolic abnormality often associated with infections, cancer, obesity, and especially non-insulin-dependent diabetes mellitus (NIDDM). We have previously demonstrated that tumor necrosis factor-alpha produced by adipose tissue is a key mediator of insulin resistance in animal models of obesity-diabetes. However, the mechanism by which TNF-alpha interferes with insulin action is not known. Since a defective insulin receptor (IR) tyrosine kinase activity has been observed in obesity and NIDDM, we measured the IR tyrosine kinase activity in the Zucker (fa/fa) rat model of obesity and insulin resistance after neutralizing TNF-alpha with a soluble TNF receptor (TNFR)-lgG fusion protein. This neutralization resulted in a marked increase in insulin-stimulated autophosphorylation of the IR, as well as phosphorylation of insulin receptor substrate 1 (IRS-1) in muscle and fat tissues of the fa/fa rats, restoring them to near control (lean) levels. In contrast, no significant changes were observed in insulin-stimulated tyrosine phosphorylations of IR and IRS-1 in liver. The physiological significance of the improvements in IR signaling was indicated by a concurrent reduction in plasma glucose, insulin, and free fatty acid levels. These results demonstrate that TNF-alpha participates in obesity-related systemic insulin resistance by inhibiting the IR tyrosine kinase in the two tissues mainly responsible for insulin-stimulated glucose uptake: muscle and fat.
829 citations
TL;DR: Using polycystic ovary syndrome as a model of insulin resistance and hyperandrogenism, the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS was assessed.
Abstract: Using polycystic ovary syndrome (PCOS) as a model of insulin resistance and hyperandrogenism, our specific aim was to assess the effect of Metformin on lipoproteins, sex hormones, gonadotropins, and blood pressure in 26 women with PCOS who were studied at baseline, received Metformin 1.5 g/d for 8 weeks, and were then restudied. None of the women had normal menstrual cycles, 100% had multiple subcapsular follicules by pelvic ultrasound, 90% were hirsute, and 85% had high free testosterone. Comparing post-Metformin versus baseline levels, the Quetelet Index (QI) decreased 1.5% (P = .04) and the waist to hip ratio (WHR) decreased 2.8% (P = .003). After covariance adjusting for changes in the QI and WHR, on Metformin the area under the insulin curve (IA) during oral glucose tolerance testing decreased 35% (P = .04), and the insulin area to glucose area ratio decreased 31% (P = .03). On Metformin, covariance-adjusted systolic blood pressure (SBP) decreased (P = .04) and apo A-1 increased (P = .05). On Metformin, with improvement in insulin sensitivity, there were sharp reductions in covariance-adjusted luteinizing hormone ([LH] P = .0007), total testosterone ([T] P = .0004), free T (P = .0001), androstenedione (P = .002), dehydroepiandrosterone sulfate ([DHEAS] P = .006), and the free androgen index ([FAI] P = .0005), with increments in follicle-stimulating hormone ([FSH] P = .04) and sex hormone-binding globulin ([SHBG] P = .04).(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Findings indicate that insulin's vasodilatory effects are mediated by stimulation of NO release, and that they play a role in the regulation of arterial pressure during physiologic hyperinsulinemia.
Abstract: Insulin exerts effects on the vasculature that (a) may play a role in the regulation of blood pressure; and (b) by boosting its own delivery to target tissues, also have been proposed to play an integral part in its main action, the promotion of glucose disposal. To study the role of nitric oxide (NO) in the mediation of insulin's effects on the peripheral vasculature, NG-monomethyl-L-arginine (L-NMMA), a specific inhibitor of the synthesis of endothelium-derived NO, was infused into the brachial arteries of healthy volunteers both before, and at the end of a 2-h hyperinsulinemic (6 pmol/kg per min) euglycemic clamp. L-NMMA (but not norepinephrine, an NO-independent vasoconstrictor) caused larger reductions in forearm blood flow during hyperinsulinemia than at baseline. Moreover, L-NMMA prevented insulin-induced vasodilation throughout the clamp. Prevention of vasodilation by L-NMMA led to significant increases in arterial pressure during insulin/glucose infusion but did not alter glucose uptake. These findings indicate that insulin's vasodilatory effects are mediated by stimulation of NO release, and that they play a role in the regulation of arterial pressure during physiologic hyperinsulinemia. Abnormalities in insulin-induced NO release could contribute to altered vascular function and hypertension in insulin-resistant states.
TL;DR: Long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid cycle.
Abstract: We tested effects of long-term exposure of pancreatic islets to free fatty acids (FFA) in vitro on B cell function. Islets isolated from male Sprague-Dawley rats were exposed to palmitate (0.125 or 0.25 mM), oleate (0.125 mM), or octanoate (2.0 mM) during culture. Insulin responses were subsequently tested in the absence of FFA. After a 48-h exposure to FFA, insulin secretion during basal glucose (3.3 mM) was severalfold increased. However, during stimulation with 27 mM glucose, secretion was inhibited by 30-50% and proinsulin biosynthesis by 3040%. Total protein synthesis was similarly affected. Conversely, previous palmitate did not impair a-ketoisocaproic acid (5 mM)-induced insulin release. Induction and reversibility ofthe inhibitory effect on glucose-induced insulin secretion required between 6 and 24 h. Addition of the carnitine palmitoyltransferase I inhibitor etomoxir (1 ,uM) partially reversed (by > 50%) FFA-associated decrease in secretory as well as proinsulin biosynthetic responses to 27 mM glucose. The inhibitory effect of previous palmitate was similar when co-culture was performed with 5.5, 11, or 27mM glucose. Exposure to palmitate or oleate reduced the production of 14CO2 from D-[U-14C1 glucose, and of "4CO2 from D-13,4-"CIglucose, both effects being reversed by etomoxir. Conclusions: long-term exposure to FFA inhibits glucose-induced insulin secretion and biosynthesis probably through a glucose fatty acid
TL;DR: It is concluded that insulin resistance is associated with impaired development in fetal life and men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant.
Abstract: Type 2 (non-insulin-dependent) diabetes mellitus may originate through impaired development in fetal life. Both insulin deficiency and resistance to the action of insulin are thought to be important in its pathogenesis. Although there is evidence that impaired fetal development may result in insulin deficiency, it is not known whether insulin resistance could also be a consequence of reduced early growth. Insulin resistance was therefore measured in 81 normoglycaemic subjects, and 22 subjects with impaired glucose tolerance, who were born in Preston, UK, between 1935 and 1943. Their birth measurements had been recorded in detail. Insulin resistance was measured by the insulin tolerance test which uses the rate of fall in blood glucose concentrations after intravenous injection of insulin as an index of insulin resistance. Men and women who were thin at birth, as measured by a low ponderal index, were more insulin resistant. The association was statistically significant (p = 0.01) and independent of duration of gestation, adult body mass index and waist to hip ratio and of confounding variables including social class at birth or currently. Thinness at birth and in adult life has opposing effects such that resistance fell with increasing ponderal index at birth but rose with increasing adult body mass index. It is concluded that insulin resistance is associated with impaired development in fetal life.
TL;DR: It is concluded that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.
Abstract: The extent to which the oral glucose tolerance test can be used to estimate insulin secretion and insulin resistance has been evaluated by comparing glucose and insulin concentrations during an oral glucose tolerance test with specific measurements of insulin secretion and insulin resistance in 85 normoglycaemic subjects and 23 subjects with impaired glucose tolerance (IGT). Insulin secretion was measured by the first phase insulin response to intravenous glucose and insulin resistance by the insulin tolerance test which measures the decline of plasma glucose after the injection of a bolus of insulin. The best measure of insulin secretion was the ratio of the 30 min increment in insulin concentration to the 30 min increment in glucose concentration following oral glucose loading. This correlated with the first phase insulin release following intravenous glucose (r=0.61, p 0.05). Insulin resistance could be estimated by the fasting insulin, proinsulin, or split proinsulin concentrations. However, fasting split proinsulin appeared to discriminate best between insulin resistance (r = −0.53, p 0.05). Relative insulin resistance estimated by homeostasis model assessment (HOMA) also correlated well with insulin resistance (r= −0.57, p 0.05). We conclude that the oral glucose tolerance test can be used to derive estimates of the relative roles of insulin secretion and insulin resistance in population studies of glucose tolerance.
TL;DR: Data are presented to indicate that, via a yet unknown interaction with the endothelium, insulin is able to increase nitric oxide synthesis and release and through this mechanism vasodilate, and it is interesting to speculate that states of insulin resistance might also be associated with a defect in insulin's action to modulate the nitrous oxide system.
Abstract: There is accumulating evidence that insulin has a physiological role to vasodilate skeletal muscle vasculature in humans. This effect occurs in a dose-dependent fashion within a half-maximal respon...
TL;DR: Although the addition of zinc retarded the absorption of LYSPRO slightly, it displays faster pharmacodynamic action than human Regular insulin when injected subcutaneously and retains its distinct profile.
Abstract: [Lys(B28, Pro(B29)]-human insulin (LYSPRO) is an insulin analogue in which the natural amino acid sequence of the B-chain at positions 28 and 29 is inverted. These changes result in an insulin molecule with a greatly reduced capacity for self-association in solution. These clinical studies were designed to compare LYSPRO with human Regular insulin after subcutaneous injection in humans. We wanted to evaluate the effect of adding zinc to LYSPRO on its pharmacokinetics and pharmacodynamics. In addition, we compared the pharmacokinetics and pharmacodynamics of LYSPRO and human Regular insulin after subcutaneous injection to those of human Regular insulin given intravenously. Thus, we compared four treatments: solutions of zinc-free LYSPRO given subcutaneously (A), zinc-containing LYSPRO given subcutaneously (B), human Regular insulin given subcutaneously (C), and human Regular insulin given intravenously (D). We gave a 10-U dose of each treatment to 10 healthy (nondiabetic) men during glucose clamps. Serum insulin concentrations peaked more than two times higher (maximum serum insulin level [Cmax], 698 vs. 308 pM, A vs. C) and in less than half the time (time to Cmax [Tmax], 42 vs. 101 min, A vs. C) after subcutaneous injection of zinc-free LYSPRO. At the same time, the glucose infusion rate peaked in about half the time (time to maximum glucose infusion rate [TRmax], 99 vs. 179 min, A vs. C) and was slightly but not significantly higher (maximum glucose infusion rate [Rmax], 3.1 vs. 2.2 mmol/min, A vs. C) than that of human Regular insulin.(ABSTRACT TRUNCATED AT 250 WORDS)
TL;DR: Results indicate IL-10 suppresses the induction and progression of autoimmune pathogenesis associated with diabetes mellitus and suggest a potential therapeutic role for this cytokine in this autoimmune disease.
TL;DR: The results show that a rapid increase in GLUT4 expression is an early adaptive response of muscle to exercise and appears to be mediated by pretranslational mechanisms that enhance replenishment of muscle glycogen stores.
TL;DR: The stable overexpression in a Chinese hamster ovary (CHO) cell line of a mutant p85 alpha (delta p85) protein, which lacks a binding site for p110, disrupted the complex formation between IRS-1 and the catalytic subunit of PI 3-kinase in intact cells during insulin stimulation, suggesting that PI 3 -kinase is required for glucose transport in insulin signaling in CHO cells.
Abstract: Insulin stimulation drives the formation of a complex between tyrosine-phosphorylated insulin receptor substrate 1 (IRS-1) and 1-phosphatidylinositol 3-kinase (PI 3-kinase; ATP:1-phosphatidyl-1D-myo-inositol 3-phosphotransferase, EC 2.7.1.137), a heterodimer consisting of regulatory 85-kDa (p85) and catalytic 110-kDa (p110) subunits. This interaction takes place via the phosphorylated YMXM motifs of IRS-1 and the Src homology region 2 (SH2) domains of p85. In this study, the stable overexpression in a Chinese hamster ovary (CHO) cell line of a mutant p85 alpha (delta p85) protein, which lacks a binding site for p110, disrupted the complex formation between IRS-1 and the catalytic subunit of PI 3-kinase in intact cells during insulin stimulation. Activation of insulin receptor kinase and the tyrosine phosphorylation of IRS-1 remained unaffected. In this cell line, both insulin-stimulated accumulation of phosphatidylinositol 3,4,5-trisphosphate and the insulin-stimulated glucose uptake due to the translocation of GLUT1 glucose transporters were markedly impaired, whereas neither phorbol 12-myristate 13-acetate-stimulated glucose uptake nor the insulin-stimulated activation of RAS was impaired. These results suggest that PI 3-kinase is required for glucose transport in insulin signaling in CHO cells.
TL;DR: Testing for anti‐GAD in adult‐onset non‐obese diabetic patients should be a routine procedure in order to detect latent insulin‐dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.
Abstract: Type 1 diabetes mellitus in adults may present in a manner similar to that of Type 2 diabetes but with a late development of insulin dependency. We studied 65 patients who presented with ‘adult-onset’ diabetes after the age of 30 years. Of these patients, 19 required insulin therapy. The insulin-treated patients were significantly younger, their onset of diabetes was at an earlier age, and their postprandial serum C-peptide levels were lower than those of the non-insulin-treated group. Moreover, the insulin-treated subjects had a higher mean concentration of antibodies to glutamic acid decarboxylase (GAD) (66.8 ± 10.2 units) than the patients who did not require insulin (9.9 ± 1.9 units) (p < 0.001) and their frequency of anti-GAD positivity was 73.7% versus 4.3% (p < 0.001). Thus, among patients attending a diabetes clinic, the majority (73.7%) of subjects who presented with diabetes after 30 years of age and who subsequently required therapy with insulin, actually have the islet cell lesion of Type 1 diabetes which progresses at a slower tempo than in children. We conclude that testing for anti-GAD in adult-onset non-obese diabetic patients should be a routine procedure in order to detect latent insulin-dependency at the earliest possible stage, since this assay can assist in the correct classification of diabetes, and more appropriate therapy.
TL;DR: Results indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight, and support a role for this cytokine in the insulin-resistant diabetic state.
Abstract: As obesity is a major risk factor for noninsulin-dependent diabetes mellitus, adipose tissue may generate a mediator that influences the activity of insulin on various target tissues. Recent evidence suggests that a cytokine, tumor necrosis factor-alpha (TNF alpha), may serve this role. This study investigates whether the expression of TNF alpha and its receptors is modulated during drug treatment to reduce insulin resistance. The effects of moderate weight loss by dietary restriction were also examined. We show here that a marked induction of TNF alpha mRNA occurs in adipose tissues from a mouse model of obesity-linked diabetes (KKAy) compared to that in nondiabetic mice (C57). Likewise, RNA transcripts encoding TNF R2 receptors (p75) were significantly increased in fat tissues of the obese diabetic animals. In muscle from these diabetic animals, RNA transcripts encoding both TNF R1 (p55) and R2 were significantly elevated, although R2 transcript abundance was less elevated than in fat. We also observed that the overexpression of mRNA for TNF alpha and both of its receptors could be at least partly normalized by treatment of the diabetic animals with the insulin-sensitizing agent pioglitazone. Treating of the obese diabetic animals by food restriction reduced the expression of mRNA for TNF R2 in muscle, but not fat. These results clearly indicate that gene expression for the TNF systems can be regulated by an insulin-sensitizing drug and reduction of body weight. Such findings support a role for this cytokine in the insulin-resistant diabetic state and show its modulation by therapies that reverse the disorder.
TL;DR: In NIDDM patients, high-carbohydrate diets compared with high-monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable.
Abstract: Objective. —To study effects of variation in carbohydrate content of diet on glycemia and plasma lipoproteins in patients with non—insulin-dependent diabetes mellitus (NIDDM). Design. —A four-center randomized crossover trial. Setting. —Outpatient and inpatient evaluation in metabolic units. Patients. —Forty-two NIDDM patients receiving glipizide therapy. Interventions. —A high-carbohydrate diet containing 55% of the total energy as carbohydrates and 30% as fats was compared with a high—monounsaturated-fat diet containing 40% carbohydrates and 45% fats. The amounts of saturated fats, polyunsaturated fats, cholesterol, sucrose, and protein were similar. The study diets, prepared in metabolic kitchens, were provided as the sole nutrients to subjects for 6 weeks each. To assess longer-term effects, a subgroup of 21 patients continued the diet they received second for an additional 8 weeks. Main Outcome Measures. —Fasting plasma glucose, insulin, lipoproteins, and glycosylated hemoglobin concentrations. Twenty-four-hour profiles of glucose, insulin, and triglyceride levels. Results. —The site of study as well as the diet order did not affect the results. Compared with the high—monounsaturated-fat diet, the high-carbohydrate diet increased fasting plasma triglyceride levels and very low-density lipoprotein cholesterol levels by 24% ( P P =.0001), respectively, and increased daylong plasma triglyceride, glucose, and insulin values by 10% ( P =.03), 12% ( P P =.02), respectively. Plasma total cholesterol, low-density lipoprotein cholesterol, and high-density lipoprotein cholesterol levels remained unchanged. The effects of both diets on plasma glucose, insulin, and triglyceride levels persisted for 14 weeks. Conclusions. —In NIDDM patients, high-carbohydrate diets compared with high—monounsaturated-fat diets caused persistent deterioration of glycemic control and accentuation of hyperinsulinemia, as well as increased plasma triglyceride and very-low-density lipoprotein cholesterol levels, which may not be desirable. ( JAMA . 1994;271:1421-1428)
TL;DR: It is concluded that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
Abstract: Hyperinsulinemia is a common finding in hyperandrogenic women, during pregnancy, and in women using oral contraceptives. To test whether sex hormone treatment can induce insulin resistance in healthy subjects, we studied the effects of administration of testosterone to 13 female to male and of ethinyl estradiol to 18 male to female transsexuals. Utilization and production of glucose and levels of sex steroids were measured during a three-step hyperinsulinemic-euglycemic clamp before and after 4 months of hormone administration. Females were treated with im injections of testosterone esters (250 mg/2 weeks); males were treated with ethinyl estradiol alone (0.1 mg/day, orally) or a combination of ethinyl estradiol and cyproterone acetate (100 mg/day, orally). Similar insulin levels were achieved at each of the three steps of the clamp studies before and during hormone administration. During step 1 of each clamp, with insulin levels in the physiological range, glucose utilization decreased from 3.5 +/- 1.2 to 2.6 +/- 0.9 mmol/kg lean body mass (LBM).h in women treated with testosterone esters (P < 0.001) and from 3.2 +/- 0.7 to 2.5 +/- 0.5 mmol/kg lean body mass.h in men treated with ethinyl estradiol (P < 0.001). The effects of sex steroids during steps 2 and 3 of the clamp at higher (supraphysiological) insulin levels were less clear. Endogenous glucose production (measured by isotope dilution with tritiated glucose) was not affected by hormone administration, indicating that the observed changes in glucose requirement were determined by a diminished peripheral glucose uptake. We conclude that sex hormone administration, i.e. testosterone treatment in females and ethinyl estradiol treatment in males, can induce insulin resistance in healthy subjects.
TL;DR: There was a highly significant linear relationship between log[viscosity] of the mixtures consumed and the glucose and insulin responses and that 79-96% of the changes in plasma glucose and diabetes levels are attributable to viscosity, and that changes occur at relatively low doses and viscosities.
Abstract: An extract from oats known as oat gum (OG) is composed mainly of the polysaccharide (1-->3) (1-->4)-beta-D-glucan, which is highly viscous in aqueous solution. Viscous polysaccharides are known to attenuate postprandial plasma glucose and insulin responses. The purposes of this study were to determine the dose-response to OG and establish quantitatively the effect of viscosity on plasma glucose and insulin levels of healthy humans consuming 50 g glucose. Increasing the dose of OG successively reduced the plasma glucose and insulin responses relative to a control without gum. Reduction of the viscosity of OG by acid hydrolysis reduced or eliminated the capacity to decrease postprandial glucose and insulin levels. The ability of OG to modify glycaemic response was unchanged following agglomeration in the presence of maltodextrin. Agglomerated gum dispersed smoothly in a drink without formation of lumps, and development of maximum viscosity was delayed. These properties improve palatability. There was a highly significant linear relationship between log[viscosity] of the mixtures consumed and the glucose and insulin responses. The relationship shows that 79-96% of the changes in plasma glucose and insulin are attributable to viscosity, and that changes occur at relatively low doses and viscosities.
TL;DR: Equimolar concentrations of equal specific activity 125I-labeled IGF-I, IGF-II, or insulin were infused into the carotid artery of anesthetized adult rats to suggest that radiolabeled IGFs and -II bind to brain capillaries and cross the blood-brain barrier into brain parenchyma more readily than radiolabelled insulin.
Abstract: Although evidence exists that insulin may cross the blood-brain barrier, little is known about the ability of insulin-like growth factors (IGF-I and -II) to cross this barrier. In the present studies, equimolar concentrations of equal specific activity 125I-labeled IGF-I, IGF-II, or insulin were infused into the carotid artery of anesthetized adult rats. The perfusions were carried out for 3 min in the presence or absence of excess unlabeled ligand or insulin, with three or more animals in each group. Immediately after the perfusion, brains were frozen and sectioned for autoradiography. All ligands were detected in choroid plexus, median eminence, and blood vessels, but [125I]IGF-I and -II were also prominently localized in brain parenchyma. Densitometric analysis of film autoradiographs (28-day exposure for all ligands) revealed that radiolabeled IGFs, especially IGF-I, were significantly more abundant throughout the forebrain than [125I]insulin, especially in the paraventricular nucleus, where [125I]IGF-I was 10-fold and [125I]IGF-II was 5-fold more abundant than [125I]insulin. The difference in [125I]IGF-I vs. [125I]insulin accumulation was confirmed by parallel measurements of radioactivity in anatomically matched brain sections using a gamma-spectrometer. The uptake of radiolabeled IGF-I, IGF-II, and insulin by brain parenchyma and vasculature was completely inhibited by excess (1,000-fold) unlabeled ligand; however, insulin (10,000-fold excess) did not completely abolish [125I]IGF-I and -II accumulation. Microscopic evaluation of nuclear emulsion-coated brain sections revealed that radioactivity associated with [125I]IGF-I and -II perfusions was selectively concentrated in capillaries and medium-sized parenchymal cells in the paraventricular nucleus and, to a lesser extent, the supraoptic nucleus and anterior nucleus of the thalamus, whereas in other brain regions the radioligands were mostly bound to capillaries. These results suggest that radiolabeled IGF-I and -II bind to brain capillaries and cross the blood-brain barrier into brain parenchyma more readily than radiolabeled insulin.
01 Jan 1994
TL;DR: A disturbance of polyamine biosynthesis occurred prior to cell growth or apoptosis elicited by oxidative stress, and effects as opposite as cell proliferation and deletion can be induced, in the same system, by varying the exposure to a prooxidant.
Abstract: Increasing concentrations (1-100 microM) of the redox cycling quinone, 2,3-dimethoxy-1,4-naphthoquinone (DMNQ), stimulated growth, triggered apoptosis, or caused necrosis of pancreatic RINm5F cells, depending on the dose and duration of the exposure. Following the exposure of RINm5F cells to 10 microM DMNQ, ornithine decarboxylase activity and polyamine biosynthesis increased. This was accompanied by enhanced cell proliferation. Conversely, exposure to 30 microM DMNQ for 3 h resulted in the inhibition of ornithine decarboxylase, intracellular polyamine depletion, and apoptotic cell killing. Pretreatment of the cultures with the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate, restored polyamine levels and prevented apoptosis. Exposure to the same DMNQ concentration for only 1 h, with subsequent re-incubation in growth medium, neither caused polyamine depletion nor resulted in apoptosis. Finally, exposure to an even higher DMNQ concentration (100 microM) for either 1 or 3 h caused rapid intracellular Ca2+ overload, ATP, NAD+, and glutathione depletion, and extensive DNA single strand breakage, which resulted in necrotic cell death. Our results show that a disturbance of polyamine biosynthesis occurred prior to cell growth or apoptosis elicited by oxidative stress. In addition, we show that effects as opposite as cell proliferation and deletion, by either apoptosis or necrosis, can be induced, in the same system, by varying the exposure to a prooxidant.
TL;DR: Resistance to the action of insulin on glucose metabolism in skeletal muscle has been proposed as the inherited basis for this syndrome and since insulin resistance is observed several decades before the onset of hyperglycemia an early detection can open the prospect of intervention in order to prevent the disease process.
Abstract: Non-insulin-dependent diabetes mellitus (NIDDM)' is phenotypically heterogenous and may therefore not be explained by one simple pathophysiological mechanism. Despite the heterogenous nature of the disease, the major form as discussed in this review is linked to overweight, arterial hypertension, dyslipidemia, and macroangiopathy (coronary heart disease), all conditions which become more common with aging (1). This form of NIDDMseems to be growing worldwide in the footsteps of Westernized life style. Around 3%in the Western world suffers from the disease, but in subjects 60 yr and older, the prevalence is as high as 10-20% (2). In certain ethnic populations as the Pima Indians and the Nauruans the prevalence approaches 40% (2). Therefore, NIDDM imposes an enormous burden on the health care system all over the world. In general, the goals of treatment are achieved in only a small subset of patients, but nevertheless progression of macroangiopathy is a more severe problem than worsening of glycemia. The overall mortality rate in patients with NIDDMis two to three times higher than in control subjects, primarily due to excess mortality of coronary heart disease (2). Of note, 40% of patients already suffer from clinical macroangiopathy at diagnosis, indicating that these complications may not be secondary to the diabetic state itself, but rather a part of the NIDDM syndrome, also referred to as Syndrome X or \"The Insulin Resistance Syndrome\" (1). Resistance to the action of insulin on glucose metabolism in skeletal muscle has been proposed as the inherited basis for this syndrome and since insulin resistance is observed several decades before the onset of hyperglycemia an early detection can open the prospect of intervention in order to prevent the disease process (4-7). The present review discusses the metabolic and genetic background of NIDDMtogether with the current knowledge of the sequence of events leading to NIDDM. Based on that a new
TL;DR: The existence of considerable IGF BP-1 production from the liver during insulinopenia is demonstrated and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels are demonstrated, indicating that insulin may play a role in determining the bioavailability of IGF -I.
Abstract: Insulin-like growth factors (IGFs) circulate attached to binding proteins (IGFBPs). Only the unbound form of IGF is suggested to be biological active. The main source of circulating IGF-I and IGFBP-1 is considered to be the liver, but that of circulating IGFBP-3 is not known. IGF-I and IGFBP-3 are GH dependent, whereas IGFBP-1 is insulin regulated. The aim of the present study was to examine the effect of insulin on the hepatic secretion of IGFBP-1, IGFBP-3, and IGF-I. Seven insulin-dependent diabetic patients in whom insulin was withheld for 12 h were studied in the overnight fasted state. Blood was sampled simultaneously from the hepatic vein, a peripheral vein, and an artery before and during insulin infusion for 3 h. The basal IGFBP-1 levels in the peripheral vein were several-fold elevated (249 +/- 44 micrograms/L) compared to those in healthy subjects (37 +/- 2 micrograms/L). Fasting IGFBP-1 concentrations were inversely correlated to the insulin levels (r = -0.918; P < 0.001). The mean IGF-I concentration (175 +/- 17 micrograms/L; -1.62 +/- 0.38 SD score) was decreased compared with that in age-matched healthy subjects. The basal IGFBP-3 levels in the peripheral vein (4.50 +/- 0.33 mg/L) were within the normal range. There was a significant correlation in the hepatic vein between fasting IGF-I and IGFBP-3 levels (r = 0.928; P < 0.001). Basal splanchnic IGFBP-1 production was 18 +/- 7 micrograms/min, whereas no basal net exchanges of IGF-I or IGFBP-3 were observed across the splanchnic area. Insulin inhibited splanchnic IGFBP-1 production within 120 min and glucose output within 20 min. Serum IGF-I, but not IGFBP-3, concentrations increased significantly during the insulin infusion. In summary, this study demonstrates the existence of considerable IGFBP-1 production from the liver during insulinopenia and the complete blocking of splanchnic IGFBP-1 production and increases in serum levels of IGF-I by insulin despite no effect on IGFBP-3 levels. Thus, insulin may play a role in determining the bioavailability of IGF-I.
TL;DR: Presence of insulin transcripts within specific neurons with extracellular secretion of the peptide suggests a specialized biological role in central mammalian neurons.