Dyslipidemia and diabetes mellitus: Role of lipoprotein species and interrelated pathways of lipid metabolism in diabetes mellitus.

Diabetes mellitus is a complex disease. We are increasingly gaining a better understanding of its mechanisms at the molecular level. From these new insights, better therapeutic approaches should emerge. Diabetes mellitus is a syndrome with many associated subphenotypes. These include mitochondrial disorders, lipodystrophies, and inflammatory disorders involving cytokines. Levels of sphingosine-1-phosphate, which has recently been shown to play a role in glucose homeostasis, are low in diabetics, whereas levels of ceramides are increased. Major phenotypes associated with diabetes mellitus are dyslipidemias, notably hypertriglyceridemia and low high-density lipoprotein cholesterol levels. Both diabetes and dyslipidemia are strongly associated with increased risk for atherosclerotic vascular disease.

Obesity-related hypoxia via miR-128 decreases insulin-receptor expression in human and mouse adipose tissue promoting systemic insulin resistance.

BACKGROUND: Insulin resistance in visceral adipose tissue (VAT), skeletal muscle and liver is a prominent feature of most patients with obesity. How this association arises remains poorly understood. The objective of this study was to demonstrate that the decrease in insulin receptor (INSR) expression and insulin signaling in VAT from obese individuals is an early molecular manifestation that might play a crucial role in the cascade of events leading to systemic insulin resistance. METHODS: To clarify the role of INSR and insulin signaling in adipose tissue dysfunction in obesity, we first measured INSR expression in VAT samples from normal-weight subjects and patients with different degrees of obesity. We complemented these studies with experiments on high-fat diet (HFD)-induced obese mice, and in human and murine adipocyte cultures, in both normoxic and hypoxic conditions. FINDINGS: An inverse correlation was observed between increasing body mass index and decreasing INSR expression in VAT of obese humans. Our results indicate that VAT-specific downregulation of INSR is an early event in obesity-related adipose cell dysfunction, which increases systemic insulin resistance in both obese humans and mice. We also provide evidence that obesity-related hypoxia in VAT plays a determinant role in this scenario by decreasing INSR mRNA stability. This decreased stability is through the activation of a miRNA (miR-128) that downregulates INSR expression in adipocytes. INTERPRETATION: We present a novel pathogenic mechanism of reduced INSR expression and insulin signaling in adipocytes. Our data provide a new explanation linking obesity with systemic insulin resistance. FUNDING: This work was partly supported by a grant from Nutramed (PON 03PE000_78_1) and by the European Commission (FESR FSE 2014-2020 and Regione Calabria).

A unique allosteric insulin receptor monoclonal antibody that prevents hypoglycemia in the SUR-1-/- mouse model of KATP hyperinsulinism.

Loss-of-function mutations of the ß-cell ATP-sensitive potassium channels (KATP) cause the most common and severe form of congenital hyperinsulinism (KATPHI), a disorder of ß-cell function characterized by severe hypoglycemia. Children with KATPHI are typically unresponsive to medical therapy and require pancreatectomy for intractable hypoglycemia. We tested the hypothesis that inhibition of insulin receptor signaling may prevent hypoglycemia in KATPHI. To test this hypothesis, we examined the effect of an antibody allosteric inhibitor of the insulin receptor, XMetD, on fasting plasma glucose in a mouse model of KATPHI (SUR-1-/- mice). SUR-1-/- and wild-type mice received twice weekly intraperitoneal injections of either XMetD or control antibody for 8 wks. Treatment with XMetD significantly decreased insulin sensitivity, and increased hepatic glucose output and fasting plasma glucose. These findings support the potential use of insulin receptor antagonists as a therapeutic approach to control the hypoglycemia in congenital hyperinsulinism.

Role of gut microbiota and oxidative stress in the progression of non-alcoholic fatty liver disease to hepatocarcinoma: Current and innovative therapeutic approaches.

Non-alcoholic fatty liver disease (NAFLD) represents the most common chronic liver disease in industrialized countries. NAFLD progresses through the inflammatory phase of non-alcoholic steatohepatitis (NASH) to fibrosis and cirrhosis, with some cases developing liver failure or hepatocellular carcinoma (HCC). Liver biopsy remains the gold standard approach to a definitive diagnosis of NAFLD and the distinction between simple steatosis and NASH. The pathogenesis of NASH is still not clear. Several theories have been proposed ranging from the "Two Hit Theory" to the "Multiple Hit Theory". However, the general consensus is that the gut microbiota, oxidative stress, and mitochondrial damage play key roles in the pathogenesis of NASH. The interaction between the gut epithelia and some commensal bacteria induces the rapid generation of reactive oxygen species (ROS). The main goal of any therapy addressing NASH is to reverse or prevent progression to liver fibrosis/cirrhosis. This problem represents the first "Achilles' heel" of the new molecules being evaluated in most ongoing clinical trials. The second is the inability of these molecules to reach the mitochondria, the primary sites of energy production and ROS generation. Recently, a variety of non-pharmacological and pharmacological treatment approaches for NASH have been evaluated including vitamin E, the thiazolidinediones, and novel molecules related to NASH pathogenesis (including obeticholic acid and elafibranor). Recently, a new isoform of human manganese superoxide dismutase (MnSOD) was isolated and obtained in a synthetic recombinant form designated rMnSOD. This protein has been shown to be a powerful antioxidant capable of mediating ROS dismutation, penetrating biological barriers via its uncleaved leader peptide, and reducing portal hypertension and fibrosis in rats affected by liver cirrhosis. Based on these distinctive characteristics, it can be hypothesized that this novel recombinant protein (rMnSOD) potentially represents a new and highly efficient adjuvant therapy to counteract the progression from NASH to HCC.

Cerebral Salt-Wasting Syndrome: Diagnosis by Urine Sodium Excretion.

BACKGROUND: Cerebral salt-wasting syndrome (CSWS) was initially described over 60 years ago in hyponatremic patients with a cerebral lesion. However, the diagnostic criteria for CSWS have not been fully established. Thus, when hyponatremia is observed in patients with CSWS, they may be misdiagnosed as having the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Thus, it is critical to differentiate between these 2 conditions because their treatments are diametrically opposed. MATERIALS AND METHODS: We carried out a retrospective study of 45 patients with CSWS and compared them to 60 normonatremic control patients, and 28 patients with SIADH. All patients had their 24-hour urine volumes and sodium (Na) excretion measured. RESULTS: In patients with CSWS, urinary Na excretion was 394 ± 369mmol/24 hours and urinary volume was 2,603 ± 996mL/24 hours; both values significantly greater than in controls (P < 0.01). By contrast, in patients with SIADH, the urine Na excretion was only 51 ± 25mmol/24 hours and urine volume was 745 ± 298mL/24 hours; values significantly lower than in patients with CSWS (P < 0.01). CONCLUSIONS: CSWS was diagnosed in patients with cerebral lesion who had (1) symptomatic hyponatremia, (2) urine Na excretion 2 standard deviations above controls and (3) increased urine volume. Patients with SIADH also had symptomatic hyponatremia but, in contrast to patients with CSWS, they had decreased Na excretion and urine volume. Thus urine Na excretion and volume are very important for diagnosing the cause of hyponatremia in patients with cerebral lesions.

An allosteric antibody to the leptin receptor reduces body weight and reverses the diabetic phenotype in the Lep(ob) /Lep(ob) mouse.

OBJECTIVE: Leptin (LEP) deficiency results in major metabolic perturbations, including obesity, dyslipidemia, and diabetes. Although LEP deficiency can be treated with daily injections of a recombinant LEP, generation of an antibody activating the LEP receptor (LEPR) that has both an intrinsically long half-life and low immunogenicity could be useful in the treatment of this condition. METHODS: Phage display technology coupled with flow cytometry and cell-based in vitro assays were employed to identify an allosteric agonist of the mouse LEPR. LEP-deficient Lep(ob) /Lep(ob) mice were used to compare in vivo effects of LEP to antibody administration. To evaluate hypothalamic effects of treatment, changes in mRNA levels of neuropeptide Y and proopiomelanocortin were measured. RESULTS: XPA.80.037 is a monoclonal antibody that demonstrates allosteric agonism of the mouse LEPR. Treatment of Lep(ob) /Lep(ob) mice with XPA.80.037 markedly reduced hyperphagia and body weight, normalized blood glucose and plasma insulin levels, and corrected dyslipidemia. These metabolic alterations correlated with changes in mRNA levels of neuropeptide Y and proopiomelanocortin, suggesting that XPA.80.037 had hypothalamic effects. CONCLUSIONS: Agonist allosteric monoclonal antibodies to the LEPR can correct metabolic effects associated with LEP deficiency in vivo and thereby have the potential to treat conditions of LEP deficiency.

Acute Treatment With XMetA Activates Hepatic Insulin Receptors and Lowers Blood Glucose in Normal Mice.

It has been proposed that monoclonal antibodies may become therapeutics for metabolic diseases such as diabetes mellitus. We have previously characterized an allosteric monoclonal antibody to the human insulin receptor (IR), XMetA, that activated metabolic signaling leading to enhanced glucose transport in cultured cells, and chronically reduced fasting blood glucose levels in mouse models of diabetes mellitus. Under acute dosing conditions, the large size of an IR-binding antibody like XMetA (∼ 150 kDa) could lead to a more rapid access into liver, an insulin sensitive tissue with well-fenestrated capillaries, when compared to other insulin sensitive tissues with non-fenestrated capillaries, such as muscle and adipose. Thus, in the present study we administered XMetA (10 mg/kg) and insulin (0.5 U/kg) via IV injection, and for 90 min compared their effects on blood glucose lowering and IR activation in three of the major insulin-sensitive tissues of the normal fasted mouse: liver, adipose, and muscle. Like insulin, XMetA lowered blood glucose levels, although the effect was less rapid. Insulin activated IR autophosphorylation and Akt phosphorylation in liver, fat, and muscle. In contrast, IR activation by XMetA was primarily observed in the liver. Both insulin and XMetA lowered ß-hydroxybutyrate levels in plasma; however, only insulin reduced both non-esterified fatty acids (NEFA) and glycerol concentrations. These data indicate that, in normal mice, acute glucose regulation by XMetA is largely mediated by its action on the liver.

Differential pathway coupling of the activated insulin receptor drives signaling selectivity by XMetA, an allosteric partial agonist antibody.

The monoclonal antibody XMetA is an allosteric partial agonist of the insulin receptor (IR), which activates the metabolic Akt kinase signaling pathway while having little or no effect on the mitogenic extracellular signal-regulated kinase (ERK) signaling pathway. To investigate the nature of this selective signaling, we have conducted a detailed investigation of XMetA to evaluate specific phosphorylation and activation of IR, Akt, and ERK in Chinese hamster ovary cell lines expressing either the short or long isoform of the human IR. Insulin activated both pathways, but the phosphorylation of Akt was more sensitive to the hormone than the phosphorylation of ERK. Maximally effective concentrations of XMetA elicited phosphorylation patterns similar to 40-100 pM insulin, which were sufficient for robust Akt phosphorylation, but had little effect on ERK phosphorylation. These data indicate that the preferential signaling of XMetA is due to an innate difference in pathway sensitivity of Akt versus ERK responses to IR activation and partial agonism by XMetA, rather than a separate pathway-biased mechanism. The metabolic selectivity of partial IR agonists like XMetA, if recapitulated in vivo, may be a desirable feature of therapeutic agents designed to regulate blood glucose levels while minimizing undesirable outcomes of excessive IR mitogenic activation.

Insulin resistance induced by hyperinsulinemia coincides with a persistent alteration at the insulin receptor tyrosine kinase domain.

Insulin resistance, the diminished response of target tissues to insulin, is associated with the metabolic syndrome and a predisposition towards diabetes in a growing proportion of the worldwide population. Under insulin resistant states, the cellular response of the insulin signaling pathway is diminished and the body typically responds by increasing serum insulin concentrations to maintain insulin signaling. Some evidence indicates that the increased insulin concentration may itself further dampen insulin response. If so, insulin resistance would worsen as the level of circulating insulin increases during compensation, which could contribute to the transition of insulin resistance to more severe disease. Here, we investigated the consequences of excess insulin exposure to insulin receptor (IR) activity. Cells chronically exposed to insulin show a diminished the level of IR tyrosine and serine autophosphorylation below that observed after short-term insulin exposure. The diminished IR response did not originate with IR internalization since IR amounts at the cell membrane were similar after short- and long-term insulin incubation. Förster resonance energy transfer between fluorophores attached to the IR tyrosine kinase (TK) domain showed that a change in the TK domain occurred upon prolonged, but not short-term, insulin exposure. Even though the altered 'insulin refractory' IR TK FRET and IR autophosphorylation levels returned to baseline (non-stimulated) levels after wash-out of the original insulin stimulus, subsequent short-term exposure to insulin caused immediate re-establishment of the insulin-refractory levels. This suggests that some cell-based 'memory' of chronic hyperinsulinemic exposure acts directly at the IR. An improved understanding of that memory may help define interventions to reset the IR to full insulin responsiveness and impede the progression of insulin resistance to more severe disease states.

Selective allosteric antibodies to the insulin receptor for the treatment of hyperglycemic and hypoglycemic disorders.

Many therapeutic monoclonal antibodies act as antagonists to receptors by targeting and blocking the natural ligand binding site (orthosteric site). In contrast, the use of antibodies to target receptors at allosteric sites (distinct from the orthosteric site) has not been extensively studied. This approach is especially important in metabolic diseases in which endogenous ligand levels are dysregulated. Herein, we review our investigations of 3 categories of human monoclonal antibodies that bind allosterically to the insulin receptor (INSR) and affect its activity: XMetA, XMetS and XMetD. XMetA directly activates the INSR either alone or in combination with insulin. XMetS, in contrast, does not directly activate the INSR but markedly enhances the receptor's ability to bind insulin and potentiate insulin signaling. Both XMetA and XMetS are effective in controlling hyperglycemia in mouse models of diabetes. A third allosteric antibody, XMetD, is an inhibitor of INSR signaling. This antibody reverses insulin-induced hypoglycemia in a mouse model of hyperinsulinemia. These studies indicate, therefore, that allosteric antibodies to INSR can modulate its signaling and correct conditions of glucose dysregulation. These studies also raise the possibility that the use of allosteric antibodies can be expanded to other receptors for the treatment of metabolic disorders.

Improved glucose metabolism in vitro and in vivo by an allosteric monoclonal antibody that increases insulin receptor binding affinity.

Previously we reported studies of XMetA, an agonist antibody to the insulin receptor (INSR). We have now utilized phage display to identify XMetS, a novel monoclonal antibody to the INSR. Biophysical studies demonstrated that XMetS bound to the human and mouse INSR with picomolar affinity. Unlike monoclonal antibody XMetA, XMetS alone had little or no agonist effect on the INSR. However, XMetS was a strong positive allosteric modulator of the INSR that increased the binding affinity for insulin nearly 20-fold. XMetS potentiated insulin-stimulated INSR signaling ∼15-fold or greater including; autophosphorylation of the INSR, phosphorylation of Akt, a major enzyme in the metabolic pathway, and phosphorylation of Erk, a major enzyme in the growth pathway. The enhanced signaling effects of XMetS were more pronounced with Akt than with Erk. In cultured cells, XMetS also enhanced insulin-stimulated glucose transport. In contrast to its effects on the INSR, XMetS did not potentiate IGF-1 activation of the IGF-1 receptor. We studied the effect of XMetS treatment in two mouse models of insulin resistance and diabetes. The first was the diet induced obesity mouse, a hyperinsulinemic, insulin resistant animal, and the second was the multi-low dose streptozotocin/high-fat diet mouse, an insulinopenic, insulin resistant animal. In both models, XMetS normalized fasting blood glucose levels and glucose tolerance. In concert with its ability to potentiate insulin action at the INSR, XMetS reduced insulin and C-peptide levels in both mouse models. XMetS improved the response to exogenous insulin without causing hypoglycemia. These data indicate that an allosteric monoclonal antibody can be generated that markedly enhances the binding affinity of insulin to the INSR. These data also suggest that an INSR monoclonal antibody with these characteristics may have the potential to both improve glucose metabolism in insulinopenic type 2 diabetes mellitus and correct compensatory hyperinsulinism in insulin resistant conditions.

Inhibition of insulin receptor function by a human, allosteric monoclonal antibody: a potential new approach for the treatment of hyperinsulinemic hypoglycemia.

Novel therapies are needed for the treatment of hypoglycemia resulting from both endogenous and exogenous hyperinsulinema. To provide a potential new treatment option, we identified XMetD, an allosteric monoclonal antibody to the insulin receptor (INSR) that was isolated from a human antibody phage display library. To selectively obtain antibodies directed at allosteric sites, panning of the phage display library was conducted using the insulin-INSR complex. Studies indicated that XMetD bound to the INSR with nanomolar affinity. Addition of insulin reduced the affinity of XMetD to the INSR by 3-fold, and XMetD reduced the affinity of the INSR for insulin 3-fold. In addition to inhibiting INSR binding, XMetD also inhibited insulin-induced INSR signaling by 20- to 100-fold. These signaling functions included INSR autophosphorylation, Akt activation and glucose transport. These data indicated that XMetD was an allosteric antagonist of the INSR because, in addition to inhibiting the INSR via modulation of binding affinity, it also inhibited the INSR via modulation of signaling efficacy. Intraperitoneal injection of XMetD at 10 mg/kg twice weekly into normal mice induced insulin resistance. When sustained-release insulin implants were placed into normal mice, they developed fasting hypoglycemia in the range of 50 mg/dl. This hypoglycemia was reversed by XMetD treatment. These studies demonstrate that allosteric monoclonal antibodies, such as XMetD, can antagonize INSR signaling both in vitro and in vivo. They also suggest that this class of allosteric monoclonal antibodies has the potential to treat hyperinsulinemic hypoglycemia resulting from conditions such as insulinoma, congenital hyperinsulinism and insulin overdose.

Detailed mechanistic analysis of gevokizumab, an allosteric anti-IL-1ß antibody with differential receptor-modulating properties.

Interleukin-1ß (IL-1ß) is a proinflammatory cytokine that is implicated in many autoinflammatory disorders, but is also important in defense against pathogens. Thus, there is a need to safely and effectively modulate IL-1ß activity to reduce pathology while maintaining function. Gevokizumab is a potent anti-IL-1ß antibody being developed as a treatment for diseases in which IL-1ß has been associated with pathogenesis. Previous data indicated that gevokizumab negatively modulates IL-1ß signaling through an allosteric mechanism. Because IL-1ß signaling is a complex, dynamic process involving multiple components, it is important to understand the kinetics of IL-1ß signaling and the impact of gevokizumab on this process. In the present study, we measured the impact of gevokizumab on the IL-1ß system using Schild analysis and surface plasmon resonance studies, both of which demonstrated that gevokizumab decreases the binding affinity of IL-1ß for the IL-1 receptor type I (IL-1RI) signaling receptor, but not the IL-1 counter-regulatory decoy receptor (IL-1 receptor type II). Gevokizumab inhibits both the binding of IL-1ß to IL-1RI and the subsequent recruitment of IL-1 accessory protein primarily by reducing the association rates of these interactions. Based on this information and recently published structural data, we propose that gevokizumab decreases the association rate for binding of IL-1ß to its receptor by altering the electrostatic surface potential of IL-1ß, thus reducing the contribution of electrostatic steering to the rapid association rate. These data indicate, therefore, that gevokizumab is a unique inhibitor of IL-1ß signaling that may offer an alternative to current therapies for IL-1ß-associated autoinflammatory diseases.

Evidence that an HMGA1 gene variant associates with type 2 diabetes, body mass index, and high-density lipoprotein cholesterol in a Hispanic-American population.

BACKGROUND: High-mobility group AT-hook 1 (HMGA1) is an important regulator of the insulin receptor gene. We have previously shown in three populations of white European ancestry that the HMGA1 gene variant rs146052672 (also designated IVS5-13insC) is associated with type 2 diabetes mellitus (T2DM). The aim of this study was to measure the frequency of this variant and to determine the degree of the association with T2DM and other features of the metabolic syndrome in a replication cohort of Hispanic Americans. METHODS: This was a retrospective cohort study of well-characterized Hispanic-American participants analyzed in the Genomic Resource in Atherosclerosis (GRA) (Cardiovascular Research Institute, University of California, San Francisco). A total of 1144 individuals were studied, 320 of whom had T2DM. We examined associations of the rs146052672 SNP with T2DM, plasma lipids, lipoproteins, and body mass index (BMI). RESULTS: In this Hispanic-American cohort, the HMGA1 rs146052672 minor allele (C-insertion) frequency (MAF) was 21.4% with a carrier frequency of 37.4%, considerably higher than we previously observed among GRA white Europeans (MAF 3.1%). The prevalence of the IVS5-13insC variant was significantly higher in those with T2DM compared to controls [42.2% vs. 35.5%; odds ratio (OR) 1.44 95% confidence interval (CI) 1.09-1.90, P=0.011). The variant was also associated with BMI (positively, P=0.045) and plasma high-density lipoprotein cholesterol (HDL-C) (negatively, P=0.047). CONCLUSIONS: As we saw previously among white Europeans, a functional HMGA1 variant was associated with T2DM in individuals of Hispanic-American ethnicity and was present at a much higher frequency.

Insulin autoimmune syndrome (Hirata Disease) in European Caucasians taking α-lipoic acid.

OBJECTIVE: Lipoic acid (LA) is a widely used nutritional supplement and is sometimes used as an adjuvant treatment for diabetic neuropathy and other conditions. Insulin autoimmune syndrome (IAS, Hirata disease) is a rare cause of spontaneous hypoglycaemia, extremely high serum insulin levels and high titres of autoantibodies against endogenous insulin despite no prior exposure to exogenous insulin. In Japanese individuals, IAS is associated with the human leucocyte antigen (HLA) HLA-DRB1*04:06 allele and often occurs upon exposure to sulphhydryl-containing compounds including LA. Only one case has been reported in Caucasians. We now report six Caucasian patients taking LA with IAS and describe a unique HLA subtype in these patients. RESEARCH DESIGN AND METHODS: Six Caucasian patients (M = 3; F = 3), median age 63 years, presented with spontaneous episodes of fasting and postabsorptive hypoglycaemia associated with mainly neuroglycopenic symptoms. No patient was treated with insulin or had an insulinoma. Hypoglycaemic symptoms appeared 30 and 120 days after taking lipoic acid (LA; 600 mg/day). Case histories and standard laboratory analyses were utilized. RESULTS: Discontinuation of LA resulted in a reduction in hypoglycaemic episodes. All patients were treated with oral or iv glucose and prednisone (12.5-25 mg/day). HLA analysis revealed the HLA-DRB1*04:03 allele in five patients, while the HLA-DRB1*04:06 allele was present in one patient. CONCLUSIONS: This is the first report of LA-related IAS in Caucasians who possess the HLA-DRB1*04:03 allele, implicating this allele in the genetic susceptibility to IAS in Caucasians. The greater occurrence of the HLA-DRB1*04:03 allele in Caucasian and other populations, combined with the growing use of LA in developed countries, may be a future predictor of additional cases of IAS.

A polymorphism of HMGA1 is associated with increased risk of metabolic syndrome and related components.

The metabolic syndrome (MetS) is a common disorder, where systemic insulin-resistance is associated with increased risk for type 2 diabetes (T2D) and cardiovascular disease. Identifying genetic traits influencing risk and progression of MetS is important. We and others previously reported a functional HMGA1 gene variant, rs146052672, predisposing to T2D. Here we investigated the association of rs146052672 variant with MetS and related components. In a case-control study from Italy and Turkey, increased risk of MetS was seen among carriers of the HMGA1 variant. In the larger Italian cohort, this variant positively correlated with BMI, hyperglycemia and insulin-resistance, and negatively correlated with serum HDL-cholesterol. Association between rs146052672 variant and MetS occurred independently of T2D, indicating that HMGA1 gene defects play a pathogenetic role in MetS and other insulin-resistance-related conditions. Overall, our results indicate that the rs146052672 variant represents an early predictive marker of MetS, as well as a predictive tool for therapy.

XOMA 052, an anti-IL-1ß monoclonal antibody, prevents IL-1ß-mediated insulin resistance in 3T3-L1 adipocytes.

OBJECTIVE: Interleukin-1ß (IL-1ß) has recently been implicated as a major cytokine that is involved in the pancreatic islet inflammation of type 2 diabetes mellitus. This inflammation impairs insulin secretion by inducing beta-cell apoptosis. Recent evidence has suggested that in obesity-induced inflammation, IL-1ß plays a key role in causing insulin resistance in peripheral tissues. DESIGN AND METHODS: To further investigate the pathophysiological role of IL-1ß in causing insulin resistance, the inhibitory effects of IL-1ß on several insulin-dependent metabolic processes in vitro has been neutralized by XOMA 052. The role IL-1ß plays in insulin resistance in adipose tissue was assessed using differentiated 3T3-L1 adipocytes and several parameters involved in insulin signaling and lipid metabolism were examined. RESULTS AND CONCLUSION: IL-1ß inhibited insulin-induced activation of Akt phosphorylation, glucose transport, and fatty acid uptake. IL-1ß also blocked insulin-mediated downregulation of suppressor of cytokine signaling-3 expression. Co-preincubation of IL-1ß with XOMA 052 neutralized nearly all of these inhibitory effects in 3T3-L1 adipocytes. These studies provide evidence, therefore, that IL-1ß is a key proinflammatory cytokine that is involved in inducing insulin resistance. These studies also suggest that the monoclonal antibody XOMA 052 may be a possible therapeutic to effectively neutralize cytokine-mediated insulin resistance in adipose tissue.

Chromium supplementation in non-obese non-diabetic subjects is associated with a decline in insulin sensitivity.

BACKGROUND: The use of chromium supplements is widespread for the prevention and treatment of diabetes mellitus but there are conflicting reports on efficacy, possibly reflecting discrepant effects across different populations. In the present studies, we test the hypothesis that chromium supplementation raises serum chromium levels and correspondingly improves insulin sensitivity. METHODS: A double blind placebo-controlled randomized trial was conducted on 31 non-obese, normoglycemic subjects. After baseline studies, the subjects were randomized to placebo or chromium picolinate 500 µg twice a day. The primary endpoint was change in insulin sensitivity as measured by euglycemic hyperinsulinemic clamp. Pre-specified secondary endpoints included fasting lipids, blood pressure, weight, body composition measured by DXA scan. RESULTS: After 16 weeks of chromium picolinate therapy there was no significant change in insulin sensitivity between groups (p=0.83). There was, however, a strong association between serum chromium and change in insulin resistance (ß = -0.83, p=0.01), where subjects with the highest serum chromium had a worsening of insulin sensitivity. This effect could not be explained by changes in physiological parameters such as body weight, truncal fat and serum lipids with chromium therapy. CONCLUSIONS: Chromium therapy did not improve insulin sensitivity in non-obese normoglycemic individuals. Further, subjects who have high serum chromium levels paradoxically had a decline in insulin sensitivity. Caution therefore should be exercised in recommending the use of this supplement. TRIAL REGISTRATION: The study was registered on the NIH registry (clinicaltrials.gov) and the identifier is NCT00846248.