This study was undertaken to test the hypothesis that short-term exposure (4 h) to physiological hyperinsulinemia in normal, healthy subjects without a family history of diabetes would induce a low grade inflammatory response independently of glycemic status. Twelve normal glucose tolerant subjects received a 4-h euglycemic hyperinsulinemic clamp with biopsies of the vastus lateralis muscle. Microarray analysis identified 121 probe sets that were significantly altered in response to physiological hyperinsulinemia while maintaining euglycemia. In normal, healthy human subjects insulin increased the mRNAs of a number of inflammatory genes (CCL2, CXCL2 and THBD) and transcription factors (ATF3, BHLHB2, HES1, KLF10, JUNB, FOS, and FOSB). A number of other genes were upregulated in response to insulin, including RRAD, MT, and SGK. CITED2, a known coactivator of PPARα, was significantly downregulated. SGK and CITED2 are located at chromosome 6q23, where we previously detected strong linkage to fasting plasma insulin concentrations. We independently validated the mRNA expression changes in an additional five subjects and closely paralleled the results observed in the original 12 subjects. A saline infusion in healthy, normal glucose-tolerant subjects without family history of diabetes demonstrated that the genes altered during the euglycemic hyperinsulinemic clamp were due to hyperinsulinemia and were unrelated to the biopsy procedure per se. The results of the present study demonstrate that insulin acutely regulates the levels of mRNAs involved in inflammation and transcription and identifies several candidate genes, including HES1 and BHLHB2, for further investigation.

Background

Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. Prevention and risk reduction are important and the identification of specific biomarkers for early diagnosis of HCC represents an active field of research. Increasing evidence indicates that fat accumulation in the liver, defined as hepatosteatosis, is an independent and strong risk factor for developing an HCC. MacroH2A1, a histone protein generally associated with the repressed regions of chromosomes, is involved in hepatic lipid metabolism and is present in two alternative spliced isoforms, macroH2A1.1 and macroH2A1.2. These isoforms have been shown to predict lung and colon cancer recurrence but to our knowledge, their role in fatty-liver associated HCC has not been investigated previously.

Methods

We examined macroH2A1.1 and macroH2A1.2 protein expression levels in the liver of two murine models of fat-associated HCC, the high fat diet/diethylnistrosamine (DEN) and the phosphatase and tensin homolog (PTEN) liver specific knock-out (KO) mouse, and in human liver samples of subjects with steatosis or HCC, using immunoblotting and immunohistochemistry.

Results

Protein levels for both macroH2A1 isoforms were massively upregulated in HCC, whereas macroH2A1.2 was specifically upregulated in steatosis. In addition, examination of human liver samples showed a significant difference (p<0.01) in number of positive nuclei in HCC (100% of tumor cells positive for either macroH2A1.1 or macroH2A1.2), when compared to steatosis (<2% of hepatocytes positive for either isoform). The steatotic areas flanking the tumors were highly immunopositive for macroH2A1.1 and macroH2A1.2.

Conclusions

These data obtained in mice and humans suggest that both macroH2A1 isoforms may play a role in HCC pathogenesis and moreover may be considered as novel diagnostic markers for human HCC.

Since activation of PPARγ is the main target for the antidiabetic effect of TZDs, especially when it heterodimerizes with RXR, we aimed to test the potential antidiabetic effect of phytol (250 mg/kg), the natural precursor of phytanic acid, a RXR ligand and/or pioglitazone (5 mg/kg) to diabetic insulin-resistant rats. Regarding the molecular docking simulation on PPARγ, phytanic acid, rather than phytol, showed a binding mode that mimics the crystal orientation of rosiglitazone and pioglitazone, forming H bonds with the same amino acids (S289, H 323, H 449 and Y 473), and the least energy level, which emphasizes their importance for PPARγ molecular recognition, activation, hence antidiabetic activity. In addition, docking on the RXRα/PPARγ heterodimer, revealed that phytanic acid has higher binding affinity and lesser energy score on RXRα, compared to the original ligand, retinoic acid. Phytanic acid binds by 3H bonds and shares retinoic acid in arginine (R 316). These results were further supported biochemically, where oral phytol and/or pioglitazone (5 mg/kg) improved significantly glucose homeostasis, lipid panel, raised serum adiponectin level and lowered TNF-α, reaching in most cases the effect of the 10 mg/kg pioglitazone. The study concluded that the insulin sensitizing/anti-diabetic effect of phytol is mediated by partly from activation of nuclear receptors and heterodimerization of RXR with PPARγ by phytanic acid.

Background

Increased risks of acute pancreatitis in patients with type 2 diabetes mellitus have been reported recently in several countries. We aimed to estimate the risks of acute pancreatitis in Japanese patients with diabetes mellitus.

Methods/Findings

We examined a large-scale hospital administrative database consisting of one million patients in 16 secondary medical care hospitals, from 2003 to 2010. The incidence rates of acute pancreatitis were estimated with cohort design; the odds ratios associated with diabetes mellitus and other comorbid risk factors were estimated with separate case-control analyses.

In cohort analysis, the incidence of acute pancreatitis was higher in 14,707 diabetic patients than in 186,032 non-diabetic patients (4.75 vs. 1.65 per 1,000 patient-years) and increased in male patients and as age advanced. The adjusted odds ratio of acute pancreatitis in patients with diabetes mellitus was 1.86 (P<0.001) compared with non-diabetic patients in case-control analysis from 1,372 cases and 5,469 matched controls, which is consistent with the ones reported in previous studies. Alcoholism and gallstones were associated with a large increase in the risk of acute pancreatitis (adjusted odds ratio 13.40 and 14.29, respectively, P<0.001), although dyslipidemia was associated with significant risk reduction (adjusted odds ratio 0.62, P<0.001).

Conclusions

This observational study ascertained the elevated incidence rates and risk of acute pancreatitis in Japanese patients with diabetes. The risk estimates in Japanese patients with diabetes were in agreement with the ones reported in previous studies, and the elevated risk of acute pancreatitis in patients with diabetes would be generalized in different locations/populations.

Introduction: Obesity is a major worldwide health threat in Western World because of its high incidence and prevalence and its association with metabolic and cardiovascular disease as well as cancer. The reduction of food intake in obese patients can be achieved only transiently (generally for no longer than 6 months), in the absence of concomitant pharmacological therapy. Only bariatric surgery provides a mean to increase satiety and/or decrease nutrients absorption in obese patients, in the long term.Areas covered: The available pharmacological treatments for obesity, as well as the pharmacology and mechanisms of action of Exenatide in obese type 2 diabetic patients.Expert opinion: Exenatide is a potential new candidate treatment for obesity, possibly in combination with other hormones that increase satiety (leptin) and slow gastric emptying (amylin).

Background

Adiposity predicts health outcomes, but this relationship could depend on population characteristics and adiposity indicator employed. In a representative sample of 11,437 US adults (National Health and Nutrition Examination Survey, 1988–1994, ages 18–64) we estimated associations with all-cause mortality for body mass index (BMI) and four abdominal adiposity indicators (waist circumference [WC], waist-to-height ratio [WHtR], waist-to-hip ratio [WHR], and waist-to-thigh ratio [WTR]). In a fasting subsample we considered the lipid accumulation product (LAP; [WC enlargement*triglycerides]).

Methods and Findings

For each adiposity indicator we estimated linear and categorical mortality risks using sex-specific, proportional-hazards models adjusted for age, black ancestry, tobacco exposure, and socioeconomic position. There were 1,081 deaths through 2006. Using linear models we found little difference among indicators (adjusted hazard ratios [aHRs] per SD increase 1.2–1.4 for men, 1.3–1.5 for women). Using categorical models, men in adiposity midrange (quartiles 2+3; compared to quartile 1) were not at significantly increased risk (aHRs<1.1) unless assessed by WTR (aHR 1.4 [95%CI 1.0–1.9]). Women in adiposity midrange, however, tended toward elevated risk (aHRs 1.2–1.5), except for black women assessed by BMI, WC or WHtR (aHRs 0.7–0.8). Men or women in adiposity quartile 4 (compared to midrange) were generally at risk (aHRs>1.1), especially black men assessed by WTR (aHR 1.9 [1.4–2.6]) and black women by LAP (aHR 2.2 [1.4–3.5]). Quartile 4 of WC or WHtR carried no significant risk for diabetic persons (aHRs 0.7–1.1), but elevated risks for those without diabetes (aHRs>1.5). For both sexes, quartile 4 of LAP carried increased risks for tobacco-exposed persons (aHRs>1.6) but not for non-exposed (aHRs<1.0).

Conclusions

Predictions of mortality risk associated with top-quartile adiposity vary with the indicator used, sex, ancestry, and other characteristics. Interpretations of adiposity should consider how variation in the physiology and expandability of regional adipose-tissue depots impacts health.

Bariatric surgery is the most effective long term weight-loss therapy for severe and morbidly obese patients. Melanocortin-4 Receptor (MC4R) mutations, the most frequent known cause of monogenic obesity, affect the regulation of energy homeostasis. The impact of such mutations on weight loss after bariatric surgery is still debated.

The objective is to determine the impact of MC4R status on weight loss in obese subjects over one year after bariatric surgery.

A total of 648 patients, who were referred to bariatric surgery in a single clinical nutrition department, were genotyped for their MC4R status. The following four groups were categorized: functional MC4R mutations, MC4R single nucleotide polymorphisms (SNPs): Val103Ile (V103L) and Ile251Leu (I251L), MC4R variant rs17782313 (downstream of MC4R) and MC4R SNP A-178C on the promoter. Each patient was matched with two randomly paired controls without mutation. Matching factors were age, sex, baseline weight and type of surgery procedure (Roux-en-Y gastric bypass and adjustable gastric banding). We compared weight loss between cases and controls at 3, 6 and 12 months after surgery.

Among 648 patients, we identified 9 carriers of functional MC4R mutations, 10 carriers of MC4R V103L and I251L SNPs, 7 carriers of the rs17792313 variant and 22 carriers of the A-178C SNP. Weight loss at 3, 6 and 12 months did not differ between cases and controls, whatever the MC4R mutations.

This is the first case-control study to show that MC4R mutations and polymorphisms do not affect weight loss and body composition over one year after bariatric surgery.

Introduction

Obesity's association with hand osteoarthritis cannot be fully explained by mechanical loading. We examined the relationship between adipokines and radiographic hand osteoarthritis severity and pain.

Methods

In a pilot study of 44 hand osteoarthritis patients (39 women and 5 men), serum adipokine concentrations and hand x-ray Kallman-scores were analyzed using linear regression models. Secondary analyses examined correlates of hand pain.

Results

The cohort had a mean age of 63.5 years for women and 72.6 for men; mean (standard deviation) Kallman-scores were 43.3(17.4) for women and 46.2(10.8) for men. Mean body-mass-index was 30 kg/m2 for women and men. Mean leptin concentration was 32.2 ng/ml (women) and 18.5 ng/ml (men); mean adiponectin-total was 7.9 ng/ml (women) and 5.3 ng/ml (men); mean resistin was 7.3 ng/ml (women) and 9.4 ng/ml (men). No association was found between Kallman-scores and adipokine concentrations (R2 = 0.00–0.04 unadjusted analysis, all p-values>0.22). Secondary analyses showed mean visual-analog-scale pain of 4.8(2.4) for women and 6.6(0.9) for men. Leptin, BMI, and history of coronary artery disease were found to be associated with visual-analog-scale scores for chronic hand pain (R2 = 0.36 unadjusted analysis, p-values≤0.04).

Conclusion

In this pilot study, we found that adipokine serum concentrations were not associated with hand osteoarthritis radiographic severity; the most important correlates of joint damage were age and disease duration. Leptin serum concentration, BMI, and coronary artery disease were associated with the intensity of chronic hand OA pain.

Background and Objective

The impact of glucose control on surgical-site infection (SSI) and death remains unclear. We examined how pre- and post-operative glucose levels and their variability are associated with the risk of SSI or in-hospital death.

Methods

This retrospective cohort study employed data on 13,800 hospitalized patients who underwent a surgical procedure at a large referral hospital in New York between 2006 and 2008. Over 20 different sources of electronic data were used to analyze how thirty-day risk of SSI and in-hospital death varies by glucose levels and variability. Maximum pre- and post-operative glucose levels were determined for 72 hours before and after the operation and glucose variability was defined as the coefficient of variation of the glucose measurements. We employed logistic regression to model the risk of SSI or death against glucose variables and the following potential confounders: age, sex, body mass index, duration of operation, diabetes status, procedure classification, physical status, emergency status, and blood transfusion.

Results

While association of pre- and post-operative hyperglycemia with SSI were apparent in the crude analysis, multivariate results showed that SSI risk did not vary significantly with glucose levels. On the other hand, in-hospital deaths were associated with pre-operative hypoglycemia (OR = 5.09, 95% CI (1.80, 14.4)) and glucose variability (OR = 1.14, 95% CI (1.03, 1.27) for 10% increase in coefficient of variation).

Conclusion

In-hospital deaths occurred more often among those with pre-operative hypoglycemia and higher glucose variability. These findings warrant further investigation to determine whether stabilization of glucose and prevention of hypoglycemia could reduce post-operative deaths.

Background

The key factors which support re-expansion of beta cell numbers after injury are largely unknown. Insulin-like growth factor II (IGF-II) plays a critical role in supporting cell division and differentiation during ontogeny but its role in the adult is not known. In this study we investigated the effect of IGF-II on beta cell regeneration.

Methodology/Principal Findings

We employed an in vivo model of ‘switchable’ c-Myc-induced beta cell ablation, pIns-c-MycERTAM, in which 90% of beta cells are lost following 11 days of c-Myc (Myc) activation in vivo. Importantly, such ablation is normally followed by beta cell regeneration once Myc is deactivated, enabling functional studies of beta cell regeneration in vivo. IGF-II was shown to be re-expressed in the adult pancreas of pIns-c-MycERTAM/IGF-II+/+ (MIG) mice, following beta cell injury. As expected in the presence of IGF-II beta cell mass and numbers recover rapidly after ablation. In contrast, in pIns-c-MycERTAM/IGF-II+/− (MIGKO) mice, which express no IGF-II, recovery of beta cell mass and numbers were delayed and impaired. Despite failure of beta cell number increase, MIGKO mice recovered from hyperglycaemia, although this was delayed.

Conclusions/Significance

Our results demonstrate that beta cell regeneration in adult mice depends on re-expression of IGF-II, and supports the utility of using such ablation-recovery models for identifying other potential factors critical for underpinning successful beta cell regeneration in vivo. The potential therapeutic benefits of manipulating the IGF-II signaling systems merit further exploration.

Background

To quantify the effect of a combination treatment of intravitreal triamcinolone acetonide (IVTA) injection, panretinal photocoagulation (PRP), and macular photocoagulation (MPC) in patients with proliferative diabetic retinopathy (PDR) and diabetic macular edema (DME).

Methodology/Principal Findings

We conducted a meta-analysis and searched for reports concerning IVTA injection combined with PRP for the treatment of PDR and DME using Medline, EMbase, Web of Science, the Cochrane Library, and Google according to Cochrane evaluation guidelines. The quality of the reports was evaluated using the Jadad score. Only four studies were ultimately included in this meta-analysis and the fixed-effects model was used. Treatment with IVTA injection combined with PRP and MPC significantly improved BCVA (p<0.001) from one to six months, compared with PRP and MPC alone. There was a statistically significant mean difference in central macular thickness (CMT), at the one-month follow-up (p<0.001). No evidence of publication bias was present. There was a low level of heterogeneity in this group of studies.

Conclusions/Significance

This meta-analysis indicates that IVTA injection combined with PRP and MPC results in an improvement of BCVA, and CMT reduction in patients with PDR and DME.

Insulin resistance, reduced β-cell mass, and hyperglucagonemia are consistent features in type 2 diabetes mellitus (T2DM). We used pancreas and islets from humans with T2DM to examine the regulation of insulin signaling and cell-cycle control of islet cells. We observed reduced β-cell mass and increased α-cell mass in the Type 2 diabetic pancreas. Confocal microscopy, real-time PCR and western blotting analyses revealed increased expression of PCNA and down-regulation of p27-Kip1 and altered expression of insulin receptors, insulin receptor substrate-2 and phosphorylated BAD. To investigate the mechanisms underlying these findings, we examined a mouse model of insulin resistance in β-cells – which also exhibits reduced β-cell mass, the β-cell-specific insulin receptor knockout (βIRKO). Freshly isolated islets and β-cell lines derived from βIRKO mice exhibited poor cell-cycle progression, nuclear restriction of FoxO1 and reduced expression of cell-cycle proteins favoring growth arrest. Re-expression of insulin receptors in βIRKO β-cells reversed the defects and promoted cell cycle progression and proliferation implying a role for insulin-signaling in β-cell growth. These data provide evidence that human β- and α-cells can enter the cell-cycle, but proliferation of β-cells in T2DM fails due to G1-to-S phase arrest secondary to defective insulin signaling. Activation of insulin signaling, FoxO1 and proteins in β-cell-cycle progression are attractive therapeutic targets to enhance β-cell regeneration in the treatment of T2DM.

Non-Alcoholic fatty liver disease (NAFLD) is characterized by accumulation of triglycerides (TG) in hepatocytes, which may also trigger cirrhosis. The mechanisms of NAFLD are not fully understood, but insulin resistance has been proposed as a key determinant.

Aims

To determine the TG content and long chain fatty acyl CoA composition profile in liver from obese non-diabetic insulin resistant (IR) and lean insulin sensitive (IS) baboons in relation with hepatic and peripheral insulin sensitivity.

Methods

Twenty baboons with varying grades of adiposity were studied. Hepatic (liver) and peripheral (mainly muscle) insulin sensitivity was measured with a euglycemic clamp and QUICKI. Liver biopsies were performed at baseline for TG content and LCFA profile by mass spectrometry, and histological analysis. Findings were correlated with clinical and biochemical markers of adiposity and insulin resistance.

Results

Obese IR baboons had elevated liver TG content compared to IS. Furthermore, the concentration of unsaturated (LC-UFA) was greater than saturated (LC-SFA) fatty acyl CoA in the liver. Interestingly, LC-FA UFA and SFA correlated with waist, BMI, insulin, NEFA, TG, QUICKI, but not M/I. Histological findings of NAFLD ranging from focal to diffuse hepatic steatosis were found in obese IR baboons.

Conclusion

Liver TG content is closely related with both hepatic and peripheral IR, whereas liver LC-UFA and LC-SFA are closely related only with hepatic IR in non-human primates. Mechanisms leading to the accumulation of TG, LC-UFA and an altered UFA: LC-SFA ratio may play an important role in the pathophysiology of fatty liver disease in humans.

Weight loss in metabolically healthy obese (MHO) subjects may result in deterioration of cardio-metabolic risk profile. We analyzed the effects of weight loss induced by laparoscopic adjustable gastric banding (LAGB) on cardio-metabolic risk factors in MHO and insulin resistant obese (IRO) individuals. This study included 190 morbidly obese non-diabetic subjects. Obese individuals were stratified on the basis of their insulin sensitivity index (ISI), estimated from an OGTT, into MHO (ISI index in the upper quartile) and IRO (ISI in the three lower quartiles). Anthropometric and cardio-metabolic variables were measured at baseline and 6-months after LAGB. Six months after LAGB, anthropometric measures were significantly reduced in both MHO and IRO. Percent changes in body weight, BMI, and waist circumference did not differ between the two groups. Fasting glucose and insulin levels, triglycerides, AST, and ALT were significantly reduced, and HDL cholesterol significantly increased, in both MHO and IRO subjects with no differences in percent changes from baseline. Insulin sensitivity increased in both MHO and IRO group. Insulin secretion was significantly reduced in the IRO group only. However, the disposition index significantly increased in both MHO and IRO individuals with no differences in percent changes from baseline between the two groups. The change in insulin sensitivity correlated with the change in BMI (r = −0.43; P<0.0001). In conclusion, our findings reinforce the recommendation that weight loss in response to LAGB intervention should be considered an appropriate treatment option for morbidly obese individuals regardless of their metabolic status, i.e. MHO vs. IRO subjects.

Background

Anxiety is a heterogeneous behavioral domain playing a role in a variety of neuropsychiatric diseases. While anxiety is the cardinal symptom in disorders such as panic disorder, co-morbid anxious behavior can occur in a variety of diseases. Stiff person syndrome (SPS) is a CNS disorder characterized by increased muscle tone and prominent agoraphobia and anxiety. Most patients have high-titer antibodies against glutamate decarboxylase (GAD) 65. The pathogenic role of these autoantibodies is unclear.

Methodology/Principal Findings

We re-investigated a 53 year old woman with SPS and profound anxiety for GABA-A receptor binding in the amygdala with (11)C-flumazenil PET scan and studied the potential pathogenic role of purified IgG from her plasma filtrates containing high-titer antibodies against GAD 65. We passively transferred the IgG fraction intrathecally into rats and analyzed the effects using behavioral and in vivo electrophysiological methods. In cell culture, we measured the effect of patient IgG on GABA release from hippocampal neurons. Repetitive intrathecal application of purified patient IgG in rats resulted in an anxious phenotype resembling the core symptoms of the patient. Patient IgG selectively bound to rat amygdala, hippocampus, and frontal cortical areas. In cultured rat hippocampal neurons, patient IgG inhibited GABA release. In line with these experimental results, the GABA-A receptor binding potential was reduced in the patient's amygdala/hippocampus complex. No motor abnormalities were found in recipient rats.

Conclusion/Significance

The observations in rats after passive transfer lead us to propose that anxiety-like behavior can be induced in rats by passive transfer of IgG from a SPS patient positive for anti-GAD 65 antibodies. Anxiety, in this case, thus may be an antibody-mediated phenomenon with consecutive disturbance of GABAergic signaling in the amygdala region.

Background

Study of endocrine pathology in animal models is critical to understanding endocrine pathology in humans.

Methods

We evaluated 434 endocrine-related diagnoses from 4,619 baboon necropsies, established the incidence of spontaneous endocrine pathology, and analyzed the clinical and biochemical data associated with the individual cases.

Results

The most common diagnoses in descending order, were pancreatic islet cell amyloidosis (n=259), ovarian cysts (n=50), pituitary adenoma (n=37), pancreatic islet cell adenoma (n=20), granulosa cell tumor (n=15), thyroid adenoma (n=11), adrenal hyperplasia (n=10), thyroid carcinoma (n=8), and pheochromocytoma (n=6). The incidence of pancreatic islet cell amyloidosis progressively increased with age. Pheochromocytomas were associated with renal and heart failure. The incidence of pancreatic islet cell amyloidosis and adrenal pathology was similar to humans; the incidence of pituitary adenoma and thyroid pathology was lower than in humans.

Conclusions

Endocrine disease in baboons is common and shares clinical and biochemical characteristics with endocrine disease in humans.

OBJECTIVE

Atherosclerosis is accelerated in subjects with type 2 diabetes by unknown mechanisms. We identified tissue inhibitor of metalloproteinase 3 (TIMP3), the endogenous inhibitor of A disintegrin and metalloprotease domain 17 (ADAM17) and other matrix metalloproteinases (MMPs), as a gene modifier for insulin resistance and vascular inflammation in mice. We tested its association with atherosclerosis in subjects with type 2 diabetes and identified Sirtuin 1 (SirT1) as a major regulator of TIMP3 expression.

RESEARCH DESIGN AND METHODS

We investigated ADAM10, ADAM17, MMP9, TIMP1, TIMP2, TIMP3, and TIMP4 expression levels in human carotid atherosclerotic plaques (n = 60) from subjects with and without diabetes. Human vascular smooth muscle cells exposed to several metabolic stimuli were used to identify regulators of TIMP3 expression. SirT1 small interference RNA, cDNA, and TIMP3 promoter gene reporter were used to study SirT1-dependent regulation of TIMP3.

RESULTS

Here, we show that in human carotid atherosclerotic plaques, TIMP3 was significantly reduced in subjects with type 2 diabetes, leading to ADAM17 and MMP9 overactivity. Reduced expression of TIMP3 was associated in vivo with SirT1 levels. In smooth muscle cells, inhibition of SirT1 activity and levels reduced TIMP3 expression, whereas SirT1 overexpression increased TIMP3 promoter activity.

CONCLUSIONS

In atherosclerotic plaques from subjects with type 2 diabetes, the deregulation of ADAM17 and MMP9 activities is related to inadequate expression of TIMP3 via SirT1. Studies in vascular cells confirmed the role of SirT1 in tuning TIMP3 expression.

OBJECTIVE

Fibroblast growth factor (FGF)-21 is highly expressed in the liver and regulates hepatic glucose production and lipid metabolism in rodents. However, its role in the pathogenesis of type 2 diabetes in humans remains to be defined. The aim of this study was to quantitate circulating plasma FGF-21 levels and examine their relationship with insulin sensitivity in subjects with varying degrees of obesity and glucose tolerance.

RESEARCH DESIGN AND METHODS

Forty-one subjects (8 lean with normal glucose tolerance [NGT], 9 obese with NGT, 12 with impaired fasting glucose [IFG]/impaired glucose tolerance [IGT], and 12 type 2 diabetic subjects) received an oral glucose tolerance test (OGTT) and a hyperinsulinemic-euglycemic clamp (80 mU/m2 per min) combined with 3-[3H] glucose infusion.

RESULTS

Subjects with type 2 diabetes, subjects with IGT, and obese subjects with NGT were insulin resistant compared with lean subjects with NGT. Plasma FGF-21 levels progressively increased from 3.9 ± 0.3 ng/ml in lean subjects with NGT to 4.9 ± 0.2 in obese subjects with NGT to 5.2 ± 0.2 in subjects with IGT and to 5.3 ± 0.2 in type 2 diabetic subjects. FGF-21 levels correlated inversely with whole-body (primarily reflects muscle) insulin sensitivity (r = −0.421, P = 0.007) and directly with the hepatic insulin resistance index (r = 0.344, P = 0.034). FGF-21 levels also correlated with measures of glycemia (fasting plasma glucose [r = 0.312, P = 0.05], 2-h plasma glucose [r = 0.414, P = 0.01], and A1C [r = 0.325, P = 0.04]).

CONCLUSIONS

Plasma FGF-21 levels are increased in insulin-resistant states and correlate with hepatic and whole-body (muscle) insulin resistance. FGF-21 may play a role in pathogenesis of hepatic and whole-body insulin resistance in type 2 diabetes.

Background

In type 1 diabetes (T1D) vascular complications such as accelerated atherosclerosis and diffused macro-/microangiopathy are linked to chronic hyperglycemia with a mechanism that is not yet well understood. End-stage renal disease (ESRD) worsens most diabetic complications, particularly, the risk of morbidity and mortality from cardiovascular disease is increased several fold.

Methods and Findings

We evaluated protein regulation and expression in skin biopsies obtained from T1D patients with and without ESRD, to identify pathways of persistent cellular changes linked to diabetic vascular disease. We therefore examined pathways that may be normalized by restoration of normoglycemia with kidney-pancreas (KP) transplantation. Using proteomic and ultrastructural approaches, multiple alterations in the expression of proteins involved in oxidative stress (catalase, superoxide dismutase 1, Hsp27, Hsp60, ATP synthase δ chain, and flavin reductase), aerobic and anaerobic glycolysis (ACBP, pyruvate kinase muscle isozyme, and phosphoglycerate kinase 1), and intracellular signaling (stratifin-14-3-3, S100-calcyclin, cathepsin, and PPI rotamase) as well as endothelial vascular abnormalities were identified in T1D and T1D+ESRD patients. These abnormalities were reversed after KP transplant. Increased plasma levels of malondialdehyde were observed in T1D and T1D+ESRD patients, confirming increased oxidative stress which was normalized after KP transplant.

Conclusions

Our data suggests persistent cellular changes of anti-oxidative machinery and of aerobic/anaerobic glycolysis are present in T1D and T1D+ESRD patients, and these abnormalities may play a key role in the pathogenesis of hyperglycemia-related vascular complications. Restoration of normoglycemia and removal of uremia with KP transplant can correct these abnormalities. Some of these identified pathways may become potential therapeutic targets for a new generation of drugs.

Background

Bariatric surgery is able to improve glucose and lipid metabolism, and cardiovascular function in morbid obesity. Aim of this study was to compare the long-term effects of malabsorptive (biliary pancreatic diversion, BPD), and restrictive (laparoscopic gastric banding, LAGB) procedures on metabolic and cardiovascular parameters, as well as on metabolic syndrome in morbidly obese patients.

Methods

170 patients studied between 1989 and 2001 were called back after a mean period of 65 months. 138 patients undergoing BPD (n = 23) or LAGB (n = 78), and control patients (refusing surgery and treated with diet, n = 37) were analysed for body mass index (BMI), blood glucose, cholesterol, and triglycerides, blood pressure, heart rate, and ECG indexes (QTc, Cornell voltage-duration product, and rate-pressure-product).

Results

After a mean 65 months period, surgery was more effective than diet on all items under evaluation; diabetes, hypertension, and metabolic syndrome disappeared more in surgery than in control patients, and new cases appeared only in controls. BPD was more effective than LAGB on BMI, on almost all cardiovascular parameters, and on cholesterol, not on triglyceride and blood glucose. Disappearance of diabetes, hypertension, and metabolic syndrome was similar with BPD and with LAGB, and no new cases were observed.

Conclusion

These data indicate that BPD, likely due to a greater BMI decrease, is more effective than LAGB in improving cardiovascular parameters, and similar to LAGB on metabolic parameters, in obese patients. The greater effect on cholesterol levels is probably due to the different mechanism of action.

Background

Non-human primates are valuable models for the study of insulin resistance and human obesity. In baboons, insulin sensitivity levels can be evaluated directly with the euglycemic clamp and is highly predicted by adiposity, metabolic markers of obesity and impaired glucose metabolism (i.e. percent body fat by DXA and HbA1c). However, a simple method to screen and identify obese insulin resistant baboons for inclusion in interventional studies is not available.

Methods

We studied a population of twenty baboons with the euglycemic clamp technique to characterize a population of obese nondiabetic, insulin resistant baboons, and used a multivariate linear regression analysis (adjusted for gender) to test different predictive models of insulin sensitivity (insulin-stimulated glucose uptake = Rd) using abdominal circumference and fasting plasma insulin. Alternatively, we tested in a separate baboon population (n = 159), a simpler model based on body weight and fasting plasma glucose to predict the whole-body insulin sensitivity (Rd/SSPI) derived from the clamp.

Results

In the first model, abdominal circumference explained 59% of total insulin mediated glucose uptake (Rd). A second model, which included fasting plasma insulin (log transformed) and abdominal circumference, explained 64% of Rd. Finally, the model using body weight and fasting plasma glucose explained 51% of Rd/SSPI. Interestingly, we found that percent body fat was directly correlated with the adipocyte insulin resistance index (r = 0.755, p < 0.0001).

Conclusion

In baboons, simple morphometric measurements of adiposity/obesity, (i.e. abdominal circumference), plus baseline markers of glucose/lipid metabolism, (i.e. fasting plasma glucose and insulin) provide a feasible method to screen and identify overweight/obese insulin resistant baboons for inclusion in interventional studies aimed to study human obesity, insulin resistance and type 2 diabetes mellitus.