Mark A. Deeg

The Effects of LY2405319, an FGF21 Analog, in Obese Human Subjects with Type 2 Diabetes

Fibroblast growth factor 21 (FGF21) is a recently discovered metabolic regulator. Exogenous FGF21 produces beneficial metabolic effects in animal models; however, the translation of these observations to humans has not been tested. Here, we studied the effects of LY2405319 (LY), a variant of FGF21, in a randomized, placebo-controlled, double-blind proof-of-concept trial in patients with obesity and type 2 diabetes. Patients received placebo or 3, 10, or 20 mg of LY daily for 28 days. LY treatment produced significant improvements in dyslipidemia, including decreases in low-density lipoprotein cholesterol and triglycerides and increases in high-density lipoprotein cholesterol and a shift to a potentially less atherogenic apolipoprotein concentration profile. Favorable effects on body weight, fasting insulin, and adiponectin were also detected. However, only a trend toward glucose lowering was observed. These results indicate that FGF21 is bioactive in humans and suggest that FGF21-based therapies may be effective for the treatment of selected metabolic disorders.

Ethanol Induces Fatty Acid Synthesis Pathways by Activation of Sterol Regulatory Element-binding Protein (SREBP)

Alcoholic fatty liver is the earliest and most common response of the liver to alcohol and may be a precursor of more severe forms of liver injury. The mechanism by which ethanol causes fatty liver and liver injury is complex. We found that in both rat H4IIEC3 and McA-RH7777 hepatoma cell lines, ethanol induced transcription of a sterol regulatory element-binding protein (SREBP)-regulated promoter via increased levels of mature SREBP-1 protein. This effect of ethanol was blocked by addition of sterols. This effect is likely mediated by acetaldehyde, because the effect was only seen in cell lines expressing alcohol dehydrogenase, and inhibition of ethanol oxidation by 4-methylpyrazole blocked the effect in the hepatoma cells. Furthermore, the aldehyde dehydrogenase inhibitor cyanamide enhanced the effect of ethanol in the hepatoma cells. Consistent with these in vitro findings, feeding mice a low fat diet with ethanol for 4 weeks resulted in a significant increase in steady-state levels of the mature (active) form of SREBP-1. Activation of SREBP-1 by ethanol feeding was associated with increased expression of hepatic lipogenic genes as well as the accumulation of triglyceride in the livers. These finding suggest that metabolism of ethanol increased hepatic lipogenesis by activating SREBP-1 and that this effect of ethanol may contribute to the development of alcoholic fatty liver.

Systemic Levels of Lipid Peroxidation and Its Metabolic and Dietary Correlates in Patients with Nonalcoholic Steatohepatitis

BACKGROUND AND AIM:Products of systemic lipid peroxidation are important in the pathogenesis of cardiovascular disease. Subjects with NASH have increased hepatic lipid peroxidation, but it is unknown if they have increased oxidative stress and lipid peroxidation systemically. Therefore, we conducted a study to measure the circulating levels of lipid peroxidation products and their metabolic and nutritional correlates in patients with NASH and controls.METHODS:Systemic lipid peroxidation was assessed by measuring the levels of oxidized LDL (ox-LDL) and thiobarbituric acid-reacting substances (TBARS) in 21 subjects with NASH and 19 controls. Correlations were made between serum lipid peroxidation and nutritional determinants of oxidative stress and defense, serum lipids, insulin resistance, transaminases, and liver histology. The short-term nutrient intake was analyzed by maintaining a 3-wk dietary diary.RESULTS:The serum levels of ox-LDL were significantly higher in NASH patients compared to controls (56 ± 16 U/L vs 40 ± 12 U/L, respectively, p < 0.001). Similarly, serum TBARS were significantly higher in NASH patients compared to controls (3.4 ± 1.3 vs 1.8 ± 0.9 nmols/ml, respectively, p= 0.0001). Insulin resistance was independently associated with ox-LDL (p= 0.01) and TBARS levels (p= 0.01). We found no differences in the intake of various macro- and micronutrients between the two groups and there was no association between nutrient intake and ox-LDL or TBARS.CONCLUSION:Subjects with NASH have significantly higher systemic levels of lipid peroxidation products and this could indicate an increased risk of cardiovascular disease. More studies are needed to evaluate this possibility.

Cholesterol, APOE genotype, and Alzheimer disease: An epidemiologic study of Nigerian Yoruba

Objective: To examine the relationship between cholesterol and other lipids, APOE genotype, and risk of Alzheimer disease (AD) in a population-based study of elderly Yoruba living in Ibadan, Nigeria. Methods: Blood samples and clinical data were collected from Yoruba study participants aged 70 years and older (N = 1,075) as part of the Indianapolis-Ibadan Dementia Project, a longitudinal epidemiologic study of AD. Cholesterol, low-density lipoprotein (LDL), high-density lipoprotein (HDL), and triglyceride levels were measured in fasting blood samples. DNA was extracted and APOE was genotyped. Diagnoses of AD were made by consensus using National Institute of Neurologic Disorders/Stroke-Alzheimers Disease and Related Disorders Association criteria. Results: Logistic regression models showed interaction after adjusting for age and gender between APOE-ε4 genotype and biomarkers in the risk of AD cholesterol*genotype (p = 0.022), LDL*genotype (p= 0.018), and triglyceride*genotype (p = 0.036). Increasing levels of cholesterol and LDL were associated with increased risk of AD in individuals without the APOE-ε4 allele, but not in those with APOE-ε4. There was no significant association between levels of triglycerides and AD risk in those without APOE-ε4. Conclusions: There was a significant interaction between cholesterol, APOE-ε4, and the risk of Alzheimer disease (AD) in the Yoruba, a population that has lower cholesterol levels and lower incidence rates of AD compared to African Americans. APOE status needs to be considered when assessing the relationship between lipid levels and AD risk in population studies.

Evaluation of Efficacy and Safety of the Glucagon Receptor Antagonist LY2409021 in Patients With Type 2 Diabetes: 12- and 24-Week Phase 2 Studies.

OBJECTIVE Type 2 diabetes pathophysiology is characterized by dysregulated glucagon secretion. LY2409021, a potent, selective small-molecule glucagon receptor antagonist that lowers glucose was evaluated for efficacy and safety in patients with type 2 diabetes. RESEARCH DESIGN AND METHODS The efficacy (HbA1c and glucose) and safety (serum aminotransferase) of once-daily oral administration of LY2409021 was assessed in two double-blind studies. Phase 2a study patients were randomized to 10, 30, or 60 mg of LY2409021 or placebo for 12 weeks. Phase 2b study patients were randomized to 2.5, 10, or 20 mg LY2409021 or placebo for 24 weeks. RESULTS LY2409021 produced reductions in HbA1c that were significantly different from placebo over both 12 and 24 weeks. After 12 weeks, least squares (LS) mean change from baseline in HbA1c was –0.83% (10 mg), –0.65% (30 mg), and –0.66% (60 mg) (all P < 0.05) vs. placebo, 0.11%. After 24 weeks, LS mean change from baseline in HbA1c was –0.45% (2.5 mg), –0.78% (10 mg, P < 0.05), –0.92% (20 mg, P < 0.05), and –0.15% with placebo. Increases in serum aminotransferase, fasting glucagon, and total fasting glucagon-like peptide-1 (GLP-1) were observed; levels returned to baseline after drug washout. Fasting glucose was also lowered with LY2409021 at doses associated with only modest increases in aminotransferases (mean increase in alanine aminotransferase [ALT] ≤10 units/L). The incidence of hypoglycemia in the LY2409021 groups was not statistically different from placebo. CONCLUSIONS In patients with type 2 diabetes, glucagon receptor antagonist treatment significantly lowered HbA1c and glucose levels with good overall tolerability and a low risk for hypoglycemia. Modest, reversible increases in serum aminotransferases were observed.

Metabolic and anthropometric evaluation of insulin resistance in nondiabetic patients with nonalcoholic steatohepatitis

OBJECTIVES:Insulin resistance is nearly universal in patients with nonalcoholic steatohepatitis (NASH) when tested by glucose tolerance tests or clamp methods. However, the pattern of insulin resistance in these patients after a physiological challenge is unknown. We conducted a study to characterize the metabolic response to a mixed meal in nondiabetic patients with NASH (NDN) and to identify anthropometric determinants of insulin resistance in these patients.METHODS:Serum insulin, C-peptide, glucose, and free fatty acid (FFA) levels were measured at 0, 30, 60, 90, and 120 min after a 500-kcal standard meal in 18 NDN and 18 age-, gender-, and body mass index (BMI)-matched controls. Correlations were made between insulin resistance and various anthropometric, calorimetric, and serological variables.RESULTS:Compared with controls, NDN had significantly higher levels of insulin and C-peptide at baseline and after the mixed meal. However, glucose levels were not different either at baseline or after the meal. NDN had higher fasting levels of FFA than the controls (459 ± 190 vs 339 ± 144 μmol/L, respectively, p = 0.03); however, meal-induced suppression in lipolysis was similar between the two groups (39 ± 113% vs 46 ± 60%, p = 0.8). Insulin resistance was significantly correlated with BMI (r = 0.39, p = 0.02) and visceral fat (r = 0.50, p = 0.004). Whereas BMI, percent total body fat, and subcutaneous abdominal fat were similar between the groups, the NASH group had significantly higher percent visceral fat compared with controls (28 ± 10% vs 22 ± 14%, p = 0.02).CONCLUSION:NDN are significantly hyperinsulinemic, both at fasting and after the mixed meal; however, their glucose homeostasis and suppression in lipolysis after a meal challenge are maintained. Insulin resistance in these patients is likely related to their higher visceral fat mass.

Association of statin use with cognitive decline in elderly African Americans

Background: Previously reported associations between statin use and incident dementia or cognitive decline have been inconsistent. We report the results from a 3-year prospective study on the association of statin use on cognitive decline and incident dementia in elderly African Americans. Methods: A community-based cohort of 1,146 African Americans aged 70 and older living in Indianapolis, Indiana, was evaluated in 2001 and 2004. The instrument used for cognitive assessment was the Community Screening Interview for Dementia (CSI-D). Cognitive decline was defined as CSI-D scores measured at 2001 minus scores at 2004. Measurements of low-density lipoprotein cholesterol (LDL-C) and C-reactive protein (CRP) were obtained from baseline blood samples. Results: Adjusting for age at baseline, gender, education, and the possession of ApoE ε4 allele, baseline statin use was associated with less cognitive decline (p = 0.0177). There were no significant interactions of statin use when LDL-C and CRP were included. Logistic regression with the four independent variables showed that statin use may be associated with a reduction in incident dementia (OR = 0.32; p = 0.0673). Association with cognitive decline was less clear when investigating statin use over time. Significance remained only for those who discontinued prior to follow-up compared to continuous users or users who started after baseline. Conclusions: The relationship between statin use and cognitive decline is complex and subjected to unknown confounders. This effect may not be associated with the cholesterol lowering or anti-inflammatory action of statins. GLOSSARY: AD = Alzheimer disease; ANCOVA = analysis of covariance; BMI = body mass index; CAMDEX = Cambridge Examination for Mental Disorders of the Elderly informant interview; CERAD = Consortium to Establish a Registry for Alzheimer’s Disease; CHIF = Clinician Home-based Interview to assess Function; CRP = C-reactive protein; CSI-D = Community Screening Instrument for Dementia; HDL = high-density lipoprotein; HMG-CoA = 3-hydroxy-3-methylglutaryl-coenzyme A; LDL-C = low-density lipoprotein cholesterol; LLAs = lipid-lowering agents; NSAIDs = nonsteroidal anti-inflammatory drugs.

Short-term administration of the glucagon receptor antagonist LY2409021 lowers blood glucose in healthy people and in those with type 2 diabetes.

To describe the clinical effects of single and multiple doses of a potent, selective, orally administered, small‐molecule antagonist of the human glucagon receptor, LY2409021, in healthy subjects and in patients with type 2 diabetes.

Glycosylphosphatidylinositol-Specific Phospholipase D Is Expressed by Macrophages in Human Atherosclerosis and Colocalizes With Oxidation Epitopes

BACKGROUND Glycosylphosphatidylinositol-specific phospholipase D (GPI-PLD) may play an important role in inflammation, because it can hydrolyze the GPI anchors of several inflammatory membrane proteins (eg, CD106, CD55, and CD59) and its hydrolytic products upregulate macrophage cytokine expression (eg, interleukin-1 and tumor necrosis factor-alpha). Because of its potential regulatory role in inflammatory reactions, we hypothesized that GPI-PLD might be expressed in atherosclerosis. METHODS AND RESULTS Immunohistochemistry using human GPI-PLD-specific rabbit polyclonal antiserum was performed on a total of 83 nonatherosclerotic and atherosclerotic human coronary arteries from 23 patients. Macrophages, smooth muscle cells, apoA-I, and oxidation epitopes also were identified immunohistochemically. Cell-associated GPI-PLD was detected in 95% of atherosclerotic segments, primarily on a subset of macrophages. Extracellular GPI-PLD was present in only 30% of atherosclerotic segments and localized to regions with extracellular apoA-I. In contrast, GPI-PLD was not detected in nonatherosclerotic segments. Expression of GPI-PLD mRNA by human macrophages was confirmed in vitro by reverse transcription/polymerase chain reaction. Further studies demonstrated that GPI-PLD-positive plaque macrophages contained oxidation epitopes, suggesting a link between oxidant stress and GPI-PLD expression. This possibility was supported by studies in which exposure of a macrophage cell line to H2O2 led to a 50+/-3% increase in steady-state GPI-PLD mRNA levels. CONCLUSIONS Collectively, these results suggest that oxidative processes may regulate GPI-PLD expression and suggest a role for GPI-PLD in inflammation and in the pathogenesis of atherosclerosis.

Pioglitazone versus Rosiglitazone: Effects on Lipids, Lipoproteins, and Apolipoproteins in Head-to-Head Randomized Clinical Studies.

Peroxisome proliferator-activated receptors (PPARs) play an important role in regulating both glucose and lipid metabolism. Agonists for both PPARγ and PPARγ have been used to treat dyslipidemia and hyperglycemia, respectively. In addition to affecting glucose metabolism, PPARγ agonists also regulate lipid metabolism. In this review, we will focus on the randomized clinical trials that directly compared the lipid effects of the thiazolidinedione class of PPARγ agonists, pioglitazone and rosiglitazone, head-to-head either as monotherapy or in combination with other lipid-altering or glucose-lowering agents