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The metabolic syndrome and uric acid nephrolithiasis: Novel features of renal manifestation of insulin resistance. Uric acid nephrolithiasis primarily results from low urinary pH, which increases the concentration of the insoluble undissociated uric acid, causing formation of both uric acid and mixed uric acid/calcium oxalate stones. These patients have recently been described as exhibiting features of insulin resistance. This study was designed to evaluate if insulin resistance is associated with excessively low urinary pH in overtly healthy volunteers (non-stone formers) and if insulin resistance may explain the excessively low urinary pH in patients with uric acid nephrolithiasis. Fifty-five healthy volunteers (non stone-formers) with a large range of body mass index and 13 patients with recurrent uric acid nephrolithiasis underwent hyperinsulinemic euglycemic clamp, 24-hour urinary studies, and anthropometric measurements of adiposity. A subgroup of 35 non-stone formers had 2-hour timed urinary collection before and during the hyperinsulinemic phase of the clamp studies. For the non-stone former population, low insulin sensitivity measured as glucose disposal rate significantly correlated with low 24-hour urinary pH (r = 0. 35; P = 0.01). In addition to the previously described acidic urine pH and hypouricosuria, patients with recurrent uric acid nephrolithiasis were found to be severely insulin resistant (glucose disposal rate: uric acid stone-formers vs. normals; 4.1 ± 1.3 vs. 6.9 ± 2.1mg/min/kg of lean body mass, P = 0.008). Acute hyperinsulinemia was associated with higher urinary pH (6.1 ± 0.7 at baseline to 6.8 ± 0.7 during hyperinsulinemia; P < 0.0001), urinary ammonia excretion (2.7 ± 1.6mEq/2hr at baseline and 4.0 ± 2.6mEq/2hr P = 0.002) and urinary citrate excretion (48 ± 33mg/2hr at baseline and 113 ± 68mg/2hr P < 0.0001). We conclude that one renal manifestation of insulin resistance may be low urinary ammonium and pH. This defect can result in increased risk of uric acid precipitation despite normouricosuria.

South Asians are susceptible to insulin resistance even without obesity. We examined the characteristics of body fat content, distribution and function in South Asian men and their relationships to insulin resistance compared to Caucasians. Twenty-nine South Asian and 18 Caucasian non-diabetic men (age 27+/-3 and 27+/-3 years, respectively) underwent euglycemic-hyperinsulinemic clamp for insulin sensitivity, underwater weighing for total body fat, MRI of entire abdomen for intraperitoneal (IP) and subcutaneous abdominal (SA) fat and biopsy of SA fat for adipocyte size. Compared to Caucasians, in spite of similar BMI, South Asians had higher total body fat (22+/-6 and 15+/-4% of body weight; p-value<0.0001), higher SA fat (3.5+/-1.9 and 2.2+/-1.3 kg, respectively; p-value = 0.004), but no differences in IP fat (1.0+/-0.5 and 1.0+/-0.7 kg, respectively; p-value = 0.4). SA adipocyte cell size was significantly higher in South Asians (3491+/-1393 and 1648+/-864 microm2; p-value = 0.0001) and was inversely correlated with both glucose disposal rate (r-value = -0.57; p-value = 0.0008) and plasma adiponectin concentrations (r-value = -0.71; p-value<0.0001). Adipocyte size differences persisted even when SA was matched between South Asians and Caucasians. Insulin resistance in young South Asian men can be observed even without increase in IP fat mass and is related to large SA adipocytes size. Hence ethnic excess in insulin resistance in South Asians appears to be related more to excess truncal fat and dysfunctional adipose tissue than to excess visceral fat.

The molecular mechanism to regulate energy balance is not completely understood. Here we observed that Egr-1 expression in white adipose tissue (WAT) was highly correlated with dietary-induced obesity and insulin resistance both in mice and humans. Egr-1 null mice were protected from diet-induced obesity and obesity-associated pathologies such as fatty liver, insulin resistance, hyperlipidemia and hyperinsulinemia. This phenotype can be largely explained by the increase of energy expenditure in Egr-1 null mice. Characterization of these mice revealed that the expression of FOXC2 and its target genes were significantly elevated in white adipose tissues, leading to WAT energy expenditure instead of energy storage. Altogether, these studies suggest an important role for Egr-1, which, by repressing FOXC2 expression, promotes energy storage in WAT and favored the development of obesity under high energy intake.

ENPP1/PC-1 K121Q Polymorphism and Genetic Susceptibility to Type 2 Diabetes Nicola Abate 1 , Manisha Chandalia 1 , Pankaj Satija 1 , Beverley Adams-Huet 2 , Scott M. Grundy 1 , Sreedharan Sandeep 3 , Venkatesan Radha 3 , Raj Deepa 3 and Viswanathan Mohan 3 1 Department of Medicine, Division of Endocrinology and Metabolism and the Center for Human Nutrition, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 2 Center for Biostatistics and Clinical Science, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas 3 M.V. Diabetes Specialties Centre and Madras Diabetes Research Foundation, Gopalapuram, Chennai, India Address correspondence and reprint requests to Nicola Abate, MD, UT Southwestern Medical Center, 6011 Harry Hines Blvd., Dallas, Texas 75390-9169. E-mail: nicola.abate{at}utsouthwestern.edu Abstract Genetic susceptibility modulates the impact of obesity on risk for type 2 diabetes. The present study evaluates the role of ENPP1 K121Q polymorphism in prediction of type 2 diabetes in three populations that differ in susceptibility to diabetes and environmental exposure. The three cohorts included 679 nonmigrant South Asians living in Chennai, India (223 with type 2 diabetes); 1,083 migrant South Asians living in Dallas, Texas (121 with type 2 diabetes); and 858 nonmigrant Caucasians living in Dallas, Texas (141 with type 2 diabetes). Patients with type 2 diabetes were included in these cohorts if they had diabetes onset before the age of 60 years. The prevalence of subjects carrying the polymorphic ENPP1 121Q allele was 25% in the nondiabetic group and 34% in the diabetic group of South Asians living in Chennai ( P = 0.01). The prevalence in the nondiabetic and diabetic groups were 33 and 45% ( P = 0.01) for the South Asians living in Dallas and 26 and 39% ( P = 0.003) for the Caucasians. Although further replication studies are necessary to test the validity of the described genotype-phenotype relationship, our study supports the hypothesis that ENPP1 121Q predicts genetic susceptibility to type 2 diabetes in both South Asians and Caucasians. AUC, area under the curve CURES, Chennai Urban Rural Epidemiological Study HOMA-IR, homeostasis model assessment of insulin resistance OGTT, oral glucose tolerance test Footnotes N.A. and M.C. contributed equally to this work. Accepted December 16, 2004. Received July 30, 2004. DIABETES

It is recognized that the ability of adipose tissue to expand in response to energy excess, i.e. adipocyte maturation, is important in determining systemic abnormalities in glucose and lipid metabolism. Ectonucleotide pyrophosphatase phosphodiesterase 1 (ENPP1, also known as PC-1) has been recently reported to be involved in the pathogenesis of insulin resistance and related diseases. However, its role on adipose tissue physiology as a mechanism of systemic insulin resistance is not understood. This study was performed to evaluate whether ENPP1 is regulated during adipogenesis and whether over-expression in adipocytes can affect adipocyte maturation, a potential novel mechanism of ENPP1-related insulin resistance. ENPP1 expression was found down-regulated during 3T3-L1 maturation, and over-expression of human ENPP1 in 3T3-L1 (pQCXIP-ENPP1 vector) resulted in adipocyte insulin resistance and in defective adipocyte maturation. Adipocyte maturation was more efficient in mesenchymal embryonal cells from ENPP1 knockout mice than from wild-type. We identify ENPP1 as a novel mechanism of defective adipocyte maturation. This mechanism could contribute to the pathogenesis of insulin resistance in absence of obesity.

Ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1) inhibits the insulin receptor. E-NPP1 mutations are associated with type 2 diabetes, and E-NPP1 expression is increased in nonobese, nondiabetic insulin-resistant subjects; E-NPP1 might therefore act as a marker for at-risk individuals and reveal new targets for prevention and treatment of diabetes and cardiovascular disease. Insulin resistance is pathogenic for type 2 diabetes and cardiovascular disease. Several inhibitors of insulin signaling have a role in human insulin resistance. The transmembrane glycoprotein ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing its β-subunit autophosphorylation. E-NPP1 is overexpressed in skeletal muscle, adipose tissue and cultured skin fibroblasts of insulin-resistant individuals who are not yet obese or diabetic, which indicates that excessive E-NPP1 expression is an early, intrinsic defect in human insulin resistance. Genetic studies also support a primary role of E-NPP1 in insulin resistance. Among other variants, a missense polymorphism, Lys121Gln, has been described.The Gln121 variant is a stronger inhibitor than Lys121 of insulin receptor function, and is associated with insulin resistance, type 2 diabetes and both cardiovascular and nephrovascular complications in diabetic patients. E-NPP1 is measurable in human serum, where it might represent a valuable biomarker of insulin resistance, but its relationship to tissue and systemic insulin resistance remains to be thoroughly elucidated. Understanding the mechanisms that regulate E-NPP1 expression and/or function might render this protein a new target for strategies to treat and prevent type 2 diabetes and cardiovascular disease. Key Points Specific inhibitors of insulin receptor signaling have a pathogenic role in insulin resistance, type 2 diabetes and cardiovascular disease Ectonucleotide pyrophosphatase phosphodiesterase 1 (E-NPP1; also known as plasma cell membrane glycoprotein PC-1) interacts with the insulin receptor and inhibits subsequent signaling by decreasing the receptor's β-subunit autophosphorylation The primary, intrinsic role of E-NPP1 in the pathogenesis of in vivo insulin resistance is suggested by its overexpression in skeletal muscle, adipose tissue and cultured skin fibroblasts of nonobese, nondiabetic insulin-resistant individuals Genetic studies have shown that, compared with the common E-NPP1 variant Lys121, the Gln121 variant is a stronger inhibitor of insulin receptor function and is associated with insulin resistance, type 2 diabetes and related cardiovascular and nephrovascular complications Overall, the data published to date on the effect of all known E-NPP1 genetic mutations and risk for type 2 diabetes in more than 19,000 people show quite consistently that E-NPP1 gene variants are associated with type 2 diabetes in several different populations Understanding the mechanisms that regulate E-NPP1 expression and/or function promises to yield important information and new targets to treat or prevent type 2 diabetes and cardiovascular disease

Genetic susceptibility modulates the impact of obesity on the risk for type 2 diabetes. One candidate gene predisposing to type 2 diabetes is ENPP1/PC1. A common polymorphism in this protein, K121Q, is associated with insulin resistance and increased susceptibility to type 2 diabetes in Caucasian, Afro-Caribbean, and South Asian populations. The goal of this study was to evaluate differences in the prevalence of the ENPP1 121Q variant in the Caucasian, African-American, and Hispanic populations in Dallas county and to establish a population-based estimate of gene variant prevalence for future investigations. We also evaluated the association between the ENPP1 121Q variant and diabetes. The Dallas Heart Study (DHS) is a multiethnic probability-based sample of the Dallas county population in which African-Americans were systematically oversampled so that the final sample was 50% African-Americans. We performed ENPP1/PC1 genotyping in 1038 non-Hispanic Whites (544 women, 494 men), 1815 African-Americans (1052 women and 763 men), and 597 Hispanics (347 women, 250 men). The frequency of ENPP1/PC1 K121Q was higher in both African-Americans (78.5%) and Hispanics (21.9%) than in the non-Hispanic White group (13.2%). The former two groups also have a higher prevalence of type 2 diabetes (African-Americans, 14.1%, and Hispanics, 11.7%) compared to non-Hispanic Whites (6.8%). Logistic regression analysis revealed significant interactions between the ENPP1 genotype, age, and body mass index within each ethnic group. After adjustment for these variables and their interactions, ENPP1 Q allele predicted diabetes when a recessive model was tested. Ethnic differences in ENPP1 121Q allele frequency may contribute to the increased susceptibility to type 2 diabetes observed in US minority groups.

The rapid increase of diabetes prevalence in the US population and across all westernized world has been associated with environmental changes that promote obesity. However, studies conducted in various ethnic groups within the US population have pointed out differences in susceptibility to diabetes within the same environmental pressure. Of particular interest is the growing evidence that Asian Indians, i.e., persons originating from the Indian Subcontinent, are at uniquely heightened risk for type 2 diabetes when compared to other populations. The elucidation of the mechanisms responsible for the heterogeneous relationship between obesity and type 2 diabetes in various ethnic groups, and particularly in Asian Indians, may give important contributions to better understand the complex mechanisms involved in the development of type 2 diabetes. This review examines epidemiological and pathophysiological aspects of the interaction between environment and ethnic predisposition to type 2 diabetes in Asian Indians migrated to the US.

Background Liraglutide, a long-acting glucagon-like peptide-1 (GLP-1) analog, has several non- glycemic properties, but its effect on carotid intima-media thickness (IMT), a recognized marker of subclinical atherosclerosis, is still unknown. Methods A prospective study of 8 months duration in 64 patients with type-2 diabetes and no prior history of coronary artery disease evaluated whether adding liraglutide to metformin affects carotid IMT, measured by color doppler ultrasound. Results After 8 months, fasting glucose decreased by 2.1 mmol/l and HbA1c by 1.9% (p < 0.01 for all). Liraglutide reduced total-cholesterol and triglycerides by 10%, and LDL-cholesterol by 19%, whereas HDL-cholesterol increased by 18% (p < 0.01 for all lipid changes). Carotid IMT decreased from 1.19 ± 0.47 to 0.94 ± 0.21 mm (p < 0.01). Yet, changes in carotid IMT did not correlate with changes in any other variable studied. Conclusions Liraglutide decreases carotid IMT after 8 months treatment independently of its effect on plasma glucose and lipids concentrations. Trial registration ClinicalTrials.gov: NCT01715428 .

Adipose tissue dysfunction rather than excess adipose tissue mass (defined as obesity) is mechanistically related to development of metabolic diseases traditionally linked to obesity: metabolic syndrome, type 2 diabetes and cardiovascular disease. Inflammation of adipose tissue seems to be an important manifestation of adipose tissue dysfunction and closely relates to insulin resistance, the mediator of obesity-related morbidity. However, it is not completely clear whether inflammation in adipose tissue leads to first, local, and then systemic insulin resistance or insulin resistance leads to adipose tissue inflammation, which, in turn, increases insulin resistance. These questions can only be answered by studying models of insulin resistance, independent of obesity. The conceptual shift from adipose tissue mass to adipose tissue function will have significant diagnostic and therapeutic implications. Our efforts in establishing markers to identify “at risk” population and finding newer therapeutic agents must focus on adipose tissue dysfunction and not on obesity alone.