bluuebunny/crossref_metadata_2025 huggingface dataset:
Increased Whole-Body and Sustained Liver Cortisol Regeneration by 11β-Hydroxysteroid Dehydrogenase Type 1 in Obese Men With Type 2 Diabetes Provides a Target for Enzyme Inhibition
Authors: Stimson Roland H. , Andrew Ruth , McAvoy Norma C. , Tripathi Dhiraj , Hayes Peter C. , Walker Brian R.
Published: January 2011

OBJECTIVE

The cortisol-regenerating enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) amplifies glucocorticoid levels in liver and adipose tissue. 11β-HSD1 inhibitors are being developed to treat type 2 diabetes. In obesity, 11β-HSD1 is increased in adipose tissue but decreased in liver. The benefits of pharmacological inhibition may be reduced if hepatic 11β-HSD1 is similarly decreased in obese patients with type 2 diabetes. To examine this, we quantified in vivo whole-body, splanchnic, and hepatic 11β-HSD1 activity in obese type 2 diabetic subjects.

RESEARCH DESIGN AND METHODS

Ten obese men with type 2 diabetes and seven normal-weight control subjects were infused with 9,11,12,12-[2H]4cortisol (40%) and cortisol (60%) at 1.74 mg/h. Adrenal cortisol secretion was suppressed with dexamethasone. Samples were obtained from the hepatic vein and an arterialized hand vein at steady state and after oral administration of cortisone (5 mg) to estimate whole-body and liver 11β-HSD1 activity using tracer dilution.

RESULTS

In obese type 2 diabetic subjects, the appearance rate of 9,12,12-[2H]3cortisol in arterialized blood was increased (35 ± 2 vs. 29 ± 1 nmol/min, P < 0.05), splanchnic 9,12,12-[2H]3cortisol production was not reduced (29 ± 6 vs. 29 ± 6 nmol/min), and cortisol appearance in the hepatic vein after oral cortisone was unchanged.

CONCLUSIONS

Whole-body 11β-HSD1 activity is increased in obese men with type 2 diabetes, whereas liver 11β-HSD1 activity is sustained, unlike in euglycemic obesity. This supports the concept that inhibitors of 11β-HSD1 are likely to be most effective in obese type 2 diabetic subjects.
Interleukin-6 Enhances Glucose-Stimulated Insulin Secretion From Pancreatic β-Cells
Authors: Suzuki Toshinobu , Imai Junta , Yamada Tetsuya , Ishigaki Yasushi , Kaneko Keizo , Uno Kenji , Hasegawa Yutaka , Ishihara Hisamitsu , Oka Yoshitomo , Katagiri Hideki
Published: January 2011

OBJECTIVE

Interleukin-6 (IL-6) has a significant impact on glucose metabolism. However, the effects of IL-6 on insulin secretion from pancreatic β-cells are controversial. Therefore, we analyzed IL-6 effects on pancreatic β-cell functions both in vivo and in vitro.

RESEARCH DESIGN AND METHODS

First, to examine the effects of IL-6 on in vivo insulin secretion, we expressed IL-6 in the livers of mice using the adenoviral gene transfer system. In addition, using both MIN-6 cells, a murine β-cell line, and pancreatic islets isolated from mice, we analyzed the in vitro effects of IL-6 pretreatment on insulin secretion. Furthermore, using pharmacological inhibitors and small interfering RNAs, we studied the intracellular signaling pathway through which IL-6 may affect insulin secretion from MIN-6 cells.

RESULTS

Hepatic IL-6 expression raised circulating IL-6 and improved glucose tolerance due to enhancement of glucose stimulated-insulin secretion (GSIS). In addition, in both isolated pancreatic islets and MIN-6 cells, 24-h pretreatment with IL-6 significantly enhanced GSIS. Furthermore, pretreatment of MIN-6 cells with phospholipase C (PLC) inhibitors with different mechanisms of action, U-73122 and neomycin, and knockdowns of the IL-6 receptor and PLC-β1, but not with a protein kinase A inhibitor, H-89, inhibited IL-6–induced enhancement of GSIS. An inositol triphosphate (IP3) receptor antagonist, Xestospondin C, also abrogated the GSIS enhancement induced by IL-6.

CONCLUSIONS

The results obtained from both in vivo and in vitro experiments strongly suggest that IL-6 acts directly on pancreatic β-cells and enhances GSIS. The PLC-IP3–dependent pathway is likely to be involved in IL-6-mediated enhancements of GSIS.
Thirty Years of Prospective Nationwide Incidence of Childhood Type 1 Diabetes
Authors: Berhan Yonas , Waernbaum Ingeborg , Lind Torbjörn , Möllsten Anna , Dahlquist Gisela ,   for the Swedish Childhood Diabetes Study Group*
Published: January 2011

OBJECTIVE

During the past few decades, a rapidly increasing incidence of childhood type 1 diabetes (T1D) has been reported from many parts of the world. The change over time has been partly explained by changes in lifestyle causing rapid early growth and weight development. The current study models and analyzes the time trend by age, sex, and birth cohort in an exceptionally large study group.

RESEARCH DESIGN AND METHODS

The present analysis involved 14,721 incident cases of T1D with an onset of 0–14.9 years that were recorded in the nationwide Swedish Childhood Diabetes Registry from 1978 to 2007. Data were analyzed using generalized additive models.

RESULTS

Age- and sex-specific incidence rates varied from 21.6 (95% CI 19.4–23.9) during 1978–1980 to 43.9 (95% CI 40.7–47.3) during 2005–2007. Cumulative incidence by birth cohort shifted to a younger age at onset during the first 22 years, but from the birth year 2000 a statistically significant reversed trend (P < 0.01) was seen.

CONCLUSIONS

Childhood T1D increased dramatically and shifted to a younger age at onset the first 22 years of the study period. We report a reversed trend, starting in 2000, indicating a change in nongenetic risk factors affecting specifically young children.
Deletion of Lkb1 in Pro-Opiomelanocortin Neurons Impairs Peripheral Glucose Homeostasis in Mice
Authors: Claret Marc , Smith Mark A. , Knauf Claude , Al-Qassab Hind , Woods Angela , Heslegrave Amanda , Piipari Kaisa , Emmanuel Julian J. , Colom André , Valet Philippe , Cani Patrice D. , Begum Ghazala , White Anne , Mucket Phillip , Peters Marco , Mizuno Keiko , Batterham Rachel L. , Giese K. Peter , Ashworth Alan , Burcelin Remy , Ashford Michael L. , Carling David , Withers Dominic J.
Published: January 2011

OBJECTIVE

AMP-activated protein kinase (AMPK) signaling acts as a sensor of nutrients and hormones in the hypothalamus, thereby regulating whole-body energy homeostasis. Deletion of Ampkα2 in pro-opiomelanocortin (POMC) neurons causes obesity and defective neuronal glucose sensing. LKB1, the Peutz-Jeghers syndrome gene product, and Ca2+-calmodulin–dependent protein kinase kinase β (CaMKKβ) are key upstream activators of AMPK. This study aimed to determine their role in POMC neurons upon energy and glucose homeostasis regulation.

RESEARCH DESIGN AND METHODS

Mice lacking either Camkkβ or Lkb1 in POMC neurons were generated, and physiological, electrophysiological, and molecular biology studies were performed.

RESULTS

Deletion of Camkkβ in POMC neurons does not alter energy homeostasis or glucose metabolism. In contrast, female mice lacking Lkb1 in POMC neurons (PomcLkb1KO) display glucose intolerance, insulin resistance, impaired suppression of hepatic glucose production, and altered expression of hepatic metabolic genes. The underlying cellular defect in PomcLkb1KO mice involves a reduction in melanocortin tone caused by decreased α-melanocyte–stimulating hormone secretion. However, Lkb1-deficient POMC neurons showed normal glucose sensing, and body weight was unchanged in PomcLkb1KO mice.

CONCLUSIONS

Our findings demonstrate that LKB1 in hypothalamic POMC neurons plays a key role in the central regulation of peripheral glucose metabolism but not body-weight control. This phenotype contrasts with that seen in mice lacking AMPK in POMC neurons with defects in body-weight regulation but not glucose homeostasis, which suggests that LKB1 plays additional functions distinct from activating AMPK in POMC neurons.
Diabetes in Mice With Selective Impairment of Insulin Action in Glut4-Expressing Tissues
Authors: Lin Hua V. , Ren Hongxia , Samuel Varman T. , Lee Hui-Young , Lu Taylor Y. , Shulman Gerald I. , Accili Domenico
Published: January 2011

OBJECTIVE

Impaired insulin-dependent glucose disposal in muscle and fat is a harbinger of type 2 diabetes, but murine models of selective insulin resistance at these two sites are conspicuous by their failure to cause hyperglycemia. A defining feature of muscle and fat vis-à-vis insulin signaling is that they both express the insulin-sensitive glucose transporter Glut4. We hypothesized that diabetes is the result of impaired insulin signaling in all Glut4-expressing tissues.

RESEARCH DESIGN AND METHODS

To test the hypothesis, we generated mice lacking insulin receptors at these sites (“GIRKO” mice), including muscle, fat, and a subset of Glut4-positive neurons scattered throughout the central nervous system.

RESULTS

GIRKO mice develop diabetes with high frequency because of reduced glucose uptake in peripheral organs, excessive hepatic glucose production, and β-cell failure.

CONCLUSIONS

The conceptual advance of the present findings lies in the identification of a tissue constellation that melds cell-autonomous mechanisms of insulin resistance (in muscle/fat) with cell-nonautonomous mechanisms (in liver and β-cell) to cause overt diabetes. The data are consistent with the identification of Glut4 neurons as a distinct neuroanatomic entity with a likely metabolic role.
Links Between Insulin Resistance, Adenosine A2B Receptors, and Inflammatory Markers in Mice and Humans
Authors: Figler Robert A. , Wang Guoquan , Srinivasan Susseela , Jung Dae Young , Zhang Zhiyou , Pankow James S. , Ravid Katya , Fredholm Bertil , Hedrick Catherine C. , Rich Stephen S. , Kim Jason K. , LaNoue Kathryn F. , Linden Joel
Published: January 2011

OBJECTIVE

To determine the mechanisms by which blockade of adenosine A2B receptors (A2BRs) reduces insulin resistance.

RESEARCH DESIGN AND METHODS

We investigated the effects of deleting or blocking the A2BR on insulin sensitivity using glucose tolerance tests (GTTs) and hyperinsulinemic-euglycemic clamps in mouse models of type 2 diabetes. The effects of diabetes on A2BR transcription and signaling were measured in human and mouse macrophages and mouse endothelial cells. In addition, tag single nucleotide polymorphisms (SNPs) in ∼42 kb encompassing the A2BR gene, ADORA2B, were evaluated for associations with markers of diabetes and inflammation.

RESULTS

Treatment of mice with the nonselective adenosine receptor agonist 5′-N-ethylcarboxamidoadensoine (NECA) increased fasting blood glucose and slowed glucose disposal during GTTs. These responses were inhibited by A2BR deletion or blockade and minimally affected by deletion of A1Rs or A2ARs. During hyperinsulinemic-euglycemic clamp of diabetic KKAY mice, A2BR antagonism increased glucose infusion rate, reduced hepatic glucose production, and increased glucose uptake into skeletal muscle and brown adipose tissue. Diabetes caused a four- to sixfold increase in A2BR mRNA in endothelial cells and macrophages and resulted in enhanced interleukin (IL)-6 production in response to NECA due to activation of protein kinases A and C. Five consecutive tag SNPs in ADORA2B were highly correlated with IL-6 and C-reactive protein (CRP). Diabetes had a highly significant independent effect on variation in inflammatory markers. The strength of associations between several ADORA2B SNPs and inflammatory markers was increased when accounting for diabetes status.

CONCLUSIONS

Diabetes affects the production of adenosine and the expression of A2BRs that stimulate IL-6 and CRP production, insulin resistance, and the association between ADORA2B SNPs and inflammatory markers. We hypothesize that increased A2BR signaling in diabetes increases insulin resistance in part by elevating proinflammatory mediators. Selective A2BR blockers may be useful to treat insulin resistance.
Diet-Induced Muscle Insulin Resistance Is Associated With Extracellular Matrix Remodeling and Interaction With Integrin α2β1 in Mice
Authors: Kang Li , Ayala Julio E. , Lee-Young Robert S. , Zhang Zhonghua , James Freyja D. , Neufer P. Darrell , Pozzi Ambra , Zutter Mary M. , Wasserman David H.
Published: January 2011

OBJECTIVE

The hypothesis that high-fat (HF) feeding causes skeletal muscle extracellular matrix (ECM) remodeling in C57BL/6J mice and that this remodeling contributes to diet-induced muscle insulin resistance (IR) through the collagen receptor integrin α2β1 was tested.

RESEARCH DESIGN AND METHODS

The association between IR and ECM remodeling was studied in mice fed chow or HF diet. Specific genetic and pharmacological murine models were used to study effects of HF feeding on ECM in the absence of IR. The role of ECM-integrin interaction in IR was studied using hyperinsulinemic-euglycemic clamps on integrin α2β1-null (itga2−/−), integrin α1β1-null (itga1−/−), and wild-type littermate mice fed chow or HF. Integrin α2β1 and integrin α1β1 signaling pathways have opposing actions.

RESULTS

HF-fed mice had IR and increased muscle collagen (Col) III and ColIV protein; the former was associated with increased transcript, whereas the latter was associated with reduced matrix metalloproteinase 9 activity. Rescue of muscle IR by genetic muscle-specific mitochondria-targeted catalase overexpression or by the phosphodiesterase 5a inhibitor, sildenafil, reversed HF feeding effects on ECM remodeling and increased muscle vascularity. Collagen remained elevated in HF-fed itga2−/− mice. Nevertheless, muscle insulin action and vascularity were increased. Muscle IR in HF-fed itga1−/− mice was unchanged. Insulin sensitivity in chow-fed itga1−/− and itga2−/− mice was not different from wild-type littermates.

CONCLUSIONS

ECM collagen expansion is tightly associated with muscle IR. Studies with itga2−/− mice provide mechanistic insight for this association by showing that the link between muscle IR and increased collagen can be uncoupled by the absence of collagen-integrin α2β1 interaction.
Hypoxia-Induced Intrauterine Growth Restriction Increases the Susceptibility of Rats to High-Fat Diet–Induced Metabolic Syndrome
Authors: Rueda-Clausen Christian F. , Dolinsky Vernon W. , Morton Jude S. , Proctor Spencer D. , Dyck Jason R.B. , Davidge Sandra T.
Published: January 2011

OBJECTIVE

It is recognized that there is a remarkable variability in the systemic response to high-fat (HF) diets that cannot be completely explained by genetic factors. In addition, pregnancy complications leading to intrauterine growth restriction (IUGR) have been associated with an increased risk of developing metabolic syndrome (MetS) later in life. Thus, we hypothesized that offspring born with IUGR exhibit permanent metabolic changes that make them more susceptible to HF diet–induced MetS.

RESEARCH DESIGN AND METHODS

SD rats born normal (control) or with hypoxia-induced IUGR were randomized to low-fat (10% fat) or HF (45% fat) diets. After 9 weeks of feeding, physiological and molecular pathways involved in the MetS were evaluated.

RESULTS

IUGR offspring exhibited decreased energy intake and physical activity relative to controls. In offspring fed a HF diet, IUGR was associated with decreased total body fat content, a relative increase in intra-abdominal fat deposition and adipocyte size, an increase in fasting plasma concentrations of leptin, triglyceride and free fatty acids, and an increased concentration of triglycerides and ceramides in both liver and skeletal muscle. These changes in lipid homeostasis were accompanied by in vivo insulin resistance and impaired glucose tolerance and associated with increased phosphorylation of protein kinase C θ, inhibition of insulin receptor substrate 1, and a decreased activation of protein kinase B (PKB; also known as Akt) in liver and skeletal muscle in response to insulin.

CONCLUSIONS

IUGR enhances specific deleterious metabolic responses to a HF diet. Our results suggest that offspring born with IUGR may require special attention and follow-up to prevent the early onset of MetS.
An Interferon-Induced Helicase (IFIH1) Gene Polymorphism Associates With Different Rates of Progression From Autoimmunity to Type 1 Diabetes
Authors: Winkler Christiane , Lauber Claudia , Adler Kerstin , Grallert Harald , Illig Thomas , Ziegler Anette-Gabriele , Bonifacio Ezio
Published: January 2011

OBJECTIVE

Genome-wide association studies have identified gene regions associated with the development of type 1 diabetes. The aim of this study was to determine whether these associations are with the development of autoimmunity and/or progression to diabetes.

RESEARCH DESIGN AND METHODS

Children (n = 1,650) of parents with type 1 diabetes were prospectively followed from birth (median follow-up 10.20 years) for the development of islet autoantibodies, thyroid peroxidase antibodies, tissue transglutaminase antibodies, and diabetes. Genotyping for single-nucleotide polymorphisms of the PTPN22, ERBB3, PTPN2, KIAA0350, CD25, and IFIH1 genes was performed using the MassARRAY system with iPLEX chemistry.

RESULTS

Islet autoantibodies developed in 137 children and diabetes developed in 47 children. Type 1 diabetes risk was associated with the IFIH1 rs2111485 single-nucleotide polymorphism (hazard ratio 2.08; 95% CI 1.16–3.74; P = 0.014). None of the other genes were significantly associated with diabetes development in this cohort. IFIH1 genotypes did not associate with the development of islet autoantibodies (P = 0.80) or autoantibodies against thyroid peroxidase (P = 0.55) and tissue transglutaminase (P = 0.66). Islet autoantibody–positive children with the IFIH1 rs2111485 GG genotype had a faster progression to diabetes (31% within 5 years) than children with the type 1 diabetes protective GA or AA genotypes (11% within 5 years; P = 0.006).

CONCLUSIONS

The findings indicate that IFIH1 genotypes influence progression from autoimmunity to diabetes development, consistent with the notion that protective genotypes downregulate responses to environmental insults after initiation of autoimmunity.
Global Gene Expression Profiles of Subcutaneous Adipose and Muscle From Glucose-Tolerant, Insulin-Sensitive, and Insulin-Resistant Individuals Matched for BMI
Authors: Elbein Steven C. , Kern Philip A. , Rasouli Neda , Yao-Borengasser Aiwei , Sharma Neeraj K. , Das Swapan K.
Published: January 2011

OBJECTIVE

To determine altered gene expression profiles in subcutaneous adipose and skeletal muscle from nondiabetic, insulin-resistant individuals compared with insulin-sensitive individuals matched for BMI.

RESEARCH DESIGN AND METHODS

A total of 62 nondiabetic individuals were chosen for extremes of insulin sensitivity (31 insulin-resistant and 31 insulin-sensitive subjects; 40 were European American and 22 were African American) and matched for age and obesity measures. Global gene expression profiles were determined and compared between ethnic groups and between insulin-resistant and insulin-sensitive participants individually and using gene-set enrichment analysis.

RESULTS

African American and European American subjects differed in 58 muscle and 140 adipose genes, including many inflammatory and metabolically important genes. Peroxisome proliferator–activated receptor γ cofactor 1A (PPARGC1A) was 1.75-fold reduced with insulin resistance in muscle, and fatty acid and lipid metabolism and oxidoreductase activity also were downregulated. Unexpected categories included ubiquitination, citrullination, and protein degradation. In adipose, highly represented categories included lipid and fatty acid metabolism, insulin action, and cell-cycle regulation. Inflammatory genes were increased in European American subjects and were among the top Kyoto Encyclopedia of Genes and Genomes pathways on gene-set enrichment analysis. FADS1, VEGFA, PTPN3, KLF15, PER3, STEAP4, and AGTR1 were among genes expressed differentially in both adipose and muscle.

CONCLUSIONS

Adipose tissue gene expression showed more differences between insulin-resistant versus insulin-sensitive groups than the expression of genes in muscle. We confirm the role of PPARGC1A in muscle and show some support for inflammation in adipose from European American subjects but find prominent roles for lipid metabolism in insulin sensitivity independent of obesity in both tissues.
Adrenergic Mediation of Hypoglycemia-Associated Autonomic Failure
Authors: Ramanathan Ranjani , Cryer Philip E.
Published: January 2011

OBJECTIVE

We tested the hypothesis that adrenergic activation, cholinergic activation, or both, mediate the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.

RESEARCH DESIGN AND METHODS

Seventeen healthy adults were studied on 2 consecutive days on three occasions. Day 1 involved hyperinsulinemic euglycemic (90 mg/dL × 1 h), then hypoglycemic (54 mg/dL × 2 h) clamps, in the morning and afternoon on all three occasions with 1) saline infusion, 2) adrenergic blockade with the nonselective α-adrenergic and β-adrenergic antagonists phentolamine and propranolol, or 3) adrenergic blockade plus cholinergic blockade with the muscarinic cholinergic antagonist atropine in random sequence. Day 2 involved similar morning euglycemic and hypoglycemic clamps, with saline infusion, on all three occasions.

RESULTS

Compared with the responses to hypoglycemia during saline infusion on day 1, the plasma epinephrine and norepinephrine responses to hypoglycemia were reduced on day 2 (351 ± 13 vs. 214 ± 22 pg/mL for epinephrine and 252 ± 4 vs. 226 ± 7 pg/mL for norepinephrine during the last hour; both P < 0.0001). However, the plasma epinephrine and norepinephrine responses to hypoglycemia were not reduced on day 2 when adrenergic or adrenergic plus cholinergic blockade was produced during hypoglycemia on day 1.

CONCLUSIONS

Adrenergic blockade prevents the effect of hypoglycemia to reduce the plasma catecholamine responses to subsequent hypoglycemia. Thus, adrenergic activation mediates the effect of recent antecedent hypoglycemia to reduce the sympathoadrenal response to subsequent hypoglycemia, the key feature of hypoglycemia-associated autonomic failure in diabetes, in humans.
Combined Small Interfering RNA Therapy and In Vivo Magnetic Resonance Imaging in Islet Transplantation
Authors: Wang Ping , Yigit Mehmet V. , Medarova Zdravka , Wei Lingling , Dai Guangping , Schuetz Christian , Moore Anna
Published: January 2011

OBJECTIVE

Recent advances in human islet transplantation are hampered by significant graft loss shortly after transplantation and inability to follow islet fate directly. Both issues were addressed by utilizing a dual-purpose therapy/imaging small interfering RNA (siRNA)-nanoparticle probe targeting apoptotic-related gene caspase-3. We expect that treatment with the probe would result in significantly better survival of transplanted islets, which could be monitored by in vivo magnetic resonance imaging (MRI).

RESEARCH DESIGN AND METHODS

We synthesized a probe consisting of therapeutic (siRNA to human caspase-3) and imaging (magnetic iron oxide nanoparticles, MN) moieties. In vitro testing of the probe included serum starvation of the islets followed by treatment with the probe. Caspase-3 gene silencing and protein expression were determined by RT-PCR and Western blot, respectively. In vivo studies included serial MRI of NOD-SCID mice transplanted with MN-small interfering (si)Caspase-3–labeled human islets under the left kidney capsule and MN-treated islets under the right kidney capsule.

RESULTS

Treatment with MN-siCaspase-3 probe resulted in decrease of mRNA and protein expression in serum-starved islets compared with controls. In vivo MRI showed that there were significant differences in the relative volume change between MN-siCaspase-3–treated grafts and MN-labeled grafts. Histology revealed decreased caspase-3 expression and cell apoptosis in MN-siCaspase-3–treated grafts compared with the control side.

CONCLUSIONS

Our data show the feasibility of combining siRNA therapy and in vivo monitoring of transplanted islets in mice. We observed a protective effect of MN-siCaspase-3 in treated islets both in vitro and in vivo. This study could potentially aid in increasing the success of clinical islet transplantation.
Ethnic Differences in Pancreatic Fat Accumulation and Its Relationship With Other Fat Depots and Inflammatory Markers
Authors: Lê Kim-Anne , Ventura Emily E. , Fisher Jessica Q. , Davis Jaimie N. , Weigensberg Marc J. , Punyanitya Mark , Hu Houchun H. , Nayak Krishna S. , Goran Michael I.
Published: January 2011

OBJECTIVE

Visceral adipose tissue (VAT) and hepatic fat are associated with insulin resistance and vary by sex and ethnicity. Recently, pancreatic fat fraction (PFF) has also been linked with increasing obesity. Our aim was to assess ethnic and sex differences in PFF and its relationship to other fat depots, circulating free fatty acids (FFA), insulin secretion and sensitivity, and inflammation in obese adolescents and young adults.

RESEARCH DESIGN AND METHODS

We examined 138 (40 males, 98 females) obese Hispanics and African Americans (13–25 years). Subcutaneous adipose tissue and VAT volumes, hepatic fat fraction (HFF), and PFF were determined by magnetic resonance imaging. Insulin sensitivity and β-cell function were assessed during an intravenous glucose tolerance test.

RESULTS

Hispanics had higher PFF than African Americans (7.3 ± 3.8 vs. 6.2 ± 2.6%, P = 0.03); this ethnic difference was higher in young adults compared with children and adolescents (ethnicity × age: P = 0.01). Males had higher PFF than females (P < 0.0001). PFF was positively correlated with VAT (r = 0.45, P < 0.0001), HFF (r = 0.29, P < 0.0001), and FFA (r = 0.32, P = 0.001). PFF positively correlated with inflammatory markers but lost significance when adjusted for VAT. In multiple stepwise regression analysis, VAT and FFA were the best predictors of PFF (adjusted R2 = 0.40). There were no significant correlations between PFF and markers of insulin sensitivity or β-cell function.

CONCLUSIONS

PFF is higher in Hispanics than African Americans, and this difference increases with age. In young obese individuals, PFF is related to VAT, HFF, and circulating FFA, thus possibly contributing to their increased risk for type 2 diabetes and related metabolic disorders.
Lifestyle Interaction With Fat Mass and Obesity-Associated (FTO) Genotype and Risk of Obesity in Apparently Healthy U.S. Women
Authors: Ahmad Tariq , Lee I-Min , Paré Guillaume , Chasman Daniel I. , Rose Lynda , Ridker Paul M. , Mora Samia
Published: January 2011

OBJECTIVE

Variation in the fat mass and obesity-associated (FTO) gene is associated with obesity. The extent to which separate and combined effects of physical activity and caloric intake modify this association remains unclear.

RESEARCH DESIGN AND METHODS

FTO polymorphism rs8050136 was measured, and physical activity, caloric intake, and anthropometrics were self-reported in 21,675 apparently healthy Caucasian women.

RESULTS

The effect of the risk allele (A) on BMI was larger among inactive or higher intake women, with additive effects of inactivity and high intake on the associated genetic risk. Specifically, each A allele was associated with mean BMI difference of +0.73 (SE 0.08) kg/m2 among inactive women (≤median, 8.8 MET-hours/week), compared with +0.31 (0.06) kg/m2, P < 0.0001, among active women (>8.8 MET-hours/week). Similarly, each A allele was associated with mean BMI difference of +0.65 (0.07) among high intake women (>median, 1,679 kcals/day), compared with +0.38 (0.07) kg/m2, P = 0.005, among low intake women (≤1,679 kcals/day). Among inactive/high intake women, each A allele was associated with mean BMI difference of +0.97 (0.11) kg/m2 vs. +0.22 (0.08) kg/m2 among inactive/low intake women, P < 0.0001. Among inactive/high intake women, each A allele carried increased risk of obesity (odds ratio 1.39, 95% CI 1.27–1.52) and diabetes (odds ratio 1.36, 95% CI 1.07–1.73).

CONCLUSIONS

In this study, lifestyle factors modified the genetic risk of FTO on obesity phenotypes, particularly among women who were both inactive and had high intake. Healthier lifestyle patterns blunted but did not completely eliminate the associated genetic risk.
Sedentary Activity Associated With Metabolic Syndrome Independent of Physical Activity
Authors: Bankoski Andrea , Harris Tamara B. , McClain James J. , Brychta Robert J. , Caserotti Paolo , Chen Kong Y. , Berrigan David , Troiano Richard P. , Koster Annemarie
Published: January 2011

OBJECTIVE

This study examined the association between objectively measured sedentary activity and metabolic syndrome among older adults.

RESEARCH DESIGN AND METHODS

Data were from 1,367 men and women, aged ≥60 years who participated in the 2003–2006 National Health and Nutrition Examination Survey (NHANES). Sedentary time during waking hours was measured by an accelerometer (<100 counts per minute). A sedentary bout was defined as a period of time >5 min. A sedentary break was defined as an interruption in sedentary time (≥100 counts per minute). Metabolic syndrome was defined according to the Adult Treatment Panel (ATP) III criteria.

RESULTS

On average, people spent 9.5 h (65% of wear time) as sedentary. Compared with people without metabolic syndrome, people with metabolic syndrome spent a greater percentage of time as sedentary (67.3 vs. 62.2%), had longer average sedentary bouts (17.7 vs. 16.7 min), had lower intensity during sedentary time (14.8 vs. 15.8 average counts per minute), and had fewer sedentary breaks (82.3 vs. 86.7), adjusted for age and sex (all P < 0.01). A higher percentage of time sedentary and fewer sedentary breaks were associated with a significantly greater likelihood of metabolic syndrome after adjustment for age, sex, ethnicity, education, alcohol consumption, smoking, BMI, diabetes, heart disease, and physical activity. The association between intensity during sedentary time and metabolic syndrome was borderline significant.

CONCLUSIONS

The proportion of sedentary time was strongly related to metabolic risk, independent of physical activity. Current results suggest older people may benefit from reducing total sedentary time and avoiding prolonged periods of sedentary time by increasing the number of breaks during sedentary time.
Urbanization, Physical Activity, and Metabolic Health in Sub-Saharan Africa
Authors: Assah Felix K. , Ekelund Ulf , Brage Soren , Mbanya Jean Claude , Wareham Nicholas J.
Published: January 2011

OBJECTIVE

We examined the independent associations between objectively measured free-living physical activity energy expenditure (PAEE) and the metabolic syndrome in adults in rural and urban Cameroon.

RESEARCH DESIGN AND METHODS

PAEE was measured in 552 rural and urban dwellers using combined heart rate and movement sensing over 7 continuous days. The metabolic syndrome was defined using the National Cholesterol Education Program-Adult Treatment Panel III criteria.

RESULTS

Urban dwellers had a significantly lower PAEE than rural dwellers (44.2 ± 21.0 vs. 59.6 ± 23.7 kJ/kg/day, P < 0.001) and a higher prevalence of the metabolic syndrome (17.7 vs. 3.5%, P < 0.001). In multivariate regression models adjusted for possible confounders, each kJ/kg/day of PAEE was associated with a 2.1% lower risk of prevalent metabolic syndrome (odds ratio 0.98, P = 0.03). This implies a 6.5 kJ/kg/day difference in PAEE, equivalent to 30 min/day of brisk walking, corresponds to a 13.7% lower risk of prevalent metabolic syndrome. The population attributable fraction of prevalent metabolic syndrome due to being in the lowest quartile of PAEE was 26.3% (25.3% in women and 35.7% in men).

CONCLUSIONS

Urban compared with rural residence is associated with lower PAEE and higher prevalence of metabolic syndrome. PAEE is strongly independently associated with prevalent metabolic syndrome in adult Cameroonians. Modest population-wide changes in PAEE may have significant benefits in terms of reducing the emerging burden of metabolic diseases in sub-Saharan Africa.
Hemoglobin A1c and Mean Glucose in Patients With Type 1 Diabetes
Authors:   Juvenile Diabetes Research Foundation Continuous Glucose Monitoring Study Group
Published: January 2011

OBJECTIVE

To determine the relationship between mean sensor glucose concentrations and hemoglobin A1c (HbA1c) values measured in the Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and Complications laboratory at the University of Minnesota in a cohort of subjects with type 1 diabetes from the Juvenile Diabetes Research Foundation continuous glucose monitoring randomized trial.

RESEARCH DESIGN AND METHODS

Near-continuous glucose sensor data (≥4 days/week) were collected for 3 months before a central laboratory–measured HbA1c was performed for 252 subjects aged 8–74 years, the majority of whom had stable HbA1c values (77% within ±0.4% of the patient mean).

RESULTS

The slope (95% CI) for mean sensor glucose concentration (area under the curve) versus a centrally measured HbA1c was 24.4 mg/dL (22.0–26.7) for each 1% change in HbA1c, with an intercept of −16.2 mg/dL (−32.9 to 0.6). Although the slope did not vary with age or sex, there was substantial individual variability, with mean sensor glucose concentrations ranging from 128 to 187 mg/dL for an HbA1c of 6.9–7.1%. The root mean square of the errors between the actual mean sensor glucose concentration versus the value calculated using the regression equation was 14.3 mg/dL, whereas the median absolute difference was 10.1 mg/dL.

CONCLUSIONS

There is substantial individual variability between the measured versus calculated mean glucose concentrations. Consequently, estimated average glucose concentrations calculated from measured HbA1c values should be used with caution.
Weight-Related Quality of Life, Health Utility, Psychological Well-Being, and Satisfaction With Exenatide Once Weekly Compared With Sitagliptin or Pioglitazone After 26 Weeks of Treatment
Authors: Best Jennie H. , Rubin Richard R. , Peyrot Mark , Li Yan , Yan Ping , Malloy Jaret , Garrison Louis P.
Published: January 2011

OBJECTIVE

To assess change in patient-reported outcomes in subjects with type 2 diabetes treated with exenatide once weekly compared with those treated with sitagliptin or pioglitazone.

RESEARCH DESIGN AND METHODS

In this 26-week randomized, multicenter, double-dummy study, 491 subjects received 2 mg of exenatide once weekly or maximum daily doses of sitagliptin (100 mg) or pioglitazone (45 mg) on a background of metformin. Weight-related quality of life, health utility, psychological well-being, and diabetes treatment satisfaction were assessed at baseline and week 26. Mean group changes from baseline to week 26 were estimated by ANCOVA.

RESULTS

Weight-related quality of life total scores improved significantly in the exenatide once weekly and sitagliptin arms only; the exenatide once weekly group experienced significantly greater improvement than the pioglitazone group in weight-related quality of life total scores and in several domain scores. Health utility scores improved significantly for exenatide once weekly and sitagliptin groups (P < 0.05) with no significant difference between the exenatide once weekly group and either comparison group. All groups experienced significant improvements on the psychological well-being global scale and all six domain scores, with no significant difference between the exenatide once weekly group and either comparator. All groups experienced significant improvements in total diabetes treatment satisfaction scores. The exenatide once weekly group experienced greater improvement than the sitagliptin group in treatment satisfaction total scores.

CONCLUSIONS

In combination with clinical outcomes from this study, these results indicate it is possible for patients treated with metformin to initiate exenatide therapy with potential benefits in both clinical and patient-reported outcomes.
Relationship Between Carotid Intima-Media Thickness and the Presence and Extent of Coronary Stenosis in Type 2 Diabetic Patients With Carotid Atherosclerosis but Without History of Coronary Artery Disease
Authors: Kasami Ryuuichi , Kaneto Hideaki , Katakami Naoto , Sumitsuji Satoru , Yamasaki Keita , Kuroda Tadashi , Tachibana Kouichi , Yasuda Tetsuyuki , Kuroda Akio , Matsuoka Taka-aki , Matsuhisa Munehide , Shimomura Iichiro
Published: January 2011

OBJECTIVE

We examined the relationship between the presence and extent of coronary stenosis and carotid intima-media thickness (CIMT) in type 2 diabetic patients without history of coronary artery disease (CAD) but with carotid atherosclerosis.

RESEARCH DESIGN AND METHODS

A total of 91 type 2 diabetic patients underwent multi-slice computed tomography coronary angiography.

RESULTS

Max-IMT in the ≥50% stenosis group by multi-slice computed tomography coronary angiography estimation was significantly greater than the 0–25 and 25–50% stenosis group (2.68 ± 0.77 vs. 1.61 ± 0.49 mm, P < 0.0005, and 2.14 ± 0.81 mm, P < 0.05, respectively), and max-IMT in the 25–50% stenosis group was significantly greater than the 0–25% stenosis group (P < 0.05) after adjustment for age, sex, duration of type 2 diabetes, hypertension, and dyslipidemia. In the analysis for trend through the categories of max-IMT, as max-IMT increased, the percentage of ≥50% stenosis increased and the percentage of 0–25% stenosis decreased.

CONCLUSIONS

Our data suggest that max-IMT might be closely associated with the extent of coronary stenosis in type 2 diabetic patients without history of CAD but with carotid atherosclerosis.
Clinical and Genetic Characteristics of Patients With Type 1 Diabetes Associated With Interferon Therapy
Authors: Nakanishi Koji , Saitoh Satoshi
Published: January 2011

OBJECTIVE

This study clarified characteristics of interferon-associated type 1 diabetes.

RESEARCH DESIGN AND METHODS

The study compared 12 patients with interferon-associated type 1 diabetes with 128 patients with type 1A diabetes with respect to clinical characteristics, and with 10 patients without diabetes despite interferon therapy and 136 normal controls with respect to HLA allele distributions.

RESULTS

Patients with interferon-associated type 1 diabetes retained higher levels of fasting serum C peptide as well as GAD65 antibodies than those with type 1A diabetes until 2 to 4 years after onset. HLA-A*2402 was increased among patients with interferon-associated type 1 diabetes compared with those without diabetes, despite interferon therapy (odds ratio [OR] 4.00 [95% CI 1.09–17.26]). The haplotype of DRB1*1302-DQA1*0102-DQB1*0604 was increased in these two groups combined compared with normal controls (OR 5.64 [95% CI 2.67–11.81]).

CONCLUSIONS

Interferon-associated type 1 diabetes is characterized clinically by high titers of GAD65 antibodies and preserved β-cell function, and genetically by addition of HLA-A*2402to DRB1*1302-DQA1*0102-DQB1*0604.
The Diabeo Software Enabling Individualized Insulin Dose Adjustments Combined With Telemedicine Support Improves HbA1c in Poorly Controlled Type 1 Diabetic Patients
Authors: Charpentier Guillaume , Benhamou Pierre-Yves , Dardari Dured , Clergeot Annie , Franc Sylvia , Schaepelynck-Belicar Pauline , Catargi Bogdan , Melki Vincent , Chaillous Lucy , Farret Anne , Bosson Jean-Luc , Penfornis Alfred ,   on behalf of the TeleDiab Study Group
Published: January 2011

OBJECTIVE

To demonstrate that Diabeo software enabling individualized insulin dose adjustments combined with telemedicine support significantly improves HbA1c in poorly controlled type 1 diabetic patients.

RESEARCH DESIGN AND METHODS

In a six-month open-label parallel-group, multicenter study, adult patients (n = 180) with type 1 diabetes (>1 year), on a basal-bolus insulin regimen (>6 months), with HbA1c ≥8%, were randomized to usual quarterly follow-up (G1), home use of a smartphone recommending insulin doses with quarterly visits (G2), or use of the smartphone with short teleconsultations every 2 weeks but no visit until point end (G3).

RESULTS

Six-month mean HbA1c in G3 (8.41 ± 1.04%) was lower than in G1 (9.10 ± 1.16%; P = 0.0019). G2 displayed intermediate results (8.63 ± 1.07%). The Diabeo system gave a 0.91% (0.60; 1.21) improvement in HbA1c over controls and a 0.67% (0.35; 0.99) reduction when used without teleconsultation. There was no difference in the frequency of hypoglycemic episodes or in medical time spent for hospital or telephone consultations. However, patients in G1 and G2 spent nearly 5 h more than G3 patients attending hospital visits.

CONCLUSIONS

The Diabeo system gives a substantial improvement to metabolic control in chronic, poorly controlled type 1 diabetic patients without requiring more medical time and at a lower overall cost for the patient than usual care.
Urinary C-Peptide Creatinine Ratio Is a Practical Outpatient Tool for Identifying Hepatocyte Nuclear Factor 1-α/Hepatocyte Nuclear Factor 4-α Maturity-Onset Diabetes of the Young From Long-Duration Type 1 Diabetes
Authors: Besser Rachel E.J. , Shepherd Maggie H. , McDonald Timothy J. , Shields Beverley M. , Knight Bridget A. , Ellard Sian , Hattersley Andrew T.
Published: January 2011

OBJECTIVE

Hepatocyte nuclear factor 1-α (HNF1A)/hepatocyte nuclear factor 4-α (HNF4A) maturity-onset diabetes of the young (MODY) is frequently misdiagnosed as type 1 diabetes, and patients are inappropriately treated with insulin. Blood C-peptide can aid in the diagnosis of MODY, but practical reasons limit its widespread use. Urinary C-peptide creatinine ratio (UCPCR), a stable measure of endogenous insulin secretion, is a noninvasive alternative. We aimed to compare stimulated UCPCR in adults with HNF1A/4A MODY, type 1 diabetes, and type 2 diabetes.

RESEARCH DESIGN AND METHODS

Adults with diabetes for ≥5years, without renal impairment, were studied (HNF1A MODY [n = 54], HNF4A MODY [n = 23], glucokinase MODY [n = 20], type 1 diabetes [n = 69], and type 2 diabetes [n = 54]). The UCPCR was collected in boric acid 120 min after the largest meal of the day and mailed for analysis. Receiver operating characteristic (ROC) curves were used to identify optimal UCPCR cutoffs to differentiate HNF1A/4A MODY from type 1 and type 2 diabetes.

RESULTS

UCPCR was lower in type 1 diabetes than HNF1A/4A MODY (median [interquartile range]) (<0.02 nmol/mmol [<0.02 to <0.02] vs. 1.72 nmol/mmol [0.98–2.90]; P < 0.0001). ROC curves showed excellent discrimination (area under curve [AUC] 0.98) and identified a cutoff UCPCR of ≥0.2 nmol/mmol for differentiating HNF1A/4A MODY from type 1 diabetes (97% sensitivity, 96% specificity). UCPCR was lower in HNF1A/4A MODY than in type 2 diabetes (1.72 nmol/mmol [0.98–2.90] vs. 2.47 nmol/mmol [1.4–4.13]); P = 0.007). ROC curves showed a weak distinction between HNF1A/4A MODY and type 2 diabetes (AUC 0.64).

CONCLUSIONS

UCPCR is a noninvasive outpatient tool that can be used to discriminate HNF1A and HNF4A MODY from long-duration type 1 diabetes. To differentiate MODY from type 1 diabetes of >5 years’ duration, UCPCR could be used to determine whether genetic testing is indicated.
Implications of Alternative Definitions of Prediabetes for Prevalence in U.S. Adults
Authors: James Cherie , Bullard Kai McKeever , Rolka Deborah B. , Geiss Linda S. , Williams Desmond E. , Cowie Catherine C. , Albright Ann , Gregg Edward W.
Published: January 2011

OBJECTIVE

To compare the prevalence of prediabetes using A1C, fasting plasma glucose (FPG), and oral glucose tolerance test (OGTT) criteria, and to examine the degree of agreement between the measures.

RESEARCH DESIGN AND METHODS

We used the 2005–2008 National Health and Nutrition Examination Surveys to classify 3,627 adults aged ≥18 years without diabetes according to their prediabetes status using A1C, FPG, and OGTT. We compared the prevalence of prediabetes according to different measures and used conditional probabilities to examine agreement between measures.

RESULTS

In 2005–2008, the crude prevalence of prediabetes in adults aged ≥18 years was 14.2% for A1C 5.7–6.4% (A1C5.7), 26.2% for FPG 100–125 mg/dL (IFG100), 7.0% for FPG 110–125 mg/dL (IFG110), and 13.7% for OGTT 140–199 mg/dL (IGT). Prediabetes prevalence varied by age, sex, and race/ethnicity, and there was considerable discordance between measures of prediabetes. Among those with IGT, 58.2, 23.4, and 32.3% had IFG100, IFG110, and A1C5.7, respectively, and 67.1% had the combination of either A1C5.7 or IFG100.

CONCLUSIONS

The prevalence of prediabetes varied by the indicator used to measure risk; there was considerable discordance between indicators and the characteristics of individuals with prediabetes. Programs to prevent diabetes may need to consider issues of equity, resources, need, and efficiency in targeting their efforts.
Improved Glycemic Control Without Hypoglycemia in Elderly Diabetic Patients Using the Ubiquitous Healthcare Service, a New Medical Information System
Authors: Lim Soo , Kang Seon Mee , Shin Hayley , Lee Hak Jong , Won Yoon Ji , Yu Sung Hoon , Kim So-Youn , Yoo Soo Young , Jung Hye Seung , Park Kyong Soo , Ryu Jun Oh , Jang Hak C.
Published: January 2011

OBJECTIVE

To improve quality and efficiency of care for elderly patients with type 2 diabetes, we introduced elderly-friendly strategies to the clinical decision support system (CDSS)-based ubiquitous healthcare (u-healthcare) service, which is an individualized health management system using advanced medical information technology.

RESEARCH DESIGN AND METHODS

We conducted a 6-month randomized, controlled clinical trial involving 144 patients aged >60 years. Participants were randomly assigned to receive routine care (control, n = 48), to the self-monitored blood glucose (SMBG, n = 47) group, or to the u-healthcare group (n = 49). The primary end point was the proportion of patients achieving A1C <7% without hypoglycemia at 6 months. U-healthcare system refers to an individualized medical service in which medical instructions are given through the patient’s mobile phone. Patients receive a glucometer with a public switched telephone network-connected cradle that automatically transfers test results to a hospital-based server. Once the data are transferred to the server, an automated system, the CDSS rule engine, generates and sends patient-specific messages by mobile phone.

RESULTS

After 6 months of follow-up, the mean A1C level was significantly decreased from 7.8 ± 1.3% to 7.4 ± 1.0% (P < 0.001) in the u-healthcare group and from 7.9 ± 1.0% to 7.7 ± 1.0% (P = 0.020) in the SMBG group, compared with 7.9 ± 0.8% to 7.8 ± 1.0% (P = 0.274) in the control group. The proportion of patients with A1C <7% without hypoglycemia was 30.6% in the u-healthcare group, 23.4% in the SMBG group (23.4%), and 14.0% in the control group (P < 0.05).

CONCLUSIONS

The CDSS-based u-healthcare service achieved better glycemic control with less hypoglycemia than SMBG and routine care and may provide effective and safe diabetes management in the elderly diabetic patients.