bluuebunny/crossref_metadata_2025 huggingface dataset:
Methylglyoxal Impairs the Insulin Signaling Pathways Independently of the Formation of Intracellular Reactive Oxygen Species
Authors: Riboulet-Chavey Audrey , Pierron Anne , Durand Isabelle , Murdaca Joseph , Giudicelli Jean , Van Obberghen Emmanuel
Published: May 2006

Nonenzymatic glycation is increased in diabetes and leads to elevated levels of advanced glycation end products (AGEs), which link hyperglycemia to the induction of insulin resistance. In hyperglycemic conditions, intracellularly formed α-ketoaldehydes, such as methylglyoxal, are an essential source of intracellular AGEs, and the abnormal accumulation of methylglyoxal is related to the development of diabetes complications in various tissues and organs. We have previously shown in skeletal muscle that AGEs induce insulin resistance at the level of metabolic responses. Therefore, it was important to extend our work to intermediates of the biosynthetic pathway leading to AGEs. Hence, we asked the question whether the reactive α-ketoaldehyde methylglyoxal has deleterious effects on insulin action similar to AGEs. We analyzed the impact of methylglyoxal on insulin-induced signaling in L6 muscle cells. We demonstrate that a short exposure to methylglyoxal induces an inhibition of insulin-stimulated phosphorylation of protein kinase B and extracellular-regulated kinase 1/2, without affecting insulin receptor tyrosine phosphorylation. Importantly, these deleterious effects of methylglyoxal are independent of reactive oxygen species produced by methylglyoxal but appear to be the direct consequence of an impairment of insulin-induced insulin receptor substrate-1 tyrosine phosphorylation subsequent to the binding of methylglyoxal to these proteins. Our data suggest that an increase in intracellular methylglyoxal content hampers a key molecule, thereby leading to inhibition of insulin-induced signaling. By such a mechanism, methylglyoxal may not only induce the debilitating complications of diabetes but may also contribute to the pathophysiology of diabetes in general.
Activation of Glucagon-Like Peptide-1 Receptor Signaling Does Not Modify the Growth or Apoptosis of Human Pancreatic Cancer Cells
Authors: Koehler Jacqueline A. , Drucker Daniel J.
Published: May 2006

Glucagon-like peptide (GLP)-1 promotes β-cell proliferation and survival through stimulation of its specific G-protein–coupled receptor; however, the potential for GLP-1 receptor (GLP-1R) agonists to promote growth and proliferation of human pancreatic-derived cells remains poorly understood. We identified five human pancreatic cancer cell lines that express the GLP-1R and analyzed cell growth and survival in response to GLP-1R activation. Although cholera toxin (an activator of Gαs) and forskolin (an activator of adenylyl cyclase) increased levels of intracellular cAMP in all cell lines, the GLP-1R agonist exendin-4 (Ex-4) increased cAMP only in CFPAC-1 cells. Conversely, Ex-4 induced extracellular regulated kinase (ERK) 1/2 activation in PL 45 cells in a GLP-1R–and epidermal growth factor receptor–dependent manner, whereas Ex-4 inhibited ERK1/2 phosphorylation in Hs 766T and CAPAN-1 cells. Ex-4 did not modulate the proliferation of these cell lines in vitro and did not inhibit apoptosis after exposure of cells to cytotoxic agents such as cycloheximide, indomethacin, LY294002, or cyclopamine. Furthermore, daily Ex-4 treatment for 4 weeks had no effect on the propagation of CFPAC-1 or PL 45 tumor cells evaluated in nude mice in vivo. Thus, acute or chronic (4 weeks) GLP-1R stimulation does not modify the growth or survival of human pancreatic cancer cells.
Insulin Secretion and Action in Subjects With Impaired Fasting Glucose and Impaired Glucose Tolerance
Authors: Abdul-Ghani Muhammad A. , Jenkinson Christopher P. , Richardson Dawn K. , Tripathy Devjit , DeFronzo Ralph A.
Published: May 2006

This study was conducted to observe changes in insulin secretion and insulin action in subjects with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT). A total of 319 subjects were studied with an oral glucose tolerance test (OGTT). Fasting plasma glucose and insulin concentrations were measured at baseline and every 30 min during the OGTT. Fifty-eight subjects also received a euglycemic-hyperinsulinemic clamp. Insulin sensitivity was calculated as the total glucose disposal (TGD) during the last 30 min of the clamp. Homeostasis model assessment of insulin resistance (HOMA-IR) was calculated from fasting plasma glucose and insulin concentrations. Subjects with IFG had TGD similar to normal glucose-tolerant subjects, while subjects with IGT and combined IFG/IGT had significantly reduced TGD. HOMA-IR in subjects with IFG was similar to that in subjects with combined IFG/IGT and significantly higher than HOMA-IR in subjects with IGT or NGT. Insulin secretion, measured by the insulinogenic index (ΔI0–30/ΔG0–30) and by the ratio of the incremental area under the curve (AUC) of insulin to the incremental AUC of glucose (0–120 min), was reduced to the same extent in all three glucose-intolerant groups. When both measurements of β-cell function were adjusted for severity of insulin resistance, subjects with IGT and combined IFG/IGT had a significantly greater reduction in insulin secretion than subjects with IFG. Subjects with IGT and IFG have different metabolic characteristics. Differences in insulin sensitivity and insulin secretion may predict different rates of progression to type 2 diabetes and varying susceptibility to cardiovascular disease.
Sex-Discordant Associations With Adiponectin Levels and Lipid Profiles in Children
Authors: Ong Ken K. , Frystyk Jan , Flyvbjerg Allan , Petry Clive J. ,   the Avon Longitudinal Study of Parents and Children Study Team, Ness Andy , Dunger David B.
Published: May 2006

In adults, lower circulating levels of the adipocyte-derived hormone adiponectin are associated with obesity, type 2 diabetes, and cardiovascular disease risks. Its use as a risk marker in children is less clear. In 839 children aged 8 years from a representative birth cohort, circulating adiponectin levels were associated with body weight, BMI, waist circumference, and fasting and 30-min insulin levels, but the associations were opposite in boys, with positive associations, and girls, with inverse associations (P = 0.008–0.00001 for interaction with sex). Girls had overall higher adiponectin, higher total cholesterol, lower HDL cholesterol, and higher triglyceride levels than boys, even after adjustment for BMI. With increasing BMI, girls showed steeper declines in HDL cholesterol (P = 0.01 for interaction) and adiponectin levels (P = 0.0005 for interaction) and a steeper increase in triglyceride levels (P = 0.009 for interaction) compared with boys. In conclusion, plasma adiponectin is not a simple marker of central fat and insulin sensitivity in children. With increasing BMI, decreasing adiponectin levels in girls could contribute to their faster deterioration in lipid profiles in comparison with boys. Our data suggest a complex age- and sex-related regulation of adiponectin secretion or clearance.
Complete Protection Against Interleukin-1β–Induced Functional Suppression and Cytokine-Mediated Cytotoxicity in Rat Pancreatic Islets In Vitro Using an Interleukin-1 Cytokine Trap
Authors: Rydgren Tobias , Bengtsson Daniel , Sandler Stellan
Published: May 2006

Cytokines, particularly interleukin (IL)-1β, have been postulated to cause β-cell destruction in type 1 diabetes. We tested the efficacy of an IL-1 cytokine trap in counteraction of suppressive and toxic effects after exposure of rat pancreatic islets in vitro to IL-1β. The IL-1 cytokine trap used herein comprised extracellular domains of the IL-1 receptor accessory protein and the human IL-1 receptor 1 arranged inline and fused to the Fc portion of human IgG1. Groups of isolated rat pancreatic islets were maintained in medium culture with or without IL-1β (150 pmol/l) for 48 h in the absence or presence of the IL-1 trap at 1-, 10-, or 100-fold excess the molar concentration of the cytokine. IL-1β alone induced a strong inhibition of insulin secretion and glucose oxidation rate and a marked increase in medium nitrite accumulation as an indicator of nitric oxide generation. When the IL-1 trap was used at a ratio 10:1 or 100:1, a complete protection against these effects were observed. Moreover, the IL-1 trap (100:1) blocked the increased islet cell death seen in islets treated with a combination of IL-1β + tumor necrosis factor-α + interferon-γ as well as functional suppression induced by the cytokine combination. In conclusion, we show that addition of an IL-1 trap can protect rat pancreatic islets in vitro against noxious effects induced by IL-1β. Exploring the IL-1 trap in relevant animal models of type 1 diabetes represents an interesting future intervention strategy.
Variation in the UCP2-UCP3 Gene Cluster Predicts the Development of Type 2 Diabetes in Healthy Middle-Aged Men
Authors: Gable David R. , Stephens Jefferey W. , Cooper Jackie A. , Miller George J. , Humphries Steve E.
Published: May 2006

The impact of the UCP2 −866G>A and UCP3 −55C>T variants on prospective risk of type 2 diabetes was examined over 15 years in 2,936 healthy middle-aged men (mean age 56 years). Conversion to diabetes (n = 169) was associated with higher BMI, blood pressure, cholesterol, triglycerides and C-reactive protein. The hazard ratio (HR) for diabetes of a BMI >30 kg/m2 was 3.96 (95% CI 2.87–5.47). Homozygosity for the UCP2A or UCP3T alleles accelerated the onset of diabetes, with significant differences in risk of diabetes at 10 years (HR [95% CI] UCP2AA vs. GA+GG 1.94 [1.18–3.19], P = 0.009; UCP3TT vs. CC+ CT 2.06 [1.06–3.99], P = 0.03) but less so at 15 years (UCP2AA 1.42 [0.92–2.19], P = 0.1; UCP3TT 1.57 [0.87–2.04], P = 0.13). Men who were homozygous for both UCP2AA and UCP3TT (1.5% of men) had a risk for diabetes at 10 years of 4.20 (1.70–10.37), P = 0.002. These genotype effects were additive with obesity, and men with a BMI >30 kg/m2 and this genotype combination had a 10-year risk of diabetes of 19.23 [5.63–63.69], P < 0.0001. Functional promoter variants UCP2 and UCP3 increase the prospective risk of diabetes. Although the mechanism of the UCP2 effect is likely to be caused by increased expression in the pancreas and subsequent reduced insulin secretion, the mechanism of the UCP3 effect is currently unknown. Both effects are exacerbated by obesity.
Plasma Phospholipid Transfer Protein Activity Is Decreased in Type 2 Diabetes During Treatment With Atorvastatin
Authors: Dallinga-Thie Geesje M. , van Tol Arie , Hattori Hiroaki , Rensen Patrick C.N. , Sijbrands Eric J.G. ,   for the Diabetes Atorvastatin Lipid Intervention (DALI) Study Group
Published: May 2006

Plasma phospholipid transfer protein (PLTP) plays an important role in lipoprotein metabolism. PLTP activity is elevated in patients with diabetes, a condition with strongly elevated risk for coronary heart disease. The aim of this study was to test the hypothesis that statins reduce PLTP activity and to examine the potential role of apolipoprotein E (apoE). PLTP activity and apoE were measured in patients with type 2 diabetes from the DALI (Diabetes Atorvastatin Lipid Intervention) Study, a 30-week randomized double-blind placebo-controlled trial with atorvastatin (10 and 80 mg daily). At baseline, PLTP activity was positively correlated with waist circumference, HbA1c, glucose, and apoE (all P < 0.05). Atorvastatin treatment resulted in decreased PLTP activity (10 mg atorvastatin: −8.3%, P < 0.05; 80 mg atorvastatin: −12.1%, P < 0.002). Plasma apoE decreased by 28 and 36%, respectively (P < 0.001). The decrease in apoE was strongly related to the decrease in PLTP activity (r = 0.565, P < 0.001). The change in apoE remained the sole determinant of the change in PLTP activity in a multivariate model. The activity of PLTP in type 2 diabetes is decreased by atorvastatin. The association between the decrease in PLTP activity and apoE during statin treatment supports the hypothesis that apoE may prevent PLTP inactivation.
Variants of the Interleukin-10 Promoter Gene Are Associated With Obesity and Insulin Resistance but Not Type 2 Diabetes in Caucasian Italian Subjects
Authors: Scarpelli Daniela , Cardellini Marina , Andreozzi Francesco , Laratta Emanuela , Hribal Marta Letizia , Marini Maria Adelaide , Tassi Vittorio , Lauro Renato , Perticone Francesco , Sesti Giorgio
Published: May 2006

Interleukin (IL)-10 is a major anti-inflammatory cytokine that has been associated with obesity and type 2 diabetes. The three polymorphisms −1082G/A, −819C/T, and −592C/A in the IL10 promoter were reported to influence IL10 transcription. We investigated whether these polymorphisms were associated with type 2 diabetes and related traits in a cohort of Italian Caucasians comprising 551 type 2 diabetic and 1,131 control subjects. The −819C/T and −592C/A polymorphisms were in perfect linkage disequilibrium (r2 = 1.0). The −1082G/A polymorphism was not associated with type 2 diabetes or related traits. Although the −592C/A polymorphism was not associated with type 2 diabetes, nondiabetic homozygous carriers of the A allele showed increased BMI and insulin resistance and lower plasma IL-10 levels compared with the other genotypes. In the nondiabetic group, the ATA haplotype was associated with an increased risk for obesity (odds ratio 1.28 [95% CI 1.02–1.60]; P = 0.02). The ATA/ATA composite genotype was associated with an increased risk for obesity (1.96 [1.16–3.31]; P = 0.01) and insulin resistance (1.99 [1.12–3.53]; P = 0.01). This study suggests that polymorphisms and haplotypes of the IL10 promoter may be associated with obesity and insulin resistance in a large sample of Italian Caucasians.
Structured Personal Diabetes Care in Primary Health Care Affects Only Women’s HbA1c
Authors: Nielsen Anni B.S. , de Fine Olivarius Niels , Gannik Dorte , Hindsberger Charlotte , Hollnagel Hanne
Published: May 2006

OBJECTIVE—Diabetic men and women differ in lifestyle and attitudes toward diabetes and may benefit differently from interventions to improve glycemic control. We explored the relation between HbA1c (A1C), sex, treatment allocation, and their interactions with behavioral and attitudinal characteristics in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—Six years after their diabetes diagnosis, a population-based sample of 874 primary care patients cluster-randomized to receive structured personal care or routine care reported lifestyle, medication, social support, diabetes-related consultations, and attitudes toward diabetes. Multivariate analyses were applied, split by sex.

RESULTS—A marked intervention effect on A1C was confined to the structured personal care women. The median A1C was 8.4% in structured personal care women and 9.2% in routine care women (P < 0.0001) and 8.5% in structured personal care men and 8.9% in routine care men (P = 0.052). Routine care women had a 1.10 times higher A1C than structured personal care women, (P < 0.0001, adjusted analysis). Structured personal care women had relatively more consultations than routine care women, but neither number of consultations nor other covariates helped to explain the sex difference in A1C. Irrespective of treatment allocation, women had more adaptive attitudes toward diabetes but lacked support compared with men.

CONCLUSIONS—In this study, the observed effect of structured personal care on A1C was present only among women, possibly because they were more inclined to comply with regular follow-up and had a tendency to have a more adaptive attitude toward diabetes.
Contributions of β-Cell Dysfunction and Insulin Resistance to the Pathogenesis of Impaired Glucose Tolerance and Impaired Fasting Glucose
Authors: Abdul-Ghani Muhammad A. , Tripathy Devjit , DeFronzo Ralph A.
Published: May 2006

Impaired glucose tolerance (IGT) and impaired fasting glucose (IFG) are intermediate states in glucose metabolism that exist between normal glucose tolerance and overt diabetes. Epidemiological studies demonstrate that the two categories describe distinct populations with only partial overlap, suggesting that different metabolic abnormalities characterize IGT and IFG. Insulin resistance and impaired β-cell function, the primary defects observed in type 2 diabetes, both can be detected in subjects with IGT and IFG. However, clinical studies suggest that the site of insulin resistance varies between the two disorders. While subjects with IGT have marked muscle insulin resistance with only mild hepatic insulin resistance, subjects with IFG have severe hepatic insulin resistance with normal or near-normal muscle insulin sensitivity. Both IFG and IGT are characterized by a reduction in early-phase insulin secretion, while subjects with IGT also have impaired late-phase insulin secretion. The distinct metabolic features present in subjects with IFG and IGT may require different therapeutic interventions to prevent their progression to type 2 diabetes.
A New Wound-Based Severity Score for Diabetic Foot Ulcers
Authors: Beckert Stefan , Witte Maria , Wicke Corinna , Königsrainer Alfred , Coerper Stephan
Published: May 2006

OBJECTIVE—Several well-accepted classification systems are available for diabetic foot ulcers. However, there are only a few and scientifically not validated severity scores. The aim of this study was to establish a new wound-based clinical scoring system for diabetic foot ulcers suitable for daily clinical practice anticipating chances for healing and risk of amputation.

RESEARCH DESIGN AND METHODS—Four clinically defined parameters, namely palpable pedal pulses, probing to bone, ulcer location, and presence of multiple ulcerations, were prospectively assessed in 1,000 consecutive patients. In the next step, a new diabetic ulcer severity score (DUSS) was created from these parameters. Palpable pedal pulses were categorized by the absence (scored as 1) or presence (scored as 0) of pedal pulses, while probing to bone was defined as yes (scored as 1) or no (scored as 0). The site of ulceration was defined as toe (scored as 0) or foot (scored as 1) ulcer. Patients with multiple ulcerations were graded as 1 compared with those with single ulcers (scored as 0). The DUSS was calculated by adding these separate gradings to a theoretical maximum of 4. Wounds were followed-up for 365 days or until healing or amputation if earlier. Probability of healing and risk of amputation were calculated by the Kaplan-Meier method.

RESULTS—Uni- and multivariate analyses showed a significantly higher probability of healing for patients with palpable pulses, no probing to bone, toe ulcers, and absence of multiple ulcerations. When patients were divided into subgroups with the same DUSS, we found significantly different probabilities for healing. We showed a decreasing probability of healing for ulcers with a high DUSS, concurrent with increasing amputation rates. An increase in the DUSS by one score point reduced the chance for healing by 35%. Similarly, the higher the ulcer score, the larger the initial wound area, the longer the wound history, and the more likely the need for surgery or hospitalization.

CONCLUSIONS—The DUSS categorizes different ulcers into subgroups with specific severity and similar clinical outcome. Using this score, the probabilities for healing, amputation, need for surgery, and hospitalization are predictable with high accuracy. This might be useful for the anticipation of health care costs and for comparison of subgroups of patients in clinical studies.
Common Presence of Non–Transferrin-Bound Iron Among Patients With Type 2 Diabetes
Authors: Lee Duk-Hee , Liu Ding Yong , Jacobs David R. , Shin Hai-Rim , Song Kyungeun , Lee In-Kyu , Kim Bowan , Hider Robert C.
Published: May 2006

OBJECTIVE—Recently, we reported increased cardiovascular disease mortality among supplemental vitamin C users with type 2 diabetes in a prospective cohort study. Because vitamin C may cause oxidative stress in the presence of redox active iron, we hypothesized that non–transferrin-bound iron (NTBI), a form of iron susceptible to redox activity, may be present in patients with type 2 diabetes.

RESEARCH DESIGN AND METHODS—We measured serum NTBI levels using high-performance liquid chromatography in 48 patients with known diabetes (at least 5 years duration since diagnosis), 49 patients with newly diagnosed diabetes, and 47 healthy control subjects (frequency matched on age and sex).

RESULTS—NTBI was commonly present in diabetes: 59% in newly diagnosed diabetes and 92% in advanced diabetes. Mean NTBI values varied significantly between the three groups, with the highest values being observed in patients with known diabetes and the lowest in the control subjects (0.62 ± 0.43 vs. 0.24 ± 0.29 vs. 0.04 ± 0.13 μmol/l Fe). Serum total iron or percent transferrin saturation were very similar among the three groups, yet NTBI was strongly associated with serum total iron (r = 0.74, P < 0.01) and percent transferrin saturation (r = 0.70, P < 0.01) among the patients with known diabetes.

CONCLUSIONS—Consistent with our hypothesis, these data demonstrate the common existence of NTBI in type 2 diabetic patients with a strong gradient with severity. Prospective cohort studies are required to clarify the clinical relevance of increased NTBI levels.
Spectrum and Prevalence of Atherogenic Risk Factors in 27,358 Children, Adolescents, and Young Adults With Type 1 Diabetes
Authors: Schwab K. Otfried , Doerfer Jürgen , Hecker Wolfgang , Grulich-Henn Jürgen , Wiemann Dagobert , Kordonouri Olga , Beyer Peter , Holl Reinhard W. ,   on behalf of the DPV Initiative of the German Working Group for Pediatric Diabetology
Published: May 2006

OBJECTIVE—The aim of this data analysis was to ascertain the type and prevalence rate as well as age and sex distribution of cardiovascular risk factors in type 1 diabetic patients up to 26 years of age.

RESEARCH DESIGN AND METHODS—Cardiovascular risk factors such as obesity, hypertension, dyslipidemia, poor glycemic control, and smoking were analyzed in 27,358 patients who were divided into three groups (prepubertal, pubertal, and adult) using specifically designed diabetes software for prospective disease documentation.

RESULTS—More than half of the patients per age-group had at least one cardiovascular risk factor. Two risk factors were age dependently found in 6.2–21.7% and three or four risk factors in 0.5–4.7%. Elevated values of HbA1c, total cholesterol, and BMI were found most frequently. Hypertension, smoking, and HDL cholesterol were observed more frequently in males, and elevated BMI, total cholesterol, and LDL cholesterol more often in females. Although 28.6% of the patients had dyslipidemia, merely 0.4% of them received medical treatment, and of the 8.1% of the patients with hypertension, only 2.1% of them were given antihypertensive medication.

CONCLUSIONS—With increasing age, a greater number of patients with cardiovascular risk factors were observed. Significant sex differences were seen in the majority of risk factors. Despite the high prevalence of risk factors, only a small minority of patients received antihypertensive or lipid-lowering treatment. Early identification, prevention, and treatment of additional risk factors seem to be necessary, particularly in light of the high incidence of future cardiovascular disease.
Additive Beneficial Effects of Fenofibrate Combined With Candesartan in the Treatment of Hypertriglyceridemic Hypertensive Patients
Authors: Koh Kwang Kon , Quon Michael J. , Han Seung Hwan , Chung Wook-Jin , Ahn Jeong Yeal , Kim Jeong-a , Lee Yonghee , Shin Eak Kyun
Published: May 2006

OBJECTIVE—Mechanisms underlying fibric acid and angiotensin II type 1 receptor blocker therapies differ. Signaling from peroxisome proliferator-activated receptor α may cross-talk with the angiotensin II system. We investigated vascular and metabolic responses to these therapies either alone or in combination in hypertriglyceridemic hypertensive patients.

RESEARCH DESIGN AND METHODS—This was a randomized, double-blind, placebo-controlled, cross-over trial with three treatment arms (each 2 months) and two washout periods (each 2 months). Forty-four patients were given 200 mg fenofibrate and placebo, 200 mg fenofibrate and 16 mg candesartan, or 16 mg candesartan and placebo daily during each treatment period.

RESULTS—Fenofibrate, combined therapy, or candesartan therapy significantly reduced blood pressure. However, combined therapy significantly reduced blood pressure more than fenofibrate or candesartan alone (P < 0.001 by ANOVA). When compared with candesartan, fenofibrate or combined therapy significantly improved the lipoprotein profile. All three treatment arms significantly improved flow-mediated dilator response to hyperemia. Combined therapy significantly decreased plasma malondialdehyde, high-sensitivity C-reactive protein, and soluble CD40L levels relative to baseline measurements. Importantly, these parameters were changed to a greater extent with combined therapy when compared with monotherapy (P < 0.001, P = 0.002, P = 0.050, and P = 0.032 by ANOVA, respectively). Fenofibrate, combined therapy, and candesartan significantly increased plasma adiponectin levels and insulin sensitivity relative to baseline measurements. However, the magnitude of these increases were not significantly different among the three therapies (P = 0.246 and P = 0.153 by ANOVA, respectively).

CONCLUSIONS—Fenofibrate combined with candesartan improves endothelial function and reduces inflammatory markers to a greater extent than monotherapy in hypertriglyceridemic hypertensive patients.
The Impact of Patient Preferences on the Cost-Effectiveness of Intensive Glucose Control in Older Patients With New-Onset Diabetes
Authors: Huang Elbert S. , Shook Morgan , Jin Lei , Chin Marshall H. , Meltzer David O.
Published: May 2006

OBJECTIVE—Cost-effectiveness analyses have reported that intensive glucose control is not cost-effective in older patients with new-onset diabetes. However, these analyses have had limited data on patient preferences concerning diabetic health states. We examined how the cost- effectiveness of intensive glucose control changes with the incorporation of patient preferences.

RESEARCH DESIGN AND METHODS—We collected health state preferences/utilities from 519 older diabetic patients. We incorporated these utilities into an established cost-effectiveness model of intensive glucose control and compared incremental cost-effectiveness analyses ratios (ICERs) (cost divided by quality-adjusted life-year [QALY]) when using the original and patient-derived utilities for complications and treatments.

RESULTS—The mean utilities were ∼0.40 for major complications, 0.76 (95% CI 0.74–0.78) for conventional glucose control, 0.77 (0.75–0.80) for intensive therapy with oral medications, and 0.64 (0.61–0.67) for intensive therapy with insulin. Incorporating our patient-derived complication utilities alone improved ICERs for intensive glucose control (e.g., patients aged 60–65 years at diagnosis, $136,000/QALY→$78,000/QALY), but intensive therapy was still not cost-effective at older ages. When patient-derived treatment utilities were also incorporated, the cost-effectiveness of intensive treatment depended on the method of glucose control. Intensive control with insulin generated fewer QALYs than conventional control. However, intensive control with oral medications was beneficial on average at all ages and had an ICER ≤$100,000 to age 70.

CONCLUSIONS—The cost-effectiveness of intensive glucose control in older patients with new-onset diabetes is highly sensitive to assumptions regarding quality of life with treatments. Cost-effectiveness analyses of diabetes care should consider the sensitivity of results to alternative utility assumptions.
Increased Cancer-Related Mortality for Patients With Type 2 Diabetes Who Use Sulfonylureas or Insulin
Authors: Bowker Samantha L. , Majumdar Sumit R. , Veugelers Paul , Johnson Jeffrey A.
Published: May 2006

OBJECTIVE—Numerous studies have identified an increased risk of cancer in type 2 diabetes. We explored the association between antidiabetic therapies and cancer-related mortality in patients with type 2 diabetes, postulating that agents that increase insulin levels might promote cancer.

RESEARCH DESIGN AND METHODS—This was a population-based cohort study using administrative databases from Saskatchewan Health. Cancer-related mortality was compared among inception cohorts of metformin users and sulfonylurea monotherapy users. Multivariate Cox regression was used to estimate the hazard ratio (HR) of cancer-related mortality, after adjusting for age, sex, insulin use, and chronic disease score. All statistical tests were two-sided.

RESULTS—We identified 10,309 new users of metformin or sulfonylureas with an average follow-up of 5.4 ± 1.9 years (means ± SD). The mean age for the cohort was 63.4 ± 13.3 years, and 55% were men. Cancer mortality over follow-up was 4.9% (162 of 3,340) for sulfonylurea monotherapy users, 3.5% (245 of 6,969) for metformin users, and 5.8% (84 of 1,443) for subjects who used insulin. After multivariate adjustment, the sulfonylurea cohort had greater cancer-related mortality compared with the metformin cohort (adjusted HR 1.3 [95% CI 1.1–1.6]; P = 0.012). Insulin use was associated with an adjusted HR of cancer-related mortality of 1.9 (95% CI 1.5–2.4; P < 0.0001).

CONCLUSIONS—Patients with type 2 diabetes exposed to sulfonylureas and exogenous insulin had a significantly increased risk of cancer-related mortality compared with patients exposed to metformin. It is uncertain whether this increased risk is related to a deleterious effect of sulfonylurea and insulin or a protective effect of metformin or due to some unmeasured effect related to both choice of therapy and cancer risk.
Mean Blood Glucose and Biological Variation Have Greater Influence on HbA1c Levels Than Glucose Instability
Authors: McCarter Robert J. , Hempe James M. , Chalew Stuart A.
Published: May 2006

OBJECTIVE—Mean blood glucose (MBG) over 2–3 months is a strong predictor of HbA1c (A1C) levels. Glucose instability, the variability of blood glucose levels comprising the MBG, and biological variation in A1C (BV) have also been suggested as predictors of A1C independent of MBG. To assess the relative importance of MBG, BV, and glucose instability on A1C, we analyzed patient data from the Diabetes Control and Complications Trial (DCCT).

RESEARCH DESIGN AND METHODS—A glucose profile set and sample for A1C were collected quarterly over the course of the DCCT from each participant (n = 1,441). The glucose profile set consisted of seven samples, one each drawn before and 90 min after breakfast, lunch, and dinner and one before bedtime. MBG and glucose instability (SD of blood glucose [SDBG]) were calculated as the arithmetic mean and SD of glucose profile set samples for each visit, respectively. A statistical model was developed to predict A1C from MBG, SDBG, and BV, adjusted for diabetes duration, sex, treatment group, stratum, and race.

RESULTS—Data from 32,977 visits were available. The overall model was highly statistically significant (log likelihood = −41,818.75, likelihood ratio χ2[7] = 7,218.71, P > χ2 = 0.0000). MBG and BV had large influences on A1C based on their standardized coefficients. SDBG had only 1/14 of the impact of MBG and 1/10 of the impact of BV.

CONCLUSIONS—MBG and BV have a large influence on A1C, whereas SDBG is relatively unimportant. Consideration of BV as well as MBG in the interpretation of A1C may enhance our ability to monitor diabetes management and predict complications.
Improving Metabolic Control Leads to Better Working Memory in Adults With Type 2 Diabetes
Authors: Ryan Christopher M. , Freed Martin I. , Rood Julie A. , Cobitz Alexander R. , Waterhouse Brian R. , Strachan Mark W.J.
Published: May 2006

OBJECTIVE—The goals of this study were to determine whether improvements in metabolic control can ameliorate the cognitive dysfunction associated with type 2 diabetes and evaluate the possibility that such improvements are mediated by changes in circulating insulin or insulin resistance.

RESEARCH DESIGN AND METHODS—This randomized double-blind trial enrolled 145 subjects at 18 centers in the U.S. Older adults with type 2 diabetes receiving metformin monotherapy received add-on therapy with either rosiglitazone, a thiazolidinedione insulin sensitizer, or glyburide. Cognitive function was assessed at baseline and week 24 using the Digit Symbol Substitution Test, the Rey Auditory Verbal Learning Test, and the Cambridge Neuropsychological Test Automated Battery.

RESULTS—Pretreatment fasting plasma glucose (FPG) in both groups was similar, and after 24 weeks both treatment groups showed similar significant reductions in FPG (2.1–2.3 mmol/l). Working memory improved with both rosiglitazone (P < 0.001) and glyburide (P = 0.017). Improvement (25–31% reduction in errors) was most evident on the Paired Associates Learning Test and was significantly correlated (r = 0.30) with improved glycemic control as measured by FPG.

CONCLUSIONS—Similar and statistically significant cognitive improvement was observed with both rosiglitazone and glyburide therapy, and the magnitude of this effect was correlated with the degree to which FPG improved. These results suggest that a cognitive benefit is achievable with pharmacological interventions targeting glycemic control.
Monocyte Telomere Shortening and Oxidative DNA Damage in Type 2 Diabetes
Authors: Sampson Mike J. , Winterbone Mark S. , Hughes Jackie C. , Dozio Nicoletta , Hughes David A.
Published: May 2006

OBJECTIVE—Telomeres are DNA sequences necessary for DNA replication, which shorten at cell division at a rate related to levels of oxidative stress. Once shortened to a critical length, cells are triggered into replicative senescence. Type 2 diabetes is associated with oxidative DNA damage, and we hypothesized that telomere shortening would characterize type 2 diabetes.

RESEARCH DESIGN AND METHODS—We studied 21 male type 2 diabetic subjects (mean age 61.2 years, mean HbA1c 7.9%) selected to limit confounding effects on telomere length and 29 matched control subjects. Telomere length was measured in peripheral venous monocyte and T-cells (naïve and memory) by fluorescent in situ hybridization and oxidative DNA damage by flow cytometry of oxidized DNA bases. Peripheral insulin resistance (homeostasis model assessment) and high-sensitivity C-reactive protein (hsCRP) were measured.

RESULTS—Mean monocyte telomere length in the diabetic group was highly significantly lower than in control subjects (4.0 [1.1] vs. 5.5 [1.1]; P < 0.0001), without significant differences in lymphocyte telomere length. There was a trend toward increased oxidative DNA damage in all diabetes cell types examined and a significant inverse relationship between oxidative DNA damage and telomere length (r = −0.55; P = 0.018) in the diabetic group. Telomere length was unrelated to plasma CRP concentration or insulin resistance.

CONCLUSIONS—Monocyte telomere shortening in type 2 diabetes could be due to increased oxidative DNA damage to monocyte precursors during cell division. This data suggests that monocytes adhering to vascular endothelium and entering the vessel wall in type 2 diabetes are from a population with shorter telomeres and at increased risk of replicative senescence within vascular plaque.
The Effect of Smoking Cessation and Subsequent Resumption on Absorption of Inhaled Insulin
Authors: Becker Reinhard H.A. , Sha Sue , Frick Annke D. , Fountaine Robert J.
Published: May 2006

OBJECTIVE—To assess the absorption profile of inhaled insulin in healthy, actively smoking subjects at baseline, after smoking cessation, and after smoking resumption and compare it with nonsmoking subjects.

RESEARCH DESIGN AND METHODS—Insulin pharmacokinetics and glucodynamics were measured in 20 male smoking subjects (10–20 cigarettes/day) and 10 matched nonsmoking subjects after receiving inhaled insulin (1 mg) or the approximate subcutaneous insulin equivalent (3 units) in a randomized cross-over fashion. All smokers then received inhaled insulin 12 h, 3 days, and 7 days into a smoking cessation period. They then resumed smoking for 2–3 days before again receiving inhaled insulin 1 h after the last cigarette.

RESULTS—Before smoking cessation, maximum insulin concentration (Cmax) and area under the curve (AUC) for insulin concentration time (AUC-Insulin0–360) with inhaled insulin were higher, and time to Cmax (tmax) shorter, in smokers than nonsmokers (Cmax 26.8 vs. 9.7 μU/ml; AUC-Insulin0–360 2,583 vs. 1,645 μU · ml−1 · min−1; tmax 20 vs. 53 min, respectively; all P < 0.05), whereas with subcutaneous insulin, systemic exposure was unchanged (AUC-Insulin0–360 2,324 vs. 2,269 μU · ml−1 · min−1; P = NS). After smoking cessation, AUC-Insulin0–360 decreased with inhaled insulin by up to 50% within 1 week and approached nonsmoker levels. Cmax decreased and tmax increased relative to baseline but were still not comparable with nonsmoker values. Smoking resumption completely reversed the effect of smoking cessation. Glucodynamics corroborated the observed findings in insulin pharmacokinetics.

CONCLUSIONS—Cessation and resumption of smoking greatly altered the pharmacokinetics of inhaled insulin. As rapid changes in systemic insulin exposure increase hypoglycemia risk, inhaled insulin should not be used in people with diabetes who choose to continue smoking. This is consistent with recommendations that people with diabetes refrain from smoking altogether.
Models for Predicting Type 1 Diabetes in Siblings of Affected Children
Authors: Mrena Samy , Virtanen Suvi M. , Laippala Pekka , Kulmala Petri , Hannila Marja-Leena , Åkerblom Hans K. , Knip Mikael ,   the Childhood Diabetes in Finland Study Group
Published: May 2006

OBJECTIVE—To generate predictive models for the assessment of risk of type 1 diabetes and age at diagnosis in siblings of children with newly diagnosed type 1 diabetes.

RESEARCH DESIGN AND METHODS—Cox regression analysis was used to assess the risk of progression to type 1 diabetes, and multiple regression analysis was used to estimate the age at disease presentation in 701 siblings of affected children. Sociodemographic, genetic, and immunological variables were included in the analyses. Subanalyses were performed in a group of 77 autoantibody-positive siblings with additional metabolic data.

RESULTS—A total of 47 siblings (6.7%) presented with type 1 diabetes during the 15-year observation period. Young age, an increasing number of detectable diabetes-associated autoantibodies at initial sampling and of affected first-degree relatives, and HLA DR–conferred disease susceptibility predicted progression to type 1 diabetes. In the subgroup of 77 autoantibody-positive siblings, young age, HLA DR–conferred susceptibility, an increasing number of autoantibodies, a reduced first-phase insulin response, and decreased insulin sensitivity in relation to first-phase insulin response were associated with increased risk of progression to type 1 diabetes. Age at diagnosis was predicted by age, insulinoma-associated protein 2 antibody levels, and number of autoantibodies at initial sampling (R2 = 0.76; P < 0.001). In the smaller cohort of autoantibody-positive subjects, first-phase insulin response and HLA DR–conferred susceptibility were additional predictors of age at diagnosis.

CONCLUSIONS—Information on autoantibody status and levels, HLA-conferred disease susceptibility, and insulin secretion and sensitivity seems to be useful in addition to age and family history of type 1 diabetes when assessing risk of progression to type 1 diabetes and time to diagnosis in siblings of children with newly diagnosed type 1 diabetes.
Correspondence Between the Adult Treatment Panel III Criteria for Metabolic Syndrome and Insulin Resistance
Authors: Sierra-Johnson Justo , Johnson Bruce D. , Allison Thomas G. , Bailey Kent R. , Schwartz Gary L. , Turner Stephen T.
Published: May 2006

OBJECTIVE—The aim of the present study was to assess the diagnostic accuracy of the Adult Treatment Panel III (ATP-III) definition of the metabolic syndrome in identifying insulin-resistant individuals and to explore alternative approaches to improve identification of insulin-resistant individuals among asymptomatic adults from the general population.

RESEARCH DESIGN AND METHODS—The sample consisted of 256 non-Hispanic white subjects without treated hypertension or diabetes, from the Rochester (Minnesota) Heart Family Study (123 men and 133 women; aged 20–60 years). Frequently sampled intravenous glucose tolerance tests were performed in all subjects. The reference standard for insulin resistance was determined by Bergman’s minimal model; insulin resistance was defined as an insulin sensitivity index <2 × 10 min−1 · μU−1 · ml−1. Component metabolic syndrome measures included blood pressure determined by sphygmomanometer; fasting serum triglycerides, HDL cholesterol, and glucose concentrations determined enzymatically; and waist circumference determined by tape measure.

RESULTS—By ATP-III criteria, the prevalence of metabolic syndrome was 15.6% (16.3% in men and 15.1% in women; P = 0.465). The presence of metabolic syndrome had low sensitivity to identify insulin resistance (45% in men and 39% in women; sex difference, P = 0.137) but high specificity (93% in men and 95% in women; sex difference, P = 0.345). Based on the area under the receiver operating characteristic curve (AUC) constructed by counting metabolic syndrome components as recommended by ATP-III, diagnostic accuracy was fair (AUC = 0.797 in men and 0.747 in women). When component metabolic syndrome measures were considered as quantitative traits rather than dichotomized, use of waist circumference alone, rather than counting metabolic syndrome components, improved diagnostic accuracy for insulin resistance (in men, AUC = 0.906, P = 0.001; in women, AUC = 0.822, P = 0.10).

CONCLUSIONS—Application of the ATP-III metabolic syndrome criteria provides good specificity but low sensitivity to screen asymptomatic white adults for insulin resistance. Measuring just waist circumference is simpler and may provide greater accuracy for identifying insulin resistance.
Cardiovascular Risk Factors and Disease Management in Type 2 Diabetic Patients With Diabetic Nephropathy
Authors: Sasso Ferdinando C. , De Nicola Luca , Carbonara Ornella , Nasti Rodolfo , Minutolo Roberto , Salvatore Teresa , Conte Giuseppe , Torella Roberto ,   for the NID-2 (Nephropathy in Diabetes-Type 2) Study Group
Published: May 2006

OBJECTIVE—The purpose of this study was to assess the prevalence of cardiorenal risk factors, their management in a routine clinical setting, and the actual achievement of international guideline targets in a large cohort of type 2 diabetic patients with diabetic nephropathy.

RESEARCH DESIGN AND METHODS—A multicentric cross-sectional study was performed in the Campania region in Italy to evaluate cardiorenal risk factors and their management in light of international guidelines. Overall, 28,550 diabetic patients were screened in the 21 participating centers; 847 (348 male and 449 female) patients with type 2 diabetes and a clinical diagnosis of diabetic nephropathy were recruited.

RESULTS—Of these subjects, 749 had microalbuminuria and 98 had macroalbuminuria. Targets for blood pressure, HbA1c, LDL cholesterol, HDL cholesterol, and triglycerides were reached in, respectively, 17.5, 32.3, 30.7, 47, and 55.2% of the patients. Chronic renal failure (glomerular filtration rate <60 ml/min) was revealed in 41% and anemia in 23.8% of the patients.

CONCLUSIONS—This is the first study to investigate a large cohort of type 2 diabetic patients with early and moderate diabetic nephropathy strictu sensu. Notably, impaired renal function can be often diagnosed in these patients even in the presence of microalbuminuria. Thus, clinical diagnosis of diabetic nephopathy allows us to identify a group of patients at very high cardiorenal risk, for whom care is really difficult. We suggest that a correct diagnosis of diabetic nephropathy should always be made and that sodium intake and anemia should be routinely evaluated in these patients.
Diabetes and Function in Different Cognitive Systems in Older Individuals Without Dementia
Authors: Arvanitakis Zoe , Wilson Robert Smith , Li Yan , Aggarwal Neelum Thanik , Bennett David Alan
Published: May 2006

OBJECTIVE—To examine the relation of type 2 diabetes to the level of function in five different cognitive systems in older individuals without dementia.

RESEARCH DESIGN AND METHODS—Participants were 882 older men and women without dementia participating in the Rush Memory and Aging Project, a longitudinal clinical-pathological study of aging and dementia. They underwent uniform evaluations, which included clinical classification of dementia, and detailed cognitive function testing from which previously established summary measures of episodic memory, semantic memory, working memory, perceptual speed, visuospatial ability, and global cognition were derived. Diabetes was identified by history and direct medication inspection.

RESULTS—Diabetes was present in 116 (13%) participants. In separate linear regression models controlling for age, sex, and education, diabetes was associated with lower levels of semantic memory (P < 0.001) and perceptual speed (P = 0.005), but not with episodic memory, working memory, or visuospatial ability or with a measure of global cognition. The associations of diabetes with cognition were reduced when controlling for several vascular variables, and the associations were substantially stronger in current smokers than in individuals who never smoked or formerly smoked.

CONCLUSIONS—These results suggest that type 2 diabetes is associated with cognitive impairment, especially in semantic memory and perceptual speed and that these effects may be modified by smoking status.
Long-Acting Injectable Progestin Contraception and Risk of Type 2 Diabetes in Latino Women With Prior Gestational Diabetes Mellitus
Authors: Xiang Anny H. , Kawakubo Miwa , Kjos Siri L. , Buchanan Thomas A.
Published: May 2006

OBJECTIVE—To investigate the impact of a long-acting injectable progestin, depo-medroxyprogesterone acetate (DMPA), compared with combination oral contraceptives (COCs) on the risk of diabetes in Latino women with prior gestational diabetes mellitus (GDM).

RESEARCH DESIGN AND METHODS—An observational cohort study of 526 Hispanic women with prior GDM who were not diabetic in their postpartum visit during January 1987 to October 1997 and who elected DMPA (n = 96) or COCs (n = 430) as initial contraception were followed for a maximum of 9.2 years with a median follow-up of ∼12 months. Oral glucose tolerance tests were performed and choice of contraception method was recorded at each visit as part of routine clinical care.

RESULTS—Annual diabetes incidence rates were 19% in the DMPA group and 12% in the COC group, with an unadjusted hazard ratio (HR) of 1.58 (95% CI 1.00–2.50; P = 0.05) for DMPA compared with COCs. Adjustment for baseline imbalances reduced the HR to 1.18 (0.67–2.28; P = 0.57). Additional adjustment for weight gain during follow-up, which was on average 1.8 kg higher in the DMPA group (P < 0.0001), reduced the HR to 1.07. DMPA interacted with baseline serum triglyceride levels and, separately, with breast-feeding to increase the diabetes risk.

CONCLUSIONS—DMPA use was associated with an increased risk of diabetes that appeared to be explained by three factors: 1) use in women with increased baseline diabetes risk, 2) weight gain during use, and 3) use with high baseline triglycerides and/or during breast-feeding.