Protection of Long-Term Treatment With Huang-Lian-Jie-Du-Tang on Vascular Endothelium in Rats With Type 2 Diabetes Mellitus

Background

Huang-Lian-Jie-Du-Tang (HLJDT) is the classical traditional Chinese recipe for heat clearance and detoxification and is used in diabetic patients in the clinical practice of traditional Chinese medicine.

Objective

The aim of this study was to evaluate the protective effects of long-term treatment with HLJDT on vascular endothelial function in rats with type 2 diabetes mellitus (T2DM).

Methods

The male T2DM model rats were induced by intraperitoneal injection of low-dose streptozotocin plus a high-fat and high-calorie laboratory diet. The T2DM animals were randomly divided into the T2DM model group, the low-dose HLJDT group (0.42 g/kg/d), and the high-dose HLJDT group (1.25 g/kg/d).

Results

Administration of HLJDT (0.42 or 1.25 g/kg/d) for 8 weeks decreased the levels of serum fasting blood glucose, malondialdehyde, and vascular tissue interleukin 6 but raised the level of serum superoxide dismutase compared with the T2DM model group in a dose-dependent manner. In addition, HLJDT treatment restored the impaired endothelial-dependent vascular relaxation in aortic preparations from the T2DM model group in a dose-dependent manner.

Conclusions

Early and long-term treatments with HLJDT could have anti-inflammatory, antioxidant properties and could protect vascular endothelium from the cardiovascular complications associated with T2DM.     

Progression of Vascular Calcification Is Increased With Statin Use in the Veterans Affairs Diabetes Trial (VADT)

OBJECTIVE

To determine the effect of statin use on progression of vascular calcification in type 2 diabetes (T2DM).

RESEARCH DESIGN AND METHODS

Progression of coronary artery calcification (CAC) and abdominal aortic artery calcification (AAC) was assessed according to the frequency of statin use in 197 participants with T2DM.

RESULTS

After adjustment for baseline CAC and other confounders, progression of CAC was significantly higher in more frequent statin users than in less frequent users (mean ± SE, 8.2 ± 0.5 mm³ vs. 4.2 ± 1.1 mm³; P < 0.01). AAC progression was in general not significantly increased with more frequent statin use; in a subgroup of participants initially not receiving statins, however, progression of both CAC and AAC was significantly increased in frequent statin users.

CONCLUSIONS

More frequent statin use is associated with accelerated CAC in T2DM patients with advanced atherosclerosis.The role of statins in prevention of cardiovascular disease (CVD) in type 2 diabetes (T2DM) is well established. Despite the wide use of statins, however, calcific atherosclerosis is accelerated in T2DM and is associated with increased risk of CVD morbidity and mortality in this population (1). The purpose of the current study was to determine the effect of statin use on progression of vascular calcification in T2DM participants with advanced atherosclerosis.     

Benefits of Liraglutide Treatment in Overweight and Obese Older Individuals With Prediabetes

OBJECTIVE

The aim was to evaluate the ability of liraglutide to augment weight loss and improve insulin resistance, cardiovascular disease (CVD) risk factors, and inflammation in a high-risk population for type 2 diabetes (T2DM) and CVD.

RESEARCH DESIGN AND METHODS

We randomized 68 older individuals (mean age, 58 ± 8 years) with overweight/obesity and prediabetes to this double-blind study of liraglutide 1.8 mg versus placebo for 14 weeks. All subjects were advised to decrease calorie intake by 500 kcal/day. Peripheral insulin resistance was quantified by measuring the steady-state plasma glucose (SSPG) concentration during the insulin suppression test. Traditional CVD risk factors and inflammatory markers also were assessed.

RESULTS

Eleven out of 35 individuals (31%) assigned to liraglutide discontinued the study compared with 6 out of 33 (18%) assigned to placebo (P = 0.26). Subjects who continued to use liraglutide (n = 24) lost twice as much weight as those using placebo (n = 27; 6.8 vs. 3.3 kg; P < 0.001). Liraglutide-treated subjects also had a significant improvement in SSPG concentration (−3.2 vs. 0.2 mmol/L; P < 0.001) and significantly (P ≤ 0.04) greater lowering of systolic blood pressure (−8.1 vs. −2.6 mmHg), fasting glucose (−0.5 vs. 0 mmol/L), and triglyceride (−0.4 vs. −0.1 mmol/L) concentration. Inflammatory markers did not differ between the two groups, but pulse increased after liraglutide treatment (6.4 vs. −0.9 bpm; P = 0.001).

CONCLUSIONS

The addition of liraglutide to calorie restriction significantly augmented weight loss and improved insulin resistance, systolic blood pressure, glucose, and triglyceride concentration in this population at high risk for development of T2DM and CVD.Approximately one-third of adults in the United States have prediabetes (1,2) and are at risk for type 2 diabetes (T2DM) and cardiovascular disease (CVD) (3). Weight loss has been demonstrated to prevent T2DM (4–7) and to improve CVD risk factors (5) in the prediabetes population. In the Diabetes Prevention Program study, a weight loss goal of 7% was associated with a significant reduction in T2DM incidence (4). However, with intensive guidance, only half of the individuals were able to attain this weight loss goal at 24 weeks, and 38% attained this goal at 3 years. With self-guided weight loss programs, the percentage who can achieve a 7% weight reduction may be <20% (8).Liraglutide, a glucagon-like peptide 1 (GLP-1) analog, is approved for the treatment of T2DM. In addition to improving glucose tolerance, GLP-1 action has been associated with weight loss in individuals with T2DM (9). Only a few studies have evaluated the effect of GLP-1 action in individuals without diabetes (10–12), and none has focused on individuals with prediabetes.The purpose of this study was to evaluate the effect of liraglutide treatment compared with matching placebo injections in older (mean age, 58 ± 8 years) overweight/obese individuals with prediabetes—those at highest risk for development of T2DM and CVD. Specifically, we assessed the ability of liraglutide treatment to augment weight loss and to improve insulin resistance, CVD risk factors, and inflammatory markers.     

Pharmacodynamic Effect of Cilostazol Plus Standard Clopidogrel Versus Double-Dose Clopidogrel in Patients With Type 2 Diabetes Undergoing Percutaneous Coronary Intervention

OBJECTIVE

To determine the effect of adding cilostazol (100 mg b.i.d.) to standard-dose clopidogrel (75 mg/d) (TRIPLE) compared with double-dose clopidogrel (150 mg/d) (DOUBLE) and the influence of the cytochrome P450 (CYP2C19*2/*3, CYP3A5*3)and ATP-binding cassette subfamily B1(ABCB1 C3435T) genetic polymorphisms in type 2 diabetes (T2DM) patients.

RESEARCH DESIGN AND METHODS

T2DM patients were treated with TRIPLE (n = 41) or DOUBLE (n = 39) after percutaneous coronary intervention. Conventional aggregometry and VerifyNow were performed at baseline and at 30 days. The primary end point was absolute change in 20-μM ADP-induced maximal platelet aggregation (ΔMPA₂₀) between baseline and switching values.

RESULTS

TRIPLE versus DOUBLE showed greater ΔMPA₂₀ (22.9 ± 11.6 vs.12.7 ± 15.5%; difference, 10.2% [95% CI 4.2–16.3]; P < 0.001). Carriage of one (β coefficient, −5.4%; P = 0.162) and two CYP2C19 loss-of-function allele(s) (−8.3%; P = 0.007) were associated with lower ΔMPA₂₀ in DOUBLE–treated patients, but not in TRIPLE-treated patients.

CONCLUSIONS

Among T2DM patients, adding cilostazol achieves greater platelet inhibition compared with clopidogrel (150 mg/d), which is not influenced by genetic polymorphisms.Patients with type 2 diabetes (T2DM) have greater morbidity and mortality from cardiovascular disease than patients without T2DM. Moreover, increased short- and long-term ischemic event occurrences have been observed in diabetes patients treated with percutaneous coronary intervention (PCI) (1). Dual-antiplatelet therapy with aspirin and a P2Y₁₂ inhibitor has been the mainstay to prevent ischemic events among T2DM patients undergoing PCI. However, the antiplatelet and clinical responses to clopidogrel in PCI-treated patients can be influenced by several single nucleotide polymorphisms of the gene encoding cytochrome P450 (CYP2C19*2/*3, CYP3A5*3) and the ATP-binding cassette gene B1 (ABCB1) (2,3).Cilostazol is a dual-inhibitor of phosphodiesterase type 3 (PDE3) and adenosine reuptake in endothelium, vascular smooth muscle cells, inflammatory cells, and platelets (4). These pleiotropic effects, in addition to platelet inhibition, may affect the occurrence of atherothrombosis in cilostazol-treated patients. The pharmacodynamic and clinical benefit of cilostazol is more prominent in high-risk settings, particularly in diabetes patients (4,5). Cilostazol maintains intraplatelet cyclic AMP levels, which are markedly abnormal in diabetes patients, making them more susceptible to cilostazol effects (5). However, cilostazol metabolism also shows the substantial interindividual variability via CYP3A5 and CYP2C19 polymorphisms (6).The current analysis evaluated the antiplatelet effect of adding cilostazol (TRIPLE) or double-dose clopidogrel (150 mg/d) (DOUBLE) compared with standard-dose clopidogrel in high-risk T2DM patients undergoing PCI. We also assessed the influence of single nucleotide polymorphisms on the effect of these regimens.     

Association Between Remission of Macroalbuminuria and Preservation of Renal Function in Patients With Type 2 Diabetes With Overt Proteinuria

OBJECTIVE

Studies on the rate of remission of macroalbuminuria in patients with type 2 diabetes mellitus (T2DM) and the effects of reduction in albuminuria on renal prognosis in a primary care setting are absolutely lacking.

RESEARCH DESIGN AND METHODS

A total of 211 T2DM patients with albuminuria ≥300 mg/g were enrolled in a prospective observational study (mean of 4.5 years). The incidence of patients with remission of macroalbuminuria at every 1-year study time point after starting intensified diabetes treatment and the factors associated with remission were evaluated. The association of reduction in albuminuria with renal events (doubling of serum creatinine and end-stage renal disease) was also investigated.

RESULTS

During the 5-year study period, remission to microalbuminuria occurred in 116 patients and the 5-year cumulative incidence was 58.3%. Notably, most cases (82.8%) obtained remission at the 1-year study time point. The remission rate increased with achieving therapeutic targets for blood pressure and blood glucose. Remission and reduction in albuminuria of ≥50% were associated with preservation of renal function. In particular, patients who obtained both remission and 50% reduction at the 1-year study time point exhibited a significantly reduced risk for renal events as compared with those with no remission and no reduction (adjusted hazard ratio 0.30 [95% CI 0.12–0.76]).

CONCLUSIONS

Remission of macroalbuminuria occurs frequently and is associated with the preservation of renal function in T2DM patients. The initial adequate diabetes treatment aimed at reducing albuminuria may lead to improved renal prognosis in the primary care setting.Diabetic nephropathy in patients with type 2 diabetes mellitus (T2DM) is a leading cause of end-stage renal disease (ESRD) all over the world (1). The typical progressive course of diabetic nephropathy is initially developing an increase in albuminuria (known as microalbuminuria), progressing to macroalbuminuria, and, thereafter, a rapid decline in renal function (1). A few decades ago, diabetic nephropathy was considered to be a progressive and irreversible chronic complication. Moreover, the progression of macroalbuminuria was considered the “point of no return.” Thus, the main therapeutic target for T2DM patients with macroalbuminuria was the prevention of the progression to ESRD. Recently, growing evidence has contradicted this point of no return concept. Several clinical studies have reported that intensive intervention including inhibition of the renin-angiotensin system could induce a reduction in macroalbuminuria and improve renal prognosis (2–7). Thus, reduction of macroalbuminuria could be considered an important therapeutic target to improve renal outcomes in diabetic patients. However, how often remission from macroalbuminuria to microalbuminuria or normoalbuminuria occurs and its effect on the deterioration of renal function of T2DM patients remain unclear. In particular, there is almost no evidence from a primary care setting. Actually, in the clinical practice, we often encounter patients with T2DM that has already been complicated by macroalbuminuria at the time when they first consulted the hospital because they were unaware that they were suffering from diabetes. Moreover, a considerable number of T2DM patients progress to advanced nephropathy because of long-standing poor diabetes control. These patients must be at high risk for the progression to ESRD. However, it remains unclear whether their renal prognosis can be improved by later intensified diabetes treatment in primary care practice.Thus, the aim of this study was to clarify the clinical characteristics of T2DM patients who showed a reduction in macroalbuminuria in the primary care practice and to estimate the rate of reduction in macroalbuminuria and its effect on renal function. In particular, we focused on T2DM patients with macroalbuminuria who had not been treated for diabetes or had not received adequate intensified diabetes treatment according to clinical recommendations before they first consulted the clinic.     

Hypercapnic acidosis in ARDS: A tolerated side effect or an important therapeutic modality?

Citation

Kregenow DA, Rubenfeld GD, Hudson LD, Swenson ER. Hypercapnic acidosis and mortality in acute lung injury. Crit Care Med 2006;34:1–7 [1].

Background

Evidence suggests that hypercapnic acidosis may be beneficial in patients with acute lung injury, though studies have not separated the effects of HA from the effects of changes in mechanical ventilation.

Methods

Objective

We tested the hypothesis that hypercapnic acidosis is associated with reduced mortality rate in patients with acute lung injury independent of changes in mechanical ventilation.

Design

Secondary analysis of randomized clinical trial data using hypothesis-driven multivariate logistic regression.

Setting

Randomized, multiple-center trial comparing 12 mL/kg to 6 mL/kg predicted body weight (PBW) tidal volumes previously published by the National Institutes of Health Acute Respiratory Distress Syndrome (ARDS) Network.

Subjects

861 acute lung injury patients enrolled in a randomized, multiple-center trial.

Intervention

None.

Measurements and main results

The adjusted odds ratio and 95% confidence intervals (CI) for 28-day mortality rate associated with hypercapnic acidosis defined as day 1 pH <7.35 and PaCO₂ >45 mm Hg were 0.14 (95% CI 0.03–0.70, p = .016) in the 12 mL/kg PBW tidal volume group and 1.18 (95% CI 0.59–2.35, p = .639) in the 6 mL/kg PBW tidal volume group. Other definitions of hypercapnic acidosis spanning a range of magnitudes suggest a dose-response association between hypercapnic acidosis and 28-day mortality in the 12 mL/kg PBW tidal volume group. None of our definitions of hypercapnic acidosis were associated with reduction in 28-day mortality in the 6 mL/kg PBW tidal volume group.

Conclusion

Hypercapnic acidosis was associated with reduced 28-day mortality in the 12 mL/kg PBW tidal volume group after controlling for co-morbidities and severity of lung injury. These results are consistent with a protective effect of hypercapnic acidosis against ventilator-associated lung injury that was not found when the further ongoing injury was reduced by 6 mL/kg PBW tidal volumes.     

Projections of Type 1 and Type 2 Diabetes Burden in the U.S. Population Aged <20 Years Through 2050: Dynamic modeling of incidence,mortality, and population growth

OBJECTIVE

To forecast the number of U.S. individuals aged <20 years with type 1 diabetes mellitus (T1DM) or type 2 diabetes mellitus (T2DM) through 2050, accounting for changing demography and diabetes incidence.

RESEARCH DESIGN AND METHODS

We used Markov modeling framework to generate yearly forecasts of the number of individuals in each of three states (diabetes, no diabetes, and death). We used 2001 prevalence and 2002 incidence of T1DM and T2DM from the SEARCH for Diabetes in Youth study and U.S. Census Bureau population demographic projections. Two scenarios were considered for T1DM and T2DM incidence: 1) constant incidence over time; 2) for T1DM yearly percentage increases of 3.5, 2.2, 1.8, and 2.1% by age-groups 0–4 years, 5–9 years, 10–14 years, and 15–19 years, respectively, and for T2DM a yearly 2.3% increase across all ages.

RESULTS

Under scenario 1, the projected number of youth with T1DM rises from 166,018 to 203,382 and with T2DM from 20,203 to 30,111, respectively, in 2010 and 2050. Under scenario 2, the number of youth with T1DM nearly triples from 179,388 in 2010 to 587,488 in 2050 (prevalence 2.13/1,000 and 5.20/1,000 [+144% increase]), with the greatest increase in youth of minority racial/ethnic groups. The number of youth with T2DM almost quadruples from 22,820 in 2010 to 84,131 in 2050; prevalence increases from 0.27/1,000 to 0.75/1,000 (+178% increase).

CONCLUSIONS

A linear increase in diabetes incidence could result in a substantial increase in the number of youth with T1DM and T2DM over the next 40 years, especially those of minority race/ethnicity.Diabetes is one of the most common and costly chronic pediatric diseases (1). The SEARCH for Diabetes in Youth study (SEARCH) estimated that in 2001 about 154,000 individuals in the U.S. aged <20 years were living with diabetes and that each year approximately 15,000 youth aged <20 years are being diagnosed with type 1 diabetes mellitus (T1DM) and 3,700 with type 2 diabetes mellitus (T2DM) (2,3). Assessing the future burden of diabetes in youth by diabetes type is crucial for implementing public health primary and secondary prevention programs and planning health care delivery services.A number of studies have estimated the burden of diagnosed diabetes through 2050 in the U.S (4,5). A limitation is that they were not able to separate the contribution of T1DM from T2DM to the projected diabetes burden. Although the majority of adults with diabetes have T2DM, the majority of youth with diabetes currently have T1DM. On the other hand, T2DM may be becoming more common in adolescents, especially among minority youth (2,3).There is substantial variation in the incidence of T1DM and T2DM across the major racial/ethnic groups in the U.S. The incidence of T1DM is highest among non-Hispanic whites (NHWs) and lowest in American Indians (3). In contrast, T2DM disproportionally affects individuals from all racial/ethnic minority groups (3). Therefore, changes in the race/ethnicity distribution of the U.S. population will substantially impact the absolute number of individuals living with T1DM or T2DM. This makes even more compelling the need for diabetes type–specific projections.To overcome the limitations of previous studies and provide contemporary estimates of the national type-specific burden of diabetes in youth, we constructed a system of dynamic equations that incorporate diabetes prevalence and incidence, as well as birth, migration, and mortality estimates. These equations model the future burden of diabetes in U.S. youth aged <20 years through 2050. In addition, we perform sensitivity analyses to assess the impact of increases in the incidence and/or changes in the risk of mortality separately for T1DM and T2DM.     

Angiopoietin-Like Protein 2 and Risk of Type 2 Diabetes in a General Japanese Population: The Hisayama Study

OBJECTIVE

To examine, for the first time, the association between a novel inflammatory cytokine, angiopoietin-like protein (ANGPTL) 2, and the development of type 2 diabetes (T2DM).

RESEARCH DESIGN AND METHODS

A total of 2,164 community-dwelling Japanese individuals aged 40 to 79 years without diabetes were followed up for 7 years. Serum ANGPTL2 levels were divided into quartile categories at baseline: <2.15, 2.16–2.71, 2.72–3.40, and ≥3.41 ng/mL. During follow-up, 221 participants developed T2DM.

RESULTS

In multivariate analyses, after adjusting for comprehensive risk factors and high-sensitivity C-reactive protein (hs-CRP) levels, the risk of developing T2DM was significantly higher in the highest ANGPTL2 quartile than in the lowest quartile (hazard ratio, 1.80; 95% CI, 1.14–2.85; P = 0.01).

CONCLUSIONS

Elevated serum ANGPTL2 levels were positively associated with the development of T2DM in a general population, independent of other risk factors including hs-CRP levels.Angiopoietin-like proteins (ANGPTLs), which are structurally similar to angiopoietins, are characterized by a coiled-coil domain in the N-terminus and a fibrinogen-like domain in the C-terminus. Seven ANGPTLs have been identified to date (1–3); one of them, ANGPTL2, has been shown to be expressed abundantly in adipose tissues and to be a key mediator linking obesity to adipose tissue inflammation and systemic insulin resistance in mice (4,5). In humans, ANGPTL2 is also closely related to adiposity and inflammation (4). However, the association of serum ANGPTL2 levels with the risk of developing type 2 diabetes (T2DM) has not been investigated to date. The objective of this study was to examine this issue in a cohort of the general Japanese population, taking into account a comprehensive range of confounders.     

Circulating Estrone Levels Are Associated Prospectively With Diabetes Risk in Men of the Framingham Heart Study

OBJECTIVE

In postmenopausal women and preclinical murine models, estrogen administration reduces diabetes risk; however, the relationship of estradiol and estrone to diabetes in men is poorly understood. We determined the relationship between circulating estradiol and estrone levels and diabetes risk in community-dwelling men of the Framingham Heart Study (FHS).

RESEARCH DESIGN AND METHODS

Cross-sectional relationships of estradiol and estrone levels with diabetes were assessed at examination 7 (1998–2001) in FHS generation 2 men (n = 1,458); prospective associations between hormone levels at examination 7 and incident diabetes were assessed 6.8 years later at examination 8. Type 2 diabetes mellitus was defined as fasting glucose >125 mg/dL, medication use, or both. Estradiol, estrone, and testosterone levels were measured with liquid chromatography–tandem mass spectrometry, and free estradiol and estrone were calculated.

RESULTS

In cross-sectional models, men with elevated estrone and estradiol had 40% and 62% increased likelihoods of existing diabetes per cross-sectional doubling of estrone and estradiol levels, respectively. Free estrone (cross-sectional odds ratio 1.28 [95% CI 1.02–1.62], P = 0.04) was associated with impaired fasting glucose at examination 7. There was an increase in risk of existing diabetes with increasing quartiles of total and free estrone and estradiol and an increase in risk of incident diabetes with increasing quartiles of estrone levels. In multivariate longitudinal analyses, a twofold increase in total or free estrone levels at examination 7 was associated with 77 and 93% increases, respectively, in odds of incident diabetes at examination 8.

CONCLUSIONS

Although both estradiol and estrone exhibit cross-sectional associations with diabetes in men, in longitudinal analyses estrone is a more sensitive marker of diabetes risk than is estradiol.Aging is associated with a decline in glucose tolerance, resulting in higher prevalence of type 2 diabetes mellitus (T2DM) and impaired fasting glucose (IFG) in older adults (1). Previous studies have suggested a role of endogenous sex hormones in the development of T2DM. Age-related decline in testosterone levels has been associated with an increased risk of T2DM in older men (2–5); however, the effects of low or high estrone and estradiol levels on T2DM risk in men are not clear.Epidemiologic studies (6,7) and randomized trials (8–10) in women have suggested that hormone therapy reduces the risk of T2DM in postmenopausal women. Furthermore, genetic disruption of estrogen receptor α (ERα) in mice is associated with adiposity and insulin resistance (11). Only a few cross-sectional studies in older men have addressed the relationships between estradiol and T2DM, and the data are conflicting; some studies have shown a positive correlation of estradiol levels with T2DM (12,13), whereas others have found no significant association (5,14). The relationship between estrone and T2DM has not been studied in men. Most studies used immunoassays for the measurement of estradiol levels, for which accuracy in the low range has been questioned (15–17).By using data from the Framingham Offspring Study, we determined whether circulating estrone and estradiol levels are associated with T2DM or IFG in community-dwelling older men. In longitudinal analyses restricted to nondiabetic men, we evaluated whether these hormones were predictive of incident T2DM during a follow-up period of approximately 7 years. This analysis is among the first population-based assessments of the association between estradiol and estrone—here measured with liquid chromatography–tandem mass spectrometry (LC-MS/MS), widely considered the reference method with the highest specificity and sensitivity—with T2DM risk in men (18).     

Type 2 Diabetes With Partial Lipodystrophy of the Limbs: A new lipodystrophy phenotype

OBJECTIVE

Lipodystrophies are categorized by the extent of fat loss (generalized vs. partial) and by inheritance (congenital vs. acquired). We examined whether a group of patients with partial lipodystrophy of the limbs (PLL), type 2 diabetes mellitus (T2DM), and an absence of a family history of lipodystrophy constitute a new clinical subtype.

RESEARCH DESIGN AND METHODS

Ten women with T2DM and PLL were identified in academic diabetes clinics and were matched by age, sex, BMI, ethnicity, and diabetes status with 10 women with control T2DM without lipodystrophy. All patients were characterized by clinical evaluation and hyperinsulinemic clamp.

RESULTS

Patients with T2DM and PLL exhibited symmetrical loss of subcutaneous fat in forearms, or forearms plus calves, and acanthosis nigricans. Maximally stimulated glucose disposal rates were markedly reduced by 56% in the T2DM with PLL group compared with the control T2DM patients, whether normalized by body weight or surface area. Most PLL patients exhibited little or no insulin-mediated glucose uptake after subtraction of non-insulin–mediated glucose uptake. The T2DM with PLL group also had greater elevations in hepatic transaminases and triglycerides and earlier onset of diabetes compared with control T2DM.

CONCLUSIONS

T2DM with PLL represents a previously unrecognized phenotype of lipodystrophy and of T2DM. These T2DM patients exhibit symmetrical lipodystrophy of the distal limbs, acanthosis nigricans, marked insulin resistance with little insulin-mediated glucose uptake, hypertriglyceridemia, and hepatic transaminase elevations, which are greater in severity than observed in patients with common T2DM.Lipodystrophies are a rare, heterogeneous group of disorders characterized by loss of subcutaneous adipose tissue together with metabolic abnormalities associated with insulin resistance. The conventional diagnostic scheme for lipodystrophy involves the extent of fat loss (general or partial) and inheritance (acquired or congenital) resulting in four categories of disease: congenital generalized lipodystrophy, acquired generalized lipodystrophy, familial partial lipodystrophy (FPL), and acquired partial lipodystrophy (APL) (1–5). In addition to selective loss of body fat, these diseases are also frequently, but not consistently, characterized by hypertriglyceridemia, steatohepatitis, type 2 diabetes mellitus (T2DM), and acanthosis nigricans. Congenital generalized lipodystrophy or Berardinelli-Seip syndrome is an autosomal recessive disorder, which can result from mutations in any one of several genes (AGPAT2, CAV1, BSCL2, PTRF), featuring generalized lack of adipose tissue exhibited at birth or within the first year of life.Patients with acquired generalized lipodystrophy or Lawrence syndrome develop progressive fat loss beginning in childhood or adolescence involving first the face and upper extremities and eventually the torso. FPL is an autosomal-dominant disorder with identifiable patterns of fat loss, including the Dunnigan variety, Kobberling variety, and mandibuloacral dysplasia. Some patients with the Dunnigan and mandibular dyscrasia phenotypes of FPL have been found to harbor gene mutations involving LMNA, PPARγ, PLIN-1, AKT2, or CIDEC. Patients with APL or the Barraquer-Simons syndrome present with cephalocaudal loss of subcutaneous fat in the face, neck, arms, and thorax, together with membranoproliferative glomerulonephritis, hypocomplementemia, and autoimmune disorders. Other forms of lipodystrophy can accompany distinct disease processes, such as progeria and the acquired partial lipodystrophy in patients with HIV/AIDS, but these are generally considered separately from the forms of congenital and acquired forms described above due to unique differences in presentation and pathophysiology.This conventional categorization of the lipodystrophies encompasses a heterogeneous group of rare disorders. Nevertheless, metabolic abnormalities observed in many of these patients are also observed in patients with metabolic syndrome and T2DM, including insulin resistance, increased circulating levels of free fatty acids (6,7) and triglycerides (8), ectopic deposition of lipid in skeletal myocytes (9,10) and hepatocytes (11), and dysregulated secretion of adipocytokines (7,12). Indeed, the loss of fat may constitute the primary cause of these metabolic abnormalities, as illustrated by adipose tissue ablation in genetically manipulated mouse models, including A-ZIP/F-1 fatless mice (13) and Agpat2-null lipodystrophic mice (14). By way of illustration, after transplantation of normal subcutaneous adipose tissue into A-ZIP/F-1 fatless mice, redistribution of ectopic lipid in muscle and liver to the transplanted fat occurred, with a significant increase in insulin-mediated glucose uptake (13). These findings suggest that the lipodystrophies and T2DM share a state of defective triglyceride storage in adipose tissue, accompanied by ectopic accumulation of lipid in muscle and liver, contributing to insulin resistance and other abnormalities associated with cardiometabolic disease (15). Also, adipose tissue in patients with metabolic syndrome and T2DM is characterized by infiltration of macrophages, fibrosis, and production of proinflammatory cytokines (16,17). Lipodystrophy can also be accompanied by inflammation, as demonstrated in aP2-nSREBP-1c lipodystrophic mice, which exhibit proinflammatory cytokine tumor necrosis factor-α and interleukin-6 elevations of 2-fold and 10-fold, respectively (18). These observations led to the question whether more subtle forms or patterns of lipodystrophy could exist in insulin-resistant patients with metabolic syndrome or T2DM and contribute to pathophysiology.In the current study, we describe patients with partial lipodystrophy of the limbs (PLL), which we believe represents a previously unrecognized phenotype of lipodystrophy occurring in patients with T2DM. The physical examination of these patients is characterized by symmetrical loss of subcutaneous fat in forearms and/or calves (or entire limbs) and acanthosis nigricans. They also manifest a profound degree of insulin resistance and marked elevations in hepatic transaminases (indicative of hepatic steatosis) and triglycerides, which are greater in severity than in patients with commonly occurring T2DM lacking PLL.     

Endothelial Progenitor Cells Are Related to Glycemic Control in Children With Type 1 Diabetes Over Time

OBJECTIVE

The risk of cardiovascular death before the age of 40 is 20-fold higher in patients with type 1 diabetes mellitus (T1DM). Endothelial progenitor cells (EPCs) predict cardiovascular morbidity and mortality in patients without diabetes. We hypothesized that EPCs are modified in children with T1DM and are related to characteristics of T1DM such as glycemic control.

RESEARCH DESIGN AND METHODS

Children (n = 190; 156 T1DM subjects and 34 control subjects) were included in an observational cohort study and matched for age and sex. EPCs were enumerated by flow cytometry at the beginning (cross-sectional) and 1 year later (longitudinal). To analyze changes of variables during the observation, Δ values were calculated.

RESULTS

EPCs were significantly reduced in T1DM children versus control subjects (609 ± 359 vs. 1,165 ± 484, P < 0.001). Multivariate regression modeling revealed that glycated hemoglobin A_1c (HbA_1c) was the strongest independent predictor of EPCs (β = −0.355, P < 0.001). Overall glycemic control at the beginning and end of study did not differ (7.8 ± 1.2 vs. 7.8 ± 1.2 relative %, P = NS), but we observed individual HbA_1c changes of −4.30/+3.10 relative %. The strongest EPC increase was observed in the patients with the most favorable HbA_1c lowering during the 1-year follow-up. Accordingly, the strongest EPC decrease was demonstrated in the patients with the strongest HbA_1c worsening during the time period.

CONCLUSIONS

This is the first prospective study demonstrating diminished EPCs in children with T1DM. The association of better glycemic control with an increase in EPC numbers within 1 year suggests that a reduction of the high cardiovascular disease burden might be mediated likewise.Over the last 30 years, a marked improvement in diabetic nephropathy, retinopathy, and neuropathy was observed in patients with type 1 diabetes mellitus (T1DM) (1–3). However, no difference for the incidence of cardiovascular disease (CVD) was observed in those patients (1–3). Thus, one can assume that late improvements in diabetes care do not reduce cardiovascular risk (1–3).Even more, despite dramatic improvement in CVD therapy, such as interventional therapy, statins, and clopidogrel, CVD mortality did not improve in T1DM over the last 10 years (1–3). In fact, the mortality of CVD before 40 years of age is 20-fold higher in patients with T1DM compared with age- and sex-adjusted healthy subjects. Between 30–40 years of age, CVD is already the first cause of death in those patients (4,5).The main contributor to the increased cardiovascular risk might be unsatisfactory glycemic control, which emerges from the very beginning of T1DM (childhood) (6–8). Other mechanisms speculated to be associated or involved independently might be endothelial dysfunction (9) and/or systemic vascular inflammation (10).Recent analysis of the Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) trial strengthened the suspicion that endothelial dysfunction and vascular inflammation might be involved in the increased susceptibility to vascular disease (11,12) in T1DM. However, the exact mechanisms linking those pathophysiological findings to manifest clinical disease are not understood.A possible link might be vascular progenitor cells, which are involved in vascular hemostasis and counteract the aberrances of vascular inflammation. Werner and Nickenig (13) argued that endothelial progenitor cells (EPCs) are the common feature of atherosclerosis, from its beginning as endothelial dysfunction to its result as end-stage ischemic heart disease. EPCs measured by colony-forming assays were demonstrated to correlate with the Framingham Risk Score and endothelial function (14), and furthermore, when measured by flow cytometry, EPCs were found to be associated with cardiovascular outcome (15).In accordance with the theory of endothelial continuum of EPCs (13), EPCs were demonstrated to be reduced in adults with T1DM in a pilot study (16). We have added that EPCs are directly related to stages of retinopathy in adults with T1DM (17) and also T2DM (18). Recently, three very interesting cross-sectional pilot-like studies have been reported. First, Sibal et al. (19) showed an association of EPCs and premature atherosclerosis in young adults with T1DM by investigating flow-mediated dilatation in those patients. However, they did not obtain a significant difference for CD34⁺/CD309⁺ cells between T1DM and control subjects. Second, DiMeglio et al. (20) demonstrated a reduction of EPCs already in young adults (mean age 20.3 ± 1.4 years) with T1DM compared with those without. Third, Palombo et al. (21) confirmed a reduction of EPCs in 16 young adults with T1DM and added an association of EPCs and intima media thickness. All three studies failed to identify any association of EPCs with characteristics of T1DM, such as glycemic control or total insulin dosage.It is tempting to speculate that diminished EPCs could be one of the pathophysiological mechanisms linking the elevated CVD risk to young patients with T1DM. We assumed that elevated inflammation and/or impaired glucose control might be associated cross-sectionally and longitudinally with diminished levels of EPCs, thereby leading to the increased risk for CVD at such a young age.     

Association Between BMI Measured Within a Year After Diagnosis of Type 2 Diabetes and Mortality

OBJECTIVE

To describe the association of BMI with mortality in patients diagnosed with type 2 diabetes.

RESEARCH DESIGN AND METHODS

Using records of 106,640 patients in Scotland, we investigated the association between BMI recorded around the diagnosis of type 2 diabetes mellitus (T2DM) and mortality using Cox proportional hazards regression adjusted for age and smoking status, with BMI 25 to <30 kg/m² as a referent group. Deaths within 2 years of BMI determination were excluded. Mean follow-up to death or the end of 2007 was 4.7 years.

RESULTS

A total of 9,631 deaths occurred between 2001 and 2007. Compared with the reference group, mortality risk was higher in patients with BMI 20 to <25 kg/m² (hazard ratio 1.22 [95% CI 1.13–1.32] in men, 1.32 [1.22–1.44] in women) and patients with BMI ≥35 kg/m² (for example, 1.70 [1.24–2.34] in men and 1.81 [1.46–2.24] in women for BMI 45 to <50 kg/m²). Vascular mortality was higher for each 5-kg/m² increase in BMI >30 kg/m² by 24% (15–35%) in men and 23% (14–32%) in women, but was lower below this threshold. The results were similar after further adjustment for HbA_1c, year of diagnosis, lipids, blood pressure, and socioeconomic status.

CONCLUSIONS

Patients categorized as normal weight or obese with T2DM within a year of diagnosis of T2DM exhibit variably higher mortality outcomes compared with the overweight group, confirming a U-shaped association of BMI with mortality. Whether weight loss interventions reduce mortality in all T2DM patients requires study.Compared with normal weight, obesity is associated with increased all-cause mortality in the general population, as well as increased cardiovascular and cancer mortality (excluding smoking-related cancers) (1–3). However, the findings in patients with type 2 diabetes mellitus (T2DM) have been variable, with some studies reporting an increase in all-cause mortality with increasing body mass (4–6), but many studies finding no relationship (7–10) or a decrease in mortality with higher BMI (11). This may be due to limited power, as those studies describing no association all included <1,000 individuals (7–10) and limitations of the analytical approaches. In the general population, the relationship between BMI and mortality is U-shaped (1) with excess mortality seen at BMI <22.5 kg/m² compared with 22.5–25 kg/m². Consequently, if the lowest BMI group is used as the reference group, excess mortality in the obese range compared with the BMI group with the lowest mortality (i.e., the low normal range) is not always apparent. There is also the potential for reverse causality as a consequence of another medical condition causing both weight loss and death and confounding by smoking, which can lead to smokers having a lower BMI than nonsmokers yet a high risk of smoking-related disease. Higher BMI is associated with increased risk of coronary heart disease and cardiovascular mortality among people with T2DM (6,12), in keeping with results from the general population. As these studies (4–11) represent cross-sections of populations with established T2DM, there is the potential that diabetes control, treatment, and duration will have influenced BMI. These complexities and conflicting results have in some way deflected attention from the potential importance of weight reduction in patients with diabetes.The aim of the present work, based on data from the Scottish Care Information Diabetes Collaboration (SCI-DC) database, was to examine the relationship between BMI within a year after diagnosis of T2DM and all-cause, cardiovascular, cancer, and respiratory mortality in the medium term. The use of a large contemporary database has allowed closer examination of any graded association between obesity and mortality than among smaller studies. The availability of BMI recorded within a year after diagnosis limits the potential effects that diabetes treatment and glycemic control can have on BMI.     

Brain Atrophy in Type 2 Diabetes: Regional distribution and influence on cognition

OBJECTIVE

Type 2 diabetes (T2DM) is associated with brain atrophy and cerebrovascular disease. We aimed to define the regional distribution of brain atrophy in T2DM and to examine whether atrophy or cerebrovascular lesions are feasible links between T2DM and cognitive function.

RESEARCH DESIGN AND METHODS

This cross-sectional study used magnetic resonance imaging (MRI) scans and cognitive tests in 350 participants with T2DM and 363 participants without T2DM. With voxel-based morphometry, we studied the regional distribution of atrophy in T2DM. We measured cerebrovascular lesions (infarcts, microbleeds, and white matter hyperintensity [WMH] volume) and atrophy (gray matter, white matter, and hippocampal volumes) while blinded to T2DM status. With use of multivariable regression, we examined for mediation or effect modification of the association between T2DM and cognitive measures by MRI measures.

RESULTS

T2DM was associated with more cerebral infarcts and lower total gray, white, and hippocampal volumes (all P < 0.05) but not with microbleeds or WMH. T2DM-related gray matter loss was distributed mainly in medial temporal, anterior cingulate, and medial frontal lobes, and white matter loss was distributed in frontal and temporal regions. T2DM was associated with poorer visuospatial construction, planning, visual memory, and speed (P ≤ 0.05) independent of age, sex, education, and vascular risk factors. The strength of these associations was attenuated by almost one-half when adjusted for hippocampal and total gray volumes but was unchanged by adjustment for cerebrovascular lesions or white matter volume.

CONCLUSIONS

Cortical atrophy in T2DM resembles patterns seen in preclinical Alzheimer disease. Neurodegeneration rather than cerebrovascular lesions may play a key role in T2DM-related cognitive impairment.Type 2 diabetes (T2DM) is associated with an increased risk of incident cognitive impairment, dementia, and Alzheimer disease as a possible result of cerebrovascular and/or neurodegenerative disease (1–3). T2DM is associated with brain infarcts (4,5) on magnetic resonance imaging (MRI) and less consistently with cerebral white matter hyperintensities (WMHs) (6,7) and cerebral microbleeds (8,9). Lower hippocampal volume (10–12) and total brain volume (13), which are features of Alzheimer disease, are also more likely to occur in T2DM. However, few studies have clarified the regional distribution of brain atrophy attributable to T2DM (14–16). These studies were small, and only one compared people with and without T2DM, with the results suggesting that temporal lobe gray matter may be affected in T2DM (15). Understanding the pattern of brain atrophy in T2DM may provide clues toward the underlying neurodegenerative process. For example, gray matter atrophy occurs early in the temporal, parietal, and limbic cortices before spreading to involve frontal and occipital regions in Alzheimer disease (17). Moreover, although some studies demonstrated associations of T2DM with brain atrophy or cerebrovascular disease, no data describe how MRI measures of atrophy and cerebrovascular disease mediate the difference in cognitive function between those with and without T2DM. Manschot et al. (18) found an association between T2DM and more deep white matter lesions, cortical and subcortical atrophy, and infarcts as well as impaired cognitive performance. In subgroup analysis of only those with T2DM, they found that cognitive performance was inversely associated with deep white matter lesion volume, atrophy, and infarcts. In the current study, we examined the distribution of brain atrophy in older people with T2DM, predicting that MRI measures of brain atrophy and cerebrovascular disease would mediate or modify the association between T2DM and cognitive function.     

A Randomized Controlled Trial Comparing Motivational Interviewing in Education to Structured Diabetes Education in Teens With Type 1 Diabetes

OBJECTIVE

To compare motivational interviewing–based education (MI) and structured diabetes education (SDE) for improving A1C and psychosocial measures in adolescents with type 1 diabetes.

RESEARCH DESIGN AND METHODS

This study was a 9-month randomized controlled trial comparing MI (n = 21) to SDE (n = 23). Interventions were at baseline (T0) and 3 months (T1), with A1C and psychosocial measures obtained at 6 months (T2) and 9 months (T3).

RESULTS

Over the 6 months of follow-up, the SDE group had lower adjusted mean A1C value (least squares mean 10.31, SE 0.32) than the MI group (least squares mean 11.35, SE 0.34) (P = 0.03, d = −0.66). There were no differences on any of the psychosocial measures.

CONCLUSIONS

SDE is effective at improving metabolic control in adolescents with type 1 diabetes. Diabetes educators were proficient in learning MI.Adolescents with poorly controlled type 1 diabetes represent a challenge. They report adequate knowledge of diabetes, yet have poor compliance with self-care activities (1). They are difficult to engage and often demonstrate poor self-awareness regarding the need for change (2).     

Knee Osteoarthritis in Type 2 Diabetes Mellitus: Does Insulin Therapy Retard Osteophyte Formation?

Objective

The aim of this study was to investigate whether or not radiographic changes observed in knee osteoarthritis (OA) in type 2 diabetes mellitus (T2DM) patients on insulin therapy differed from those not on insulin.

Material and Methods

A cross-sectional study was performed in 311 subjects: 211 T2DM patients and 100 without diabetes (controls) in Mubarak Hospital, Kuwait. Patients were categorized into 3 groups: T2DM patients not on insulin (G1, n = 99), T2DM patients on insulin (G2, n = 112) and a nondiabetic control group (G3, n = 100). Plain X-ray of both knees was used to assess the changes of knee OA and graded using the Kellegren-Lawrence scale (0-4) and the Osteoarthritis Research Society International Atlas grading scale (0-3). A total of 622 knee X-rays were evaluated. SPSS version 21.0 was used for data analysis.

Results

A highly significant association (p < 0.0001) was observed for joint space narrowing (JSN) as well as for osteophyte formation between the three groups. Comparing G2 and G3, a highly significant association (p < 0.0001) was retained for JSN [201 (89.7%) vs. 199 (99.5%)] and for osteophyte formation [26 (11.7%) vs. 72 (36.0%)]. Comparing G1 and G2, significantly less osteophyte formation was noted in G2 patients compared to G1 patients [26 (11.7%) vs. 39 (19.7%), p = 0.02]. Multivariate logistic regression analysis showed that the G2 group had less chance of osteophyte formation than either the G1 group or G3 control group (OR = 0.294, p = 0.008 and OR = 0.098, p < 0.001, respectively).

Conclusion

Our findings show that T2DM patients with OA knees on insulin therapy have less radiographic osteophytes compared to T2DM patients not on insulin.Key Words: Osteoarthritis, Diabetes mellitus, Insulin, Kuwait     

Islet Transplantation Stabilizes Hemostatic Abnormalities and Cerebral Metabolism in Individuals With Type 1 Diabetes

OBJECTIVE

Islets after kidney transplantation have been shown to positively affect the quality of life of individuals with type 1 diabetes (T1D) by reducing the burden of diabetes complications, but fewer data are available for islet transplantation alone (ITA). The aim of this study was to assess whether ITA has a positive impact on hemostatic and cerebral abnormalities in individuals with T1D.

RESEARCH DESIGN AND METHODS

Prothrombotic factors, platelet function/ultrastructure, and cerebral morphology, metabolism, and function have been investigated over a 15-month follow-up period using ELISA/electron microscopy and magnetic resonance imaging, nuclear magnetic resonance spectroscopy, and neuropsychological evaluation (Profile of Mood States test and paced auditory serial addition test) in 22 individuals with T1D who underwent ITA (n = 12) or remained on the waiting list (n = 10). Patients were homogeneous with regard to metabolic criteria, hemostatic parameters, and cerebral morphology/metabolism/function at the time of enrollment on the waiting list.

RESULTS

At the 15-month follow-up, the group undergoing ITA, but not individuals with T1D who remained on the waiting list, showed 1) improved glucose metabolism; 2) near-normal platelet activation and prothrombotic factor levels; 3) near-normal cerebral metabolism and function; and 4) a near-normal neuropsychological test.

CONCLUSIONS

ITA, despite immunosuppressive therapy, is associated with a near-normalization of hemostatic and cerebral abnormalities.     

Costimulation Modulation With Abatacept in Patients With Recent-Onset Type 1 Diabetes: Follow-up 1 Year After Cessation of Treatment

OBJECTIVE

We previously reported that 2 years of costimulation modulation with abatacept slowed decline of β-cell function in recent-onset type 1 diabetes (T1D). Subsequently, abatacept was discontinued and subjects were followed to determine whether there was persistence of effect.

RESEARCH DESIGN AND METHODS

Of 112 subjects (ages 6–36 years) with T1D, 77 received abatacept and 35 received placebo infusions intravenously for 27 infusions over 2 years. The primary outcome—baseline-adjusted geometric mean 2-h area under the curve (AUC) serum C-peptide during a mixed-meal tolerance test (MMTT) at 2 years—showed higher C-peptide with abatacept versus placebo. Subjects were followed an additional year, off treatment, with MMTTs performed at 30 and 36 months.

RESULTS

C-peptide AUC means, adjusted for age and baseline C-peptide, at 36 months were 0.217 nmol/L (95% CI 0.168–0.268) and 0.141 nmol/L (95% CI 0.071–0.215) for abatacept and placebo groups, respectively (P = 0.046). The C-peptide decline from baseline remained parallel with an estimated 9.5 months’ delay with abatacept. Moreover, HbA_1c levels remained lower in the abatacept group than in the placebo group. The slightly lower (nonsignificant) mean total insulin dose among the abatacept group reported at 2 years was the same as the placebo group by 3 years.

CONCLUSIONS

Costimulation modulation with abatacept slowed decline of β-cell function and improved HbA_1c in recent-onset T1D. The beneficial effect was sustained for at least 1 year after cessation of abatacept infusions or 3 years from T1D diagnosis.     

Erythropoietin Ameliorates Oxidative Stress and Tissue Injury following Renal Ischemia/Reperfusion in Rat Kidney and Lung

Objective

To study the effect of erythropoietin (EPO) treatment on renal and lung injury following renal ischemia/reperfusion (I/R).

Materials and Methods

Thirty male Wistar rats were assigned to three groups of 10 rats each. The first group was sham-operated, the second was subjected to renal I/R (30 min of ischemia followed by 24 h of reperfusion). The third group was subjected to renal I/R and treated with EPO in two doses: the first dose 1 h prior to ischemia (1,000 U/kg) and the second dose 6 h after ischemia (1,000 U/kg).

Results

The renal and lung tissue injury index, tissue serum blood urea nitrogen and creatinine (Cr) were higher in the renal I/R group compared to the renal I/R + EPO group; the difference was statistically significant (p < 0.05). Kidney and lung tissue glutathione peroxidase and superoxide dismutase levels were higher in the renal I/R + EPO group than the renal I/R group; the difference was also statistically significant (p < 0.05).

Conclusion

The data showed that EPO pretreatment could be effective in reducing renal and lung injury following renal I/R and could improve the cellular antioxidant defense system. Hence EPO pretreatment may be effective for attenuating renal and lung injury after renal I/R-induced injury during surgical procedures, hypotension, renal transplantation and other conditions inducing renal I/R.Key Words: Erythropoietin, Ischemia/reperfusion, Kidney, Lung