This study sought to determine the frequency of aspirin resistance in an ambulatory population of patients with type 1 diabetes mellitus (T1D) or type 2 diabetes mellitus (T2D). Platelet aggregation ...was assessed during the routine clinical evaluation of 203 ambulatory patients with diabetes (T1D, n = 92; T2D, n = 111) who were recommended aspirin for primary or secondary cardiovascular protection. Consecutively received laboratory samples were evaluated using the Ultegra Rapid Platelet Function Assay-ASA. Resistance to aspirin was detected in 18.7% of diabetic aspirin users, with similar rates in T1D (21.7%, p = 0.5) and T2D (16.2%, p = 0.6). Aspirin resistance was not related to age, glycohemoglobin, total cholesterol, or a history of cardiovascular disease. Female gender was a strong independent predictor of aspirin resistance in patients with T1D (p = 0.001). Platelet aggregation was correlated with high-density lipoprotein (HDL) cholesterol in the entire cohort (r = 0.21, p = 0.005) and in patients with T1D (r = 0.32, p = 0.04) or T2D (r = 0.21, p = 0.04), such that patients with low HDL cholesterol levels were more likely to be aspirin sensitive. The results suggest that aspirin can inhibit platelet aggregation in most patients with diabetes and is a reasonable first-line antiplatelet agent in patients with diabetes.
In type 2 diabetes, impaired insulin signaling leads to hyperglycemia and other metabolic abnormalities. To study a new class of antidiabetic agents, we compared two small, nonpeptide molecules that ...activate insulin receptor (IR) beta-subunit tyrosine kinase activity: Merck L7, a direct IR agonist, and Telik's TLK16998, an IR sensitizer. In rat hepatoma cells (HTCs) that overexpress the IR (HTC-IR), IR autophosphorylation was directly activated by L7 in the absence of insulin. TLK16998 did not directly activate IR autophosphorylation, but it enhanced IR autophosphorylation in the presence of insulin. Tyrosine phosphorylation of an endogenous 185-kDa IR substrate was also significantly enhanced by both Merck L7 alone and TLK16998 plus insulin. Adding TLK16998 to L7 produced synergistic effects, further indicating that these two compounds act on the IR through separate mechanisms. We next studied HTC-IR(Delta485-599) cells, which overexpress a mutant IR with a deletion in the alpha-subunit connecting domain that does not undergo autophosphorylation in response to insulin binding. L7 was able to directly activate autophosphorylation of the deletion mutant IR in these cells, whereas TLK16998 had no effect. Compounds were then tested in three other cell models of impaired IR function. Both TLK16998 and Merck L7 improved IR autophosphorylation in cells with diminished IR signaling due to either treatment with tumor necrosis factor-alpha or overexpression of membrane glycoprotein PC-1. However, in TPA (tetradecanoylphorbol acetate)-treated cells, TLK16998 but not Merck L7 was able to significantly reverse the impaired insulin-stimulated IR autophosphorylation. In summary, these two classes of IR activators selectively increased IR function in a variety of insulin-resistant cell lines.
Wound healing is impaired in diabetes, resulting in significant morbidity and mortality. Neutrophils are the main leukocytes involved in the early phase of healing. As part of their anti-microbial ...defense, neutrophils form extracellular traps (NETs) by releasing decondensed chromatin lined with cytotoxic proteins. NETs, however, can also induce tissue damage. Here we show that neutrophils isolated from type 1 and type 2 diabetic humans and mice were primed to produce NETs (a process termed NETosis). Expression of peptidylarginine deiminase 4 (PAD4, encoded by Padi4 in mice), an enzyme important in chromatin decondensation, was elevated in neutrophils from individuals with diabetes. When subjected to excisional skin wounds, wild-type (WT) mice produced large quantities of NETs in wounds, but this was not observed in Padi4(-/-) mice. In diabetic mice, higher levels of citrullinated histone H3 (H3Cit, a NET marker) were found in their wounds than in normoglycemic mice and healing was delayed. Wound healing was accelerated in Padi4(-/-) mice as compared to WT mice, and it was not compromised by diabetes. DNase 1, which disrupts NETs, accelerated wound healing in diabetic and normoglycemic WT mice. Thus, NETs impair wound healing, particularly in diabetes, in which neutrophils are more susceptible to NETosis. Inhibiting NETosis or cleaving NETs may improve wound healing and reduce NET-driven chronic inflammation in diabetes.
To compare the effect of Roux-en-Y gastric bypass (RYGB) surgery versus intensive medical diabetes and weight management (IMWM) on clinical and patient-reported outcomes in obese patients with type 2 ...diabetes.
We prospectively randomized 38 obese patients with type 2 diabetes (15 male and 23 female, with mean ± SD weight 104 ± 16 kg, BMI 36.3 ± 3.4 kg/m
, age 52 ± 6 years, and HbA
8.5 ± 1.3% 69 ± 14 mmol/mol) to laparoscopic RYGB (
= 19) or IMWM (
= 19). Changes in weight, HbA
, cardiovascular risk factors (UKPDS risk engine), and self-reported health status (the 36-Item Short-Form SF-36 survey, Impact of Weight on Quality of Life IWQOL instrument, and Problem Areas in Diabetes Survey PAID) were assessed.
After 3 years, the RYGB group had greater weight loss (mean -24.9 kg 95% CI -29.5, -20.4 vs. -5.2 -10.3, -0.2;
< 0.001) and lowering of HbA
(-1.79% -2.38, -1.20 vs. -0.39% -1.06, 0.28 -19.6 mmol/mol {95% CI -26.0, -13.1} vs. -4.3 {-11.6, 3.1};
< 0.001) compared with the IMWM group. Changes in cardiometabolic risk for coronary heart disease and stroke were all more favorable in RYGB versus IMWM (
< 0.05 to
< 0.01). IWQOL improved more after RYGB (
< 0.001), primarily due to subscales of physical function, self-esteem, and work performance. SF-36 and PAID scores improved in both groups, with no difference between treatments. A structural equation model demonstrated that improvement in overall quality of life was more strongly associated with weight loss than with improved HbA
and was manifest by greater improvements in IWQOL than with either SF-36 or PAID.
Three years after randomization to RYGB versus IMWM, surgery produced greater weight loss, lower HbA
, reduced cardiovascular risk, and improvements in obesity-related quality of life in obese patients with type 2 diabetes.
In normoglycemic offspring of two type 2 diabetic parents, low insulin sensitivity (SI) and low insulin-independent glucose effectiveness (SG) predict the development of diabetes one to two decades ...later. To determine whether low SI, low SG, or low acute insulin response to glucose are predictive of diabetes in a population at low genetic risk for disease, 181 normoglycemic individuals with no family history of diabetes (FH-) and 150 normoglycemic offspring of two type 2 diabetic parents (FH+) underwent i.v. glucose tolerance testing (IVGTT) between the years 1964-82. During$25\pm6$years follow-up, comprising 2,758 person years, the FH- cohort$(54\pm9\>years)$had an age-adjusted incidence rate of type 2 diabetes of 1.8 per 1,000 person years, similar to that in other population-based studies, but significantly lower than 16.7 for the FH+ cohort. Even when the two study populations were subdivided by initial values of SIand SGderived from IVGTT's performed at study entry, there was a 10- to 20-fold difference in age-adjusted incidence rates for diabetes in the FH- vs. FH+ individuals with low SIand low SG. The acute insulin response to glucose was not predictive of the development of diabetes when considered independently or when assessed as a function of SI, i.e., the glucose disposition index. These data demonstrate that low glucose disposal rates are robustly associated with the development of diabetes in the FH+ individuals, but insulin resistance per se is not sufficient for the development of diabetes in individuals without family history of disease and strongly suggest a familial factor, not detectable in our current measures of the dynamic responses of glucose or insulin to an IVGTT is an important risk factor for type 2 diabetes. Low SIand low SG, both measures of glucose disposal, interact with this putative familial factor to result in a high risk of type 2 diabetes in the FH+ individuals, but not in the FH- individuals.
OBJECTIVE:--Sedentary lifestyle and a western diet promote subacute-chronic inflammation, obesity, and subsequently dysglycemia. The aim of the current study was to evaluate the efficacy of the ...anti-inflammatory drug salsalate to improve glycemia by reducing systemic inflammation in obese adults at risk for the development of type 2 diabetes. RESEARCH DESIGN AND METHODS--In a double-masked, placebo controlled trial, we evaluated 20 obese nondiabetic adults at baseline and after 1 month of salsalate or placebo. RESULTS:--Compared with placebo, salsalate reduced fasting glucose 13% (P < 0.002), glycemic response after an oral glucose challenge 20% (P < 0.004), and glycated albumin 17% (P < 0.0003). Although insulin levels were unchanged, fasting and oral glucose tolerance test C-peptide levels decreased in the salsalate-treated subjects compared with placebo (P < 0.03), consistent with improved insulin sensitivity and a known effect of salicylates to inhibit insulin clearance. Adiponectin increased 57% after salsalate compared with placebo (P < 0.003). Additionally, within the group of salsalate-treated subjects, circulating levels of C-reactive protein were reduced by 34% (P < 0.05). CONCLUSIONS:--This proof-of-principle study demonstrates that salsalate reduces glycemia and may improve inflammatory cardiovascular risk indexes in overweight individuals. These data support the hypothesis that subacute-chronic inflammation contributes to the pathogenesis of obesity-related dysglycemia and that targeting inflammation may provide a therapeutic route for diabetes prevention.
In breast and certain other cancers, receptor tyrosine kinases, including the insulin-like growth factor I receptor (IGF-IR), play an important role in promoting the oncogenic process. The IGF-IR is ...therefore an important target for developing new anti-breast cancer therapies. An initial screening of a chemical library against the IGF-IR in breast cancer cells identified a diaryl urea compound as a potent inhibitor of IGF-IR signaling. This class of compounds has not been studied as inhibitors of the IGF-IR. We studied the effectiveness of one diaryl urea compound, PQ401, at antagonizing IGF-IR signaling and inhibiting breast cancer cell growth in culture and in vivo. PQ401 inhibited autophosphorylation of the IGF-IR in cultured human MCF-7 cells with an IC50 of 12 micromol/L and autophosphorylation of the isolated kinase domain of the IGF-IR with an IC50 <1 micromol/L. In addition, PQ401 inhibited the growth of cultured breast cancer cells in serum at 10 micromol/L. PQ401 was even more effective at inhibiting IGF-I-stimulated growth of MCF-7 cells (IC50, 6 micromol/L). Treatment of MCF-7 cells with PQ401 was associated with a decrease in IGF-I-mediated signaling through the Akt antiapoptotic pathway. Twenty-four hours of treatment with 15 micromol/L PQ401 induced caspase-mediated apoptosis. In vivo, treatment with PQ401 (i.p. injection thrice a week) reduced the growth rate of MCNeuA cells implanted into mice. These studies indicate that diaryl urea compounds are potential new agents to test in the treatment of breast and other IGF-I-sensitive cancers.
Obesity results from an imbalance between energy intake and expenditure. In rodents and newborn humans, brown adipose tissue helps regulate energy expenditure by thermogenesis mediated by the ...expression of uncoupling protein 1 (UCP1), but brown adipose tissue has been considered to have no physiologic relevance in adult humans.
We analyzed 3640 consecutive (18)F-fluorodeoxyglucose ((18)F-FDG) positron-emission tomographic and computed tomographic (PET-CT) scans performed for various diagnostic reasons in 1972 patients for the presence of substantial depots of putative brown adipose tissue. Such depots were defined as collections of tissue that were more than 4 mm in diameter, had the density of adipose tissue according to CT, and had maximal standardized uptake values of (18)F-FDG of at least 2.0 g per milliliter, indicating high metabolic activity. Clinical indexes were recorded and compared with those of date-matched controls. Immunostaining for UCP1 was performed on biopsy specimens from the neck and supraclavicular regions in patients undergoing surgery.
Substantial depots of brown adipose tissue were identified by PET-CT in a region extending from the anterior neck to the thorax. Tissue from this region had UCP1-immunopositive, multilocular adipocytes indicating brown adipose tissue. Positive scans were seen in 76 of 1013 women (7.5%) and 30 of 959 men (3.1%), corresponding to a female:male ratio greater than 2:1 (P<0.001). Women also had a greater mass of brown adipose tissue and higher (18)F-FDG uptake activity. The probability of the detection of brown adipose tissue was inversely correlated with years of age (P<0.001), outdoor temperature at the time of the scan (P=0.02), beta-blocker use (P<0.001), and among older patients, body-mass index (P=0.007).
Defined regions of functionally active brown adipose tissue are present in adult humans, are more frequent in women than in men, and may be quantified noninvasively with the use of (18)F-FDG PET-CT. Most important, the amount of brown adipose tissue is inversely correlated with body-mass index, especially in older people, suggesting a potential role of brown adipose tissue in adult human metabolism.
Obesity is accompanied by chronic, low-grade inflammation of adipose tissue, which promotes insulin resistance and type-2 diabetes. These findings raise the question of how fat inflammation can ...escape the powerful armamentarium of cells and molecules normally responsible for guarding against a runaway immune response. CD4(+) Foxp3(+) T regulatory (T(reg)) cells with a unique phenotype were highly enriched in the abdominal fat of normal mice, but their numbers were strikingly and specifically reduced at this site in insulin-resistant models of obesity. Loss-of-function and gain-of-function experiments revealed that these T(reg) cells influenced the inflammatory state of adipose tissue and, thus, insulin resistance. Cytokines differentially synthesized by fat-resident regulatory and conventional T cells directly affected the synthesis of inflammatory mediators and glucose uptake by cultured adipocytes. These observations suggest that harnessing the anti-inflammatory properties of T(reg) cells to inhibit elements of the metabolic syndrome may have therapeutic potential.
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