Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0011860 (type 2 diabetes)
 57,723 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

As men age, testosterone levels decline, and decreased testosterone levels are associated with increased risks of osteoporosis, metabolic syndrome, type 2 diabetes mellitus and mortality. Nevertheless, it is still uncertain whether reduced testosterone level is a cause of ill-health or a marker of pre-existing disease, as systemic illness lowers testosterone levels. Most circulating testosterone is bound to sex-hormone-binding globulin (SHBG) and albumin, whereas a small proportion circulates as free testosterone. Decreased SHBG level is associated with increased risks for insulin resistance and metabolic syndrome, although it would also be expected to be associated with increased free testosterone level. During male aging, total and free testosterone levels fall while SHBG level rises. Thus, associations between decreasing androgens and negative health outcomes might differ across men of various ages. Trials of testosterone therapy report benefits for body composition and BMD, but there are limited data on the effect of testosterone supplementation on cardiovascular risk. Whereas men who have androgen deficiency should be considered for testosterone therapy, the role of testosterone supplementation in older men who are not clearly hypogonadal requires further clarification. Further studies are also needed to establish whether the age-related decline in circulating testosterone level in men can be modified or prevented.
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PMID:Testosterone and ill-health in aging men. 1916 23

The association of bone with the metabolic syndrome and its features, visceral fat accumulation or insulin resistance, remains unclear. We determined visceral and subcutaneous fat areas (V and S) by computed tomography on 187 men (28-83 years) and 125 postmenopausal women (46-82 years) with type 2 diabetes. Men whose V was 100 cm(2) or more had significantly lower urinary N-terminal cross-linked telopeptide of type-I collagen (p=0.005), higher femoral neck bone mineral density (FN-BMD) (p=0.004), and lower prevalence of vertebral fractures (VFs) (p=0.04) than controls. Fat mass, V, S, and lean body mass positively correlated with FN-BMD in men and with lumbar (L) and FN-BMD in women. When adjusted for weight, these correlations became negative. Urinary C-peptide positively correlated with FN-BMD in both genders. Multivariate logistic regression analysis adjusted for age, height, weight, L-BMD, duration of diabetes, and diabetes therapies identified V in men and urinary C-peptide in women as factors inversely associated with the presence of VFs [odds ratio (OR)=0.61 per SD increase, p=0.04, and OR=0.32, p=0.01, respectively]. These findings suggest that, of the components of the metabolic syndrome, body fat in gravity and hyperinsulinemia could increase FN-BMD in diabetic subjects. Visceral fat in men and hyperinsulinemia in women may protect against VFs independent of weight, L-BMD, diabetes duration, or therapies.
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PMID:Associations between components of the metabolic syndrome versus bone mineral density and vertebral fractures in patients with type 2 diabetes. 1944 53

Inverse relationships have been observed between BMD and vascular calcification (VC), suggesting an underlying metabolic pathway linking these processes. Bone morphogenetic proteins (BMPs) are potential candidate genes that may mediate this relationship. Four single nucleotide polymorphisms (SNPs) in the BMP2 gene, 2 SNPs in BMP4, and 16 SNPs in BMP7 were tested for association with measures of VC using CT (coronary and carotid arteries, abdominal aorta), and BMD was measured using DXA (lumbar spine, hip, and distal radius) and quantitative CT (QCT; thoracic and lumbar spine) in 920 European Americans from 374 Diabetes Heart Study families: 762 with type 2 diabetes. Variance components quantitative trait locus association analysis was computed using SOLAR software, and a bivariate principal component analysis (PCA) assessed for genetic relationships between BMD and VC. Association was observed between several measures of BMD and BMP7 rs17404303 (thoracic spine QCT p = 0.03; lumbar spine QCT p = 0.02; hip DXA p = 0.06, dominant models). In addition, 6 of 16 BMP7 SNPs showed significant and opposing effects on the bivariate PCA for VC and BMD (two-sided exact test, p = 0.0143). Polymorphisms in BMP7 are associated with inverse relationships between bone mineralization and VC in the coronary, carotid, and abdominal aorta in a diabetes-enriched cohort of European Americans.
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PMID:Bone morphogenetic protein 7 (BMP7) gene polymorphisms are associated with inverse relationships between vascular calcification and BMD: the Diabetes Heart Study. 1945 55

We evaluated sex differences in the prospective association between adiponectin with BMD, bone loss, and fractures. Adiponectin, an adipose-derived protein with insulin-sensitizing properties, is also expressed in bone-forming cells. Conflicting results and sex differences in the adiponectin-BMD association have been reported in cross-sectional studies. Serum adiponectin was measured in fasting blood samples obtained in 1984-1987 in 447 postmenopausal women (mean age: 76 yr) and 484 men (mean age: 75 yr). Four years later, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. In 1992-1996, axial BMD was remeasured in 261 women and 264 men. Multivariable analysis adjusted for age, weight, calcium intake, type 2 diabetes, alcohol intake, and exercise. Among women, adiponectin was inversely associated with BMD at the femoral neck (beta = -0.002, p = 0.007), total hip (beta = -0.002, p = 0.009), lumbar spine (beta = -0.003, p = 0.008), and midshaft radius (beta = -0.002, p = 0.01) after 4.4 yr and at the femoral neck and total hip 8.6 yr later. Among men, adiponectin was inversely associated with BMD at the femoral neck, (beta = -0.002, p = 0.03), total hip (beta = -0.004, p < 0.001), and midshaft radius (beta = -0.003, p < 0.001) after 4.4 yr and at the hip 8.6 yr later. Adiponectin was not associated with 4-yr bone loss in either sex but was associated with vertebral fractures (adjusted OR: 1.13; 95% CI: 1.08-1.23; p = 0.009) among men only. Adiponectin was inversely associated with BMD; however, sex differences were observed by anatomical site and with regards to vertebral fractures.
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PMID:Sex differences in the association between adiponectin and BMD, bone loss, and fractures: the Rancho Bernardo study. 1945 56

Despite some controversies, especially in 2008, evidence is mounting by a number of randomised controlled trials in recent years that blood-glucose-lowering therapy (as an integral part of multifactorial therapy) reduces cardiovascular disease (CVD) for longer term, both in type 1 and type 2 diabetes. In particular, cardiovascular events are reduced by approximately 10-15% per 1% absolute reduction of HbA1c, on top of other CVD-risk-reducing therapies. With regard to mortality, the situation is less clear, as those intervention studies need at least a 10-year follow-up. In fact, some risks involved with blood-glucose-lowering therapy, for example, hypoglycaemia and weight gain, especially in patients with prior CVD, may also impact unfavourably on (cardiovascular) mortality. Therefore, blood glucose lowering is a highly individualised therapy with a target for HbA1c <or=7.0% or 6.5%, which takes time to tailor (poly-)pharmacotherapy gently to the patient's needs. Drug-specific effects, both advantageous and disadvantageous, of blood-glucose-lowering therapy cannot be excluded currently and warrant further studies.
Best Pract Res Clin Endocrinol Metab 2009 Jun
PMID:The impact of glucose-lowering therapy on cardiovascular outcomes. 1952 Mar 12

We examined whether or not BMD or bone markers were useful for assessing the risk of vertebral fractures in 248 Japanese men with type 2 diabetes. We analyzed the relationships between bone markers (osteocalcin [OC], bone-specific alkaline phosphatase [BAP], urinary N-terminal cross-linked telopeptide of type-I collagen) or BMD and HbA(1c), urinary C-peptide, insulin-like growth factor-I (IGF-I), parathyroid hormone, 1,25(OH)(2) vitamin D, and the presence of prevalent vertebral fractures. Multiple regression analysis adjusted for age, body height, weight, duration of diabetes, and serum creatinine showed that serum OC and OC/BAP ratio were correlated negatively with HbA(1c) (P < 0.01) and positively with IGF-I (P < 0.01). Multivariate logistic regression analysis adjusted for the above parameters showed that serum OC/BAP ratio was inversely associated with the presence of vertebral fractures (odds ratio = 0.695, P < 0.05). This association was still significant after additional adjustment for lumbar or femoral neck BMD. Our results suggest that poor diabetic control and lower IGF-I level are linked to impaired bone formation and resultant reduction in OC/BAP ratio in men with type 2 diabetes. The OC/BAP ratio could be clinically useful for assessing the risk of vertebral fractures independent of BMD in diabetic men.
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PMID:Serum osteocalcin/bone-specific alkaline phosphatase ratio is a predictor for the presence of vertebral fractures in men with type 2 diabetes. 1964 39

Postprandial glycaemia is now recognised as the major determinant of average glycaemic control in type 2 diabetes, as assessed by glycated haemoglobin. Therefore, an understanding of the factors influencing both the rise in blood glucose and insulin secretion after a meal is fundamental to the development of dietary and pharmacological approaches to optimise glycaemic control. The gastrointestinal tract regulates the rate at which carbohydrate and other nutrients are absorbed and is the source of regulatory peptides that stimulate pancreatic insulin secretion in the setting of elevated blood glucose levels. This article highlights the importance of the gastrointestinal tract in insulin secretion and glucose homeostasis and discusses potential strategies directed at modification of gastrointestinal function in order to improve glycaemic control in the management of diabetes.
Best Pract Res Clin Endocrinol Metab 2009 Aug
PMID:Insulin secretion in healthy subjects and patients with Type 2 diabetes--role of the gastrointestinal tract. 1974 59

The incretin effect, that is, the postprandial augmentation of insulin secretion by gastrointestinal hormones, mediates approximately 50-70% of the overall insulin responses after a mixed meal or glucose ingestion in healthy subjects. In patients with type 2 diabetes, the incretin effect is markedly reduced, and this has been attributed to defects in the secretion and insulinotropic action of the two main incretin hormones, namely gastric inhibitory polypeptide (GIP) and glucagon-like peptide 1 (GLP-1). It has been speculated that a reduced incretin effect might precede the onset of hyperglycaemia in patients with type 2 diabetes. However, the secretion and action of GIP and GLP-1 is relatively unaltered in normal glucose-tolerant individuals at high risk for type 2 diabetes (e.g., first-degree relatives) and a diminished incretin effect is also detectable in other types of diabetes, thereby arguing against such reasoning. This article will describe the defects in the incretin system in patients with type 2 diabetes, summarise their relevance in the development of hyperglycaemia and discuss the potential individual roles of GIP and GLP-1 in the pathogenesis of type 2 diabetes.
Best Pract Res Clin Endocrinol Metab 2009 Aug
PMID:The contribution of incretin hormones to the pathogenesis of type 2 diabetes. 1974 61

The incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP, gastric inhibitory peptide) are secreted from intestinal L and K cells and stimulate insulin secretion from pancreatic beta cells. However, they are immediately inactivated mainly via N-terminal degradation by dipeptidyl peptidase IV (DPP IV, CD26), a specialised enzyme located on the cell surface enzyme of endothelial, epithelial and some other cell types. Cleavage by neprilysin (neutral endopeptidase) is a minor degradation route, and renal clearance eliminates incretin/fragments, but appears of less importance for regulating incretin bioactivities. Based on these observations two novel types of drugs for the treatment of type 2 diabetes have been developed: DPP IV inhibitors and DPP IV-resistant incretin analogues. Both have distinct advantages and disadvantages. Potential side effects of DPP IV inhibitors may result from affecting the bioactivity of other hormones, neuropeptides or chemokines and also by their cross-reactivity with DPP IV-related enzymes.
Best Pract Res Clin Endocrinol Metab 2009 Aug
PMID:Mechanisms underlying the rapid degradation and elimination of the incretin hormones GLP-1 and GIP. 1974 62

This article focusses on the antidiabetic therapeutic potential of the incretin hormone glucagon-like peptide-1 (GLP-1) in the treatment of patients with type 2 diabetes mellitus (T2DM). T2DM is characterised by insulin resistance, impaired glucose-induced insulin secretion and inappropriately regulated glucagon secretion, which in combination eventually result in hyperglycaemia and, in the longer term, microvascular and macrovascular diabetic complications. Traditional treatment modalities - even multidrug approaches - for T2DM are often unsatisfactory in making patients reach glycaemic goals as the disease progresses caused by a steady, relentless decline in pancreatic beta-cell function. Furthermore, current treatment modalities are often limited by inconvenient dosing regimens and safety and tolerability issues, the latter including hypoglycaemia, body weight gain, oedema and gastrointestinal side effects. Therefore, the actions of GLP-1, which include the potentation of meal-induced insulin secretion and trophic effects on the beta-cell, have attracted a lot of interest. GLP-1 also inhibits glucagon secretion and suppresses food intake and appetite.
Best Pract Res Clin Endocrinol Metab 2009 Aug
PMID:The spectrum of antidiabetic actions of GLP-1 in patients with diabetes. 1974 63


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