Advanced glycation endproducts—role in pathology of diabetic complications.
Diabetes mellitus is a common endocrine disorder characterised by hyperglycaemia and predisposes to chronic complications affecting the eyes, blood vessels, nerves and kidneys. Hyperglycaemia has an important role in the pathogenesis of diabetic complications by increasing protein glycation and the gradual build-up of advanced glycation endproducts (AGEs) in body tissues. These AGE form on intra- and extracellular proteins, lipids, nucleic acids and possess complex structures that generate protein fluorescence and cross-linking. Protein glycation and AGE are accompanied by increased free radical activity that contributes towards the biomolecular damage in diabetes. There is considerable interest in receptors for AGEs (RAGE) found on many cell types, particularly those affected in diabetes. Recent studies suggest that interaction of AGEs with RAGE alter intracellular signalling, gene expression, release of pro-inflammatory molecules and free radicals that contribute towards the pathology of diabetic complications. This review introduces the chemistry of glycation and AGEs and examines the mechanisms by which they mediate their toxicity. The role of AGEs in the pathogenesis of retinopathy, cataract, atherosclerosis, neuropathy, nephropathy, diabetic embryopathy and impaired wound healing are considered. There is considerable interest in anti-glycation compounds because of their therapeutic potential. The mechanisms and sites of action of selected inhibitors, together with their potential in preventing diabetic complications are discussed.
Diabetes Res Clin Pract. 2005 Jan;67(1):3-21
Incidence of newly diagnosed diabetes attributable to atypical antipsychotic medications.
OBJECTIVE: The purpose of the study was to determine the proportion of patients with schizophrenia with a stable regimen of antipsychotic monotherapy who developed diabetes or were hospitalized for ketoacidosis. METHOD: Patients with schizophrenia for whom a stable regimen of antipsychotic monotherapy was consistently prescribed during any 3-month period between June 1999 and September 2000 and who had no diabetes were followed through September 2001 by using administrative data from the Department of Veterans Affairs. Cox proportional hazards models were developed to identify the characteristics associated with newly diagnosed diabetes and ketoacidosis. RESULTS: Of the 56,849 patients identified, 4,132 (7.3%) developed diabetes and 88 (0.2%) were hospitalized for ketoacidosis. Diabetes risk was highest for clozapine (hazard ratio=1.57) and olanzapine (hazard ratio=1.15); the diabetes risks for quetiapine (hazard ratio=1.20) and risperidone (hazard ratio=1.01) were not significantly different from that for conventional antipsychotics. The attributable risks of diabetes mellitus associated with atypical antipsychotics were small, ranging from 0.05% (risperidone) to 2.03% (clozapine). CONCLUSIONS: Although clozapine and olanzapine have greater diabetes risk, the attributable risk of diabetes mellitus with atypical antipsychotics is small.
Am J Psychiatry. 2004 Sep;161(9):1709-11
Hyperglycemia associated with antipsychotic treatment in a multicenter drug safety project.
The introduction of new antipsychotics has resulted in the availability of drugs with improved safety and tolerability as well as proven efficacy compared to the older antipsychotics. New compounds might show new or different adverse effects that arise in the post-marketing phase when a greater number of patients are treated. One goal of the drug safety program in psychiatry AMSP (Arzneimittelsicherheit in der Psychiatrie) is the detection and description of severe, new, or rare adverse drug reactions (ADRs). Between 1993 and 2000, 122,562 patients were monitored in 35 psychiatric institutions, 86,349 patients of which received antipsychotics. Hyperglycemia related to antipsychotics was observed in association with only two compounds so far: clozapine and olanzapine (clozapine 2 cases, olanzapine 7 cases). In 6 of 9 patients, weight gain preceded hyperglycemia. The relative frequency of these adverse drug related events was 0.013% for clozapine and 0.075% for olanzapine. The symptomatology included reversible hyperglycemia, worsening of existing diabetes, and new-onset diabetes. Control for glycemic dysregulation should be maintained in clinical practice with these drugs.
Pharmacopsychiatry. 2004 Mar;37 Suppl 1:S79-83
Daily stress and glycaemic control in Type 1 diabetes: individual differences in magnitude, direction, and timing of stress-reactivity.
The aim of this study was to investigate the relationships between daily stress and glycaemic control in 54 people with Type 1 diabetes over 21 days. Measures included daily reports of stress (hassles), four-times-daily blood glucose measurements, and HbA1c levels. Time-series analyses revealed considerable variation between individuals in the nature and extent of blood glucose response to stress (stress-reactivity). In approximately one-third of the sample, stress was significantly associated with either same- or next-day blood glucose levels (r-range: -0.79 to 0.58). The majority of stress-reactive individuals (20.4% of the sample) demonstrated a positive association between hassles and same-day blood glucose levels. A much less common effect was found in two individuals (3.7%), where hassles were related to decreased same-day blood glucose. ‘Stress-reactive’ individuals tended to have high HbA1c values at baseline (t(52) = 2.2; P < 0.05), and significant relationships between emotion-focused coping and blood glucose levels (r = 0.93; P < 0.01). In conclusion, although a significant majority of this sample was resistant to the effects of stress, marked individual differences were found in the nature and extent of stress-reactivity. Our study goes beyond other published results as it is longitudinal, uses time-series analyses and includes a relatively larger sample. Clinicians need to be aware of these individual differences in order to advise patients about anticipating and preventing stress-related disruptions of glycaemic control.
Diabetes Res Clin Pract. 2004 Dec;66(3):237-44
Moderate alcohol intake and markers of inflammation and endothelial dysfunction among diabetic men.
AIMS/HYPOTHESIS: Type 2 diabetes mellitus is characterised by heightened inflammation and endothelial dysfunction. Moderate alcohol intake has been associated with a reduced risk of cardiovascular disease in type 2 diabetic patients. It remains to be determined whether there is an association between alcohol and inflammation in individuals with diabetes. METHODS: We investigated the relationship between alcohol intake and inflammation in 726 of 18,159 men who returned blood samples in the Health Professionals Follow-up Study and had confirmed type 2 diabetes at blood draw. RESULTS: In age-adjusted analyses, alcohol intake was associated with lower levels of HbA1c, fibrinogen, soluble tumour necrosis factor receptor-2 (sTNF-R2) and soluble vascular adhesion molecule-1 (sVCAM-1), and with higher levels of HDL cholesterol and adiponectin (p value for trends <0.05). After adjustment for age, HbA1c, insulin use, fasting status, smoking, BMI, physical activity, aspirin use, prevalence of cardiovascular disease and dietary factors, each additional drink per day was related to increased HDL cholesterol (0.053 mmol/l, p<0.0001) and adiponectin (0.8 microg/ml, p=0.01), and decreased sTNFR-2 (73 pg/ml, p=0.03), fibrinogen (0.302 micromol/l, p=0.02) and sVCAM-1 (33 ng/ml, p=0.02). The relationship between alcohol and inflammatory biomarkers persisted when subjects were stratified according to HbA1c levels. CONCLUSIONS/INTERPRETATION: Moderate alcohol intake may have a beneficial effect on markers of inflammation and endothelial dysfunction in type 2 diabetic patients.
Diabetologia. 2004 Oct;47(10):1760-7
Acute alcohol consumption improves insulin action without affecting insulin secretion in type 2 diabetic subjects.
OBJECTIVE: Long-term exposure to alcohol is associated with an improvement in insulin sensitivity. At this time, however, there is no definitive proof that alcohol per se has an effect on the insulin sensitivity index (S(i)) in type 2 diabetes patients. The aim of the present study was to assess the role of acute moderate alcohol intake on insulin sensitivity and insulin secretion in comparable subjects with and without type 2 diabetes. RESEARCH DESIGN AND METHODS: Frequently sampled intravenous glucose tolerance tests (FSIGTs) were performed twice on eight healthy and eight type 2 diabetic volunteers. Forty grams of alcohol (vodka 40% wt/vol) or tap water were sipped from time -60 min to the end of the FSIGT. RESULTS: Lactate area under the curve (AUC) was higher in both groups during the alcohol study than in the control study. Free fatty acid (FFA) AUC was higher in type 2 diabetic subjects than in control subjects; alcohol slightly reduced FFA by 17% in control subjects (34 +/- 4 mmol. min(-1). l(-1); P = 0.1) but significantly decreased FFA by 23% in type 2 diabetic subjects (54 +/- 10; P = 0.007). Beta-cell response was markedly reduced in type 2 diabetic subjects regardless of the type of study. Alcohol significantly increased S(i) in both groups. CONCLUSIONS: Acute alcohol consumption improves insulin action without affecting beta-cell secretion. This effect may be partly due to the inhibitory effect of alcohol on lipolysis. Alcohol intake increases insulin sensitivity and may partly explain both the J-shaped relationship between the prevalence of diabetes and the amount of alcohol consumption and the decreased mortality for myocardial infarction.
Diabetes Care. 2004 Jun;27(6):1369-74