OBJECTIVE -The aim of the study was to determine whether the loss of fasting and postprandial glycemic control occurs in parallel or sequentially in the evolution of type 2 diabetes.RESEARCH DESIGN AND METHODS -In 130 type 2 diabetic patients, 24-h glucose profiles were obtained using a continuous glucose monitoring system. The individuals with type 2 diabetes were divided into five groups according to A1C levels: 1 (Ͻ6.5%, n ϭ 30), 2 (6.5-6.9%, n ϭ 17), 3 (7-7.9%, n ϭ 32), 4 (8 -8.9%, n ϭ 25), and 5 (Ն9%, n ϭ 26). The glucose profiles between the groups were compared. The overall glucose concentrations for the diurnal, nocturnal, and morning periods, which represent the postprandial, fasting, and the dawn phenomenon states, respectively, were also compared.RESULTS -Glucose concentrations increased steadily from group 1 to 5 in a stepwise manner. The initial differences in mean glucose concentrations reaching statistical significance occurred 1) between groups 1 and 2 (6.4 vs. 7.7 mmol/l, P ϭ 0.0004) for daytime postprandial periods, followed by differences; 2) between groups 2 and 3 (7.5 vs. 9.3 mmol/l, P ϭ 0.0003) for the morning periods (dawn phenomenon); and finally 3) between groups 3 and 4 (6.3 vs. 8.4 mmol/l, P Ͻ 0.0001) for nocturnal fasting periods.CONCLUSIONS -The deterioration of glucose homeostasis in individuals with type 2 diabetes progressed from postprandial to fasting hyperglycemia following a three-step process. The first step related to the three diurnal postmeal periods considered as a whole, the second step occurred during the morning period, and the third and final step corresponded to sustained hyperglycemia over the nocturnal fasting periods. Such a description of the key stages in the evolution of type 2 diabetes may be of interest for implementing antidiabetes treatment. Diabetes Care 30:263-269, 2007T he steady decline in the quality of glucose homeostasis (1) as observed in type 2 diabetes results from an increasing defect (2) in both insulin sensitivity and secretion (3). The data from the UK Prospective Diabetes Study indicate that the gradual increase in both A1C levels and fasting glucose concentrations is mainly due to a relentless linear deterioration in -cell function from the time of diagnosis. In contrast, the years that precede the development of type 2 diabetes are characterized by a progressive decline in both insulin action and defects in the early phase of the insulin secretion (4,5). Such abnormalities lead to a progressive transition from normal glucose tolerance to impaired glucose tolerance and finally to frank type 2 diabetes. As impaired glucose tolerance is acknowledged as a prediabetic stage, it has been postulated that losses of postprandial glucose control occur before deterioration in fasting glucose concentration (4,6,7). In a previous study (8), we have demonstrated that postprandial glucose increments are predominant contributors to the overall hyperglycemia in patients with an A1C Ͻ7.3%, while fasting increments represent the major contributor to worsenin...
Chronic obstructive pulmonary disease (COPD) is associated with a continuous systemic inflammatory response. Furthermore, COPD is associated with an excess risk for cardiovascular disease and type II diabetes. Systemic inflammation in other populations is a factor in atherogenesis and has been associated with insulin resistance. We assessed the association between systemic inflammation and insulin resistance in non-hypoxaemic patients with COPD. Fasting plasma glucose, insulin and inflammatory mediators were measured in 56 patients and 29 healthy subjects. Body mass index (BMI) and height squared fat- and fat-free-mass index were similar between subject groups. Using homeostatic modelling techniques, mean (SD) insulin resistance was greater in the patients, 1.68 (2.58) and 1.13 (2.02) in healthy subjects, p=0.032. Fasting plasma insulin was increased in patients while glucose was similar to that in healthy subjects. Patients had increased circulating inflammatory mediators. Insulin resistance was related to interleukin-6 (IL-6), r=0.276, p=0.039, and tumour necrosis factor alpha soluble receptor I, r=0.351, p=0.008. Both IL-6 and BMI were predictive variables of insulin resistance r(2)=0.288, p<0.05. We demonstrated greater insulin resistance in non-hypoxaemic patients with COPD compared with healthy subjects, which was related to systemic inflammation. This relationship may indicate a contributory factor in the excess risk of cardiovascular disease and type II diabetes in COPD.
Context:Patients with polycystic ovary syndrome (PCOS) have an increased prevalence of insulin resistance and display subclinical evidence of early cardiovascular disease. Metformin improves insulin sensitivity and circulating markers of cardiovascular risk in patients with PCOS, but it is unclear whether this translates into improvements in vascular function.Objective: Our objective was to evaluate the effects of metformin on arterial stiffness and endothelial function in women with PCOS. Design and Intervention:Thirty women with PCOS were assigned to consecutive 12-wk treatment periods of metformin or placebo in a randomized, double-blind, crossover design separated by an 8-wk washout. Main Outcome Measures:The primary outcome measures were assessments of arterial stiffness [augmentation index (AIx), central blood pressure, and brachial and aortic pulse wave velocity (PWV)] and endothelial function. Anthropometry, testosterone, and metabolic biochemistry (lipids, homeostasis model of assessment for insulin resistance, high-sensitivity C-reactive protein, adiponectin, and plasminogen activator inhibitor-1) were also assessed.Results: Metformin improved AIx [Ϫ6.1%; 95% confidence interval (CI) for the difference Ϫ8.5 to Ϫ3.5%; P Ͻ 0.001], aortic PWV (Ϫ0.76 m/sec; 95% CI for the difference Ϫ1.12 to Ϫ0.4 m/sec; P Ͻ 0.001), brachial PWV (Ϫ0.73 m/sec; 95% CI for the difference Ϫ1.09 to Ϫ0.38; P Ͻ 0.001), central blood pressure (P Ͻ 0.001), and endothelium-dependent (AIx after albuterol; P ϭ 0.003) and endothelium-independent (AIx after nitroglycerin; P Ͻ 0.001) vascular responses. Metformin also reduced weight (P Ͻ 0.001), waist circumference (P Ͻ 0.001), and triglycerides (P ϭ 0.004) and increased adiponectin (P ϭ 0.001) but did not affect testosterone or other metabolic measures.Conclusions: Short-term metformin therapy improves arterial stiffness and endothelial function in young women with PCOS. (J Clin Endocrinol Metab 95: 722-730, 2010) P olycystic ovary syndrome (PCOS) is the commonest endocrinopathy in women of reproductive age, affecting approximately 7% of the premenopausal population (1). In addition to its effects on reproductive health, it is now well recognized that PCOS is a metabolic disorder, characterized by increased insulin resistance (2), which leads to an excess lifetime risk of type 2 diabetes (3, 4). Patients with this condition display a cluster of metabolic disturbances, including obesity (5), dyslipidemia (6), impaired fibrinolysis (7), and hypertension (8) Abbreviations: AIx, Augmentation index; AMPK, AMP kinase; aPWV, aortic PWV; BMI, body mass index; bPWV, brachial PWV; FAI, free androgen index; HDL, high-density lipoprotein cholesterol; hsCRP, high-sensitivity C-reactive protein; HOMA-IR, homeostasis model assessment method for insulin resistance; LDL, low-density lipoprotein cholesterol; NTG, nitroglycerin; PAI-1, plasminogen activator inhibitor-1; PCOS, polycystic ovary syndrome; PWV, pulse wave velocity; TC, total cholesterol; T R , estimated aortic pulse wave velocity.
Immunotherapy using short immunogenic peptides of disease-related autoantigens restores immune tolerance in preclinical disease models. We studied safety and mechanistic effects of injecting human leukocyte antigen-DR4()-restricted immunodominant proinsulin peptide intradermally every 2 or 4 weeks for 6 months in newly diagnosed type 1 diabetes patients. Treatment was well tolerated with no systemic or local hypersensitivity. Placebo subjects showed a significant decline in stimulated C-peptide (measuring insulin reserve) at 3, 6, 9, and 12 months versus baseline, whereas no significant change was seen in the 4-weekly peptide group at these time points or the 2-weekly group at 3, 6, and 9 months. The placebo group's daily insulin use increased by 50% over 12 months but remained unchanged in the intervention groups. C-peptide retention in treated subjects was associated with proinsulin-stimulated interleukin-10 production, increased FoxP3 expression by regulatory T cells, low baseline levels of activated β cell-specific CD8 T cells, and favorable β cell stress markers (proinsulin/C-peptide ratio). Thus, proinsulin peptide immunotherapy is safe, does not accelerate decline in β cell function, and is associated with antigen-specific and nonspecific immune modulation.
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