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.

To examine glycemic and glucoregulatory responses to resistance exercise (RE) sessions of different volume in type 1 diabetes (T1DM). Eight T1DM (seven males: one female; age: 38 ± 6 years, HbA1C : 8.7 ± 1.0%/71 ± 11 mmol/mol) attended the research facility fasted and on four separate occasions, having taken their usual basal insulin, but omitted morning rapid-acting insulin. Participants completed a 1SET (14 min), 2SET (28 min), 3SET (42 min) RE session (eight exercises × 10 repetitions) at 67 ± 3% one-repetition-maximum followed by 60-min recovery, or a resting trial (CON). Venous blood samples were taken before and after exercise. Data (mean ± SEM) were analyzed using repeated-measures analysis of variance (P ≤ 0.05). RE did not induce hypoglycemia (BG < 4 mmol/L). During recovery, blood glucose (BG) concentrations remained above pre-exercise after 1SET (15-60 min, P < 0.05) and 2SET (0-60 min, P < 0.05) but comparable (P > 0.05) with pre-exercise after 3SET. BGIAUC(area-under-curve) (mmol/L/60 min) was greater after 1SET and 2SET vs CON (1SET 103.6 ± 36.9 and 2SET 128.7 ± 26.1 vs CON -24.3 ± 15.2, P < 0.05), but similar between 3SET and CON (3SET 40.7 ± 59.3, P > 0.05). Under all trials, plasma creatine kinase levels at 24 h post-exercise were similar (P > 0.05) to pre-exercise. RE does not induce acute hypoglycemia or damage muscle. BG progressively rose after one and two sets of RE. However, inclusion of a third set attenuated exercise-induced hyperglycemia and returned BG to that of a non-exercise trial.

Aims/hypothesis: The pharmacokinetic and pharmacodynamic properties of biphasic insulin aspart (BIAsp 30) (30% soluble, 70% protaminated insulin aspart [IAsp]) and insulin glargine (IGlarg) were compared. Methods: Twelve people with type 2 diabetes took part in two 24-h isoglycaemic clamp studies, 1 week apart. Patients were randomised to treatment with 0.5 U/kg of BIAsp 30 (0.25 U/kg at 08.30 h and 0.25 U/kg at 20.30 h) or 0.50 U/kg IGlarg at 08.30 h. Both insulins were given by subcutaneous injection into the anterior abdominal wall. The plasma glucose, glucose infusion rates, plasma insulin and C-peptide concentrations were measured. Results: All 12 patients were men; mean (±SD) age was 58.8 (8.9) years, BMI 31.0 (3.0) kg/m 2 and HbA 1c 7

OBJECTIVE -To study the effects of exercise on the absorption of the basal long-acting insulin analog insulin glargine (Lantus), administered subcutaneously in individuals with type 1 diabetes.RESEARCH DESIGN AND METHODS -A total of 13 patients (12 men, 1 woman) with type 1 diabetes on a basal-bolus insulin regimen were studied.125 I-labeled insulin glargine at the usual basal insulin dose was injected subcutaneously into the thigh on the evening (2100) before the study day on two occasions 1 week apart. Patients were randomly assigned to 30 min intense exercise (65% peak oxygen uptake [VO 2peak ]) on one of these visits. The decay of radioactive insulin glargine was compared on the two occasions using a thallium-activated Nal gamma counter. Blood samples were collected at regular intervals on the study days to assess plasma glucose and insulin profiles. RESULTS -No significant difference was found in the125 I-labeled insulin glargine decay rate on the two occasions (exercise vs. no exercise; repeated-measures ANOVA, P ϭ 0.548). As expected, a significant fall in plasma glucose was observed over the exercise period (area under curve above fasting [⌬AUC] glucose: Ϫ0.39 Ϯ 0.11 vs. Ϫ1.30 Ϯ 0.16 mmol ⅐ l Ϫ1 ⅐ h Ϫ1 ; nonexercise vs. exercise; P ϭ 0.001), but insulin levels did not differ significantly on the two occasions (⌬AUC insulin: Ϫ2.1 Ϯ 3.9 vs. 1.5 Ϯ 6.2 pmol ⅐ l Ϫ1 ⅐ h Ϫ1 ; nonexercise versus exercise; P ϭ 0.507).CONCLUSIONS -An intense 30-min period of exercise does not increase the absorption rate of the subcutaneously injected basal long-acting insulin analog insulin glargine in patients with type 1 diabetes. Diabetes Care 28:560 -565, 2005

The aim of this study was to examine the effectiveness of either a standard care programme (n = 9) or a 12-week supported exercise programme (n = 10) on glycaemic control, β-cell responsiveness, insulin resistance, and lipid profiles in newly diagnosed Type 2 diabetes patients. The standard care programme consisted of advice to exercise at moderate to high intensity for 30 min five times a week; the supported exercise programme consisted of three 60-min supported plus two unsupported exercise sessions per week. Between-group analyses demonstrated a difference for changes in low-density lipoprotein cholesterol only (standard care programme 0.01 mmol · L(-1), supported exercise programme -0.6 mmol · L(-1); P = 0.04). Following the standard care programme, within-group analyses demonstrated a significant reduction in waist circumference, whereas following the supported exercise programme there were reductions in glycosylated haemoglobin (6.4 vs. 6.0%; P = 0.007), waist circumference (101.4 vs. 97.2 cm; P = 0.021), body mass (91.7 vs. 87.9 kg; P = 0.007), body mass index (30.0 vs. 28.7 kg · m(-2); P = 0.006), total cholesterol (5.3 vs. 4.6 mmol · L(-1); P = 0.046), low-density lipoprotein cholesterol (3.2 vs. 2.6 mmol · L(-1); P = 0.028), fasting β-cell responsiveness (11.5 × 10(-9) vs. 7.0 × 10(-9) pmol · kg(-1) · min(-1); P = 0.009), and insulin resistance (3.0 vs. 2.1; P = 0.049). The supported exercise programme improved glycaemic control through enhanced β-cell function associated with decreased insulin resistance and improved lipid profile. This research highlights the need for research into unsupported and supported exercise programmes to establish more comprehensive lifestyle advice for Type 2 diabetes patients.