Background Chronic inflammation is believed to be a major mechanism underlying the pathophysiology of type 2 diabetes. Periodontitis is a cause of systemic inflammation. We aimed to assess the effects of periodontal treatment on glycaemic control in people with type 2 diabetes. Methods In this 12 month, single-centre, parallel-group, investigator-masked, randomised trial, we recruited patients with type 2 diabetes, moderate-to-severe periodontitis, and at least 15 teeth from four local hospitals and 15 medical or dental practices in the UK. We randomly assigned patients (1:1) using a computer-generated table to receive intensive periodontal treatment (IPT; whole mouth subgingival scaling, surgical periodontal therapy [if the participants showed good oral hygiene practice; otherwise dental cleaning again], and supportive periodontal therapy every 3 months until completion of the study) or control periodontal treatment (CPT; supra-gingival scaling and polishing at the same timepoints as in the IPT group). Treatment allocation included a process of minimisation in terms of diabetes onset, smoking status, sex, and periodontitis severity. Allocation to treatment was concealed in an opaque envelope and revealed to the clinician on the day of first treatment. With the exception of dental staff who performed the treatment and clinical examinations, all study investigators were masked to group allocation. The primary outcome was between-group difference in HbA,, at 12 months in the intention-to-treat population. This study is registered with the ISRCTN registry, number ISRCTN83229304.

Glucagon and glucagon-like peptide (GLP)-1 are the primary products of proglucagon processing from the pancreas and gut, respectively. Giving dual agonists with glucagon and GLP-1 activity to diabetic, obese mice causes enhanced weight loss and improves glucose tolerance by reduction of food intake and by increase in energy expenditure (EE). We aimed to observe the effect of a combination of glucagon and GLP-1 on resting EE and glycemia in healthy human volunteers. In a randomized, double-blinded crossover study, 10 overweight or obese volunteers without diabetes received placebo infusion, GLP-1 alone, glucagon alone, and GLP-1 plus glucagon simultaneously. Resting EE—measured using indirect calorimetry—was not affected by GLP-1 infusion but rose significantly with glucagon alone and to a similar degree with glucagon and GLP-1 together. Glucagon infusion was accompanied by a rise in plasma glucose levels, but addition of GLP-1 to glucagon rapidly reduced this excursion, due to a synergistic insulinotropic effect. The data indicate that drugs with glucagon and GLP-1 agonist activity may represent a useful treatment for type 2 diabetes and obesity. Long-term studies are required to demonstrate that this combination will reduce weight and improve glycemia in patients.

We have been interested in environmental factors which may contribute to the development of non-insulin-dependent diabetes mellitus (NIDDM). Previous analysis of dietary factors in a cohort of elderly Dutch people has shown that regular fish eating reduced the 4-year risk of glucose intolerance in normoglycaemic individuals [1]. Experimentally vitamin D is required for normal insulin secretion and glucose tolerance [2]. Since fish can be an important dietary source of vitamin D this sub-study was designed to determine whether variation in vitamin D status relates to glucose intolerance. Subjects, materials and methods Study population:In 1960 a population-based random sample of 878 men (born 1900-1920) were enrolled in the Zutphen Study, the Dutch contribution to the Seven Countries Study. Clinical examinations and dietary surveys were conducted initially and at regular intervals thereafter. In 1990 all living participants (314) were invited for the 30-year follow-up and 238 (77 %) agreed. Men known by then to have diabetes were excluded (n = 29). Complete data on diet and BMI from both the 10-and 30-year surveys and on glucose tolerance at the 30-year survey were available on 158 subjects. Serum for 25-hydroxyvitamin D (25(OH)D) analysis was available on 142 of those who formed the study group.Protocol: All men were examined as in previously reported surveys [3]. At the 30-year follow-up an OGTT conforming to World Health Organization (WHO) guidelines [4] was performed with samples at 0, 1 and 2 h after the glucose load. Plasma glucose was measured in fluoridated samples using hexokinase methodology. WHO criteria were used to classify the men into those with newly diagnosed NIDDM, impaired glucose tolerance or as normoglycaemic [4]. Serum total insulin was assayed by radioimmunoassay (Pharmacia Diagnostics, Uppsala, Sweden; cross-reaction with proinsulin 100 %).Clinical examinations and anthropomorphic measurements were made by physicians specifically trained for the study as

Aims/hypothesis It is not known whether the beneficial effects of exercise training on insulin sensitivity are due to changes in hepatic and peripheral insulin sensitivity or whether the changes in insulin sensitivity can be explained by adaptive changes in fatty acid metabolism, changes in visceral fat or changes in liver and muscle triacylglycerol content. We investigated the effects of 6 weeks of supervised exercise in sedentary men on these variables. Subjects and methods We randomised 17 sedentary overweight male subjects (age 50±2.6 years, BMI 27.6±0.5 kg/ m 2 ) to a 6-week exercise programme (n=10) or control group (n=7). The insulin sensitivity of palmitic acid production rate (Ra), glycerol Ra, endogenous glucose Ra (EGP), glucose uptake and glucose metabolic clearance rate were measured at 0 and 6 weeks with a two-step hyperinsulinaemic-euglycaemic clamp [step 1, 0.3 (low dose); step 2, 1.5 (high dose) mU kg −1 min −1 ]. In the exercise group subjects were studied >72 h after the last training session. Liver and skeletal muscle triacylglycerol content was measured by magnetic resonance spectroscopy and visceral adipose tissue by cross-sectional computer tomography scanning. Results After 6 weeks, fasting glycerol, palmitic acid Ra (p=0.003, p=0.042) and NEFA concentration (p=0.005) were decreased in the exercise group with no change in the control group. The effects of low-dose insulin on EGP and of high-dose insulin on glucose uptake and metabolic clearance rate were enhanced in the exercise group but not in the control group (p=0.026; p=0.007 and p=0.04). There was no change in muscle triacylglycerol and liver fat in either group. Conclusions/interpretation Decreased availability of circulating NEFA may contribute to the observed improvement in the insulin sensitivity of EGP and glucose uptake following 6 weeks of moderate exercise.

OBJECTIVEPeptide YY3–36 (PYY3–36), a Y2 receptor agonist, and oxyntomodulin, a glucagon-like peptide 1 (GLP-1) receptor agonist, are cosecreted by intestinal L-cells after each meal. Separately each hormone acts as an endogenous satiety signal and reduces appetite in humans when infused intravenously. The aim of the current study was to investigate whether the anorectic effects of PYY3–36 and oxyntomodulin can be additive.RESEARCH DESIGN AND METHODSTwelve overweight or obese human volunteers underwent a randomized, double-blinded, placebo-controlled study. An ad libitum test meal was used to measure energy intake during intravenous infusions of either PYY3–36 or oxyntomodulin or combined PYY3–36/oxyntomodulin.RESULTSEnergy intake during coadministration of PYY3–36 and oxyntomodulin was reduced by 42.7% in comparison with the saline control and was significantly lower than that during infusions of either hormone alone.CONCLUSIONSThe anorectic effects of PYY3–36 and oxyntomodulin can be additive in overweight and obese humans. Coadministration of Y2 receptor agonists and GLP-1 receptor agonists may be a useful treatment strategy for obesity.

Our data demonstrates that there is no association between cabergoline treatment for hyperprolactinaemia and valvulopathy. This study therefore supports continued use of low-dose cabergoline for patients with hyperprolactinaemia.

Gut peptides, or gut-peptide mimetics, show great promise for use as therapeutic agents for the treatment of obesity and cachexia.

Some patients with severe insulin resistance develop pathological tissue growth reminiscent of acromegaly. Previous studies of such patients have suggested the presence of a selective postreceptor defect of insulin signaling, resulting in the impairment of metabolic but preservation of mitogenic signaling. As the activation of phosphoinositide 3-kinase (PI 3-kinase) is considered essential for insulin's metabolic signaling, we have examined insulin-stimulated PI 3-kinase activity in anti-insulin receptor substrate (IRS)-1 immunoprecipitates from cultured dermal fibroblasts obtained from pseudoacromegalic (PA) patients and controls. At a concentration of insulin (1 nM) similar to that seen in vivo in PA patients, the activation of IRS-1-associated PI 3-kinase was reduced markedly in fibroblasts from the PA patients (32+/-7% of the activity of normal controls, P < 0.01). Genetic and biochemical studies indicated that this impairment was not secondary to a defect in the structure, expression, or activation of the insulin receptor, IRS-1, or p85alpha. Insulin stimulation of mitogenesis in PA fibroblasts, as determined by thymidine incorporation, was indistinguishable from controls, as was mitogen-activated protein kinase phosphorylation, confirming the integrity of insulin's mitogenic signaling pathways in this condition. These findings support the existence of an intrinsic defect of postreceptor insulin signaling in the PA subtype of insulin resistance, which involves impairment of the activation of PI 3-kinase. The PA tissue growth seen in such patients is likely to result from severe in vivo hyperinsulinemia activating intact mitogenic signaling pathways emanating from the insulin receptor.