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Aims/hypothesis: Endogenous NO inhibits insulin release in isolated beta cells and insulin-degrading enzyme activity in hepatocytes, while NO release from endothelial cells has been suggested to enhance insulin action. We assessed the overall effect of systemic inhibition of endogenous NO synthesis on glucose homeostasis in humans. Methods: Twenty-four non-diabetic volunteers underwent two hyperglycaemic (+7 mmol/l) clamps with either saline or L-NG-nitroarginine methyl ester ( l-NAME, at rates of 2.5, 5, 10 and 20 μg min kg) infusion. Another five volunteers underwent an OGTT with either saline or l-NAME (20 μg min kg) infusion. Blood pressure and heart rate were measured to monitor NO blockade; during the OGTT, endothelial function was assessed by peripheral arterial tonometry and insulin secretion by C-peptide deconvolution and insulin secretion modelling. Results: Compared with saline, l-NAME at the highest dose raised mean blood pressure (+20 ± 2 mmHg), depressed heart rate (−12 ± 2 bpm) and increased insulin clearance (+50%). First-phase insulin secretion was impaired, but insulin sensitivity ( M/I index) was unchanged. During the OGTT, l-NAME raised 2 h plasma glucose by 1.8 mmol/l ( p < 0.01), doubled insulin clearance and impaired beta cell glucose sensitivity while depressing endothelial function. Conclusions/interpretation: In humans, systemic NO blockade titrated to increase blood pressure and induce endothelial dysfunction does not affect insulin action but significantly impairs glucose tolerance by increasing plasma insulin clearance and depressing insulin secretion, namely first-phase and beta cell glucose sensitivity. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Glucagon-like peptide-1 (GLP-1) lowers glucose levels by potentiating glucose-induced insulin secretion and inhibiting glucagon release. The question of whether GLP-1 exerts direct effects on the liver, independently of the hormonal changes, is controversial. We tested whether an exogenous GLP-1 infusion, designed to achieve physiological postprandial levels, directly affects endogenous glucose production (EGP) under conditions mimicking the fasting state in diabetes. Methods: In 14 healthy volunteers, we applied the pancreatic clamp technique, whereby plasma insulin and glucagon levels are clamped using somatostatin and hormone replacement. The clamp was applied in paired, 4 h experiments, during which saline (control) or GLP-1(7-37)amide (0.4 pmol min kg) was infused. Results: During the control study, plasma insulin and glucagon were maintained at basal levels and plasma C-peptide was suppressed, such that plasma glucose rose to a plateau of ∼10.5 mmol/l and tracer-determined EGP increased by ∼60%. During GLP-1 infusion at matched plasma glucose levels, the rise of EGP from baseline was fully prevented. Lipolysis (as indexed by NEFA concentrations and tracer-determined glycerol rate of appearance) and substrate utilisation (by indirect calorimetry) were similar between control and GLP-1 infusion. Conclusions/interpretation: GLP-1 inhibits EGP under conditions where plasma insulin and glucagon are not allowed to change and glucose concentrations are matched, indicating either a direct effect on hepatocytes or neurally mediated inhibition. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Type 2 diabetes and insulin resistance are often associated with the co-occurrence of coronary atherosclerosis and cardiac dysfunction. The aim of this study was to define the independent relationships between left ventricular dysfunction or ischaemia and patterns of myocardial perfusion and metabolism in type 2 diabetes. Methods: Twenty-four type 2 diabetic patients-12 with coronary artery disease (CAD) and preserved left ventricular function and 12 with non-ischaemic heart failure (HF)-were enrolled in a cross-sectional study. Positron emission tomography (PET) was used to assess myocardial blood flow (MBF) at rest, after pharmacological stress and under euglycaemic hyperinsulinaemia. Insulin-mediated myocardial glucose disposal was determined with 2-deoxy-2-[F]fluoroglucose PET. Results: There was no difference in myocardial glucose uptake (MGU) between the healthy myocardium of CAD patients and the dysfunctional myocardium of HF patients. MGU was strongly influenced by levels of systemic insulin resistance in both groups (CAD, r = 0.85, p = 0.005; HF, r = 0.77, p = 0.01). In HF patients, there was an inverse association between MGU and the coronary flow reserve ( r = −0.434, p = 0.0115). A similar relationship was observed in non-ischaemic segments of CAD patients. Hyperinsulinaemia increased MBF to a similar extent in the non-ischaemic myocardial of CAD and HF patients. Conclusions/interpretation: In type 2 diabetes, similar metabolic and perfusion patterns can be detected in the non-ischaemic regions of CAD patients with normal cardiac function and in the dysfunctional non-ischaemic myocardium of HF patients. This suggests that insulin resistance, rather than diagnosis of ischaemia or left ventricular dysfunction, affects the metabolism and perfusion features of patients with type 2 diabetes. [ABSTRACT FROM AUTHOR]

The mechanisms responsible for the accelerated atherosclerosis observed in type 2 diabetes are not fully understood. One of the earliest events in the development of atherosclerosis is endothelial dysfunction, namely, a reduction in nitric oxide (NO) synthesis or its bioavailability within the peri-endothelial environment, where it is responsible for maintenance of vascular tissue integrity. The clinical evaluation of this pathway is hampered by the fact that in vivo NO cannot be directly measured; however, exploiting a novel, complex and elegant experimental setup, McVeigh and co-workers ( Diabetologia;35:771-776) were the first to document that NO bioavailability in type 2 diabetic patients is indeed reduced. In this edition of 'Then and now' that paper is reappraised not only for its originality, but also for the broad and extensive evaluation of the vascular functions explored, the complete clinical characterisation of patients enrolled and for the fact that all the major findings were subsequently replicated. [ABSTRACT FROM AUTHOR]

ims/hypothesis: Bariatric surgery consistently induces remission of type 2 diabetes. We tested whether there are diabetes-specific mechanisms in addition to weight loss. Methods: We studied 25 morbidly obese patients (BMI 51.7 ± 1.5 kg/m [mean ± SEM]), 13 with non-insulin-treated type 2 diabetes (HbA 7.1 ± 0.5% [54 ± 5 mmol/mol]), before and at 2 weeks and 1 year after Roux-en-Y gastric bypass (RYGB). Lean ( n = 8, BMI 23.0 ± 0.5 kg/m) and obese ( n = 14) volunteers who were BMI-matched (36.0 ± 1.2) to RYGB patients at 1 year after surgery served as controls. We measured insulin-stimulated glucose disposal ( M) and substrate utilisation (euglycaemic clamp/indirect calorimetry), endogenous glucose production (EGP) by 6,6-[H]glucose, lipolysis (rate of appearance of [H]glycerol) and beta cell function (acute insulin response to i.v. glucose [AIR] as determined by C-peptide deconvolution). Results: At baseline, all obese groups showed typical metabolic abnormalities, with M, glucose oxidation and non-oxidative disposal impaired, and EGP, lipolysis, lipid oxidation and energy expenditure increased. Early after RYGB plasma glucose and insulin levels, and energy expenditure had decreased, while lipid oxidation increased, with M, EGP and AIR unchanged. At 1 year post-RYGB (BMI 34.4 ± 1.1 kg/m), all diabetic patients were off glucose-lowering treatment and mean HbA was 5.4 ± 0.14% (36 ± 2 mmol/mol) ( p = 0.03 vs baseline); AIR also improved significantly. In all RYGB patients, M, substrate oxidation, EGP, energy expenditure and lipolysis improved in proportion to weight loss, and were therefore similar to values in obese controls, but still different from those in lean controls. Conclusions/interpretation: In morbidly obese patients, RYGB has metabolic effects on liver, adipose tissue, muscle insulin sensitivity and pattern of substrate utilisation; these effects can be explained by energy intake restriction and weight loss, the former prevailing early after surgery, the latter being dominant in the longer term. [ABSTRACT FROM AUTHOR]

ims/hypothesis: The natural history and physiological determinants of glucose intolerance in subjects living in Europe have not been investigated. The aim of this study was to increase our understanding of this area. Methods: We analysed the data from a population-based cohort of 1,048 non-diabetic, normotensive men and women (aged 30-60 years) in whom insulin sensitivity was measured by the glucose clamp technique ( M/ I index; average glucose infusion rate/steady-state insulin concentration) and beta cell function was estimated by mathematical modelling of the oral glucose tolerance test at baseline and 3 years later. Results: Seventy-seven per cent of the participants had normal glucose tolerance (NGT) and 5% were glucose intolerant both at baseline and follow up; glucose tolerance worsened in 13% (progressors) and improved in 6% (regressors). The metabolic phenotype of the latter three groups was similar (higher prevalence of familial diabetes, older age, higher waist-to-hip ratio, higher fasting and 2 h plasma glucose, higher fasting and 2 h plasma insulin, lower insulin sensitivity and reduced beta cell glucose sensitivity with increased absolute insulin secretion). Adjusting for these factors in a logistic model, progression was predicted by insulin resistance (bottom M/ I quartile, OR 2.52 [95% CI 1.51-4.21]) and beta cell glucose insensitivity (bottom quartile, OR 2.39 [95% CI 1.6-3.93]) independently of waist-to-hip ratio (OR 1.44 [95% CI 1.13-1.84] for one SD). At follow up, insulin sensitivity and beta cell glucose sensitivity were unchanged in the stable NGT and stable non-NGT groups, worsened in progressors and improved in regressors. Conclusions/interpretation: Glucose tolerance deteriorates over time in young, healthy Europids. Progressors, regressors and glucose-intolerant participants share a common baseline phenotype. Insulin sensitivity and beta cell glucose sensitivity predict and track changes in glucose tolerance independently of sex, age and obesity. [ABSTRACT FROM AUTHOR]

ims/hypothesis: In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance. Methods: A sample of 368 non-diabetic participants (age 43.0 ± 8.2 years, BMI 26.0 ± 4.0 kg/m; mean ± SD) whose endogenous glucose production (EGP) was measured with [6-6H]glucose in the fasting state and during the euglycaemic-hyperinsulinaemic clamp were included in the study. EGP multiplied by fasting plasma insulin (FPI) concentration was the reference measurement for liver insulin resistance (liver IR). Liver IR index was calculated with linear regression analysis including age, obesity indices, lipids, lipoproteins and several variables regulating glucose metabolism. Results: The following variables were significantly associated with liver IR in multiple forward stepwise regression analysis: insulin AUC in an OGTT, fat mass, HDL-cholesterol and BMI. Liver IR index correlated significantly with EGP×FPI ( r = 0.65, p < 0.001). In participants with abnormal glucose tolerance, the correlation of liver IR with EGP×FPI was slightly stronger ( r = 0.69, p < 0.001) than in those with normal glucose tolerance ( r = 0.62, p < 0.001). Conclusions/interpretation: We generated a novel surrogate index for liver insulin resistance correlating strongly with EGP × FPI. [ABSTRACT FROM AUTHOR]

ims/hypothesis: Of the confirmed type 2 diabetes susceptibility loci only a few are known to affect insulin sensitivity. We examined the association of indices of hepatic and adipocyte insulin resistance (IR) with 19 confirmed type 2 diabetes risk loci in a large population-based study. Methods: Non-diabetic participants ( n = 8,460, age 57.3 ± 7.0 years, BMI 26.8 ± 3.8 kg/m; mean ± SD) from a population-based cohort underwent an OGTT. Of them, 6,733 non-diabetic men were genotyped for single nucleotide polymorphisms (SNPs) in or near PPARG2 (also known as PPARG), KCNJ11, TCF7L2, SLC30A8, HHEX, CDKN2B, IGF2BP2, CDKAL1, HNF1B, WFS1, JAZF1, CDC123, TSPAN8, THADA, ADAMTS9, NOTCH2, KCNQ1, MTNR1B and SNP rs7480010 . We investigated hepatic IR with a new index of liver IR. The adipocyte IR index was defined as a product of fasting NEFA and plasma insulin levels. Results: Type 2 diabetes risk SNPs in or near KCNJ11 and HHEX were significantly ( p < 0.0013), and those in or near CDKN2B, NOTCH2 and MTNR1B were nominally ( p < 0.05), associated with decreased liver IR index. The Pro12 allele of PPARG2 was significantly associated with a high adipocyte IR index and nominally associated with high liver IR. Conclusions/interpretation: The Pro12 allele of PPARG2 seems to impair insulin's antilipolytic effect, leading to high NEFA release in the fasting state and IR. In addition, the type 2 diabetes risk alleles of KCNJ11 and HHEX, which are known to impair insulin secretion, were associated with increased hepatic insulin sensitivity. [ABSTRACT FROM AUTHOR]

It is commonly thought that hyperglycaemia results from insufficient compensation of insulin secretion for insulin resistance. To verify this hypothesis, we assessed beta cell function and insulin sensitivity (IS) in a large cohort of volunteers with normal glucose tolerance (NGT) or impaired glucose regulation (IGR), i.e. impaired glucose tolerance or impaired fasting glucose. In men and women with NGT ( n = 1,123) or IGR ( n = 156) (age 44 ± 8 years, BMI 25 ± 4 kg/m2, mean ± SD) we measured: (1) IS by clamp; (2) insulin secretion rates (ISR) and beta cell glucose sensitivity (=slope of the insulin secretion/plasma glucose dose–response) by C-peptide deconvolution and OGTT modelling; and (3) acute insulin response to intravenous glucose. After controlling for centre, sex, age and BMI, fasting and total ISR were inversely related to IS in both groups, whereas beta cell glucose sensitivity was not. Acute insulin response was reciprocally related to IS in both groups, but the relationships were incompatible with inadequate compensation and significance was lost after controlling for fasting ISR. In IGR vs NGT, IS was impaired (92 [75] vs 133 [86] μmol min−1 [kg fat-free mass]−1 [nmol/l]−1, median [interquartile range], p < 0.0001) as was beta cell glucose sensitivity (69 [46] vs 119 [83] pmol min−1 m−2 [nmol/l]−1, p < 0.0001), whereas fasting and total ISR were increased (35% and 25%, respectively, p < 0.0001). In fully adjusted models, beta cell glucose sensitivity was the strongest determinant of OGTT glucose levels. Insulin resistance normally upregulates the secretory tone, with no evidence of defective compensation in IGR. In contrast, beta cell glucose sensitivity is independent of insulin resistance, but a key determinant of glucose tolerance. This suggests that hyperglycaemia results from an intrinsic beta cell defect rather than from inadequate compensation for insulin resistance. [ABSTRACT FROM AUTHOR]

The predisposition to thrombogenesis is increased in essential hypertension, and hypertensive patients are prone to develop more vulnerable atherosclerotic plaques. To evaluate the possible influence of family history of hypertension on some indicators of early atherosclerosis, we studied eighty-five healthy normotensive individuals with (FH+) or without (FH−) family history of essential hypertension by measuring metabolic profile and concentrations of P-selectin, interleukin 6 and matrix metalloproteinase (MMP)-2, MMP-9, and tissue inhibitor of metalloproteinase (TIMP)-1. In a subset of individuals, MMP-9 activity was assessed in monocytes by zymography, and TIMP-1 expression by western blot. As compared with FH− individuals, FH+ individuals had significantly higher P-selectin but similar interleukin-6 levels. Although no difference was observed in MMP-2 levels between the two groups, MMP-9 and TIMP-1 were higher in FH+ individuals, who also had higher intracellular MMP-9 levels and TIMP-1 protein expression. P-selectin (r=−0.32; P<0.01), MMP-9 (r=−0.37; P<0.001) and TIMP-1 (r=−0.23; P<0.05) levels were inversely related to high density lipoprotein (HDL) cholesterol. P-selectin was also directly related to serum triglycerides (r=0.30; P<0.01). We conclude that a positive family history of hypertension is associated with an initial increase in markers of inflammation and plaque instability in otherwise healthy young normotensive individuals, likely conveying a predisposition to develop early atherothrombosis. [ABSTRACT FROM AUTHOR]

Objective:Increased thyroid-stimulating hormone (TSH) and FT3 levels are often found in clinically euthyroid obese individuals. Information on thyroid gene expression in human adipose tissue is scarce. The objective of this study was to measure the expression of the TSH receptor (TSHR) and the thyroid hormone receptor (TRα1) genes in subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) in obese individuals and to test the effect of weight loss on these genes.Study Design and Participants:This study is a prospective study involving 107 obese (body mass index (BMI)=46±8 kg m−2, 52 with type 2 diabetes or impaired glucose tolerance) and 12 lean nondiabetic participants. A total of 27 obese patients were restudied 1 year after gastric bypass surgery. Total RNA was extracted from SAT and VAT obtained at baseline from all participants, and from SAT in obese patients post surgery.Results:Circulating TSH and FT3 levels were 170 and 36%, respectively, higher in obese patients than in controls. In SAT, TSHR and TRα1 were reduced in the obese by 67 and 33%, respectively, regardless of glucose tolerance. A similar trend was found in VAT. Post surgery, a BMI decrease of 33% was associated with a decrease in TSH and FT3 levels and with a 150 and 70% increase in SAT of TSHR and TRα1, respectively.Conclusion:In both subcutaneous and visceral fat, the thyroid gene expression (especially TSHR) is reduced in obesity. The reversal of these changes with major weight loss and the reciprocal changes in plasma TSH and FT3 levels suggest a role for adipocytes in the regulation of TSH and thyroid hormones. [ABSTRACT FROM AUTHOR]

The value of diagnostic categories of glucose intolerance for predicting type 2 diabetes is much debated. We therefore sought to estimate relative and population-attributable risk of different definitions based on fasting (impaired fasting glucose [IFG]) or 2 h plasma glucose concentrations (impaired glucose tolerance [IGT]) and to describe the associated clinical phenotypes. We prospectively observed a population-based cohort of 1,963 non-diabetic participants (mean age 47 years), in whom an OGTT was performed at baseline and 7 years later. IGT was fivefold more prevalent (13.5%) than IFG. In both categories, participants were older, heavier, hyperinsulinaemic, hyperproinsulinaemic and dyslipidaemic compared with participants with normal glucose tolerance. Relative risk of incident diabetes was similar for IFG and IGT categories (3.73 [95% CI: 2.18–6.39] and 4.01 [95% CI: 3.12–5.14], respectively), but the population-attributable risk was fivefold higher for IGT (29% [95% CI: 26–32]) than for IFG (6% [95% CI: 5–7]). Isolated IFG carried no increase in risk. Lowering the threshold to 5.6 mmol/l raised the population-attributable risk of IFG to 23% (95% CI: 20–25); its contribution to diabetes progression, however, was largely due to co-existent IGT. In multivariate analysis adjusting for sex, age, familial diabetes and BMI, fasting and 2 h glucose were independent predictors. Fasting and 2 h glucose values are independent predictors of incident diabetes. Isolated IFG is not a high-risk condition; lowering the diagnostic threshold increases the population-attributable risk of IFG fourfold, but performing an OGTT captures additional diabetes progressors compared with the number identified by IFG. [ABSTRACT FROM AUTHOR]

The consensus algorithm for the medical management of type 2 diabetes was published in August 2006 with the expectation that it would be updated, based on the availability of new interventions and new evidence to establish their clinical role. The authors continue to endorse the principles used to develop the algorithm and its major features. We are sensitive to the risks of changing the algorithm cavalierly or too frequently, without compelling new information. An update to the consensus algorithm published in January 2008 specifically addressed safety issues surrounding the thiazolidinediones. In this revision, we focus on the new classes of medications that now have more clinical data and experience. [ABSTRACT FROM AUTHOR]

Moderate obesity is known to be associated with multiple endocrine abnormalities. Less information is available on the hormonal status of patients with morbid obesity and on the effects of major weight loss. We studied 16 severely obese (BMI 40.6–69.9 kg/m2) nondiabetic patients and 7 nonobese (BMI range 24.6–27.7 kg/m2), sex- and age-matched healthy volunteers. During 24 h in a metabolic ward, four meals were administered and hourly blood samples were drawn from a central venous catheter for the measurement of glucose, insulin, leptin, thyrotropic hormone (TSH), growth hormone (GH) and prolactin. Insulin sensitivity was measured by a euglycaemic hyperinsulinaemic clamp. Studies were repeated 6 months after biliopancreatic diversion, a mainly malabsorptive surgical approach, which caused an average weight loss of 35±4 kg (or 26±2% of initial weight). Compared with controls, patients were hyperinsulinaemic (290±31 vs 88±4 pmol l−1, P=0.0002), insulin resistant (23.5±2.8 vs 52.9±4.9 μmol min−1 kgFFM−1, P=0.0006) and hyperleptinaemic (52.5±5.8 vs 10.9±3 ng ml−1, P=0.0002). Plasma TSH levels were increased throughout the day–night cycle (averaging 2.02±0.18 vs 1.09±0.19 μU ml−1 of controls, P=0.01), whereas serum GH levels were suppressed (0.46±0.10 vs 3.01±1.15, P=0.002). Following surgery, the hyperinsulinaemia and insulin resistance were fully normalized; in concomitance with a major drop in leptin levels (to 14.4±2.7 ng ml−1, P=0.02), TSH decreased and GH increased to near-normal levels. In the whole dataset, mean 24-h leptin levels were directly related to mean 24-h TSH levels after controlling for confounders this relationship was lost only after adjusting for fat mass. We conclude that in morbid obesity leptin is a determinant of changes in pituitary function.International Journal of Obesity (2009) 33, 166–172; doi:10.1038/ijo.2008.226; published online 9 December 2008 [ABSTRACT FROM AUTHOR]

Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals. A total of 1,211 non-diabetic individuals underwent metabolic assessment including an OGTT, from which measures of beta cell function were derived. Individuals were genotyped at each of the risk loci and then classified according to the total number of risk alleles that they carried. Initial analysis focused on CDKAL1, HHEX/IDE and TCF7L2 loci, which were individually associated with a decrease in beta cell function in our cohort. Risk alleles for CDKN2A/B, SLC30A8, IGF2BP2 and KCNJ11 loci were subsequently included into the analysis. The diabetes-risk alleles for CDKAL1, HHEX/IDE and TCF7L2 showed an additive model of association with measures of beta cell function. Beta cell glucose sensitivity was decreased by 39% in those individuals with five or more risk alleles compared with those individuals with no risk alleles (geometric mean [SEM]: 84 [1.07] vs 137 [1.11] pmol min−1 m−2 (mmol/l)−1, p = 1.51 × 10−6). The same was seen for the 30 min insulin response ( p = 4.17 × 10−7). The relationship remained after adding in the other four susceptibility loci (30 min insulin response and beta cell glucose sensitivity, p < 0.001 and p = 0.003, respectively). This study shows how individual type 2 diabetes-risk alleles combine in an additive manner to impact upon pancreatic beta cell function in non-diabetic individuals. [ABSTRACT FROM AUTHOR]

Inflammation is a mechanism of glomerular damage in chronic glomerulopathies. LDL may increase the production of inflammatory cytokines in renal tissues. However, the relative role of native, oxidised and glycated LDL in promoting this process has been only partially elucidated. We tested the inflammatory and proapoptotic effects of native, oxidised and glycated LDL in human mesangial cells (HMCs) by measuring levels of IL6, CD40 and macrophage migration inhibitory factor (MIF) genes, MIF protein, release of IL6, soluble CD40, fibronectin and laminin, early and late apoptosis, and extracellular regulated kinases (ERK) 1/2 and c-Jun N-terminal kinase (JNK) activation. IL6 and CD40 mRNA were dose-dependently upregulated by all three species; this was closely paralleled by their increased release. MIF mRNA was potently stimulated by modified LDL, as confirmed by immunostaining. Fibronectin and laminin release was stimulated by both oxidised and glycated, but not native, LDL. All LDL species induced some increase in late, but not early, apoptosis, and similarly activated JNK2/3 phosphorylation; in contrast, ERK1/2 phosphorylation was more strongly upregulated by oxidised than either native or glycated LDL. In HMCs, the production and release of IL6 and CD40 is stimulated by both native and modified LDL, while MIF is more strongly stimulated by oxidised LDL. Regarding the pattern of mesangial expansion, fibronectin and laminin are upregulated by oxidised and glycated LDL. Apoptosis, if modest, is induced by all species. Intracellular signalling of native and modified LDL involves JNK2/3 and, perhaps more specifically, ERK1/2. Tight control of the lipid profile may be useful in preserving kidney function in patients with metabolic alterations. [ABSTRACT FROM AUTHOR]

Hyperglycaemia and hyperinsulinaemia have opposite effects on endothelium-dependent vasodilatation in microcirculation, but the net effect elicited by glucose ingestion and the separate influence of glucose tolerance are unknown. In participants with normal glucose tolerance (NGT), impaired glucose tolerance (IGT) or diabetic glucose tolerance, multiple plasma markers of both oxidative stress and endothelial activation, and forearm vascular responses (plethysmography) to intra-arterial acetylcholine (ACh) and sodium nitroprusside (SNP) infusions were measured before and after glucose ingestion. In another IGT group, we evaluated the time-course of the skin vascular responses (laser Doppler) to ACh and SNP (by iontophoresis) 1, 2 and 3 h into the OGTT; the plasma glucose profile was then reproduced by means of a variable intravenous glucose infusion and the vascular measurements repeated. Following oral glucose, plasma antioxidants were reduced by 5% to 10% ( p < 0.01) in all patient groups. The response to acetylcholine was not affected by glucose ingestion in any group, while the response to SNP was attenuated, particularly in the IGT group. The ACh:SNP ratio was slightly improved therefore in all groups, even in diabetic participants, in whom it was impaired basally. A time-dependent improvement in ACh:SNP ratio was also observed in skin microcirculation following oral glucose; this improvement was blunted when matched hyperglycaemia was coupled with lower hyperinsulinaemia (intravenous glucose). Regardless of glucose tolerance, oral glucose does not impair endothelium-dependent vasodilatation either in resistance arteries or in the microcirculation, despite causing increased oxidative stress; the endogenous insulin response is probably responsible for countering any inhibitory effect on vascular function. [ABSTRACT FROM AUTHOR]

Both energy restriction (ER) per se and weight loss improve glucose metabolism in obese insulin-treated type 2 diabetic patients. Short-term ER decreases basal endogenous glucose production (EGP) but not glucose disposal. In contrast the blood glucose-lowering mechanism of long-term ER with substantial weight loss has not been fully elucidated. The aim of this study was to investigate the effect of loss of 50% of excess weight [50% excess weight reduction (EWR)] on EGP, whole-body insulin sensitivity and the disturbed myocellular insulin-signalling pathway in ten obese insulin-treated type 2 diabetic patients. A euglycaemic–hyperinsulinaemic clamp with stable isotopes ([6,6-2H2]glucose and [2H5]glycerol) combined with skeletal muscle biopsies was performed during a very low energy diet (VLED; 1,883 kJ/day) on day 2 and again after 50% EWR. Oral blood glucose-lowering agents and insulin were discontinued 3 weeks prior to the VLED and at the start of the VLED, respectively. Loss of 50% EWR (20.3 ± 2.2 kg from day 2 to day of 50% EWR) normalised basal EGP and improved insulin sensitivity, especially insulin-stimulated glucose disposal (18.8 ± 2.0 to 39.1 ± 2.8 μmol kg fat-free mass−1 min−1, p = 0.001). The latter was accompanied by improved insulin signalling at the level of the recently discovered protein kinase B/Akt substrates AS160 and PRAS40 along with a decrease in intramyocellular lipid (IMCL) content. Considerable weight loss in obese, insulin-treated type 2 diabetic patients normalises basal EGP and improves insulin sensitivity resulting from an improvement in insulin signal transduction in skeletal muscle. The decrease in IMCL might contribute to this effect. [ABSTRACT FROM AUTHOR]

Objective:To investigate whether adiponectin receptor genes (AdipoR1 and AdipoR2) expression in human subcutaneous (SAT) and visceral (VAT) adipose tissue in severely obese patients with or without diabetes is related to adiponectin gene (APM1) expression and in vivo metabolic parameters.Design:Cross-sectional, clinical research study.Subjects:Total RNA was extracted from SAT and VAT tissue obtained during surgery from 13 lean controls, 30 obese diabetic patients, 19 obese glucose-intolerant patients and 54 obese subjects with normal glucose tolerance.Measurements:Tissue expression of APM1, AdipoR1 and AdipoR2, tissue concentration of adiponectin (ApN), and metabolic variables.Results:APM1 expression was higher in SAT than VAT (1.06±0.76 vs 0.69±0.52, P<0.0001) as was AdipoR1 (1.17±0.70 vs 0.66±0.38, P<0.0001) and AdipoR2 (7.02±6.19 vs 0.75±0.64, P<0.0001). In SAT, APM1 and AdipoR1 expression tended to be lower – by 0.38±0.22 and 0.35±0.22, respectively – and AdipoR2 expression was markedly depressed – by 4.82±1.93 – in association with obesity, whereas presence of diabetes had no additional effect. In VAT, APM1 and AdipoR1 expressions were also reduced – by 0.36±0.16 and 0.30±0.11, respectively – in association with obesity. Within both SAT and VAT, expression levels of APM1, AdipoR1 and AdipoR2 were all positively interrelated. Tissue ApN concentrations in SAT were similar across groups, whereas ApN levels in VAT were substantially lower in association with obesity (by an average of 63±12 ng/mg total protein, P<0.0001). In multivariate models adjusting for sex, age and obesity, serum triglyceride concentrations were reciprocally related to APM1 (r=−0.27, P<0.02), AdipoR1 (r=−0.37, P<0.002 and AdipoR2 expression (r=−0.37, P<0.002) in VAT. Likewise, plasma insulin concentrations were inversely related only to APM1 in VAT (r=−0.25, P<0.03).Conclusions:Severe obesity is associated with suppressed expression of both ApN and its receptors in both SAT and VAT, the expression levels in VAT are specifically linked with hyperinsulinemia and dyslipidemia.International Journal of Obesity (2007) 31, 1843–1848; doi:10.1038/sj.ijo.0803676; published online 3 July 2007 [ABSTRACT FROM AUTHOR]

Hyperproinsulinaemia and relative hyperglucagonaemia are features of type 2 diabetes. We hypothesised that raised fasting glucagon and proinsulin concentrations may be associated with insulin resistance (IR) in non-diabetic individuals. We measured IR [by a euglycaemic–hyperinsulinaemic (240 pmol min−1 m−2) clamp technique] in 1,296 non-diabetic (on a 75 g OGTT) individuals [716 women and 579 men, mean age 44 years, BMI 26 kg/m2 (range 18–44 kg/m2)] recruited at 19 centres in 14 European countries. IR was related to fasting proinsulin or pancreatic glucagon concentrations in univariate and multivariate analyses. Given its known relationship to IR, serum adiponectin was used as a positive control. In either sex, both glucagon and proinsulin were directly related to IR, while adiponectin was negatively associated with it (all p < 0.0001). In multivariate models, controlling for known determinants of insulin sensitivity (i.e . sex, age, BMI and glucose tolerance) as well as factors potentially affecting glucagon and proinsulin (i.e. fasting plasma glucose and C-peptide concentrations), glucagon and proinsulin were still positively associated, and adiponectin was negatively associated, with IR. Finally, when these associations were tested as the probability that individuals in the top IR quartile would have hormone levels in the top quartile of their distribution independently of covariates, the odds ratio was ∼2 for both glucagon ( p = 0.05) and proinsulin ( p = 0.02) and 0.36 for adiponectin ( p < 0.0001). Whole-body IR is independently associated with raised fasting plasma glucagon and proinsulin concentrations, possibly as a result of IR at the level of alpha cells and beta cells in pancreatic islets. [ABSTRACT FROM AUTHOR]

Gestational diabetes (GDM) carries a high risk of subsequent diabetes. We asked what impact prior GDM has on beta cell function and insulin action in women who maintain normal glucose tolerance (NGT) for a long time. Ninety-one women with NGT (aged 41 ± 8 years, mean±SD) were studied (by mathematical modelling of the C-peptide response to an OGTT) 7 [6] years (median [interquartile range]) after the index pregnancy, during which 52 had GDM (pGDM) and 39 had NGT (pNGT). In all women an OGTT had also been performed at 29 ± 3 weeks of the index pregnancy. Women with pGDM were matched with women with pNGT for age, familial diabetes, time and weight gain since index pregnancy, parity, BMI (25.4 ± 3.9 vs 26.8 ± 6.4 kg/m2), and fasting (4.64 ± 0.56 vs 4.97 ± 0.46 mmol/l) and 2 h plasma glucose levels (5.91 ± 1.14 vs 5.91 ± 1.21 mmol/l). Nonetheless, fasting (49 [29] vs 70 [45] pmol min−1 m−2, p < 0.001) and total insulin secretion (32 [17] vs 48 [21] nmol m−2, p < 0.0001) and beta cell glucose sensitivity (slope of the insulin secretion/plasma glucose concentration–response function) (95 [71] vs 115 [79] pmol min−1 m−2 (mmol/l)−1, p = 0.025) were reduced in the pGDM group compared with the pNGT group, while insulin sensitivity was preserved (424 [98] vs 398 [77] ml min−1 m−2). At index pregnancy, women with pGDM and those with pNGT had similar age and BMI. However, both insulin sensitivity (359 [93] vs 417 [92] ml min−1 m−2, p = 0.0012) and the insulin/glucose incremental area ratio (an empirical index of beta cell function; 98 [74] vs 138 [122] pmol/mmol, p = 0.028) were reduced in women with pGDM. Even in women who maintain normal insulin sensitivity, impaired beta cell function is carried over into the NGT status several years after a GDM pregnancy. [ABSTRACT FROM AUTHOR]

Atherosclerosis is particularly aggressive in patients with diabetes. Hyperhomocysteinaemia causes oxidative stress and cytokine secretion: its atherogenic effect is mediated by an enhanced inflammatory response. Matrix metalloproteinases (MMPs) regulate extracellular matrix degradation and remodelling, and contribute to the vulnerability of the atherosclerotic lesion. Fibroblasts contribute to collagen biosynthesis and participate in plaque remodelling via expression and release of MMP2 and MMP9. To explore the role of hyperhomocysteinaemia in cellular pathways involved in plaque growth and stability in diabetic patients, we studied the effect of hyperhomocysteinaemia in human fibroblasts grown in the presence of normal or high glucose concentrations. In fibroblasts of five normal subjects, grown at 5.5 or 22 mmol/l glucose and treated with homocysteine, we determined: (1) MMP2, MMP9 and tissue inhibitor of metalloproteinases (TIMP)-1 (an MMP inhibitor) production by western blot analysis; (2) their activity by zymography; (3) TGFB1 expression by real-time PCR; and (4) TGFB, fibronectin and IL6 release by ELISA. Hyperhomocysteinaemia increased the production and enzymatic activity of MMP2 and MMP9, the effect being more pronounced in high glucose. Conversely, TIMP1 production was reduced by hyperhomocysteinaemia in both conditions, especially in high glucose. Hyperhomocysteinaemia also stimulated IL6 release, at least in part through nuclear factor-κB activation. TGFB1 expression was not affected by hyperhomocysteinaemia either in normal or in high glucose. Homocysteine upregulates the MMP–TIMP pathway and IL6 release, the effect being stronger in the presence of high glucose. These actions of homocysteine may contribute to the increased atherogenesis observed in diabetic patients with poor metabolic control. [ABSTRACT FROM AUTHOR]

Aims/hypothesis The aim of this study was to analyse the mechanisms underlying the improvement in glucose tolerance seen in morbidly obese patients undergoing biliopancreatic diversion (BPD). Subjects and methods We evaluated glucose tolerance (by OGTT), insulin sensitivity (euglycaemic-hyperinsulinaemic clamp and the OGTT index OGIS) and beta cell function (OGTT modelling analysis) in 32 morbidly obese (BMI=52± 7 kg/m², mean±SD) patients (12 with NGT, 9 with IGT and 11 with type 2 diabetes), before and after BPD, and in 22 lean control subjects. Patients were studied before and from 7 days to 60 months after surgery. Results BPD improved glucose tolerance in all subjects, who after surgery all had normal glucose tolerance. Insulin sensitivity was restored to normal levels in all subjects (pre-BPD 341±79 ml min-1 m-2, post-BPD 511±57 ml min-1 m-2, lean 478±49 ml min-1 m-2). The insulin sensitivity change was detectable within 10 days of BPD. At baseline, beta cell sensitivity to glucose was impaired in diabetic subjects (25 [18] pmol min-1 m-2 l mmol-1, median [interquartile range]) compared with lean subjects (82 [98]; p≤0.05). After BPD, beta cell glucose sensitivity showed a tendency towards improvement but remained impaired in diabetic subjects (30 [62]; p<0.01 vs lean). Total insulin output decreased in parallel with the insulin sensitivity increase in all groups. In the whole patient group, mean OGTT glucose levels were inversely related to both insulin sensitivity and beta cell glucose sensitivity (r²=0.67, partial r=-0.76 and -0.41, respectively). NEFAs, leptin and adiponectin were related to insulin sensitivity but could not explain the early improvement. Conclusions/interpretation Following BPD, glucose tolerance was restored mainly as a result of a rapid and large improvement in insulin sensitivity. [ABSTRACT FROM AUTHOR]

Objective:Inflammation plays a pivotal role in the atherosclerotic process, and some chemokines seem to be crucial in the pathogenesis of vascular damage. High-serum homocysteine, recently recognized as an independent risk factor for vascular disease might increase cytokine and chemokine levels, thus amplifying endothelial damage; moreover, it might worse insulin resistance, thus further contributing to enhance cardiovascular risk. The effect of folic acid supplementation in improving in vivo endothelial function is still debated. In this study, we investigated the effect of folic acid supplementation on insulin sensitivity and peripheral markers of inflammation in overweight healthy subjects.Design:The study was performed as an unmasked randomized placebo-controlled trial of 12 weeks duration.Subjects:Sixty healthy volunteers with normal glucose tolerance and BMI between 25 and 29 kg/m2 were enrolled.Measurements:Biochemical parameters and plasma concentrations of homocysteine and of some inflammatory molecules were measured at baseline and at the end of the study, together with an estimation of insulin sensitivity.Results:Subjects receiving folic acid supplementation showed a decrement of homocysteine and an amelioration of insulin sensitivity; this treatment was also associated with a significant drop in the circulating concentration of monocyte chemoattractant protein-1, interleukin-8 and C-reactive protein, in the absence of any significant variation of BMI or fat mass.Conclusions:In healthy overweight subjects a short-term folic acid supplementation reduces the circulating level of some inflammatory mediators independently of weight change, thus suggesting a potential therapeutic role for folic acid in the protection from atherogenesis and cardiovascular diseases.International Journal of Obesity (2006) 30, 1197–1202. doi:10.1038/sj.ijo.0803265; published online 21 February 2006 [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Insulin resistance, which manifests itself as endogenous glucose overproduction and reduced insulin-mediated glucose uptake, is a core defect in type 2 diabetes. Metformin and the peroxisome proliferator-activated receptor-? agonists, the thiazolidinediones (TZDs), both lower glucose, although their mechanism of action is still subject to debate. This review analyses the evidence relevant to these mechanisms in vivo. Materials and methods: A systematic search of MEDLINE identified a total of 42 clinical studies that investigated the effects of TZDs (n=23) and/or metformin (n=19) on endogenous glucose production (using tracer glucose techniques) and peripheral glucose disposal (using the euglycaemic-hyperinsulinaemic clamp) in patients with type 2 diabetes (n=549). The original variables assessed were converted into standardised units and their mean group values were listed separately for open and placebo-controlled studies. Statistical analysis was carried out, treating mean group values as individual values and comparing results (both as absolute values and percentage changes from baseline) across study categories (open vs placebo-controlled, TZDs vs metformin). Results: Both TZDs and metformin enhance insulin suppression of endogenous glucose production and fasting plasma glucose clearance. TZDs, but not metformin, also improve insulin-mediated glucose uptake at all insulin levels. Conclusions/interpretation: In patients with type 2 diabetes, metformin improves fasting hepatic insulin sensitivity and glucose clearance; TZDs improve fasting hepatic insulin sensitivity and glucose clearance, and potentiate glucose disposal under insulinised conditions. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: The aim of this prospective study was to investigate predictors of deteriorating glucose tolerance in subjects of British extraction. Methods: A total of 156 non-diabetic subjects (86 with a family history of type 2 diabetes) underwent a 75-g OGTT and anthropometric assessment at baseline and 5 years later. Pancreatic beta cell function and whole-body insulin sensitivity were studied by model assessment. Subjects were classified as progressors if glucose tolerance moved one or more steps from normal, impaired fasting glucose, impaired glucose tolerance and diabetes over the follow-up period. Results: At baseline, the progressors (n=22) had increased adiposity and a higher proportion of familial diabetes and abnormal glucose tolerance than non-progressors. Baseline pancreatic beta cell sensitivity to changes in glucose (p«0.02) and whole-body insulin sensitivity (p«0.0001) were decreased in the progressors. Logistic regression revealed that baseline and follow-up changes in beta cell glucose sensitivity and insulin sensitivity, rather than the classical clinical predictors (adiposity, familial diabetes and glucose levels), were the key independent predictors of progression (explaining over 50%of the progression). Conclusions/ interpretation: Impaired pancreatic beta cell glucose sensing and whole-body insulin sensitivity predict progression to hyperglycaemia. Strikingly, these pathophysiological changes override the importance of the clinical risk factors and highlight potential metabolic targets for prevention strategies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis: Preferential visceral adipose tissue (VAT) accumulation has been clearly associated with insulin resistance. In contrast, the impact of visceral obesity on beta cell function is controversial. Methods: In 62 non-diabetic women and men (age 24–69 years, BMI 21–39 kg/m²), we measured VAT and subcutaneous adipose tissue (SAT) fat mass by magnetic resonance imaging. We also measured insulin secretion and beta cell function by C-peptide deconvolution and physiological modelling of data from a frequently sampled, 75-g, 3-h OGTT, respectively. Results: VAT (range 0.1–3.1 kg) was strongly related to sex, age and BMI; SAT was related to sex and BMI. Controlling for sex, age, BMI and SAT by multivariate analysis, excess VAT was associated with a clinical phenotype comprising higher plasma glucose levels, BP, heart rate and serum transaminases. The corresponding metabolic phenotype consisted of insulin resistance (partial r=-0.38) and hyperinsulinaemia (partial r=0.29). The latter, however, was appropriate for the degree of insulin resistance regardless of obesity and abdominal fat distribution. Moreover, none of the model-derived parameters describing beta cell function (glucose sensitivity, rate sensitivity and potentiation) was independently associated with excess VAT. Conclusions/interpretation: In non-diabetic Caucasian adults of either sex, preferential visceral fat deposition in itself is part of an insulin-resistant phenotype. The insulin secretory response to a physiological challenge is increased to fully compensate for the insulin resistance, but the dynamics of beta cell function (glucose sensitivity, rate sensitivity and potentiation) are largely preserved. curve . AUCI: AUC for insulin concentration curve . AUCNEFA: AUC for NEFA concentration curve . FSIVGTT: frequently sampled IVGTT . MRI: magnetic resonance imaging . SAT: subcutaneous adipose tissue . SI: insulin sensitivity . VAT: visceral adipose tissue. [ABSTRACT FROM AUTHOR]

Background: The term ‘metabolic syndrome’ refers to a clustering of specific cardiovascular disease (CVD) risk factors whose underlying pathophysiology is thought to be related to insulin resistance. Methods: Since the term is widely used in research and clinical practice, we undertook an extensive review of the literature in relation to the syndrome's definition, underlying pathogenesis, association with cardiovascular disease and to the goals and impact of treatment. Discussion: While there is no question that certain CVD risk factors are prone to cluster, we found that the metabolic syndrome has been imprecisely defined, there is a lack of certainty regarding its pathogenesis, and there is considerable doubt regarding its value as a CVD risk marker. Our analysis indicates that too much critically important information is missing to warrant its designation as a ‘syndrome’. Conclusion: Until much-needed research is completed, clinicians should evaluate and treat all CVD risk factors without regard to whether a patient meets the criteria for diagnosis of the ‘metabolic syndrome’. [ABSTRACT FROM AUTHOR]

Aims/Hypothesis: Non-alcoholic fatty liver dis- ease (NAFLD) has been associated with the metabolic syndrome. However, it is not clear whether insulin resistance is an independent feature of NAFLD, and it remains to be determined which of the in vivo actions of insulin are im- paired in this condition. Methods: We performed a two- step (1.5 and 6 pmol min1 kg1) euglycaemic insulin clamp coupled with tracer infusion ([6,6-2H2]glucose and [2H5] glycerol) and indirect calorimetry in 12 non-obese, normolipidaemic, normotensive, non-diabetic patients with biopsy-proven NAFLD and six control subjects. Results: In NAFLD patients, endogenous glucose production (basal and during the clamp) was normal; however, peripheral glucose disposal was markedly decreased (by 30% and 45% at the low and high insulin doses, respectively, p

Aims/hypothesis. We investigated the effect of elevated circulating NEFA on insulin-mediated hepatic glucose uptake (HGU) and whole-body glucose disposal (M) in eight healthy male subjects. Methods. Studies were performed using positron emission tomography (PET) and [18F]-2-fluoro-2-deoxyglucose ([18F]FDG) during euglycaemic hyperinsulinaemia (0–120 min) and an Intralipid/heparin infusion (IL/Hep; -90–120 min). On a different day, similar measurements were taken during euglycaemic hyperinsulinaemia and saline infusion (SAL). Graphical and compartmental analyses were used to model liver data. Results. Circulating NEFA increased approximately three-fold during IL/Hep, and declined by 81±7% in the SAL study (p≤0.01). Both M (-28±7%) and HGU (-25±9%) were significantly lowered by NEFA elevation (p=0.004 and p=0.035 respectively). In the whole data set, the decreases in M and HGU were positively correlated (r=0.78, p=0.038). No evidence of [18F]FDG outflow was detected during the scanning time. HGU was correlated with the phosphorylation rate parameter (r=0.71, p=0.003) as derived by compartmental modelling. Conclusions/interpretation. In healthy men, NEFA impair insulin-mediated HGU and whole-body glucose uptake to a similar extent. Our data suggest that multiple intracellular NEFA targets may concur to down-regulate glucose uptake by the liver. [ABSTRACT FROM AUTHOR]

The importance of both insulin resistance and beta cell dysfunction in the pathogenesis of glucose intolerance is widely recognised. Also popular is the concept that beta cell secretory function must be viewed in the context of extant insulin resistance. This For Debate moves from the premise that, whilst insulin action in vivo can be measured directly by a variety of essentially coherent techniques, measurement of beta cell function is more problematic. We therefore concisely survey the principal in vivo techniques that explore the diverse aspects of beta cell function and conclude that: (i) inter-correlation of clinical tests is only modest in non-diabetic subjects and poor in diabetic individuals; (ii) no single clinical test allows beta cell function to be assessed with accuracy and specificity comparable to those of insulin sensitivity; and (iii) short of complex experiments, mathematical modelling is necessary to interpret insulin secretory responses. Next we discuss the hyperbola paradigm used to describe the reciprocal relation of beta cell function to insulin sensitivity and suggest that: (i) insulin responses reflecting the basal beta cell tone are indeed inversely related to insulin action across degrees of glucose intolerance; (ii) modes of beta cell function that selectively reflect the dynamic response to acutely changing glucose concentrations are largely independent of insulin action; and (iii) when measured by experiment or resolved by modelling, quantitatively the most important of these dynamic secretion parameters is the glucose dose-response curve (glucose sensitivity). In fact, glucose excursions following glucose ingestion (i.e. glucose tolerance) are best explained by dynamic parameters of beta cell function. [ABSTRACT FROM AUTHOR]

Type I interferons are currently used for the treatment of chronic viral hepatitis, multiple sclerosis and several hematological and solid tumors. Side effects are not uncommon, and include multiple alterations in thyroid function, some of which are unrelated to autoimmunity. Review of the literature revealed an overall mean prevalence of incident thyroid dysfunction of 6.2%, hypothyroidism occurring more frequently (3.9%) than hyperthyroidism (2.3%). Destructive thyroiditis characterized by early transient thyrotoxicosis followed by hypothyroidism has also been described. Thyroid dysfunction was mainly subclinical, and spontaneous resolution occurred in almost 60% of patients with or without withdrawal of interferon. Risk factors for developing thyroid abnormalities were female sex and the presence of pre-existing autoimmune thyroiditis. Whether prolonged interferon therapy will increase the likelihood of experiencing thyroid dysfunction, as well as the relationship between incident thyroid autoimmunity and the efficacy of interferon therapy, are still open questions. Although the most-likely explanation for thyroid disease occurring with type I interferon therapy remains an autoimmune reaction or immune system dysregulation, a direct inhibitory effect on thyrocytes may be presumed in patients who developed hypothyroidism without autoimmunity. However, the mechanisms of thyroid damage induced by type I interferons have not yet been clarified in detail. We recommend routine evaluation of serum thyroid-stimulating hormone during interferon therapy. A systematic thyroid assessment is useful only for those patients with pre-existing thyroiditis or incident dysfunction. Although discontinuation of interferon therapy is seldom required, it may be necessary in patients who develop Graves’ disease and overt hyperthyroidism. [ABSTRACT FROM AUTHOR]

Aims/hypotheses. Insulin resistance is thought to be a key predictor for the development of Type 2 diabetes mellitus and cardiovascular disease (CVD), a leading cause of morbidity and premature mortality in Europe. Insulin resistance is influenced by both genetic and lifestyle factors (e.g. obesity and physical inactivity). The RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) Study is using the infrastructure of an extended European collaborative research group to study insulin resistance and CVD risk in 1500 healthy people aged 30 to 60 years from 20 centres in 13 countries. Methods. Baseline measurements of glucose tolerance and insulin sensitivity are made by the oral glucose tolerance test and the euglycaemic insulin clamp, respectively; carotid artery intima-medial thickness (by ultrasound), ankle/brachial pressure index and electrocardiography will enable evaluation of subclinical CVD at baseline and at follow-up. Classic CVD risk factors, as well as socioeconomic and lifestyle factors will be recorded at baseline; samples for measurement of biochemical and genetic markers will be collected and stored for future analyses. Investigations will be repeated after 3 and 10 years to evaluate the relationship between insulin resistance and the development of atherosclerosis as measured by carotid artery intima-media thickness. Development of Type 2 diabetes, dyslipidaemia, obesity, hypertension and cardiovascular events are additional endpoints. Conclusions. This study will evaluate the importance of insulin resistance in the development of CVD and diabetes, and has implications for the development of prevention and treatment strategies. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Both insulin resistance and beta-cell dysfunction play a role in the transition from normal glucose tolerance (NGT) to Type 2 diabetes (T2DM) through impaired glucose tolerance (IGT). The aim of the study was to define the level of glycaemia at which beta-cell dysfunction becomes evident in the context of existing insulin resistance. Methods. Insulin response (OGTT) and insulin sensitivity (euglycaemic insulin clamp) were evaluated in 388 subjects in the San Antonio Metabolism (SAM) study (138 NGT, 49 IGT and 201 T2DM). In all subjects the insulin secretion/insulin resistance index (ΔI/ΔG÷IR) was calculated as the ratio of the increment in plasma insulin to the increment in plasma glucose during the OGTT divided by insulin resistance, as measured during the clamp. Results. In lean NGTs with a 2-h plasma glucose concentration (2-h PG) between 5.6 and 6.6 and between 6.7 and 7.7 mmol/l, there was a progressive decline in ΔI/ΔG÷IR compared with NGTs with a 2-h PG less than 5.6 mmol/l. There was a further decline in ΔI/ΔG÷IR in IGTs with a 2-h PG between 7.8 and 9.3 and between 9.4 and 11.0 mmol/l, and in Type 2 diabetic patients with a 2-h PG greater than 11.1 mmol/l. Lean and obese subjects showed coincident patterns of relation of 2-h PG to ΔI/ΔG÷IR. Conclusion/interpreation. When the plasma insulin response to oral glucose is related to the glycaemic stimulus and severity of insulin resistance, there is a progressive decline in beta-cell function that begins in “normal” glucose tolerant individuals. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Impaired glucose tolerance (IGT) is an insulin-resistant state and a risk factor for Type 2 diabetes. The relative roles of insulin resistance and insulin deficiency in IGT have been disputed. Methods. In 40 IGT subjects and 63 sex-, age-, and weight-matched controls with normal glucose tolerance (NGT), we measured (i) indices of insulin sensitivity of fasting glucose production (by tracer glucose) and glucose disposal (M value on a 240 pmol·min–1·m–2 insulin clamp) and (ii) indices of beta-cell function (glucose sensitivity, rate sensitivity, and potentiation) derived from model analysis (Am J Physiol 283:E1159–E1166, 2002) of the insulin secretory response (by C-peptide deconvolution) to oral glucose. Results. In comparison with NGT, IGT were modestly insulin resistant (M=29±2 vs 35±2 µmol·min-1·kgFFM-1, p=0.01); insulin sensitivity of glucose production also was reduced, in approximate proportion to M. Despite higher baseline insulin secretion rates, IGT was characterized by a 50% reduction in glucose sensitivity [53 (36) vs 102 (123) pmol·min-1·m–2·mM–1, median (interquartile range), p=0.001] and impaired potentiation [1.6 (0.8) vs 2.0 (1.5) units, p<0.04] of insulin release, whereas rate sensitivity [1.15 (1.15) vs 1.38 (1.28) nmol·m–2·mM–1] was not significantly reduced. Glucose sensitivity made the single largest contribution (~50%) to the observed variability of glucose tolerance. Conclusion/interpretation. In IGT the defect in glucose sensitivity of insulin release quantitatively predominates over insulin resistance in the genesis of the reduced tolerance to oral glucose. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. In case-control studies, polymorphisms at the atrial natriuretic peptide gene (ANP) locus have been associated with presence of albuminuria in Type 1 and Type 2 diabetes. We evaluated the relationship between the ScaI and BstxI polymorphisms and albuminuria in the general population of the Mexico City Diabetes Study. Methods. Allele/genotype frequencies were analysed by PCR-RFLP analysis using ScaI (wild, A2 vs mutated, A1) and BstxI (wild, C708 vs mutated, T708) enzyme. Results. Among 1288 subjects, hypertension was present in 112 subjects, Type 2 diabetes in 191 and impaired glucose tolerance in 136; microalbuminuria was present in 464 subjects, and clinical proteinuria in 199. General frequencies were 0.93 and 0.96 for the wild alleles, and 0.07 and 0.04 for the mutated alleles, respectively for ScaI and BstxI. Frequency of A1was 0.08 in normoalbuminuric, 0.05 in microalbuminuric, and 0.05 in proteinuric patients (χ2=7.3, p=0.025). Frequency of T708 was 0.06 in normoalbuminuric and 0.03 microalbuminuric and 0.03 in proteinuric subjects (χ2=8.1, p=0.017). By multivariate analysis, the associations between A1 or T708 allele and albuminuria were independent of age, sex, BMI, diabetes, and hypertension, (odds ratio (OR) 0.60, p=0.01, (OR) 0.51, p=0.004, respectively). Conclusion/interpretation. In the general population of Mexico City, both polymorphisms of ANP are associated with albuminuria independently of hypertension, and could play a role in protecting subjects against development of albuminuria. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. We investigated the effect of physiological hyperinsulinaemia on global and regional myocardial blood flow and glucose uptake in five patients with Type II (non-insulin-dependent) diabetes mellitus and seven healthy control subjects. Methods. Myocardial blood flow was assessed by positron emission tomography with oxygen-15 labelled water (H215O) either before or after 1 h of euglycaemic hyperinsulinaemia. Myocardial glucose uptake was assessed by positron emission tomography and fluorine-18 labelled fluorodeoxyglucose (18FDG). Results. During hyperinsulinaemia, myocardial blood flow increased from 0.91±0.03 to 1.00±0.03 ml.min–1.g–1 in control subjects (p<0.005) and from 0.81±0.02 to 0.95±0.04 ml.min–1.g–1 in diabetic patients (p<0.0005). Corresponding glucose uptakes were 0.56±0.01 and 0.36±0.02 µmol.min–1.g–1 (p<0.0001), respectively. During hyperinsulinaemia, the regional distribution of myocardial blood flow and glucose uptake showed higher values in the septum and anterolateral wall (short axis) and in the mid-ventricle (long axis) in control subjects, and insulin action was circumscribed to these regions. In diabetic patients, the regional distribution of glucose uptake was similar; however, insulin-induced increase of myocardial blood flow was mainly directed to the postero-inferior areas (short axis) and to the base (long axis) of the heart, thus cancelling the predominance of the anterior wall observed before insulin administration. Conclusion/interpretation. These results provide evidence that insulin-mediated regulation of global myocardial blood flow is preserved in Type II diabetic patients. In contrast, the regional re-distribution of myocardial blood flow induced by insulin is directed to different target areas when compared with healthy subjects, thereby resulting in a mismatch between blood flow and glucose metabolism. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Autoantibodies against CD38 have been found in some patients with Type II (non-insulin-dependent) diabetes mellitus and have been shown to stimulate insulin secretion by cultured human islets. We tested whether this new form of autoimmunity, (i) overlaps with anti-GAD autoimmunity, (ii) identifies an insulin-deficient phenotype, (iii) is under the influence of genetic factors. Methods. We screened 496 adults by immuno-blot analysis in the Botnia Study (298 with Type II and 98 with Type I (insulin-dependent) diabetes mellitus, 100 non-diabetic control subjects). Results. CD38-autoantibodies were found in 8.4% of Type II diabetic patients (p<0.003 vs 0% of control subjects), particularly in anti-GAD positive (14% vs 6% of anti-GAD negative, p=0.0004). CD38ab were also found in 4% of Type I diabetic patients; in the whole study group, 59% of anti-CD38 positive had DQB1*02 compared with 38% of anti-CD38 negative (p=0.04). On the OGTT, beta-cell function (as the ratio of insulin-to-glucose areas) was impaired (p=0.02) only in association with anti-GAD positivity (3.2±3.1 U/mol, mean ± SD) but not in anti-CD38 positive patients (5.6±2.9) as compared with patients free of autoimmunity (4.5±4.6, p=NS). In 44 Type II diabetic patients (22 negative and 22 positive for anti-CD38), no mutations were detected in any of the 8 exons, 5′ end of intron 1 or the 5′ and 3′ untranslated regions of the CD38 gene. The previously described missense mutation (Arg140Trp) in exon 3 was not found in this cohort. There was no association between the PvUII polymorphism and clinical phenotype. Conclusion. Anti-CD38 autoimmunity identifies a clinical phenotype similar to non-autoimmune Type II diabetes, with relative preserved beta-cell function and weak genetic influence. [ABSTRACT FROM AUTHOR]

Aim/hypothesis. To gain insight into the physiologic determinants of postabsorptive endogenous glucose output (EGO) in humans.¶Methods. We analysed the data of 344 non-diabetic subjects (212 men and 132 women) with a wide range of age (18–85 years) and body mass index (15–55 kg/m2) who participated in the European Group for the Study of Insulin Resistance (EGIR) project. Whole-body endogenous glucose output was measured by tracer ([3H]glucose) dilution at steady-state, peripheral insulin sensitivity (Ñ glucose clearance/Ñ insulin) was measured by the euglycaemic insulin (7 pmol × min–1× kg–1) clamp technique.¶Results. Whole-body endogenous glucose output showed a large variability (mean = 768 ± 202 μmol · min–1, range 209–1512) and was strongly related to lean body mass (r = 0.63, p < 0.0001). This association entirely explained the endogenous glucose output being higher in men than in women (827 ± 189 vs 674 × 187 μmol × min–1, p < 0.0001), its relation to body mass (+ 10 ± 2 per unit of body mass index, p < 0.0001) and its trend to decline with age (–1.1 ± 0.7 μmol · min–1 per year, p = 0.10). Although inversely related to one another (r = –0.41, p < 0.0001), peripheral insulin sensitivity and fasting plasma insulin were both independently associated with endogenous glucose output in an inverse fashion (with partial r's of 0.19 and 0.21, respectively, after adjusting for lean body mass and centre, p < 0.0001 for both).¶Conclusion/interpretation. Among non-diabetic subjects in the postabsorptive condition, total body endogenous glucose output variability is wide and is largely explained by the amount of lean mass; this, in turn, explains differences in total endogenous glucose output due to sex, obesity and age. Independently of the amount of lean mass, peripheral insulin resistance is associated with a higher endogenous glucose output independently of fasting plasma insulin concentration, suggesting coupled regulation of insulin action in peripheral tissues and the liver. [Diabetologia (2000) 43: 1266–1272] [ABSTRACT FROM AUTHOR]

We report a family with 6 members affected by a long-lasting paroxysmal exertion-induced dyskinesia. Fasting and stress were precipitating factors. All the patients of this family had also epileptic seizures mainly of generalised type with a favourable outcome. All patients were submitted to a neurophysiological study which included somatosensory evoked potentials by median nerve stimulation (MN-SEPs), somatosensory evoked potentials by posterior tibial nerve stimulation (PTN-SEPs), brainstem auditory evoked potentials (BAEPs), visual evoked potentials (VEPs), motor evoked potentials (MEPs) by magnetic transcranial cortical stimulation (TCS) and electromyography (EMG). The neurophysiological findings suggest a hyperexcitability at the muscular and brain membrane levels, probably due to an ion channel disorder. [ABSTRACT FROM AUTHOR]

Aims/hypothesis. Prevalence and incidence of coronary heart disease (CHD) are increased in patients with Type II (non-insulin-dependent) diabetes mellitus; whether this is entirely due to more extensive coronary atherosclerosis is, however, controversial. Methods. We analysed the clinical, angiographic and follow-up data of 2253 consecutive patients undergoing coronary angiography over the decade 1983–1992. Results. Abnormal coronary arteries (≥ 50 % stenosis) were found more frequently in diabetic than in non-diabetic subjects (85 vs 67 %, p < 0.0001), the excess being explained by a higher prevalence of three-vessel disease (36 vs 17 %, p < 0.0001). The sum of all angiographically detectable lumen stenoses (atherosclerosis score, ATS) was higher in diabetic than in non-diabetic subjects (352 ± 232 vs 211 ± 201 units, p < 0.0001). After adjusting for measured cardiovascular risk factors, diabetes was still associated with an excess ATS (114 units in men and 187 units in women, p < 0.0001 for both, p < 0.03 for the interaction ATS x sex). Within the diabetic group, the only variable that was independently (of sex and age) associated with ATS was serum cholesterol, whereas plasma glucose concentration, disease duration and type of treatment were not correlated with the severity of coronary atherosclerosis. In contrast, clinical grade proteinuria was not associated with a more diffuse coronary atherosclerosis either in diabetic (366 ± 243 vs 354 ± 233 units) or non-diabetic subjects (231 ± 201 vs 207 ± 197 units). Over a mean follow-up period of 88 months, 19 % of diabetic patients compared with 10 % of non-diabetic patients died of a cardiac cause (age and sex-adjusted odds ratio OR = 1.34 [1.14–1.57]). In a Cox model adjusting for age, sex and all major risk factors, diabetes was still associated with a significant excess risk of dying of a cardiac cause (OR = 1.37 [1.14–1.60]); this excess was similar to, and independent of, that carried by the presence of prior myocardial infarction in the whole population (OR = 1.42 [1.25–1.62]). Proteinuria was associated with a higher risk of cardiac death, particularly in diabetic patients, independently of coronary atherosclerosis (adjusted OR = 1.46 [1.03–1.99]). Conclusion/interpretation. In patients undergoing angiography, diabetes, especially in women, is associated with more severe and diffuse coronary atherosclerosis which is not explained by either the traditional risk factors or the presence of proteinuria. On follow-up, these patients experience an excess of cardiac deaths, to which coronary atherosclerosis and proteinuria make independent, quantitative contributions. [Diabetologia (2000) 43: 632–641] [ABSTRACT FROM AUTHOR]

Maternal diabetes mellitus is complicated by fetal macrosomia and predisposes the offspring to diabetes, but recent evidence indicates that a low, not high, birthweight is associated with a higher incidence of Type 2 (non-insulin dependent) diabetes in adult life. To clarify the relationships between maternal glucose and insulin levels and birthweight, we measured oral glucose tolerance and neonatal weight in a large group ( n = 529) of women during the 26th week of pregnancy. Women with gestational diabetes ( n = 17) had more familial diabetes, higher pre-pregnancy body weight, and tended to have large-for-gestational-age babies. In contrast, women with essential hypertension ( n = 10) gave birth to significantly ( p <0.01) smaller babies. In the normal group (without gestational diabetes or hypertension, n = 503), maternal body weight before pregnancy and at term, maternal height, week of delivery, gender of the newborn, and parity were all significant, independent predictors of birthweight, together explaining 23% of the variability of neonatal weight. In addition, both fasting ( p <0.006) and 2-h post-glucose ( p = 0.03) maternal plasma glucose concentrations were positively associated with birthweight independent of the other physiological determinants, accounting, however, for only 10% of the explained variability. In a subgroup of 134 normal mothers with prepregnancy body mass index of less than 25 kg · m, in whom plasma insulin measurements were available, the insulin area-under-curve was inversely related to birthweight ( p <0.02) after simultaneously adjusting for physiological factors and glucose area. When glucose and insulin measurements were combined in the I/G ratio (ratio of insulin to glucose area), this was still inversely related to birthweight. Furthermore, maternal insulinaemia was directly related to blood pressure levels ( p <0.001) independently of body weight. We conclude that in normal pregnancy, whereas physiological factors account for most of the explainable variability of infant weight, the influence of the maternal metabolic milieu is dual, positive for glucose levels but negative for insulin concentrations. Maternal hyperinsulinaemia during pregnancy may be one trait linking low birthweight with predisposition to diabetes in adult life. [ABSTRACT FROM AUTHOR]

In a population-based survey of 2,930 subjects, prevalence rates for obesity, Type 2 (non-insulin-dependent) diabetes mellitus, impaired glucose tolerance, hypertension, hypertriglyceridaemia, and hypercholesterolaemia were 54.3, 9.3, 11.1, 9.8, 10.3 and 9.2%, respectively. The prevalence, however, of each of these conditions in its isolated form (free of the other five) was 29.0% for obesity, 1.3% for Type 2 diabetes, 1.8% for impaired glucose tolerance, 1.5% for hypertension, 1.0% for hypertriglyceridaemia, and 1.7% for hypercholesterolaemia. Two-by-two associations were even rarer. The large differences in prevalence between isolated and mixed forms indicate a major overlap among the six disorders in multiple combinations. In the isolated form, each condition was characterized by hyperinsulinaemia (both fasting and 2 h after oral glucose), suggesting the presence of insulin resistance. In addition, in any isolated condition most of the variables categorising other members of the sextet were still significantly altered in comparison with 1,049 normal subjects. In the whole of the subjects who presented with one or another disorder (1,881 of 2,930 or 64%), marked fasting and post-glucose hyperinsulinaemia was associated with higher body mass index, waist:hip ratio, fasting and post-glucose glycaemia, systolic and diastolic blood pressure, serum triglycerides and total cholesterol levels, and with lower HDL-cholesterol concentrations (all p <0.001). We conclude that (1) insulin sensitivity, glucose tolerance, blood pressure, body fat mass and distribution, and serum lipids are a network of mutually interrelated functions; and (2) an insulin resistance syndrome underlies each and all of the six disorders carrying an increased risk of coronary artery disease. [ABSTRACT FROM AUTHOR]