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Background First-degree offspring (OFF) of type 2 diabetic (T2DM) patients bear a ~40% lifetime risk of developing T2DM. They are insulin resistant and carry a risk of premature atherosclerosis, the extent of which can be estimated by intima media thickness (IMT) of the carotid artery (CA). Thus, this study examines parameters of glucose and lipid metabolism, insulin sensitivity, beta cell function (BCF) and IMT with their interrelationships in middle-aged OFF. Materials and methods T2DM-OFF ( n = 18, 14f/4m, 45·6 ± 2·1 years, BMI: 26 ± 1 kg m−2) were compared with 18 matching humans without a family history of diabetes (CON; 14f/4m, 44·5 ± 2·1 years, BMI: 24 ± 1 kg m−2; each P > 0·30), all with normal glucose tolerance as tested by three-hour (75 g) oral glucose tolerance tests (OGTT). Two-hour hyperinsulinaemic (40 mU min−1·m−2)isoglycaemic clamp tests were performed with simultaneous measurement of endogenous glucose (D-[6,6-2H2]glucose) production (EGP). IMT [internal (ICA), common CA, and bulb] were measured sonographically. BCF was assessed by Adaptation Index (AI). Results Before and during OGTT, both groups were similar in plasma glucose, insulin, C-peptide and free fatty acids (FFA), whereas OFF showed ~30% lower ( P < 0·03) fasting plasma triglycerides before OGTT. During hyperinsulinaemic clamps, insulin sensitivity was ~38% lower ( P < 0·03) in OFF who showed higher plasma FFA (44 ± 9 µmol L−1) than CON (26 ± 3 µmol L−1, P < 0·05) after 90 min. EGP was similar in both groups. OFF had 38% ( P < 0·007) reduced AI. ICA-IMT was ~18% higher in OFF ( P < 0·002), but did not correlate with insulin sensitivity. Conclusion The data obtained show middle-aged T2DM-OFF with normal glucose tolerance displaying reduced total insulin sensitivity and impaired beta cell function, which relates to impaired insulin-dependent suppression of plasma FFA and increased ICA-IMT. [ABSTRACT FROM AUTHOR]

Background Elevated circulating free fatty acids (FFAs) induce insulin resistance and play a crucial role in the development of type 2 diabetes, in which fasting hepatic glucose production (HGP) is increased. However, direct effects of FFAs on fasting HGP are still unclear because indirect endocrine and metabolic effects contribute to FFA action. Thus, we aimed to investigate acute direct effects of specific FFAs on fasting HGP, lactate uptake, and insulin signalling. Materials and methods Isolated livers obtained from 20 h fasted rats were perfused with albumin-bound palmitate or oleate (200 µmol L−1 each) or vehicle (control) for 180 min ( n = 5–7/group). Results Compared to control, hepatic lactate uptake was increased by palmitate and oleate (~+40%; P < 0·05), while HGP from lactate (~3 mmol L−1) and liver glycogen content were similar. Tyrosine phosphorylation (pY) of insulin-receptor-substrate-(IRS)-2 and p70S6-kinase phosphorylation were not affected by FFAs. Palmitate decreased insulin-receptor-β pY, IRS-1 pY and phosphoinositol-3-kinase expression by 46 ± 16%, 46 ± 11% and 20 ± 9%, respectively ( P < 0·03), while oleate reduced Akt phosphorylation by 85 ± 7% ( P < 0·006). Conclusions Isolated liver perfusion with saturated or unsaturated FFAs reduced insulin signalling protein phosphorylation at different sites and increased lactate uptake without affecting HGP or glycogen content. These results suggest that at fasting, both saturated and unsaturated FFAs increase hepatic glucose precursor uptake and may, independently of insulin's presence, accelerate protein dephosphorylation of the insulin signalling cascade at different sites. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In response to hyperglycemia, beta-cells release insulin and C-peptide, as well as islet amyloid pancreatic polypeptide, which is involved in glucose homeostasis. After successful pancreas-kidney transplantation (PKT), type 1 diabetic patients may revert to a nondiabetic metabolism without exogenous insulin therapy and re-secrete all beta-cell hormones. RESEARCH DESIGN AND METHODS: Using mathematical models, we investigated hormone (amylin, insulin, C-peptide) and metabolite (glucose, free fatty acids) kinetics, beta-cell sensitivity to glucose, and oral glucose insulin sensitivity index (OGIS) in 11 nondiabetic type 1 diabetic patients after PKT (BMI 25 +/- 1 kg/m2, 47 +/- 2 years of age, 4 women/7 men, glucocorticoid-free), 6 matching nondiabetic patients after kidney transplantation (25 +/- 1 kg/m2, 50 +/- 5 years, 3 women/3 men, on glucocorticoids), and 9 matching nondiabetic control subjects (24 +/- 1 kg/m2, 47 +/- 2 years, 4 women/5 men) during a 3-h 75-g oral glucose tolerance test (OGTT). RESULTS: PKT patients had higher fasting amylin (19 +/- 3 vs. control subjects: 7 +/- 1 pmol/l) and insulin (20 +/- 2 vs. control subjects: 10 +/- 1 microU/ml; each P < 0.01) levels. Kidney transplant subjects showed increased OGTT plasma insulin at 90 min and C-peptide levels (each P < 0.05). In PKT patients, plasma glucose from 90 to 150 min was 9-31% higher (P < 0.05 vs. control subjects). Amylin clearance was comparable in all groups. Amylin's plasma concentrations and area under the concentration curve were up to twofold higher in PKT patients during OGTT (P < 0.05). OGIS was not significantly different between groups. beta-Cell sensitivity to glucose was reduced in PKT patients (-64%, P < 0.009). Fasting plasma amylin was inversely associated with beta-cell sensitivity to glucose (r = -0.543, P < 0.004). CONCLUSIONS: After successful PKT, type 1 diabetic patients with nondiabetic glycemia exhibit increased fasting and post-glucose load plasma amylin, which appears to be linked to impaired beta-cell function. Thus, higher amylin release in proportion to insulin might also reflect impaired beta-cell function in type 1 diabetic patients after PKT. [ABSTRACT FROM AUTHOR]

Objective: The efficacy of DMARD therapy in rheumatoid arthritis (RA) can be judged by radiological analysis. This study aimed to determine the time-dependent progression of joint damage, acute-phase response, and rates of radiologic progression in early DMARD-treated RA patients over 10 years.Patients and Methods: We evaluated outpatient records, and radiographs of hands and feet of 54 early RA patients on DMARDs for 10 years. Radiographs were quantified by the Larsen method using recently developed quantification software.Results: Radiological damage attenuated, with disease progression from baseline to Year 10 [correlation coefficient (r)=0.95, probability (p)<0.001]. Radiographic scores progressed more rapidly during the first 5 years than thereafter. Cumulative erythrocyte sedimentation rate (ESR) was strongly correlated with radiological progression (p<0.001, r=0.88).Conclusion: Our findings reveal a higher amount of radiographic RA progression during the first years of DMARD treatment. Thus, our data provide strong evidence for the importance of both early DMARD therapy and continuous radiographic assessments in RA. [ABSTRACT FROM AUTHOR]

Objective Successful simultaneous pancreas-kidney transplantation (SPK) in Type 1 diabetic (T1DM) patients results in improved cardiovascular outcome and survival. However, it is doubtful whether the impairment of cardiovascular and endothelial function in T1DM can be completely reversed. Methods Pulse-wave velocity, stroke volume, heart rate, serological markers of endothelial dysfunction (soluble intercellular, vascular cell-adhesion molecules, E-selectin, and plasminogen-activator-inhibitor-1) were measured in 10 T1DM patients after SPK with non-diabetic glucose levels, 10 T1DM patients with poor [T1DM>8; glycated haemoglobin (HbA1c)>8%], and 10 with good glucose control (T1DM<7, HbA1c<7%), in 6 non-diabetic patients after kidney transplantation (KT) and 9 non-diabetic control subjects (CON), matching for major anthropometric characteristics. Results Pulse-wave velocity was increased in SPK (P < 0.02 vs. CON, KT, T1DM<7) and in T1DM>8 (P < 0.02 vs. T1DM<7). Systolic blood pressure was increased in SPK (P < 0.05 vs. CON). Stroke volume was reduced in SPK, T1DM>8 and T1DM<7 and KT (P < 0.01 vs. CON). Heart rate was elevated in SPK and in T1DM>8 (P < 0.0003 vs. CON and T1DM<7). In SPK, soluble intercellular and vascular cell-adhesion molecules were 100% and 44% higher (P < 0.03 vs. CON), respectively, while plasminogen-activator-inhibitor-1 was decreased in SPK (P < 0.02 vs. CON). Conclusion T1DM patients after SPK experience arterial stiffness, a higher heart-rate and blood pressure, reduced stroke volume and serological signs of endothelial dysfunction. Thus, functional and structural cardiovascular alterations as a result of glucotoxicity, uraemia and hypertension in T1DM might not be completely resolved by SPK. [ABSTRACT FROM AUTHOR]

Aims Tobacco smoking is known to increase the long-term risk of developing Type 2 diabetes mellitus, but the mechanisms involved are poorly understood. This observational, cross-sectional study aims to compare measures of insulin sensitivity and β-cell function in current, ex- and never-smokers. Methods The study population included 1246 people without diabetes (mean age 44 years, 55% women) from the EGIR-RISC population, a large European multicentre cohort. Insulin sensitivity was measured using a hyperinsulinaemic, euglycaemic clamp and the homeostatic model assessment - insulin resistance (HOMA-IR) index. Two β-cell function parameters were derived from measures during an oral glucose tolerance test: the early insulin response index and β-cell glucose sensitivity. Additionally, the areas under the curve during the oral glucose tolerance test were calculated for glucose, insulin and C-peptide. Results According to smoking habits, there were differences in insulin sensitivity, which was lower in women who smoked, and in β-cell glucose sensitivity, which was lower in men who smoked, but these associations lost significance after adjustment. However, after adjustment, the areas under the glucose and the C-peptide curves during the oral glucose tolerance test were significantly higher in men who smoked. Conclusions Smoking habits were not independently associated with insulin sensitivity or β-cell function in a healthy middle-aged European population. Health-selection bias, methodological shortcomings or a true lack of causal links between smoking and impaired insulin sensitivity/secretion are possible explanations. The mechanisms behind the observed increased glucose and C-peptide areas under the curve during the oral glucose tolerance test in male smokers need to be further evaluated. [ABSTRACT FROM AUTHOR]

Background In patients with type 1 diabetes mellitus (T1 DM), insulin is usually replaced systemically (subcutaneously) and not via the physiological portal route. According to previous studies, the liver's capacity to store glycogen is reduced in T1 DM patients, but it remains unclear whether this is due to hyperglycaemia, or whether the route of insulin supply could contribute to this phenomenon. T1 DM patients after successful pancreas-kidney transplantation with systemic venous drainage (T1 DM- PKT) represent a suitable human model to further investigate this question, because they are normoglycaemic, but their liver receives insulin from the pancreas transplant via the systemic route. Materials and methods In nine T1 DM- PKT, nine controls without diabetes ( CON) and seven patients with T1 DM (T1 DM), liver glycogen content was measured at fasting and after two standardized meals employing 13C-nuclear-magnetic-resonance-spectroscopy. Circulating glucose and glucoregulatory hormones were measured repeatedly throughout the study day. Results The mean and fasting concentrations of peripheral plasma glucose, insulin, glucagon and C-peptide were comparable between T1 DM- PKT and CON, whereas T1 DM were hyperglycaemic and hyperinsulinaemic ( P < 0·05 vs T1 DM- PKT and CON). Total liver glycogen content at fasting and after breakfast did not differ in the three groups. After lunch, T1 DM- PKT and T1 DM had a 14% and 21% lower total liver glycogen content than CON ( P < 0·02). Conclusion In spite of normalized glycaemic control, postprandial liver glycogen content was reduced in T1 DM- PKT with systemic venous drainage. Thus, not even optimized systemic insulin substitution is able to resolve the defect in postprandial liver glycogen storage seen in T1 DM patients. [ABSTRACT FROM AUTHOR]

Aims Thiazoledinediones decrease blood glucose by their insulin-sensitizing properties. Here, we examined whether pioglitazone plus nateglinide ( PIO) interferes with hepatocellular lipid ( HCL) content and/or improves insulin sensitivity in well-controlled non-obese patients with type 2 diabetes mellitus ( T2DM). Methods Sixteen patients [body mass index ( BMI): 28 ± 1 kg/m2; HbA1c: 7.1 ± 0.6%] were studied in a randomized, double-blind, 12-week parallel group trial, whereas matched healthy humans [non-diabetic control subjects ( CON), BMI: 26 ± 1 kg/m2] were studied once. Treatment with pioglitazone (30 mg/day) plus nateglinide ( PIO arm) to control for glimepiride-induced insulin secretion was compared to treatment with glimepiride (2 mg/day) plus placebo ( GLI arm). Multinuclei magnetic resonance spectroscopy ( MRS) was combined with pancreatic normoglycaemic-two-step-insulin clamps and stable isotopes to assess glucose turnover, glucose transport/phosphorylation, HCL and intramyocellular lipid ( IMCL) contents, non-esterified fatty acids ( NEFA) and adipokines. Results At baseline, HCL was approximately 5.6-fold higher in T2DM (p < 0.05 vs. CON). This was paralleled by approximately doubled leptin : adiponectin ratios (p < 0.05). HCL decreased by approximately 39% (p < 0.05) after PIO and only tended to decrease after GLI (p = 0.12). Treatment with PIO did not affect leptin : adiponectin ratios, but slightly improved (p < 0.05) insulin-mediated NEFA suppression, which related to lower HCL. PIO further prevented the insulin-induced increase in IMCL content of soleus and tibialis anterior muscles. Peripheral and hepatic insulin sensitivity, glucose transport and glycaemic control did not change in both groups. Conclusion Short-term, low-dose thiazolidendione treatment improves insulin sensitivity of lipolysis and HCL, without affecting muscle and liver insulin sensitivity. It appears that metabolic PIO action in T2DM is primarily mediated via a decline in HCL associated with greater sensitivity of lipolysis to insulin. [ABSTRACT FROM AUTHOR]

Objective: Recent work has shown that insulin stimulates its own secretion in insulin-sensitive humans, suggesting that insulin resistance in the β-cell could cause β-cell dysfunction. We have tested whether insulin exposure and insulin sensitivity modulate β-cell function in subjects with normal glucose tolerance (NGT) and whether they contribute to dysglycemia in impaired glucose regulation (IGR).Research Design and Methods: Insulin sensitivity (by euglycemic clamp), insulin-induced secretory response at isoglycemia (IISR) (as C-peptide percent change from basal during the clamp), glucose-induced secretory response (GISR) to an intravenous glucose bolus, and β-cell glucose sensitivity (β-GS) (by oral glucose tolerance test [OGTT] modeling) were measured in 1,151 NGT and 163 IGR subjects from the RISC (Relationship between Insulin Sensitivity and Cardiovascular Disease) study.Results: In NGT, IISR was related to both insulin sensitivity and antecedent insulin exposure; GISR was related to insulin exposure. IISR was positively, if weakly, related to β-GS (r= 0.16, P < 0.0001). Both IISR (-23 [39] vs. -9 [2]%, median [interquartile range], P < 0.03) and β-GS (69 [47] vs. 118 [83] pmol ⋅ min(-1) ⋅ m(-2) ⋅ mmol(-1) ⋅ L, P < 0.0001) were decreased in IGR compared with NGT. Insulin sensitivity and β-GS were the major determinants of mean OGTT glucose in both NGT and IGR, with a minor role for IISR. In a multivariate logistic model, IGR was predicted by β-GS (odds ratio 4.84 [95% CI 2.89-8.09]) and insulin sensitivity (3.06 [2.19-4.27]) but not by IISR (1.11 [0.77-1.61]).Conclusions: Pre-exposure to physiological hyperinsulinemia stimulates insulin secretion to a degree that depends on insulin sensitivity. However, this phenomenon has limited impact on β-cell dysfunction and dysglycemia. [ABSTRACT FROM AUTHOR]

Leptin is primarily secreted by the adipose tissue. It binds not only to hypothalamic structures involved in energy regulation but also to many peripheral tissues including the liver. Leptin circulates in free and receptor-bound forms. Both components are differentially regulated under various pathophysiological conditions and serve different physiological functions. They are released from adipose tissue but previous data suggest an additional formation outside the fat compartment. Here we tested the contribution of the liver in binding and modulating leptin in the circulation.In vivoexperiments were performed with radioactive labelled leptin with and without pretreatment with unlabelled leptin in freely moving, chronic intravenously cannulated male rats. Livers were investigated by immunohistochemistry andin situhybridization and immunoblotting was performed, followed byex vivoliver perfusion studies with human recombinant leptin.Inin vivoexperiments radioactively labelled leptin (at low concentrations) is avidly bound to rat liver (greater than 80% of basal serum values 90 min following i.v. infusion). Pre-treatment with excess of unlabelled leptinin vivorevealed a rapid hepatic down-regulation of leptin receptor isoforms when tested byin situhybridization, immunoblotting or immunohistochemistry.Ex vivoperfusion of rat liver with human recombinant leptin induced a dose- and time-dependent formation of receptor-bound leptin in the perfusate.The present data support an active role of the liver in the modulation of the leptin signal through different regulation of the soluble leptin receptor, the bound and free forms of the hormone, which may have important implications for leptin's central efficacy and the development of‘leptin resistance’.Eur J Clin Invest 2004; 34 (12): 831 –837 [ABSTRACT FROM AUTHOR]