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Aims Amino acid (AA) metabolism is altered in type 2 diabetes (T2D), and fasting levels of α-hydroxybutyrate (α-HB), a biomarker for insulin resistance, have been suggested to track AA metabolism. We investigated the changes in AA and α-HB induced by a mixed-meal tolerance test (MTT) and the effects of sitagliptin treatment. Methods Forty-seven T2D patients [56 ± 7 years, body mass index (BMI) 29.9 ± 4.2 kg/m2] were randomized to sitagliptin (100 mg/day, 6 weeks) or placebo. Seven age- and BMI-matched non-diabetic subjects served as control (CT). Results During a 5-h MTT, branched-chain AA (BCAA) peaked earlier in T2D than CT [75(25) vs. 62(3) mmol/l·h over 2 h, median(interquartile range), p = 0.05], and rose higher [5-h increment: 31(23) vs. 19(24) mmol/l·h, p = 0.05]. Fasting α-HB was higher [7.5(2.7) vs. 5.9(1.3) µg/ml, p = 0.04 T2D vs. CT], and its meal-induced increments were larger [24(99) vs. −41(86) µg/ml·h, p = 0.006]. Plasma non-esterified fatty acids (NEFA) declined during MTT, but their increments were greater in patients (53 ± 16 vs. 35 ± 10 mEq/l·h, p = 0.005). Compared to placebo, both BCAA [−6.4(21.1) vs. 0.0(48.0) mmol/l·h, p = 0.01] and α-HB increments [−114(250) vs. 114(428) µg/ml·h, p = 0.002] decreased with sitagliptin, and meal-induced NEFA suppression was improved. Changes in BCAA and α-HB were reciprocally related to changes in insulin sensitivity ( ρ = −0.37 and −0.43, p ≤ 0.01). Conclusions T2D is associated with a hyperaminoacidaemic response to MTT, which circulating α-HB levels track. Sitagliptin-induced glycaemic improvement was associated with reductions in BCAA and α-HB excursions and better NEFA suppression, in parallel with improved insulin sensitivity, confirming that α-HB is a readout of metabolic overload. [ABSTRACT FROM AUTHOR]

No data are present in the literature regarding chemokine (CXC motif) ligand (CXCL)9 and CXCLll circulating levels in cryoglobulinemia associated with hepatitis C (MC+HCV), in presence/absence of autoimmune thyroiditis (AT). Serum CXCL9 and CXCLll have been measured in 38 MC+HCV patients without AT (MCo), 38 MC+HCV patients with AT (MC+AT), and in matched controls without (control 1) or with thyroiditis (control 2). Serum CXCL9 and CXCLll were significantly higher: in control 2 than control 1 (p<0.05); in MCo than control 1 and control 2 (p<0.001, for both); in MC+AT than control 1 and control 2 (p<0.0001, for both), and than MCo (p=0.01, for both). Our study demonstrates markedly high serum levels of CXCL9 and CXCLll in patients with MC+HCV compared to healthy controls; in MC+HCV patients increased CXCL9 and CXCLll levels were significantly associated with the presence of AT. Moreover, a strong relation between circulating CXCL9 and CXCLll in MC+HCV has been shown. [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]

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]

We explored the mechanisms by which a 4-month, placebo-controlled pioglitazone treatment (45 mg/day) improves glycemic control in type II diabetic patients (T2D, n=27) using physiological testing (6-h mixed meal) and a triple tracer technique ([6,6-2H2]glucose infusion, 2H2O and [6-3H]glucose ingestion) to measure endogenous glucose production (EGP), gluconeogenesis (GNG), insulin-mediated glucose clearance and β-cell glucose sensitivity (by c-peptide modeling). Compared to sex/age/weight-matched non-diabetic controls, T2D patients showed inappropriately (for prevailing insulinemia) raised glucose production (1.05[0.53] vs 0.71[0.36]mmol min−1 kgffm−1 pM, P=0.03) because of enhanced GNG (73.1±2.4 vs 59.5±3.6%, P<0.01) persisting throughout the meal, reduced insulin-mediated glucose clearance (6[5] vs 12[13]ml min−1 kgffm−1 nM−1, P<0.005), and impaired β-cell glucose-sensitivity (27[38] vs 71[37]pmol min−1 m−2 mM−1, P=0.002). Compared to placebo, pioglitazone improved glucose overproduction (P=0.0001), GNG and glucose underutilization (P=0.05) despite lower insulinemia. GNG improvement was quantitatively related to raised adiponectin. β-cell glucose sensitivity was unchanged. In mild-to-moderate T2D, pioglitazone monotherapy decreased fasting and post-prandial glycemia, principally via inhibition of gluconeogenesis, improved hepatic and peripheral insulin resistance.Clinical Pharmacology & Therapeutics (2007) 81, 205–212. doi:10.1038/sj.clpt.6100034 [ABSTRACT FROM AUTHOR]

Gluconeogenesis (GNG) is enhanced in type 2 diabetes. In experimental animals, insulin at high doses decreases the incorporation of labeled GNG precursors into plasma glucose. Whether physiological hyperinsulinemia has any effect on total GNG in humans has not been determined. We combined the insulin clamp with the (2)H(2)O technique to measure total GNG in 33 subjects with type 2 diabetes (BMI 29.0 +/- 0.6 kg/m(2), fasting plasma glucose 8.1 +/- 0.3 mmol/l) and in 9 nondiabetic BMI-matched subjects after 16 h of fasting and after euglycemic hyperinsulinemia. A primed-constant infusion of 6,6-(2)H-glucose was used to monitor endogenous glucose output (EGO); insulin (40 mU. min(-1). m(-2)) was then infused while clamping plasma glucose for 2 h (at 5.8 +/- 0.1 and 4.9 +/- 0.2 mmol/l for diabetic and control subjects, respectively). In the fasting state, EGO averaged 15.2 +/- 0.4 micromol. min(-1). kg(-1)(ffm) (62% from GNG) in diabetic subjects and 12.2 +/- 0.7 micromol. min(-1). kg(-1)(ffm) (55% from GNG) in control subjects (P < 0.05 or less for both fluxes). Glycogenolysis (EGO - GNG) was similar in the two groups (P = NS). During the last 40 min of the clamp, both EGO and GNG were significantly (P < 0.01 or less, compared with fasting) inhibited (EGO 7.1 +/- 0.9 and 3.6 +/- 0.5 and GNG 7.9 +/- 0.5 and 4.5 +/- 1.0 respectively) but remained significantly (P < 0.05) higher in diabetic subjects, whereas glycogenolysis was suppressed completely and equally in both groups. During hyperinsulinemia, GNG micromol. min(-1). kg(-1)(ffm) in diabetic and control subjects, was reciprocally related to plasma glucose clearance. In conclusion, physiological hyperinsulinemia suppresses GNG by approximately 20%, while completely blocking glycogenolysis. Resistance of GNG (to insulin suppression) and resistance of glucose uptake (to insulin stimulation) are coupled phenomena. In type 2 diabetes, the excess GNG of the fasting state is carried over to the insulinized state, thereby contributing to glucose overproduction under both conditions. [ABSTRACT FROM AUTHOR]