Mutant prolactin receptor and familial hyperprolactinemia.

Hyperprolactinemia that is not associated with gestation or the puerperium is usually due to tumors in the anterior pituitary gland and occurs occasionally in hereditary multiple endocrine neoplasia syndromes. Here, we report data from three sisters with hyperprolactinemia, two of whom presented with oligomenorrhea and one with infertility. These symptoms were not associated with pituitary tumors or multiple endocrine neoplasia but were due to a heterozygous mutation in the prolactin receptor gene, PRLR, resulting in an amino acid change from histidine to arginine at codon 188 (His188Arg). This substitution disrupted the high-affinity ligand-binding interface of the prolactin receptor, resulting in a loss of downstream signaling by Janus kinase 2 (JAK2) and signal transducer and activator of transcription 5 (STAT5). Thus, the familial hyperprolactinemia appears to be due to a germline, loss-of-function mutation in PRLR, resulting in prolactin insensitivity.

Effects of oral L-carnitine supplementation on insulin sensitivity indices in response to glucose feeding in lean and overweight/obese males.

Infusion of carnitine has been observed to increase non-oxidative glucose disposal in several studies, but the effect of oral carnitine on glucose disposal in non-diabetic lean versus overweight/obese humans has not been examined. This study examined the effects of 14 days of L-carnitine L-tartrate oral supplementation (LC) on blood glucose, insulin, NEFA and GLP-1 responses to an oral glucose tolerance test (OGTT). Sixteen male participants were recruited [lean (n = 8) and overweight/obese (n = 8)]. After completing a submaximal predictive exercise test, participants were asked to attend three experimental sessions. These three visits were conducted in the morning to obtain fasting blood samples and to conduct 2 h OGTTs. The first visit was a familiarisation trial and the final two visits were conducted 2 weeks apart following 14 days of ingestion of placebo (PL, 3 g glucose/day) and then LC (3 g LC/day) ingested as two capsules 3×/day with meals. On each visit, blood was drawn at rest, at intervals during the OGTT for analysis of glucose, insulin, non-esterified fatty acids (NEFA) and total glucagon-like peptide-1 (GLP-1). Data obtained were used for determination of usual insulin sensitivity indices (HOMA-IR, AUC glucose, AUC insulin, 1st phase and 2nd phase ß-cell function, estimated insulin sensitivity index and estimated metabolic clearance rate). Data were analysed using RMANOVA and post hoc comparisons where appropriate. There was a significant difference between groups for body mass, % fat and BMI with no significant difference in age and height. Mean (SEM) plasma glucose concentration at 30 min was significantly lower (p < 0.05) in the lean group on the LC trial compared with PL [8.71(0.70) PL; 7.32(0.36) LC; mmol/L]. Conversely, plasma glucose concentration was not different at 30 min, but was significantly higher at 90 min (p < 0.05) in the overweight/obese group on the LC trial [5.09(0.41) PL; 7.11(0.59) LC; mmol/L]. Estimated first phase and second phase ß-cell function both tended to be greater following LC in the lean group only. No effects of LC were observed on NEFA or total GLP-1 response to OGTT. It is concluded that LC supplementation induces changes in blood glucose handling/disposal during an OGTT, which is not influenced by GLP-1. The glucose handling/disposal response to oral LC is different between lean and overweight/obese suggesting that further investigation is required. LC effects on gastric emptying and/or direct 'insulin-like' actions on tissues should be examined in larger samples of overweight/obese and lean participants, respectively.

Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study: specific elevations in alanine aminotransferase and triglycerides suggest hepatic fat accumulation as a potential contributing factor.

To examine metabolic changes (lipids, liver enzymes, blood pressure, and weight) potentially associated with conversion to diabetes, we analyzed serial glucose and other metabolic measures obtained every 6 months within the West of Scotland Coronary Prevention Study trial. Changes in parameters for 86 men who converted to new-onset diabetes ("converters": two consecutive glucose levels > or =7 mmol/l) were compared with 860 "nonconverters" matched for age and treatment allocation. Eighteen months before the diagnosis, converters to diabetes had elevated (P < 0.01) fasting glucose, weight, triglyceride, alanine aminotransferase (ALT), blood pressure, and white cell count and lower HDL cholesterol compared with nonconverters. The mean (SD) increase in fasting glucose over 18 months in converters was 1.80 (1.52) mmol/l, compared with 0.10 (0.57) in nonconverters. Of parameters measured, only ALT (P = 0.0005) and triglyceride (P = 0.030) increased significantly more over the 18 months in converters compared with nonconverters, but neither parameter increased significantly in nonconverters with high baseline glucose concentrations (>6.1 mmol/l). Finally, only sustained increases in ALT predicted a higher risk for diabetes. We conclude that a relatively rapid rise in fasting glucose levels is frequent in converters to diabetes and that associated increases over time in ALT and potentially triglyceride suggest hepatic fat accumulation as a contributing factor for conversion to diabetes in men at risk.

Hypoglycemia and Clinical Outcomes in Hospitalized Patients With Diabetes: Does Association With Adverse Outcomes Remain When Number of Glucose Tests Performed Is Accounted For?

BACKGROUND: Hypoglycemia is associated with increased length of stay in hospital patients, but previous studies have not considered the confounding effect of increased hypoglycemia detection associated with increased capillary blood glucose (CBG) measurement in prolonged admissions. We aimed to determine the effect of recorded hypoglycemia on length of stay of hospital inpatients (LOS) when this mathematical association is subtracted. METHODS: CBG data were analyzed for inpatients within our health board area (01/2009-01/2015). A simulated CBG data set was generated for each patient with an identical sampling frequency to the measured CBG data set. The mathematical component of increased LOS was determined using the simulated data set. Subtraction of this confounding mathematical association was used to provide measurement of the true clinical association between recorded hypoglycemia (CBG < 4 mmol [< 72mg/dl]) and LOS. RESULTS: A total of 196 962 admissions of 52 475 individuals with known diabetes were analyzed. 68 809 admissions of 29 551 individuals had >4 CBG measurements made and were included in analysis. After subtraction of the mathematical association of increased sample number, the clinical effect of recorded hypoglycemia is reduced-but persists-compared to previous studies. 1-2 days with recorded hypoglycemia has a relatively minor effect on LOS. LOS increases rapidly if there are ≥3 days with recorded hypoglycemia, with an increase of 0.75 days LOS per additional day with hypoglycemia. CONCLUSIONS: This technique increases accuracy of economic modeling of the impact of hypoglycemia on health care systems. This could assist study of the impact of hypoglycemia on other outcomes by factoring for bias of increased sample numbers.

Effects of a moderate exercise session on postprandial lipoproteins, apolipoproteins and lipoprotein remnants in middle-aged men.

Prior moderate exercise reduces postprandial triglyceride concentrations. Its effects on the concentrations, compositions and potential atherogenicity of lipoprotein subfractions were investigated in the present study. Twenty normoglycaemic middle-aged men each underwent two fat tolerance tests (blood taken fasting and for 8 h after a meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Prior exercise significantly reduced postprandial concentrations of chylomicrons (Sf >400) by 28.6% (absolute reduction 14.6 mg dl(-1)), of large VLDL1 (Sf 60-400) by 34.4% (39.7 mg dl(-1)) and of small VLDL2 (Sf 20-60) by 23.0% (9.6 mg dl(-1)). Over 95% of VLDL1 and VLDL2 comprised apolipoprotein (apo) B100-containing particles. Exercise also reduced postprandial remnant-like lipoprotein cholesterol (by 35%) and triglyceride concentrations (by 29%). Postprandial apo CIII/apo B and apo E/apo B ratios in VLDL1 were lower following exercise. Postprandial cholesteryl ester/triglyceride ratios were lower in VLDL1 and VLDL2 and higher in HDL2 following exercise. These data suggest that the effect of prior moderate exercise on VLDL1 is quantitatively greater than its effect on chylomicrons and that, in addition to reducing lipoprotein concentrations, exercise induces compositional changes to lipoprotein species which are likely to influence their metabolism and atherogenicity.

Effects of prior moderate exercise on postprandial metabolism and vascular function in lean and centrally obese men.

OBJECTIVES: We investigated whether a session of prior exercise could ameliorate postprandial endothelial dysfunction. BACKGROUND: Endothelial function is impaired after fat ingestion, and this may be related to rises in triglyceride concentrations. Exercise reduces postprandial triglyceride concentrations. METHODS: Ten lean (waist <90 cm) and 10 centrally obese (waist >100 cm) middle-aged men each underwent two oral fat tolerance tests (blood taken fasting and for 8 h after a high-fat meal containing 80 g fat and 70 g carbohydrate). On the afternoon before one test, subjects performed a 90-min treadmill walk (exercise); no exercise was performed before the control test. Endothelium-dependent and -independent microvascular function was assessed using laser Doppler imaging in the fasted state and at two hourly intervals during the 8-h postprandial period. RESULTS: Exercise reduced both fasting and postprandial triglyceride concentrations by 25% in both the lean and centrally obese groups (p < 0.0005). For all subjects taken together, exercise improved fasting endothelium-dependent function by 25% (p < 0.05), and, although there was a significant postprandial decrease in both endothelium-dependent and -independent function in both the control and exercise trials (p < 0.01), postprandial endothelium-dependent and -independent function were 15% and 20% higher, respectively, in the exercise trial than the control trial (both p < 0.05). CONCLUSIONS: A session of prior exercise improves fasting and postprandial vascular function in middle-aged men. This may be one mechanism by which exercise influences cardiovascular risk.

Cardiovascular risk in double diabetes mellitus--when two worlds collide.

Historically, clinical management of patients with type 1 diabetes mellitus (T1DM) has been focused on glycaemic control, which is sometimes achieved at the expense of weight gain on intensive insulin regimes. Although HbA(1c) level is an important contributor to increased macrovascular risk, several prospective studies have concluded that factors related to obesity, metabolic syndrome and insulin resistance are more important than HbA(1c) for the prediction of cardiovascular risk, especially for coronary heart disease events. 'Double diabetes mellitus' describes a combination of T1DM with characteristics associated with type 2 diabetes mellitus, including central adiposity and exacerbation of insulin resistance. In lean patients with T1DM, portal insulinopaenia might actually confer cardioprotective effects via changes in hepatic lipid profiles (mainly increased HDL cholesterol levels) and a reduction in hepatic steatosis. In patients with double diabetes mellitus, this situation is reversed and atherothrombotic pathophysiology is potentially accelerated by the combination of chronic hyperglycaemia and abnormal lipid partitioning. The prevalence of double diabetes mellitus is increasing in parallel with the societal trend of increased adiposity. This Review discusses how to identify patients susceptible to double diabetes mellitus and suggests alterations to their clinical management that might reduce their risk of future premature coronary disease.

Allopurinol and nitric oxide activity in the cerebral circulation of those with diabetes: a randomized trial.

OBJECTIVE: Type 2 diabetes increases risk of stroke, perhaps because of impaired cerebrovascular basal nitric oxide (NO) activity. We investigated whether this activity is improved by a 2-week course of the xanthine oxidase inhibitor allopurinol. RESEARCH DESIGN AND METHODS: We performed a randomized, double-blind, placebo-controlled crossover study. We measured the response to infusion of NG-monomethyl-L-arginine (l-NMMA) in males with type 2 diabetes before and after allopurinol or placebo. The primary end point was the change in internal carotid artery flow following L-NMMA infusion, expressed as the area under the flow-per-time curve. RESULTS: We enrolled 14 participants. Allopurinol improved responses to L-NMMA when compared with responses associated with placebo (P = 0.032; median reduction in internal carotid artery flow following L-NMMA of 3,144 ml [95% CI 375-7,143]). CONCLUSIONS: Xanthine oxidase inhibition with allopurinol appears to improve cerebral NO bioavailability, as evidenced by a greater response to infusion of L-NMMA.

Rosiglitazone stimulates nitric oxide synthesis in human aortic endothelial cells via AMP-activated protein kinase.

The thiazolidinedione anti-diabetic drugs increase activation of endothelial nitric-oxide (NO) synthase by phosphorylation at Ser-1177 and increase NO bioavailability, yet the molecular mechanisms that underlie this remain poorly characterized. Several protein kinases, including AMP-activated protein kinase, have been demonstrated to phosphorylate endothelial NO synthase at Ser-1177. In the current study we determined the role of AMP-activated protein kinase in rosiglitazone-stimulated NO synthesis. Stimulation of human aortic endothelial cells with rosiglitazone resulted in the time- and dose-dependent stimulation of AMP-activated protein kinase activity and NO production with concomitant phosphorylation of endothelial NO synthase at Ser-1177. Rosiglitazone stimulated an increase in the ADP/ATP ratio in endothelial cells, and LKB1 was essential for rosiglitazone-stimulated AMPK activity in HeLa cells. Infection of endothelial cells with a virus encoding a dominant negative AMP-activated protein kinase mutant abrogated rosiglitazone-stimulated Ser-1177 phosphorylation and NO production. Furthermore, the stimulation of AMP-activated protein kinase and NO synthesis by rosiglitazone was unaffected by the peroxisome proliferator-activated receptor-gamma inhibitor GW9662. These studies demonstrate that rosiglitazone is able to acutely stimulate NO synthesis in cultured endothelial cells by an AMP-activated protein kinase-dependent mechanism, likely to be mediated by LKB1.

Effect of prior moderate exercise on postprandial metabolism in men with type 2 diabetes: heterogeneity of responses.

UNLABELLED: Prior moderate exercise has been shown consistently to reduce postprandial triglyceride (TG) concentrations in non-diabetic adults, but its effects in men with type 2 diabetes are not known. This study aimed to determine the effect of moderate exercise on postprandial metabolism in men with type 2 diabetes. Ten middle-aged men with type 2 diabetes underwent two oral fat tolerance tests (blood taken fasting and for 8 h after a meal containing 80 g fat, 70 g carbohydrate) in random order. On the afternoon before one test, participants performed a 90-min treadmill walk (Exercise); no exercise was performed before the CONTROL test. Exercise significantly reduced fasting glucose ( CONTROL: 9.08+/-0.75 mmol l(-1), Exercise: 8.40+/-0.72 mmol l(-1), p=0.033) and insulin ( CONTROL: 8.01+/-0.98 microU ml(-1), Exercise: 6.81+/-0.93 microU ml(-1), p=0.046) and increased fasting 3-hydroxybutyrate ( CONTROL: 87.1+/-19.2 micromol l(-1), Exercise: 134.3+/-28.4 micromol l(-1), p=0.011); reduced postprandial insulin by 11.0% (p=0.04) and increased postprandial 3-hydroxybutyrate by 31.8% (p=0.03); but did not significantly change fasting or postprandial triglyceride or NEFA concentrations. However, the exercise-induced change in postprandial triglyceride concentration ranged from -32.3 to +28.3% and the exercise-induced change in fasting 3-hydroxybutyrate concentration (a marker of hepatic fatty acid oxidation) was highly correlated with the exercise-induced changes in fasting and postprandial triglyceride (r=0.68, p=0.03 for both). Thus, inter-individual variation in propensity to increase hepatic fatty acid oxidation following exercise may account for the considerable heterogeneity in triglyceride responses to moderate exercise observed in men with type 2 diabetes.