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Biomedical subjects

J H Pinkney

Publications and source records attributed to J H Pinkney.

At least 19 recordsLinked to original sources
PubMed2006

Gut peptides and the regulation of appetite.

There is a growing worldwide epidemic of obesity. Obese people have a higher incidence of type 2 diabetes and cardiovascular disease, and hence present increasing social, financial and health burdens. Weight loss is always difficult to achieve through lifestyle changes alone, and currently licensed anti-obesity drug treatments, such as orlistat and sibutramine, if tolerated, only achieve modest weight loss. Therefore, there is a need to identify more potent pharmacological targets. In the last 10 years, discoveries of new hormones such as leptin and ghrelin, together with greater understanding of previously described hormones such as cholecystokinin (CCK), pancreatic polypeptide (PP), peptide YY (PYY) and glucagon-like peptide 1 (GLP-1), have led to a rapid increase in our knowledge of the regulation of energy balance. Among the most important factors, controlling appetite and satiety are peptide hormones released from the gut. In this paper, we provide a full up-to-date overview of the current state of knowledge of this field, together with the potential of these peptides as drugs, or as other therapeutic targets, in the treatment of obesity. Finally, we propose an integrated model to describe the complex interplay of these hormones in the broader physiology of energy balance.

Appetite Regulation↗
PubMed2006

Prevalence of obesity in type 2 diabetes in secondary care: association with cardiovascular risk factors.

AIMS: To determine the prevalence of overweight and obesity among patients with type 1 and type 2 diabetes mellitus attending a secondary care diabetes clinic in the United Kingdom, and to assess the impact of overweight and obesity on glycaemic control and cardiovascular risk factors in patients with type 2 diabetes. METHODS: 3637 patients with diabetes were identified from the hospital electronic diabetes register, 916 with type 1 diabetes (mean (SD) age 40.4 (15.1) years, 496 male) and 2721 with type 2 diabetes (mean (SD) age 62.5 (11.8) years, 1436 male). Data on body mass index (BMI), glycaemic control, lipid profiles, and blood pressure were extracted. RESULTS: Of patients with type 1 diabetes, 55.3% were overweight (BMI >or=25 kg/m(2)), 16.6% were obese (BMI >or=30 kg/m(2)), and 0.4% had morbid obesity (BMI >or=40 kg/m(2)). In contrast, 86% of patients with type 2 diabetes were overweight or obese, 52% were obese, and 8.1% had morbid obesity. Obese patients with type 2 diabetes were younger, had poorer glycaemic control, higher blood pressures, worse lipid profiles, and were more likely to be receiving antihypertensive and lipid lowering drugs compared with patients with BMI <30 kg/m(2). CONCLUSIONS: Obesity is the rule among patients attending this hospital diabetes clinic, with 86% of those with type 2 diabetes overweight or obese. Obesity is associated with significantly worse cardiovascular risk factors in this patient group, suggesting that more active interventions to control weight gain would be appropriate.

Adult↗
PubMed2005

Adipokines and the insulin resistance syndrome in familial partial lipodystrophy caused by a mutation in lamin A/C.

AIMS/HYPOTHESIS: Familial partial lipodystrophy (FPLD) and obesity are both associated with increased risks of type 2 diabetes and cardiovascular disease. Although adipokines have been implicated, few data exist in subjects with FPLD; therefore we investigated a family with FPLD due to a lamin A/C mutation in order to determine how abnormalities of the plasma adipokine profile relate to insulin resistance and the metabolic syndrome. METHODS: Plasma levels of adiponectin, leptin, resistin, IL-1beta, IL-6 and TNF-alpha in 30 subjects (ten patients, 20 controls) were correlated with indices of metabolic syndrome. RESULTS: Compared with controls, FPLD patients had significantly lower plasma levels of adiponectin (3.7+/-1.0 in FDLP cases vs 7.1+/-0.72 mug/ml in controls, p=0.02), leptin (1.23+/-0.4 vs 9.0+/-1.3 ng/ml, p=0.002) and IL-6 (0.59+/-0.12 vs 1.04+/-0.17 pg/ml, p=0.047) and elevated TNF-alpha (34.8+/-8.1 vs 13.7+/-2.7 pg/ml, p=0.028), whereas IL-1beta and resistin were unchanged. In both groups, adiponectin levels were inversely correlated with body fat mass (controls, r=-0.44, p=0.036; FDLP, r=-0.67, p=0.025), insulin resistance (controls, r=-0.62, p=0.003; FDLP, r=-0.70, p=0.025) and other features of the metabolic syndrome. TNF-alpha concentrations were positively related to fat mass (controls, r=0.68, p=0.001; FDLP, r=0.64, p=0.048) and insulin resistance (controls, r=0.86, p=0.001; FDLP, r=0.75, p=0.013). IL-6, IL-1beta and resistin did not demonstrate any correlations with the metabolic syndrome in either group. CONCLUSIONS/INTERPRETATION: Low adiponectin and leptin and high TNF-alpha were identified as the major plasma adipokine abnormalities in FPLD, consistent with the hypothesis that low adiponectin and high TNF-alpha production may be mechanistically related, and perhaps responsible for the development of insulin resistance and cardiovascular disease in FPLD.

Adiponectin↗
PubMed2001

Intracellular pH, intrauterine growth and the insulin resistance syndrome.

Defects of both sodium-hydrogen exchange (NHE) and sodium-lithium countertransport (SLC) have been described in subjects at increased risk of coronary heart disease (CHD). Sodium transport is linked to the regulation of cell volume, intracellular pH and cell growth, which may explain aspects of this association. However, impaired growth in early life is also linked to adult CHD, and 'programmed' alterations of cell behaviour are postulated to be responsible for this. In this study, therefore, we examined whether NHE or SLC in adults are predicted by anthropometric measures at birth, as well as being associated with insulin resistance syndrome (IRS) variables in adulthood. Red cell SLC was measured in 26 adults, and NHE in dermal fibroblasts from another 15 subjects characterized anthropometrically at birth. SLC activity correlated with LDL cholesterol, triglycerides and urate (r=0.42 - 0.49; 0.05 > P>0.01), but not birth anthropometry. NHE V(max) correlated with plasma insulin (r=0.80; P<0.001), but birth weight was unrelated to V(max), K(m) or Hill coefficient for H(i)(+). However, pH(i) correlated with birth weight (r=0.74; P=0.002), insulin sensitivity (r=0.52; P<0.05), fasting glucose (r=-0.52; P<0.05) 2 h insulin (r=0.51; P<0.05) 2 h glucose (r=-0.54; P<0.05). In conclusion, red cell SLC is related to IRS variables, but not with birth weight measures. In contrast, low intracellular pH(i) is related to both low birth weight and adult insulin resistance, suggesting it might be a 'programmed' cell phenotype, although this is not apparently explained by altered NHE kinetics.

Anthropometry↗
PubMed2001

Evidence for the regulation of levels of plasma adhesion molecules by proinflammatory cytokines and their soluble receptors in type 1 diabetes.

OBJECTIVES: To investigate the regulation of soluble adhesion molecules by tumour necrosis factor-alpha (TNF-alpha) and interleukin-6 (IL-6), and relationships with circulating cytokine receptors, in vivo, in type 1 diabetes. DESIGN: Cross-sectional study. SETTING: University hospital diabetes clinic. SUBJECTS: A total of 47 non-nephropathic, Caucasian type 1 diabetics and 39 nondiabetic controls. OUTCOME MEASURES: Plasma levels of TNF-alpha, IL-6, their soluble receptors and adhesion molecules intercellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), sE-selectin and von Willebrand factor (vWF), and risk factors for cardiovascular disease. RESULTS: Plasma concentrations of IL-6 were elevated in diabetic patients compared with controls [median (interquartiles) 1.28 (0.89-2.65) vs. 0.66 (0.45-1.73) pg mL(-1): P=0.016], and in these patients IL-6 and soluble IL-6 receptor (sIL-6R) levels correlated with concentrations of sICAM-1 (r = 0.41, P = 0.012 and r = 0.31, P = 0.04, respectively). Tumour necrosis factor-alpha soluble receptor-2 (sTN-FRII), but not TNF-alpha or tumour necrosis factor soluble receptor-1 (sTNFRI), was elevated in diabetic subjects (P = 0.027). Plasma TNF-alpha levels correlated with sVCAM-1 (r = 0.39, P = 0.008), triglycerides (r = 0.36, P = 0.02 1) and diastolic blood pressure (r = 0.35; P = 0.024). Both sTNFRI and sTNFRII correlated with blood pressure (r = 0.46, P = 0.002; r = 0.32, P = 0.034) and triglycerides (r = 0.33, P = 0.033; r = 0.29, P = 0.05). In contrast, HDL-cholesterol and triglyceride were related to sE-selectin (r = -0.45 and +0.45; both P < 0.001). Neither sE-selectin nor vWF were related to cytokine concentrations. Finally, both TNF-alpha and sIL-6R correlated sTNFRI and RII (r = 0.44-0.49, P < 0.001). None of these interactions were apparent in control subjects. CONCLUSIONS: (i) IL-6, through effects on sICAM-1, and TNF-alpha via effects on sVCAM-1, may promote vascular adhesion; (ii) plasma levels of TNF-alpha are associated with dyslipidaemia and increased blood pressure, adding to vascular disease risk; (iii) the actions of both cytokines are probably modified by altered production of soluble receptors in diabetic subjects.

Adult↗
PubMed2001

Endothelial dysfunction in chronic renal failure: roles of lipoprotein oxidation and pro-inflammatory cytokines.

BACKGROUND: Chronic renal failure (CRF) is associated with an increased risk of ischaemic heart disease (IHD), but the mechanisms responsible are controversial. We investigated the relationship of two sets of candidate mechanisms-indices of LDL oxidation and markers of inflammatory activity-with vascular endothelial dysfunction (VED). METHODS: We carried out cross-sectional analysis of 23 dialysed and 16 non-dialysed CRF patients, 28 healthy controls, and 20 patients with stable angina and normal renal function. The following were determined: (i) LDL oxidation by Cu(2+) and ultraviolet light, serum autoantibodies to oxidized LDL (oxLDL); (ii) forearm flow-mediated vasodilatation, plasma concentrations of adhesion molecules, and von Willebrand factor (vWF); and (iii) circulating levels of TNF-alpha and IL-6, C-reactive protein (CRP), and fibrinogen. RESULTS: Endothelium-dependent vasodilatation (EDV) was lower in angina, pre-dialysis, and dialysis CRF patients than in controls (all P<0.005). Compared with controls, vWf (P<0.005) and adhesion molecules (vCAM-1, P<0.005; iCAM-1, P=0.01; E-selectin, P=0.05) were raised in dialysis, and vCAM-1 (P=0.01) in pre-dialysis CRF patients. Dialysed patients had lower HDL cholesterol (P=0.01) and higher triglyceride (P=0.05) than controls, but LDL-oxidation was similar in all groups. Autoantibodies to oxLDL were raised in angina (P<0.005) and pre-dialysis (P=0.006), but were absent in most dialysed patients. Concentrations of IL-6, TNF-alpha, CRP and fibrinogen were elevated in CRF compared with control and angina patients (P<0.005). In the whole population, IL-6 and TNF-alpha correlated negatively with EDV, HDL cholesterol, and positively with triglyceride, blood pressure, vWf, iCAM-1, vCAM-1 and E-selectin (r=-0.43 to +0.70, all P<0.05). CONCLUSIONS: Endothelial dysfunction is unrelated to LDL oxidation, suggesting that LDL oxidation might not be a major cause of VED in CRF. In contrast VED was more severe in CRF than in angina patients and is associated with increased acute-phase proteins and plasma cytokines, demonstrating a chronic inflammatory state. These observations may explain the VED and increased IHD risk of patients with CRF.

Adult↗
PubMed2000

beta-Adrenergic regulation of proinflammatory cytokines in humans.

OBJECTIVES: To investigate the effects of beta-adrenergic stimulation on IL-6 secretion in humans, and to determine the potential contribution to this response of adipocytes and peripheral blood cells (PBC). DESIGN: Experimental study in 8 human volunteers, and in vitro studies on murine adipocyte cell-line, 3T3.L1 and 3T3.F442A, and human PBC. MEASUREMENTS: Plasma IL-6 and TNFalpha responses to isoprenaline infusion. Cytokine secretion from differentiated adipocyte cell-lines and PBC in response to isoprenaline. RESULTS: Plasma IL-6 levels increased ninefold (median) by 180 min (baseline median 0.51 [interquartile range 0.47-1.4] vs 180 mins 4.53 [2.58-5.69] pg ml(-1), P=0.01). One hour after infusion, IL-6 levels (2.9 [1.27-3.98]) were lower than at 180 min (P=0.05), but higher than baseline (P=0.01). TNFalpha levels were unchanged. Differentiated adipocytes incubated in isoprenaline (0-0.1 microM) released significantly increased amounts of IL-6 whereas no response was elicited from PBC. CONCLUSIONS: The induction of IL-6 observed in vivo may be attributed to the beta-adrenergic stimulation of IL-6 release specifically from adipocytes, as opposed to circulating blood cells.

3T3 Cells↗
PubMed2000

Thyroid and sympathetic influences on plasma leptin in hypothyroidism and hyperthyroidism.

OBJECTIVES: To determine the dependence of plasma leptin concentrations upon circulating noradrenaline (NA) and thyroid hormones (TH) in humans. DESIGN: Cross-sectional study in 40 newly diagnosed untreated patients with primary thyroid disease, and 69 lean and obese euthyroid control subjects. MEASUREMENTS: Plasma leptin, NA, free T3 (fT3) and TSH in the fasting state. Anthropometry and % body fat (electrical bioimpedance). RESULTS: Leptin levels were highest in 37 obese euthyroid and 22 hypothyroid (median [interquartiles]31.5 [19.0- 48.0], 19.2 [11.5-31.5] ng ml(-1)), and lowest in 32 lean euthyroid and 18 hyperthyroid subjects (6.6 [3.9-14.4], 8.9 [5.5-11.1]; ANOVA, P< 0.0001). Plasma NA was similar in all groups (P= n.s.). In obese controls, TSH correlated with % body fat and leptin (r= 0.67, r= 0.61; P< 0.001). Treatment of hypothyroidism (n= 10) with T4 reduced leptin from 20.8 [11.8-31.6] to 12.9[4.6-21.2] (P= 0.005) with no change in BMI. CONCLUSIONS: Thyroid status modifies leptin secretion independently of adiposity and NA. The data suggest leptin-thyroid interactions at hypothalamic and adipocyte level.

Female↗
PubMed2000

Physiological relationships of uncoupling protein-2 gene expression in human adipose tissue in vivo.

The physiological significance of changes in uncoupling protein-2 (UCP-2) gene expression is controversial. In this study we investigated the biochemical and functional correlates of UCP-2 gene expression in sc abdominal adipose tissue in humans in vivo. UCP-2 messenger ribonucleic acid expression was quantified by nuclease protection in adipose tissue from lean and obese humans in both the fasting and postprandial states. Plasma fatty acids, insulin, and leptin were all determined in paired samples from the superficial epigastric vein and radial artery, and local production rates were calculated from 133Xe washout. In the fasting state UCP-2 expression correlated inversely with body mass index (r = -0.45; P = 0.026), percent body fat (r = -0.41; P = 0.05), plasma insulin (r = -0.47; P = 0.02), epigastric venous fatty acids (r = -0.45; P = 0.04), and leptin (r = -0.50; P = 0.018). UCP-2 expression remained inversely related with plasma leptin after controlling for percent body (r = -0.45; P = 0.038). At 2 or 4 h postprandially, there were no significant relationships between UCP-2 expression and biochemical parameters. In conclusion, 1) UCP-2 messenger ribonucleic acid expression in sc adipose tissue is inversely related to adiposity and independently linked to local plasma leptin levels; and 2) UCP-2 expression is not acutely regulated by food intake, insulin, or fatty acids. Reduced UCP-2 expression may be a maladaptive response to sustained energy surplus and could contribute to the pathogenesis and maintenance of obesity.

Adipose Tissue↗
PubMed1999

Insulin-like growth factor binding protein-1 in NIDDM: relationship with the insulin resistance syndrome.

OBJECTIVE: In order to examine the role of insulin-like growth factors in the pathogenesis of accelerated macrovascular disease in noninsulin-dependent diabetes mellitus (NIDDM), we investigated the relationship between the insulin resistance syndrome and the IGF axis. DESIGN: Cross-sectional analysis of the relationship between insulin resistance syndrome variables and concentrations of IGF-1, IGF-2, IGFBP-1 and IGFBP-3 in 80 subjects with NIDDM. RESULTS: After correcting for age, sex and body mass index, concentrations of IGFBP-1, correlated with those of HDL-cholesterol (r = 0.40; P < 0.001), triglycerides (r = -0.24; P = 0.04), insulin (r = -0.39; P < 0.001), intact proinsulin (r = -0.32; P = 0.006), des 31,32 proinsulin (r = -0.40; P = 0.001), and with insulin sensitivity (r = 0.38; P = 0.001) and PAI-1 activity (r = -0.24; P = 0.05); IGF-1 levels only correlated with those of HDL-cholesterol (r = -0.33; P = 0.005), and this was not explained by IGFBP-1 or insulin sensitivity. With additional correction for insulin, concentrations of IGFBP-1 still correlated with HDL-cholesterol (r = 0.40; P < 0.001), but not those of triglycerides or PAI-1 activity. There were no significant relationships between levels of IGF-2 and any of the variables investigated, and IGFBP-3 levels only correlated with those of total cholesterol (r = 0.24, P = 0.04). CONCLUSIONS: In NIDDM, concentrations of IGFBP-1 are related to those of insulin, insulin sensitivity, serum lipoproteins and PAI-1 activity. The relationship between concentrations of IGFBP-1 and HDL-cholesterol is not explained by insulin. Concentrations of IGF-1 are linked to HDL-cholesterol, and this is not explained by levels of IGFBP-1. IGFBP-1 concentrations were related to PAI-1 activity, and this may be explained by insulin, which regulates the production of IGFBP-1 and PAI-1.

Analysis of Variance↗
PubMed1999

Endothelial dysfunction in Type 1 diabetes mellitus: relationship with LDL oxidation and the effects of vitamin E.

AIMS: To examine the hypothesis that increased susceptibility of low density lipoproteins (LDL) to oxidation predisposes to endothelial dysfunction in patients with Type 1 diabetes mellitus. METHODS: A cross-sectional study of 46 non-nephropathic diabetic and 39 control subjects and in the diabetic patients, a 3-month duration, randomized, placebo-controlled double-blind trial of vitamin E 500 U/day. Flow-mediated vasodilatation (FMD) was measured in the forearm by high resolution ultrasound. LDL oxidation by Cu2+ was measured in vitro. RESULTS: Diabetic patients had greater basal and reactive forearm blood flow (geometric mean (SD%) flow (ml/min) 110.15 (19.19%) vs. 74.99 (23.17%); P=0.045, and 344.35 (20.84%) vs. 205.17 (21.48%); P=0.007), compared with controls, but there was no difference in FMD (median (interquartile range) 0.00 (-0.01-0.02) vs. 0.02 (-0.01-0.02) cm2; P=0.78). Diabetic LDL oxidation lag time correlated with postdilatation brachial artery area (r= 0.32; P=0.05) but not with FMD. Lag-times and total LDL oxidation by Cu2+, lipoprotein and vitamin E concentrations were similar in diabetic and control groups. Antibody titres to oxidized LDL (oxLDL) were higher in non-diabetic than diabetic subjects, and were unrelated to FMD. In diabetic patients, vitamin E increased mean (SD) plasma vitamin E levels (24.0 (6.5) to 47.5 (7.5) gmol/l; P=0.0006) and resulted in increased FMD (delta 0.00 (-0.02-0.01) vs. 0.01 (0.01-0.02)) cm2; P=0.0036), but no changes in LDL Cu2+ oxidation profiles were observed. CONCLUSIONS: FMD is no different in Type 1 diabetic and non-diabetic subjects and nor are indices of lipid peroxidation and in vitro LDL oxidation although levels of antibody to oxLDL are lower in diabetes. Vitamin E supplementation increases plasma vitamin E levels and may enhance FMD in diabetes but, in the absence of changes in LDL oxidation, this may not be mediated by reduced oxidation of LDL.

Adult↗
PubMed1998

Adipose tissue as an endocrine and paracrine organ.

The discovery of leptin has imparted great impetus to adipose tissue research by demonstrating a more active role for the adipocyte in energy regulation. Besides leptin, however, the adipose tissue also secretes a large number other signals. Cytokine signals, TNFalpha and IL-6, and components of the alternative pathway of complement influence peripheral fuel storage, mobilization and combustion, as well as energy homeostasis. In addition to the acute regulation of fuel metabolism, adipose tissue also influences steroid conversion and sexual maturation. In this way, adipose tissue is an active endocrine organ, influencing many aspects of fuel metabolism through a network of local and systemic signals, which interact with the established neuroendocrine regulators of adipose tissue. Thus, insulin, catecholamines and anterior pituitary endocrine axes interact at multiple levels with both cytokines and leptin. It may be proposed that the existence of this network of adipose tissue signalling pathways, arranged in an hierarchical fashion, constitutes a metabolic repertoire which enables the organism to adapt to a range of different metabolic challenges, including starvation, reproduction, times of physical activity, stress and infection, as well as short periods of gross energy excess. However, the occurrence of more prolonged periods of energy surplus, leading to obesity, is an unusual state in evolutionary terms, and the adipose tissue signalling repertoire, although sophisticated, adapts poorly to these conditions. Rather, the responses of the adipose tissue endocrine network to obesity are maladaptive, and lay the foundations of metabolic disease.

Adipose Tissue↗
PubMed1998

Effect of isoprenaline on plasma leptin and lipolysis in humans.

OBJECTIVE: The sympathetic nervous system may play a central role in the regulation of both lipolysis and leptin production. Therefore, we investigated the effect of intravenous infusions of the beta-adrenergic agonist isoprenaline on plasma concentrations of leptin and nonesterified fatty acids. DESIGN AND PATIENTS: Eight lean, healthy human volunteers, (4M:4F; median (interquartile range) age 36.5 (30.8-40.0) years; BMI 22.9 (20.1-29.2) kg.m-2; % body fat 24.5 (17.9-26.3)), were studied following an overnight fast. Intravenous infusion of isoprenaline was carried out for 3 h, followed by a 1 hour recovery phase. The isoprenaline infusion rates (0.5-3.5 micrograms.min-1) were titrated individually for each subject in order to achieve similar biological sympathetic responses based on heart rate (target heart rates were > 100 min-1 but < twice resting heart rate). MEASUREMENTS: Plasma leptin was determined using an in-house radioimmunoassay, nonesterified fatty acids estimated with an enzymatic colourimetric assay and insulin concentrations were assayed using a specific, two-site immunoenzymometric assay. RESULTS: Fasting preinfusion plasma leptin concentrations (6.3 (3.0-12.8) micrograms/l) correlated with percentage body fat measured by bioimpedance (r = 0.95; P < 0.001). Plasma leptin concentrations were rapidly suppressed by isoprenaline, with maximal suppression (20.5 (15.0-25.0)% of preinfusion levels (Wilcoxon rank sum test; P < 0.05)), observed after 2 h. In the recovery period, plasma leptin concentrations rapidly returned to preinfusion levels (postinfusion vs maximally suppressed leptin concentrations P < 0.05; vs preinfusion leptin concentrations P = NS). Plasma nonesterified fatty acids and insulin concentrations showed opposite changes to those observed with leptin. CONCLUSION: Plasma leptin concentrations are rapidly and reversibly suppressed by the infusion of isoprenaline in humans in vivo.

Adrenergic beta-Agonists↗
PubMed1998

Leptin and the pituitary-thyroid axis: a comparative study in lean, obese, hypothyroid and hyperthyroid subjects.

OBJECTIVE: To study interactions between leptin and the pituitary-thyroid axis, both in euthyroid and dysthyroid states. SUBJECTS AND MEASUREMENTS: We investigated the relationships of plasma leptin to levels of free thyroid hormones and TSH in 18 patients with newly diagnosed hyperthyroidism, 22 with newly diagnosed primary hypothyroidism, and 32 lean (body mass index [BMI] < 30) and 37 obese (BMI > 30 kg/m2) euthyroid subjects. Hypothyroid patients were restudied during thyroxine replacement treatment. RESULTS: Median [interquartile range] plasma leptin concentrations were highest in obese euthyroid subjects (31.5 [19.0-48.0] and in untreated hypothyroid patients (19.2 [11.5-31.5]), and lowest levels in untreated hyperthyroid patients (8.9 [5.5-11.1]) and lean euthyroid control subjects (6.6 [3.9-14.4] micrograms/l (Kruskall-Wallis one-way analysis of variance; P < 0.0001). In euthyroid subjects, plasma leptin levels were higher in obese than in lean subjects (P < 0.00001). In obese subjects plasma levels of TSH correlated with percentage body fat (r = 0.67; P < 0.001) and plasma leptin (r = 0.61; P < 0.001). In untreated hyperthyroid subjects plasma leptin was unrelated to free T3, and in untreated hypothyroidism plasma leptin was unrelated to either free T3 or TSH concentrations (all P = NS). In untreated hyperthyroid, but not hypothyroid, patients plasma leptin concentrations correlated with BMI (r = 0.57; P = 0.02). Treatment of hypothyroidism with thyroxine resulted in a significant reduction in plasma leptin concentrations from 20.8 (11.8 to 31.6) to 12.9 (4.6-21.2) micrograms/l (P = 0.005), but BMI did not change significantly in the hypothyroid subjects being studied prospectively. CONCLUSIONS: (i) In euthyroid subjects, plasma leptin and TSH levels correlate, and both are positively correlated with adiposity. (ii) Plasma leptin was significantly elevated in hypothyroid subjects, to levels similar to those seen in obese euthyroid subjects. (iii) Treatment of hypothyroidism resulted in a reduction in the raised plasma leptin levels. The data are consistent with the hypothesis that leptin and the pituitary-thyroid axis interact in the euthyroid state, and that hypothyroidism reversibly increases leptin concentrations.

Adult↗
PubMed1997

Relationships between plasma leptin and insulin concentrations, but not insulin resistance, in non-insulin-dependent (type 2) diabetes mellitus.

In non-diabetic subjects, insulin concentrations and insulin resistance are clearly connected, and both correlate with leptin levels, making interpretations about mechanisms difficult. In non-insulin-dependent (Type 2) diabetes mellitus (NIDDM), however, insulin concentrations and insulin resistance are less closely associated. Therefore, we examined the relationship of plasma leptin concentrations within insulin resistance and insulin levels in 32 subjects with NIDDM, who underwent measurement of insulin resistance with an insulin sensitivity test. Plasma leptin was measured with an in-house monoclonal immunoradiometric assay. Fasting leptin level correlated with BMI (r = 0.78; p < 0.001), metabolic clearance rate of glucose (= -0.44; p = 0.015), and fasting specific insulin (r = 0.58; p = 0.001), but not with age, cholesterol, triglycerides or blood pressure (r = -0.26 to 0.21; p = NS). In linear regression analysis, after adjustment for BMI and gender, leptin concentrations correlated with those of insulin (partial r = 0.42; p = 0.025), but not insulin resistance (partial r = -0.10; p = NS). We conclude that in NIDDM, concentrations of plasma leptin are closely related to those of insulin per se and to obesity, but not to insulin resistance. Insulin may be an important regulator of leptin concentration in NIDDM.

Blood Glucose↗
PubMed1997

Endothelial dysfunction: cause of the insulin resistance syndrome.

Insulin resistance has been proposed as the metabolic basis of atherogenesis. This hypothesis is based on the concept of the "insulin resistance syndrome," according to which insulin resistance is viewed as the primary abnormality that gives rise to dyslipidemia, essential hypertension, impaired glucose tolerance, and NIDDM. However, this hypothesis takes no account of the well-established and central role of vascular endothelium in the atherogenic process. Although endothelial injury is an early and prominent feature of atherogenesis, relatively little attention has been given to its metabolic consequences. In subjects with NIDDM, we have shown that endothelial dysfunction is associated with insulin resistance, raising the question of whether this relationship could be causal. In this article, we review the factors that are considered to be responsible for the development of endothelial dysfunction during atherogenesis, together with the metabolic consequences of endothelial dysfunction. While dysfunction of the endothelium in large and medium-sized arteries plays a central role in atherogenesis, we argue that dysfunction of peripheral vascular endothelium, at arteriolar and capillary level, plays the primary role in the pathogenesis of both insulin resistance and the associated features of the insulin resistance syndrome. We propose that the insulin resistance syndrome, together with many aspects of atherogenesis, can be viewed as the diverse consequences of endothelial dysfunction in different vascular beds. This new and testable hypothesis accounts for both the endothelial and metabolic abnormalities associated with atherogenesis.

Animals↗