Francis M. Finucane

Correlation of the leptin:adiponectin ratio with measures of insulin resistance in non-diabetic individuals

Aims/hypothesisObesity is the dominant cause of insulin resistance. In adult humans it is characterised by a combination of adipocyte hypertrophy and, to a lesser extent, adipocyte hyperplasia. As hypertrophic adipocytes secrete more leptin and less adiponectin, the plasma leptin:adiponectin ratio (LAR) has been proposed as a potentially useful measure of insulin resistance and vascular risk. We sought to assess the usefulness of the LAR as a measure of insulin resistance in non-diabetic white adults.MethodsLeptin and adiponectin levels were measured in 2,097 non-diabetic individuals from the Ely and European Group for the Study of Insulin Resistance (EGIR) Relationship between Insulin Sensitivity and Cardiovascular Risk (RISC) study cohorts. LAR was compared with fasting insulin and HOMA-derived insulin sensitivity (HOMA-S) in all individuals and with the insulin sensitivity index (M/I) from hyperinsulinaemic–euglycaemic clamp studies in 1,226 EGIR RISC participants.ResultsThe LAR was highly correlated with HOMA-S in men (r = −0.58, p = 4.5 × 10−33 and r = −0.65, p = 1.1 × 10−66 within the Ely and EGIR RISC study cohorts, respectively) and in women (r = −0.51, p = 2.8 × 10−36 and r = −0.61, p = 2.5 × 10−73). The LAR was also strongly correlated with the clamp M/I value (r = −0.52, p = 4.5 × 10−38 and r = −0.47, p = 6.6 × 10−40 in men and women, respectively), similar to correlations between HOMA-S and the M/I value.Conclusions/interpretationThe leptin:adiponectin ratio is a useful measure of insulin resistance in non-diabetic white adults. These data highlight the central role of adipocyte dysfunction in the pathogenesis of insulin resistance. Given that variations between fasting and postprandial leptin and adiponectin levels tend to be small, the leptin to adiponectin ratio might also have potential value in assessing insulin sensitivity in the non-fasted state.

Subjects with early-onset type 2 diabetes show defective activation of the skeletal muscle PGC-1α/mitofusin-2 regulatory pathway in response to physical activity.

OBJECTIVE Type 2 diabetes is associated with insulin resistance and skeletal muscle mitochondrial dysfunction. We have found that subjects with early-onset type 2 diabetes show incapacity to increase Vo2max in response to chronic exercise. This suggests a defect in muscle mitochondrial response to exercise. Here, we have explored the nature of the mechanisms involved. RESEARCH DESIGN AND METHODS Muscle biopsies were collected from young type 2 diabetic subjects and obese control subjects before and after acute or chronic exercise protocols, and the expression of genes and/or proteins relevant to mitochondrial function was measured. In particular, the regulatory pathway peroxisome proliferator–activated receptor γ coactivator (PGC)-1α/mitofusin-2 (Mfn2) was analyzed. RESULTS At baseline, subjects with diabetes showed reduced expression (by 26%) of the mitochondrial fusion protein Mfn2 and a 39% reduction of the α-subunit of ATP synthase. Porin expression was unchanged, consistent with normal mitochondrial mass. Chronic exercise led to a 2.8-fold increase in Mfn2, as well as increases in porin, and the α-subunit of ATP synthase in muscle from control subjects. However, Mfn2 was unchanged after chronic exercise in individuals with diabetes, whereas porin and α-subunit of ATP synthase were increased. Acute exercise caused a fourfold increase in PGC-1α expression in muscle from control subjects but not in subjects with diabetes. CONCLUSIONS Our results demonstrate alterations in the regulatory pathway that controls PGC-1α expression and induction of Mfn2 in muscle from patients with early-onset type 2 diabetes. Patients with early-onset type 2 diabetes display abnormalities in the exercise-dependent pathway that regulates the expression of PGC-1α and Mfn2.

Ultrasound Measurements of Visceral and Subcutaneous Abdominal Thickness to Predict Abdominal Adiposity Among Older Men and Women

Accurate measures of visceral and abdominal subcutaneous fat are essential for investigating the pathophysiology of obesity. Classical anthropometric measures such as waist and hip circumference cannot distinguish between these two fat depots. Direct imaging methods such as computed tomography and magnetic resonance imaging (MRI) are restricted in large‐scale studies due to practical and ethical issues. We aimed to establish whether ultrasound is a valid alternative method to MRI for the quantitative assessment of abdominal fat depots in older individuals. The study population comprised 74 white individuals (41 men and 33 women, aged 67–76 years) participating in the Hertfordshire Birth Cohort Physical Activity trial. Anthropometry included height, weight, waist and hip circumferences. Abdominal fat was measured by ultrasound in two compartments: visceral fat defined as the depth from the peritoneum to the lumbar spine; and subcutaneous fat defined as the depth from the skin to the abdominal muscles and compared to reference measures by MRI (10‐mm single‐slice image). Ultrasound measures were positively correlated with MRI measures of visceral and subcutaneous fat (visceral: r = 0.82 and r = 0.80 in men and women, respectively; subcutaneous: r = 0.63 and 0.68 in men and women, respectively). In multiple regression models, the addition of ultrasound measures significantly improved the prediction of visceral fat and subcutaneous fat in both men and women over and above the contribution of standard anthropometric variables. In conclusion, ultrasound is a valid method to estimate visceral fat in epidemiological studies of older men and women when MRI and computed tomography are not feasible.

Incidence and pathophysiology of severe hyponatraemia in neurosurgical patients

Background: Hyponatraemia is a well-recognised complication of neurosurgical conditions, but the incidence and implications have not been well documented. Objective: To define the incidence, pathophysiology and clinical implications of significant hyponatraemia in several neurosurgical conditions. Methods: All patients admitted to the Irish National Neurosciences Centre at Beaumont Hospital, Dublin with traumatic brain injury, subarachnoid haemorrhage, intracranial neoplasm, pituitary disorders and spinal disorders who developed significant hyponatraemia (plasma sodium <130 mmol/l) from January 2002 to September 2003 were identified from computerised laboratory records. Data were collected by retrospective case note analysis. Results: Hyponatraemia was more common in patients with pituitary disorders (5/81, 6.25%; p = 0.004), traumatic brain injury (44/457, 9.6%; p<0.001), intracranial neoplasm (56/355, 15.8%; p<0.001) and subarachnoid haemorrhage (62/316, 19.6%; p<0.001) than in those with spinal disorders (4/489, 0.81%). The pathophysiology of hyponatraemia was: syndrome of inappropriate antidiuretic hormone secretion (SIADH) in 116 cases (62%) (31 (16.6%) drug-associated), hypovolaemic hyponatraemia in 50 cases (26.7%) (which included patients with insufficient data to assign to the cerebral salt-wasting group (CSWS)), CSWS in nine cases (4.8%), intravenous fluids in seven cases (3.7%) and mixed SIADH/CSWS in five cases (2.7%). Hyponatraemic patients with cerebral irritation had significantly lower plasma sodium concentrations (mean (SD) 124.8 (0.34) mmol/l) than asymptomatic patients (126.6 (0.29) mmol/l) (p<0.0001). Hyponatraemic patients had a significantly longer hospital stay (median 19 days (interquartile range (IQR) 12–28)) than normonatraemic patients (median 12 days (IQR 10.5–15)) (p<0.001). Conclusions: Hyponatraemia is common in intracerebral disorders and is associated with a longer hospital stay. Cerebral irritation is associated with more severe hyponatraemia. SIADH is the most common cause of hyponatraemia and is often drug-associated.

Obesity is associated with altered lung function independently of physical activity and fitness.

Measures of obesity, especially central adiposity, have been associated with reduced lung function. However, previous studies may have been affected by confounding by physical activity and fitness. This study aimed to examine the relationship among body fatness, fat distribution, and lung function, adjusted for physical activity energy expenditure (PAEE) and aerobic fitness (VO2max), in a cohort of British white adults with a family history of type 2 diabetes. A total of 320 adults (mean age 40.4 ± 6.0 years) attended for anthropometric and VO2max testing, and had ambulatory heart rate monitoring for 4 days to determine PAEE. Spirometry was used to measure forced expiratory volume in 1 s (FEV1) and forced vital capacity (FVC). The tests were repeated 12 months later, and a cross‐sectional analysis using linear regression with repeated measures was performed. Measures of obesity (BMI, waist circumference (WC), fat mass (FM), body fat percentage (BF%)) were associated with lower lung function in men and women (P < 0.01), while waist‐to‐hip ratio (WHR) was associated with lower lung function in men only (P < 0.001). Associations remained after adjusting for age, smoking status, height, PAEE, and VO2max. The estimated difference in mean FEV1 and FVC per unit increase in the exposure measures were consistently stronger in men compared to women (P for interaction <0.001). Obesity is inversely associated with lung function in adults, but central fat distribution appears to have a stronger relationship with respiratory mechanics in men than in women. These associations were independent of the degree of physical activity and aerobic fitness in this cohort.

Abnormal regulation of thirst and vasopressin secretion following surgery for craniopharyngioma

objective  In this study we aimed to establish the frequency of postoperative diabetes insipidus and the incidence and characteristics of abnormalities of thirst in a cohort of patients with craniopharyngioma, in whom neurosurgery had been performed.

Altered C-Fiber Function as an Indicator of Early Peripheral Neuropathy in Individuals With Impaired Glucose Tolerance

OBJECTIVE This study explored the importance of glycemic burden compared with features of the metabolic syndrome in the pathogenesis of diabetic neuropathy by comparing C-fiber function in people with type 1 diabetes to that in people with impaired glucose tolerance (IGT). RESEARCH DESIGN AND METHODS The axon reflex–elicited flare areas (LDIflares) were measured with a laser Doppler imager (LDI) in age-, height-, and BMI-matched groups with IGT (n = 14) and type 1 diabetes (n = 16) and in healthy control subjects (n = 16). RESULTS The flare area was reduced in the IGT group compared with the control (2.78 ± 1.1 vs. 5.23 ± 1.7 cm2, P = 0.0001) and type 1 diabetic (5.16 ± 2.3 cm2, P = 0.002) groups, whereas the flare area was similar in the type 1 diabetic and control groups. CONCLUSIONS This technique suggests that small-fiber neuropathy is a feature of IGT. The absence of similar small-fiber neuropathy in those with longstanding type 1 diabetes suggests that glycemia may not be the major determinant of small-fiber neuropathy in IGT.

Plasma visfatin is reduced after aerobic exercise in early onset type 2 diabetes mellitus.

Visfatin is an adipokine [1] that has been shown to be significantly elevated in people with type 2 diabetes mellitus and independently associated with waist–hip ratio [2] and body mass index (BMI) [3]. However, no correlations have been found between visfatin and insulin sensitivity [3–5]. We showed that short-term exercise training in obese middle-aged subjects with type 2 diabetes resulted in a 50% increase in glucose disposal [6]. We recently reported, however, that in young subjects with type 2 diabetes, neither glucose disposal nor VO2 max were improved after 3 months of aerobic training [7]. We measured plasma visfatin in this cohort of young patients at baseline and after 3 months of aerobic exercise. Methods

Conventional glucocorticoid replacement overtreats adult hypopituitary patients with partial ACTH deficiency

background  Glucocorticoid therapy is associated with potentially serious side‐effects, but there is no information available regarding glucocorticoid requirement in adult hypopituitary patients with partial ACTH deficiency.

Contrasting clinical and cardiovascular risk status between early and later onset type 2 diabetes

The prevalence of type 2 diabetes (T2DM) is increasing rapidly and the age of presentation is falling. These changes are likely to be linked to the current obesity epidemic. Our objective was to compare the characteristics of younger patients with T2DM (diagnosed at age < 40 years) with those of older patients (diagnosed at age 50–70 years). We identified 149 younger patients with T2DM, from our diabetes clinic database, and compared them with 217 older T2DM patients randomly identified from the same database. Younger patients with T2DM were more obese, more hypertriglyceridaemic, with lower high-density lipoprotein (HDL) cholesterol, higher total cholesterol/HDL ratio and worse initial and ongoing glycaemic control than older patients from the same clinic. Additional cardiovascular risk factors are associated with T2DM in the young. Treatment should be aimed at early modification of lifestyle and other forms of therapy to avoid long-term complications.