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Aim: To determine prospectively the association of baseline hypertriglyceridaemic waist phenotype with incident diabetes in Asian-Indian men with impaired glucose tolerance., Methods: In a randomized 2-year diabetes prevention trial in 517 men with impaired glucose tolerance, 123 (23.8%) developed diabetes. Baseline anthropometric, metabolic and clinical variables were estimated. Associations of hypertriglyceridaemic waist phenotype (waist circumference ≥ 90cm and a serum triglyceride level of ≥ 1.7 mmol/l) with insulin resistance and incident diabetes were assessed using multiple linear regression and Cox's proportional hazard models, respectively., Results: Men with an isolated enlarged waistline and hypertriglyceridaemic waist phenotype had significantly higher BMI and percentage of total body fat compared with the group with normal waistline and triglyceride levels and the group with isolated hypertriglyceridaemia. The men with hypertriglyceridaemic waist phenotype had higher insulin resistance (mean ± sd homeostasis model assessment of insulin resistance value: 3.6 ± 1.5) compared with those in the isolated enlarged waistline, the isolated hypertriglyceridaemia or the normal waistline and triglyceride level groups (3.1 ± 1.4, 2.7 ± 1.0 and 2.5 ± 1.1, respectively, all P < 0.05 compared with hypertriglyceridaemic waist phenotype). Multiple linear regression analyses showed that hypertriglyceridaemic waist phenotype was significantly associated with insulin resistance after adjusting for age, BMI, family history, percentage of total body fat, smoking, alcohol intake, 2-h plasma glucose and HDL cholesterol level. Hypertriglyceridaemic waist phenotype was independently associated with incident diabetes after adjusting for the above confounders and gamma-glutamyl transferase (hazard ratio 1.49, 95% CI 1.01-2.21; P = 0.047). The association of hypertriglyceridaemic waist phenotype with incident diabetes was abolished when insulin resistance was introduced into the model (hazard ratio 1.39, 95% CI 0.092-2.10; P=0.12)., Conclusions: Hypertriglyceridaemic waist phenotype is a simple clinical proxy measurement for insulin resistance and is strongly associated with incident diabetes in Asian-Indian men with impaired glucose tolerance., (© 2014 The Authors. Diabetic Medicine © 2014 Diabetes UK.)

Aims: Cardiovascular mortality remains high despite intensive treatment of people with Type 2 diabetes mellitus. Meta-analyses on rosiglitazone have raised concerns regarding its cardiovascular safety. We studied the effects of rosiglitazone on ultrasonic indices of carotid arterial disease and inflammatory markers in a group of Type 2 diabetic patients at high cardiovascular risk., Methods: A trial of rosiglitazone in Type 2 diabetic patients with high cardiovascular risk and internal carotid artery plaque compared changes in carotid ultrasound intima-media thickness (IMT), plaque thickness, arterial stiffness and compliance, and inflammatory markers at baseline, 26 and 52 weeks., Results: In the rosiglitazone group (n=28), carotid artery plaque thickness was reduced by 0.08 mm, compared with an increase of 0.19 mm (P=0.075) in the placebo group (n=29). There were no significant differences in changes of IMT, carotid wall compliance and stiffness between the two groups. Glycated haemoglobin reduced by -0.9 vs. 0.1% (-7 vs. 2 mmol/mol), (P<0.001); insulin resistance (HOMA-IR) reduced by -37.6 vs. -1.1% (P=0.016); and B cell function (HOMA-B) increased by 36.8 vs. 0.7% (P=0.009). Non-esterified fatty acids reduced by -23.5 vs. 7.9% (P=0.005); tissue plasminogen activator reduced by -25.0 vs. 0.6% (P=0.001); and plasminogen activator inhibitor activity reduced by -57.4 vs. -34.6% (P=0.052)., Conclusions: Rosiglitazone reduced carotid artery plaque thickness, though not significantly, and there was no significant change in intima media thickness or other ultrasonic indices of carotid arterial disease. There were significant improvements in glycaemic control, insulin sensitivity and fibrinolytic, but not inflammatory, markers. There was no evidence in this study of any adverse effects on progression of carotid arterial disease., (© 2010 The Authors. Diabetic Medicine © 2010 Diabetes UK.)

Glucose monitoring technology has been used in the management of diabetes for three decades. Traditional devices use enzymatic methods to measure glucose concentration and provide point sample information. More recently continuous glucose monitoring devices have become available providing more detailed data on glucose excursions. In future applications the continuous glucose sensor may become a critical component of the closed loop insulin delivery system and, as such, must be selective, rapid, predictable and acceptable for continuous patient use. Many potential sensing modalities are being pursued including optical and transdermal techniques. This review aims to summarize existing technology, the methods for assessing glucose sensing devices and provide an overview of emergent sensing modalities.

Aims: To determine whether rate of change and variability in risk factors provides insight into the development of impaired fasting glucose (IFG), impaired glucose tolerance (IGT) or Type 2 diabetes (DM)., Methods: In a nested case-control study, repeated risk factor measurements (mean number 4.3, duration 11.4 years) culminated in 59 men developing IFG (n = 37), IGT (n = 14) and/or DM (n = 11). For each case, two control subjects were matched for age and equivalence of follow-up. Rates of change and variability in diabetes risk factors prior to diagnosis were quantified by regression analysis. Changes between penultimate and diagnostic visits were also analysed., Results: The age-related rise in body mass index (BMI) was attenuated prior to IFG compared with control subjects (+0.102 vs. +0.772 kg/m2/decade, P = 0.02). There was also some evidence for this prior to IGT and DM (IGT: -1.530 vs. +0.158 kg/m2/decade, P = 0.09; DM: -1.146 vs. +0.332 kg/m2/decade, non-significant). Prior to onset, IGT cases were distinguished by higher inflammatory marker levels, a decline in insulinogenic index and greater variability in oral glucose tolerance test (OGTT) insulin, and DM cases by lower insulin sensitivity and higher liver enzyme activities. Fasting and OGTT glucose levels changed little during the mean 8.9 years prior to onset of IFG, IGT or DM. The transition to IGT or DM was accompanied by a fall in insulin sensitivity., Conclusions: Except for BMI, change or variability in risk factor levels appears relatively unimportant in the development of clinically elevated glucose levels. Deterioration in glucose levels to IGT or DM occurs as a rapid, incremental increase accompanied by a decline in insulin sensitivity.

The Department of Health has funded a national diabetes network to support clinical research. The network will facilitate recruitment into clinical trials and has been widely welcomed by clinicians. However, if the network is to reach its full potential, all those involved will need to advocate a change in attitude towards clinical trials and research, encouraging participation and contribution of data. Clinicians need to be willing to take a proactive view about research studies, and to encourage patients to adopt a positive and altruistic attitude towards trial participation. The future of trials and other important clinical research in the UK may depend on it.

Aims: It has been reported that short individuals are more likely to have abnormalities of glucose homeostasis. The aim of this study was to examine the relationship between adult height and gestational diabetes mellitus (GDM), taking into account possible artefactual or confounding explanations., Methods: Three hundred and forty-six women with previous GDM (169 European, 102 South Asian, 75 Afro-Caribbean) and 470 control women with no previous history of GDM (282 European, 94 South Asian and 94 Afro-Caribbean) were studied. Post-partum glucose status and height were measured., Results: European and South Asian women with previous GDM were shorter than control women from the same ethnic groups (European: (mean +/- SD) 162.9 +/- 6.1 vs. 165.3 +/- 6.8 cm, P < 0.0001; South Asian: 155.2 +/- 5.4 vs. 158.2 +/- 6.3 cm, P = 0.003, adjusted for age). A similar, but non-significant trend was observed among Afro-Caribbean women (162.2 +/- 6.2 vs. 163.7 +/- 6.1 cm, P = 0.1). Similar, significant height differences were observed in Europeans and South Asians when analysis was restricted to those GDM women who had received insulin during pregnancy. There was no association between height and glucose tolerance postpartum within the GDM group., Conclusions: European and South Asian women with previous GDM are shorter than control women from the same ethnic groups. The data demonstrate that this is unlikely to be an artefact resulting from the use of an fixed 75 g load in women of differing sizes, and suggest that there are likely to be common pathophysiological mechanisms underlying GDM and the determination of final adult height.

Type 2 diabetes is characterized by resistance to insulin action of glucose metabolism and lipolysis. First-degree relatives of diabetic patients are at increased risk of developing diabetes themselves and early metabolic abnormalities in these relatives may represent primary defects in the pathogenesis of diabetes. Our previous work has demonstrated impaired suppression of lipolysis after an oral glucose load in glucose-tolerant relatives of Asian origin, but not in European relatives. To investigate whether a more subtle defect exists in the European population we studied 8 first-degree relatives of European patients and 9 matched control subjects. All had normal glucose tolerance. Glycerol and glucose turnovers were measured using a primed constant infusion of the stable isotopic tracers [1,1,1,2,3(2)H5] glycerol and [6,6(2)H] glucose, basally and in response to a very low dose insulin infusion (0.005 units kg-1 h-1). The relatives had higher basal insulin concentrations (median (range): 49 (30 to 113) vs 28 (18 to 66) pmol 1(-1), p < 0.05) compared to controls, but basal glycerol and glucose turnovers and plasma concentrations of glycerol, glucose, and non-esterifed fatty acids (NEFA) were similar. Following insulin, the suppression of glycerol appearance in the circulation measured isotopically was significantly less complete in the relatives compared with controls (mean change +/- SEM: + 0.06 +/- 0.21 vs - 0.51 +/- 0.16 mumol kg-1 min-1, p < 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Mutations of the glucokinase gene (chromosome 7p) have been shown to cause some cases of familial maturity onset diabetes of youth (MODY) but few, if any, cases of late onset familial Type 2 diabetes. A further single large pedigree with MODY has shown linkage to a marker for the adenosine deaminase gene (ADA, chromosome 20q), although the diabetes susceptibility gene at this locus has not been identified. We have studied members of 19 families with familial Type 2 diabetes (including 10 European families, 6 families from the Indian subcontinent, and 3 families of Afro-Caribbean origin), 2 of which were of MODY type (and both European), with a glucokinase marker and a marker linked to ADA, to examine whether glucokinase, or the unknown defect on chromosome 20, are implicated in diabetes in our pedigrees. Several models were constructed for standard two-point linkage analysis. Glucokinase is not the cause of diabetes in all of these families but was excluded in only one MODY family. It was possible to exclude both loci in the second MODY pedigree. No evidence was found of linkage to either marker in this multi-ethnic population under the models used. At least one further locus is involved in determining susceptibility to MODY.

Type 2 diabetes is associated with abnormal lipoprotein levels and altered plasma concentrations of insulin, intact and 32, 33 split proinsulin. To investigate whether these are early features of the disease, we studied 36 normoglycaemic first-degree relatives of patients with Type 2 diabetes (13 European, 15 of Asian (Indian-subcontinent), and 8 of Afro-Caribbean origin) and 36 control subjects with no family history of diabetes. Relatives and controls were matched for age (mean +/- S.E. 33 +/- 2 vs 34 +/- 2 years), body mass index (23.7 +/- 0.5 vs 23.7 +/- 0.6 kg m-2), sex (17 M, 19 F) and ethnic origin. After an overnight fast, blood was sampled for measurement of serum lipids, plasma glucose and insulin, intact and 32, 33 split proinsulin by specific immunoradiometric assays. Relatives and controls had similar fasting concentrations of glucose (5.0 +/- 0.1 vs 4.9 +/- 0.1 mmol l-1), total cholesterol (4.51 +/- 0.13 vs 4.54 +/- 0.17 mmol l-1), HDL-cholesterol (1.21 +/- 0.06 vs 1.10 +/- 0.05 mmol l-1), LDL-cholesterol (2.84 +/- 0.14 vs 2.96 +/- 0.14 mmol l-1) and triglyceride (median (range) 0.78 (0.44-2.45) vs 0.83 (0.41-4.03) mmol l-1). Fasting levels of insulin (50.4 (18.9-174.0) vs 51.6 (10.0-118.0) pmol l-1, intact proinsulin (2.8 (0.1-15.0) vs 2.1 (0.6-6.4) pmol l-1 and 32, 33 split proinsulin (2.0(0-23.7) vs 1.6 (0.3-6.0) pmol l-1) were not significantly different between relatives and controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Type 2 (non-insulin dependent) diabetes is so common that it has been hypothesized that in the course of evolution the predisposition to it may have conferred some advantage, before or during the reproductive years. It is frequently preceded by gestational diabetes. In order to test the basis for the hypothetical advantage, energy expenditure was investigated in 10 women with documented transient diabetes in a previous pregnancy. They were studied early in a subsequent pregnancy while glucose tolerance wa still normal and 9 were re-studied after pregnancy. Their results were compared with normal matched controls. During pregnancy, resting energy expenditure was similar in the study group and controls (6.58 (5.77-7.55) median (range) vs 6.91 (6.56-7.36) MJ day-1, respectively). However, the energy response to a mixed meal (42 kJ, kg-1 lean body mass) was decreased in the study group (45 (33-68) vs 76 (50-89) kJ, p < 0.05). After pregnancy resting energy expenditure was again similar in the two groups, but the decrease in postprandial thermogenesis persisted (78 (59-84) vs 92 (79-105) kJ, p < 0.05). The patients were resistant to exogenous insulin, 0.05 U kg-1 intravenously (slope of the plasma glucose decline in the 15 min after insulin; during pregnancy patients 52 (37-92) vs controls 111 (104-121) mumol l-1 min-1, p < 0.01; after pregnancy 130 (88-156) vs controls 186 (152-221) mumol l-1 min-1, p < 0.01). The postprandial energy saving in these women could constitute an evolutionary advantage. Insulin resistance may be the mechanism for limiting postprandial thermogenesis.

Insulin analogues have been produced with high affinity for the insulin receptor and with affinity lower than that of native insulin, but differences in activity when administered in vivo to man are unconvincing. We have used very low dose insulin (0.005 units kg-1 h-1) to investigate possible differences in effect of these insulin analogues on lipolysis in seven healthy subjects. Only minor effects on blood glucose concentration were observed and glucose turnover measured isotopically with 6,6 2H glucose and leucine turnover measured with 1-13C leucine did not change significantly. Fatty acid levels decreased with insulin (area under curve, median (range) -23 (-41-10) mmol l-1) and with the low affinity analogue (-28 (-42-19) mmol l-1 h,), but the high affinity analogue had no significant effect compared with controls (high affinity analogue -8 (-28-35) mmol l-1 h; control +15 (11-53) mmol l-1). Glycerol production measured isotopically decreased with insulin (-0.54 (-1.50-0.63) mumol kg-1 min-1) and with the low affinity analogue (-0.74 (-1.76-0.72) mumol kg-1 min-1), but the high affinity analogue at these doses had no significant effect on glycerol turnover (-0.19 (-0.74-1.13) mumol kg-1 min-1). Thus at these low infusion rates insulin itself and the low affinity analogue suppressed lipolysis, as assessed by glycerol turnover and by circulating fatty acid concentrations. The high affinity analogue was cleared rapidly from the circulation producing no measurable increase in immunoreactive insulin concentrations, and no effect was observed on lipolysis.

Insulin sensitivity and postprandial thermogenesis were investigated at various stages of pregnancy to assess if changes in insulin sensitivity contribute to energy conservation during pregnancy. Cross-sectional and longitudinal studies were undertaken. Sixteen control non-pregnant women were compared with 10 women in the second trimester (2nd) and thirteen women in the third trimester (3rd) of uncomplicated pregnancy. Six women were studied at all three time points. The slope of plasma glucose decline following a bolus of intravenous insulin was used as an index of insulin sensitivity. Resting energy expenditure was measured with continuous indirect calorimetry. Postprandial thermogenesis was measured as the change in energy expenditure for the 2 h after a mixed meal. Results are expressed as mean +/- SEM or median (interquartile range). Insulin sensitivity was lower as pregnancy progressed (non-pregnant control 181 (177-205) vs 2nd 111 (100-112) vs 3rd 96 (80-109) mumol l-1 min-1, p < 0.001). Fasting insulin levels were significantly higher in the third trimester but not in the second trimester (non-pregnant control 1.9 (1.5-6.0) vs 2nd 3.1 (2.8-5.2) vs 3rd 8.6 (4.8-9.7) mU l-1, p < 0.05). Meal stimulated insulin levels were higher in the second and third trimesters compared to non-pregnant women (insulin area over 2 h, postmeal, non-pregnant control 78 +/- 10 vs 2nd 92 +/- 14 vs 3rd 145 +/- 14 mU l-1 h-1, p < 0.005). Postprandial thermogenesis was lowest in the third trimester (non-pregnant control 103 +/- 5 vs 2nd 74 +/- 8 vs 3rd 48 +/- 8 kJ, p < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)

The influence of ethnic origin, body mass index, and parity on the frequency of gestational diabetes was assessed in 11,205 consecutive women attending a multiracial antenatal clinic in London, where all women were screened for gestational diabetes. Logistic regression was used to model the relationship between gestational diabetes and ethnic origin, age, body mass index (BMI), and parity. Results were presented as adjusted odds ratios, where the reference categories are White women, age < 25 years, BMI < 27, and parity < 3. Ethnic origin was the dominant influence on the prevalence of gestational diabetes. Women from ethnic groups other than White had a higher frequency of gestational diabetes than White women (2.9% vs 0.4%, p < 0.001). Compared to White women the relative risk of gestational diabetes in the other ethnic groups was: Black 3.1 (95% confidence limits 1.8-5.5), South East Asian 7.6 (4.1-14.1), Indian 11.3 (6.8-18.8), and miscellaneous 5.9 (3.5-9.9). Increasing age was an independent risk factor. The relative risk was higher in women > or = 35 years in all ethnic groups other than in South East Asian women. Obesity (BMI > or = 27) was a further independent risk factor in all ethnic groups except in the Indian and South East Asian women. Parity > or = 3 increased the relative risk of gestational diabetes in the White, Black, and South East Asian women only.(ABSTRACT TRUNCATED AT 250 WORDS)

The plasma glucose and insulin responses to oral glucose were studied in 44 women who had previously had gestational diabetes, but had reverted to normal glucose tolerance. Twenty were White, 14 Black, and 10 Asian. A group of race-, age- and weight-matched controls was also studied. Fasting values of glucose and insulin did not differ significantly between the study group and controls. During the 2 h 75-g OGTT the White and Black previously gestational-diabetic women had similar plasma glucose values to their controls, while the Asian previously gestational-diabetic women had significantly higher glucose values at 30 min (9.2 +/- 0.6 (+/- SE) vs 7.1 +/- 0.3 mmol l-1, p less than 0.02) and at 60 min (8.6 +/- 0.8 vs 6.2 +/- 0.4 mmol l-1, p less than 0.02). Compared with their race-matched controls, the White previously gestational-diabetic women had significantly lower insulin values at 60 min (median 41 range 2-91) vs 56 (15-118) mU l-1, p less than 0.05), and the Black previously gestational-diabetic women had lower values at both 30 min (17 (4-116) vs 53 (22-197) mU l-1) and 60 min (36 (4-148) vs 99 (12-169) mU l-1, p less than 0.05). The insulin values were similar during the OGTT in the Asian previously gestational-diabetic women and their controls.(ABSTRACT TRUNCATED AT 250 WORDS)

Fourteen male patients with Type 2 diabetes were studied to identify relationships between insulin-mediated glucose disposal, basal and glucose-stimulated insulin secretion, fasting lipoproteins and apolipoproteins, and the activities of lipoprotein lipase and hepatic lipase. Sensitivity of glucose disposal to exogenous insulin correlated positively with HDL-cholesterol (r = 0.65, p less than 0.05), HDL2-cholesterol (r = 0.59, p less than 0.05), and apolipoprotein A1 (r = 0.57, p less than 0.05) and negatively with apolipoprotein B (r = -0.53, p less than 0.05) and total: HDL-cholesterol ratio (r = -0.68, p less than 0.01). Fasting C-peptide correlated negatively with HDL-cholesterol (r = -0.76, p less than 0.01), HDL2-cholesterol (r = -0.80, p less than 0.001) and apoprotein A1 (r = -0.56, p less than 0.05) and positively with total: HDL-cholesterol ratio (r = 0.64, p less than 0.05). Neither fasting plasma glucose nor the indices of stimulated insulin secretion (glucose-stimulated plasma insulin and C-peptide) were related to any of the lipoprotein measures. Insulin insensitivity and hyperinsulinaemia were both associated with higher levels of hepatic lipase activity but did not influence lipoprotein lipase activity. In multiple linear regression analysis, hepatic lipase activity was related to HDL-cholesterol independent of insulin insensitivity. In addition, fasting C-peptide alone accounted for 70% of the variance in hepatic lipase activity and this was independent of insulin sensitivity and body mass index. We propose that the abnormalities of HDL-cholesterol in Type 2 diabetes are closely related to enhanced hepatic lipase activity brought about by increased insulin secretion which, in turn, is secondary to the defect in insulin action.

To determine firstly whether body fat distribution could predict the presence of atherogenic risk factors better than overall adiposity in Type 2 diabetes, and secondly whether sex differences in these risk factors could be explained by sex differences in fat distribution, waist-to-hip girth ratio (WHR), serum lipids, lipoproteins, apolipoproteins, plasma lipolytic activity, and blood pressure were assessed in 47 patients with Type 2 diabetes, 21 women matched for age, body mass index (BMI) and blood glucose control with 26 men. The men had higher WHR (0.95 (range 0.83-1.07) vs 0.82 (0.74-0.94), p less than 0.001), lower HDL-cholesterol (1.03 +/- 0.05 vs 1.38 +/- 0.06 mmol l-1, p less than 0.001) and apolipoprotein A1 (1.40 +/- 0.06 vs 1.76 +/- 0.06 gl-1, p less than 0.001) concentrations, and higher hepatic lipase activities (16.2 (6.4-38.0) vs 8.6 (2.3-23.1) mmol h-1 l-1, p less than 0.01). In both men and women, BMI and WHR were positively related to serum triglyceride, insulin and C-peptide concentrations. In women, HDL-cholesterol was negatively related to BMI (r = -0.45, p less than 0.05) but only possibly related to WHR (r = -0.33, NS). In men, by contrast, WHR was related negatively to HDL-cholesterol (r = -0.60, p less than 0.005), HDL2-cholesterol (r = -0.43, p less than 0.05), and apolipoprotein A1 (r = -0.70, p less than 0.001) and positively to hepatic lipase activity (r = 0.65, p less than 0.001), whereas the same relationships with BMI were not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

Growth hormone (GH) has long been considered to have importance in diabetes. With poor control in Type 1 diabetes GH levels are high and may aggravate poor metabolic control. Pharmacological suppression of GH release at this stage might reverse the metabolic changes, with the possible added benefit of lower plasma insulin concentrations. Diabetic patients with life-long GH deficiency rarely develop retinopathy, while pituitary ablation in patients with retinopathy often leads to improvement. Growth hormone release inhibiting factor, somatostatin, has a short plasma half-life, and multiple effects on the endocrine system and on the gastrointestinal tract, making it unsuitable for clinical use as a GH suppressant. Long-acting analogues have a long half-life, but remain non-specific in their effects. In Type 2 diabetes the analogue Octreotide suppresses insulin and glucagon release, leaving glucose levels either unchanged or somewhat elevated. Gastrointestinal side-effects have been common, but may diminish with long-term treatment. In Type 1 diabetes insulin requirement is decreased by Octreotide, but as in Type 2 diabetes GH suppression has been observed consistently only when the drug was given at bed-time. The decrease in insulin requirement may reflect suppression of glucagon release and/or gut effects. Amelioration of the 'dawn phenomenon' has not proved possible, and hypoglycaemia has proved a particular problem with Octreotide given subcutaneously at night. The lack of effective GH suppression (particularly in patients with proliferative retinopathy), lack of specificity, and the gut and hypoglycaemic side-effects, argue strongly against a clinical role for the current somatostatin analogues in diabetes mellitus.