B. M. Singh

LMNA, encoding lamin A/C, is mutated in partial lipodystrophy

The lipodystrophies are a group of disorders characterized by the absence or reduction of subcutaneous adipose tissue. Partial lipodystrophy (PLD; MIM 151660) is an inherited condition in which a regional (trunk and limbs) loss of fat occurs during the peri-pubertal phase. Additionally, variable degrees of resistance to insulin action, together with a hyperlipidaemic state, may occur and simulate the metabolic features commonly associated with predisposition to atherosclerotic disease. The PLD locus has been mapped to chromosome 1q with no evidence of genetic heterogeneity. We, and others, have refined the location to a 5.3-cM interval between markers D1S305 and D1S1600 (refs 5 , 6). Through a positional cloning approach we have identified five different missense mutations in LMNA among ten kindreds and three individuals with PLD. The protein product of LMNA is lamin A/C, which is a component of the nuclear envelope. Heterozygous mutations in LMNA have recently been identified in kindreds with the variant form of muscular dystrophy (MD) known as autosomal dominant Emery-Dreifuss MD (EDMD–AD; ref. 7) and dilated cardiomyopathy and conduction-system disease (CMD1A). As LMNA is ubiquitously expressed, the finding of site-specific amino acid substitutions in PLD, EDMD–AD and CMD1A reveals distinct functional domains of the lamin A/C protein required for the maintenance and integrity of different cell types.

Exenatide therapy in insulin-treated type 2 diabetes and obesity.

BACKGROUND Exenatide, a GLP-1 analogue, is used in combination with oral anti-diabetic agents in type 2 diabetes and obesity, and promotes weight loss. Exenatide use in combination with insulin in insulin-treated type 2 diabetes and obesity is unlicensed in the UK and outcomes are unclear. AIMS To assess the effectiveness of exenatide in insulin-treated type 2 diabetes with obesity. DESIGN AND METHODS This prospective study included 174 consecutive patients with insulin-treated type 2 diabetes and obesity initiated on exenatide in our out-patient, between October 2007 and November 2008. Weight, BMI, HbA1c, serum fructosamine, total cholesterol, HDL-cholesterol and insulin doses were recorded at baseline, 3, 6 and 12 months. Side effect profiles were recorded. RESULTS Fourteen patients discontinued exenatide before 3 months of initiation, because of side effects, and were excluded. Data were analysed on remaining 160 people all of whom completed 6 months and 57 completed 12 months treatment. Mean weight loss was 10.7 +/- 5.7 kg and 12.8 +/- 7.5 kg (P < 0.001) at 6 and 12 months. Insulin doses dropped significantly (mean 144 +/- 90 U/day at baseline to 51 +/- 55 U/day and 55 +/- 53 U/day at 6 and 12 months). At 3 months, 25% came off insulin. There was little change in HbA1c. CONCLUSION Exenatide therapy in insulin-treated type 2 diabetes and obesity was associated with very significant reductions in weight and insulin doses. Exenatide should be considered in people with type 2 diabetes on insulin and have obesity, weight gain and poor glycaemic control.

Combination of insulin and thiazolidinedione therapy in massively obese patients with Type 2 diabetes.

Aims To evaluate the influence of addition of rosiglitazone to insulin therapy over a 24‐week period in massively obese patients with poorly controlled Type 2 diabetes taking large doses of insulin.

Evidence for Consistency of the Glycation Gap in Diabetes

OBJECTIVE Discordance between HbA1c and fructosamine estimations in the assessment of glycemia is often encountered. A number of mechanisms might explain such discordance, but whether it is consistent is uncertain. This study aims to coanalyze paired glycosylated hemoglobin (HbA1c)-fructosamine estimations by using fructosamine to determine a predicted HbA1c, to calculate a glycation gap (G-gap) and to determine whether the G-gap is consistent over time. RESEARCH DESIGN AND METHODS We included 2,263 individuals with diabetes who had at least two paired HbA1c-fructosamine estimations that were separated by 10 ± 8 months. Of these, 1,217 individuals had a third pair. The G-gap was calculated as G-gap = HbA1c minus the standardized fructosamine-derived HbA1c equivalent (FHbA1c). The hypothesis that the G-gap would remain consistent in individuals over time was tested. RESULTS The G-gaps were similar in the first, second, and third paired samples (0.0 ± 1.2, 0.0 ± 1.3, and 0.0 ± 1.3, respectively). Despite significant changes in the HbA1c and fructosamine, the G-gap did not differ in absolute or relative terms and showed no significant within-subject variability. The direction of the G-gap remained consistent. CONCLUSIONS The G-gap appears consistent over time; thus, by inference any key underlying mechanisms are likely to be consistent. G-gap calculation may be a method of exploring and evaluating any such underlying mechanisms.

Association of Glycation Gap With Mortality and Vascular Complications in Diabetes

OBJECTIVE The “glycation gap” (G-gap), an essentially unproven concept, is an empiric measure of disagreement between HbA1c and fructosamine, the two indirect estimates of glycemic control. Its association with demographic features and key clinical outcomes in individuals with diabetes is uncertain. RESEARCH DESIGN AND METHODS The G-gap was calculated as the difference between measured HbA1c and a fructosamine-derived standardized predicted HbA1c in 3,182 individuals with diabetes. The G-gap’s associations with demographics and clinical outcomes (retinopathy, nephropathy, macrovascular disease, and mortality) were determined. RESULTS Demographics varied significantly with G-gap for age, sex, ethnic status, smoking status, type and duration of diabetes, insulin use, and obesity. A positive G-gap was associated with retinopathy (odds ratio 1.24 [95% CI 1.01–1.52], P = 0.039), nephropathy (1.55 [1.23–1.95], P < 0.001), and, in a subset, macrovascular disease (1.91 [1.18–3.09], P = 0.008). In Cox regression analysis, the G-gap had a “U”-shaped quadratic relationship with mortality, with both negative G-gap (1.96 [1.50–2.55], P < 0.001) and positive G-gap (2.02 [1.57–2.60], P < 0.001) being associated with a significantly higher mortality. CONCLUSIONS We confirm published associations of G-gap with retinopathy and nephropathy. We newly demonstrate a relationship with macrovascular and mortality outcomes and potential links to distinct subpopulations of diabetes.

Insulin resistance in the regulation of lipolysis and ketone body metabolism in non-insulin dependent diabetes is apparent at very low insulin concentrations

The insulin sensitivity of intermediary metabolism was studied in 8 non-obese men with well-controlled diet-treated non-insulin dependent diabetes (NIDDM) using a low dose incremental insulin infusion (basal, 0.005 and 0.01 U/kg h-1). Results were compared to 8 healthy male control subjects matched (NIDDM vs. controls, mean +/- S.E.M.) for age (56 +/- 3 vs. 54 +/- 3 years, NS) and body mass index (24.6 +/- 0.7 vs. 25.3 +/- 0.5 kg/m2, NS). Basal fasting concentrations of insulin (4.7 +/- 0.8 vs. 3.2 +/- 0.8 mU/l, NS), glucose, total ketone bodies (TKB), and non-esterified fatty acids (NEFA) were not significantly different between the groups but glycerol concentrations were significantly elevated in NIDDM patients (0.072 +/- 0.007 vs. 0.049 +/- 0.003 mmol/l, P < 0.05). During incremental insulin infusion, plasma insulin concentrations rose to 12.8 +/- 1.5 vs. 10.0 +/- 1.0 mU/l in NIDDM patients vs. control and metabolite concentrations fell significantly (P < 0.001). Significant linear dose-response relationships were found between plasma insulin (log) and glucose, TKB (log), NEFA, and glycerol concentrations by analysis of variance applied to regression (all P < 0.001). For glucose and TKB (log), the group regression lines were parallel but were significantly right-shifted in the NIDDM group (P < 0.001). In contrast, the relationships of insulin (log) and both glycerol and NEFA concentrations converged over the observed range of insulin concentrations. Significant displacement of glycerol and NEFA dose-response relationships were found in NIDDM patients at an insulin concentration of 5 mU/l (P < 0.001) but not at 12.5 mU/l.(ABSTRACT TRUNCATED AT 250 WORDS)

Changing Sex Ratio in Diabetic Ketoacidosis

An annual audit of diabetic ketoacidosis and hyperosmolar non‐ketotic state was made in one hospital from 1971 to 1988. There were 846 episodes of ketoacidosis and 126 episodes of hyperosmolar state. A relative fall occurred in the number of episodes of ketoacidosis compared with hyperosmolar state over this time (p < 0.05), and there was a change of female:male ratio for episodes of ketoacidosis occurring in established diabetes from 2.79 to 1.59 (p < 0.01). In contrast the female:male ratio remained unchanged (mean 1.16) for episodes of hyperosmolar state and remained less than 1.0 for all episodes of ketoacidosis in previously undiagnosed diabetes mellitus. Among patients who suffered recurrent ketoacidosis there was a reduction in the number of episodes occurring in female patients and an increase in the number of episodes occurring in male patients in each successive 6‐year period with consequent change in female:male ratio for this subgroup from 7.33 to 4.75 to 1.12 (p < 0.001).

Does HbA1C predict isolated impaired fasting glycaemia in the oral glucose tolerance test in subjects with impaired fasting glycaemia

Abstract Background To assess the usefulness of erythrocyte glycated haemoglobin (HbA1C) as a screening tool to identify those subjects with impaired fasting glycaemia (IFG) who do not have impaired glucose tolerance (IGT) or diabetes mellitus (DM) on a 75 g oral glucose tolerance test (OGTT). Design and methods All subjects undergoing an OGTT had HbA1C measured at baseline. Receiver operator characteristics analysis was used to identify optimal HbA1C cut-off values for diagnosing and excluding IGT and DM. Results We studied 140 subjects (69 women) with IFG (fasting capillary plasma glucose between 6.1–6.9 mmol/L). Using World Health Organisation criteria, 27 had isolated IFG, 56 had IGT and 57 had DM. HbA1C was higher (P < 0.001) in patients with DM (6.8 ± 0.93%) when compared with those with IGT (6.3 ± 0.68%) and isolated IFG (6.2 ± 0.30%), but HbA1C was similar in those with IGT and isolated IFG. There was no HbA1C cut-off value differentiating isolated IFG from IGT or DM. None of the subjects with isolated IFG had HbA1C concentration of >6.8%, but 76% and 54% subjects with IGT and DM, respectively, had HbA1C of ≤6.8%. Conclusions HbA1C measurement is of limited value in differentiating isolated IFG, IGT and DM in subjects with IFG. It cannot be used to identify which subjects with IFG do not require an OGTT.

High Variability of Glycated Hemoglobin Concentrations in Patients With IDDM Followed Over 9 years: What is the best index of long-term glycemic control?

OBJECTIVE To determine variability of long-term glycemic control in patients with IDDM. RESEARCH DESIGN AND METHODS A retrospective analysis of HbA1 among 122 IDDM patients followed over 9 years. RESULTS Annual group mean HbA1 ranged from 8.4 to 9.3% with large standard deviations (1.7–2.0%), indicating marked variability among individuals. Fluctuations of more than ± 1% HbA1 occurred in 50% of the patients year to year, and over 9 years the minimum-maximum range was > 3 and > 5% HbA1 in 55 and 11% of patients, respectively. In any one year, 22–43% of patients had HbA1 < 8%, but over 9 years only 3.3% were consistently < 8%. Groups divided according to baseline HbA1 of < 8, 8–10, and > 10% were significantly separated over 9 years by frequency distribution analysis of individual mean HbA1 but were indistinguishable when analyzed by individual HbA1 interquartile range (measure of variability). CONCLUSIONS High variability of long-term glycemic control is a marked feature of IDDM, the extent of which may be relevant to microvascular risk.

Impaired glucose tolerance is characterized by multiple abnormalities in the regulation of intermediary metabolism

The responses of circulating intermediary metabolites to a low‐dose sequential insulin infusion (basal, 0.005, 0.01, and 0.05 U kg‐1 h‐1) were assessed in eight non‐obese men with Impaired Glucose Tolerance (IGT), and in eight healthy control subjects with normal glucose tolerance matched for age, gender, and body mass index. Fasting hyperinsulinaemia was observed in the subjects with IGT (7.4 ± 1.0 vs 2.9 ± 0.3 mU l‐1, p < 0.001). While there was no significant difference (p < 0.1) in fasting venous glucose levels between the groups, fasting concentrations of lactate (p < 0.02), alanine (p > 0.01), and glycerol (p < 0.05) were significantly elevated in the subjects with IGT. During the incremental insulin infusion, overall concentrations of glucose (p < 0.05), lactate (p < 0.05), alanine (p < 0.05), glycerol (p < 0.05), immunoreactive insulin (p < 0.001), and C‐peptide (p < 0.01) were significantly higher in the subjects with IGT. Linear dose–response relationships (p < 0.005) for circulating immunoreactive insulin (log) vs metabolite concentrations were demonstrated by analysis of variance for glucose, non‐esterified fatty acids (NEFA), glycerol, and total ketone bodies. For glucose, glycerol, and NEFA, group dose–response regression lines for the subjects with IGT were displaced significantly to the right (p < 0.001 for each) of those for the normal control subjects, implying insulin insensitivity. In addition to the recognized defect in glucose homeostasis, these results indicate impaired regulation of multiple aspects of intermediary metabolism including lipolysis in IGT.