Long-term glycaemic control directly correlates with glomerular filtration rate in early Type 1 diabetes mellitus before the onset of microalbuminuria

Hyperfiltration occurs early in diabetes mellitus and has been implicated in the development of microalbuminuria. Our aim was to re-examine the controversial relationship between glycaemic control and glomerular filtration (GFR) in normoalbuminuric, normotensive, non-obese patients with short duration Type 1 diabetes mellitus (DM). We studied 75 Type 1 DM patients, 35 male, aged 18–42 years, with a duration of diabetes of 4–8 years. GFR was determined by inulin clearance; hyperfiltration was defined as above 145 ml min⁻¹ 1.73 m⁻² (equivalent to 2 SD above mean for a control population). Analysis was by paired Student’s t-testing and linear regression. GFR correlated significantly with HbA_1c (r = 0.47, p < 0.0001) and fructosamine (r = 0.24, p = 0.035). Mean HbA_1c and fructosamine in the 13 patients with hyperfiltration was significantly higher than in the rest of the group (HbA_1c: 9.2 % (95 % C.I. 7.9–10.4 %) vs 7.6 % (7.2–7.9), p = 0.002; fructosamine: 479 μmol l⁻¹ (450–507) vs 410 μmol l⁻¹ (388–432), p = 0.009. This significant difference persisted even when the two highest values of HbA_1c or fructosamine were removed from analysis. Effective renal plasma flow, assessed by PAH clearance, also correlated in all patients with HbA_1c (r = 0.31, p = 0.039). We conclude that poor glycaemic control directly correlates with hyperfiltration and renal hyperperfusion in early Type 1 DM. Copyright © 1998 John Wiley & Sons, Ltd.     

Insulin Therapy Increases Low Plasma Growth Hormone Binding Protein in Children with New-onset Type 1 Diabetes

This study was undertaken (1) to evaluate growth hormone binding protein (GHBP) levels in newly diagnosed patients with Type 1 diabetes before and after insulin therapy and (2) to determine the relationship of GHBP to glycaemic control, C-peptide level and blood pH. GHBP, expressed as a percentage of (¹²⁵I)GH bound, was determined in 33 patients with Type 1 diabetes (M/F = 19/14, 12.3 ± 0.4 years) before (day 0), after 5 days (day 5) and after 3 months (month 3) of insulin therapy. At day 0, GHBP was lower in Type 1 diabetes compared with 38 matched healthy control subjects (3.9 ± 0.4 vs 8.2 ± 0.4 %, p < 0.001). There was no significant improvement in GHBP at day 5 (4.4 ± 0.3 %). At month 3, GHBP increased to (6.0 ± 0.4 %, p < 0.001 vs day 0), but was still lower than controls, p < 0.001. At day 0 GHBP correlated with BMI (r = 0.50, p = 0.001), blood glucose (r = ?0.43 p = 0.006) and pH (r = 0.48, p = 0.004), but not HbA₁. GHBP at month 3 correlated with day 0 C-peptide (r = 0.41, p = 0.02). Thus, (1) circulating GHBP is low in newly diagnosed patients with Type 1 diabetes, and increases after 3 months of insulin therapy but does not normalize and (2) the severity of biochemical derangement and residual β-cell function at diagnosis may determine GHBP status and its recovery. We conclude that insulin is an important modulator of GH binding protein in newly diagnosed children with Type 1 diabetes.     

Atrial natriuretic peptide in Type 2 diabetes mellitus: response to a physiological mixed meal and relationship to renal function

Relatively few data exist on atrial natriuretic peptide (ANP) characteristics in Type 2 diabetes mellitus (DM). Therefore, plasma immunoreactive ANP concentrations were measured before and for 4 h following the ingestion of a physiological mixed meal in 8 newly diagnosed, normotensive, normoalbuminuric, patients with Type 2 DM and 6 normotensive, non-diabetic controls. In patients with Type 2 DM, basal plasma ANP concentrations were 4.0 ± 2.0 and not significantly changed following ingestion of the meal, with peak levels of 4.9 ± 2.8 pmol l⁻¹. Non-diabetic controls had higher basal plasma ANP concentrations, 8.7 ± 3.4 pmol l⁻¹ (p < 0.05), significantly increasing to a peak of 11.9 ± 6.3 pmol l⁻¹ at 30 min post meal. Extracellular fluid volume (ECV) was not different between diabetic patients and controls (15877 ± 2679 vs 13668 ± 1792 ml³). Glomerular filtration rate (GFR) (isotopic clearance corrected for body surface area) was elevated in diabetic patients (mean ± SD) 130 ± 39 vs 98 ± 10 ml min⁻¹, p < 0.05). For the DM subjects, basal ANP levels were negatively correlated with GFR (r_s − 0.74, p < 0.05) and effective renal plasma flow (ERPF) (r_s − 0.8, p < 0.05). We conclude that patients with Type 2 DM demonstrate reduced basal plasma ANP concentrations which are inversely correlated to renal function. In contrast to non-diabetic controls, ANP in Type 2 DM does not rise in response to feeding. © 1998 John Wiley & Sons, Ltd.     

Increased Red Cell Sodium Lithium Countertransport Activity,Total Exchangeable Sodium,and Hormonal Control of Sodium Balance in Normoalbuminuric Type 1 Diabetes

The relationship between erythrocyte sodium lithium countertransport activity (SLC), total exchangeable sodium (NaE), and hormonal control of renal function was examined in 40 normotensive, normoalbuminuric, non-neuropathic Type 1 diabetic subjects, of whom 8 had elevated SLC (> 0.40 mmol Li h^?1l^?1 rbc). Eleven health controls with normal SLC, who were of comparable age, body mass, and blood pressure were also studied. By contrast with healthy controls, SLC in Type 1 diabetes was not associated with plasma renin activity (PRA), aldosterone, systolic blood pressure or lean body mass. SLC was also unrelated to atrial natriuretic peptide (ANP) (Type 1 diabetes only) and NaE. NaE was not correlated with any other variables. The relationships between PRA and aldosterone in healthy controls were retained in Type 1 diabetes (R² 0.37 supine, p = 0.00001, and 0.27 ambulant, p = 0.0005), as were respective direct and inverse relations between vasopressin and ANP and both PRA (r_s 0.54 to 0.57, r_s ?0.43 to ?0.53), and aldosterone (r_s 0.78 to 0.80, r_s ?0.71 to ?0.80). Fasting free serum insulin and vasopressin were both inversely related to ANP (r_s ?0.91 and ?0.71, respectively). In the absence of autonomic dysfunction, hypertension or early nephropathy in Type 1 diabetes, increased SLC or exchangeable sodium were unrelated to each other or with hormonal control of sodium balance, but the homeostatic factors controlling hormonal interaction appear to be maintained. The interaction between insulin and hormonal control of sodium and water balance may be modified by circulating free insulin concentrations.     

Dietary Advice Based on the Glycaemic Index Improves Dietary Profile and Metabolic Control in Type 2 Diabetic Patients

The effect of dietary education incorporating information about the glycaemic index of carbohydrate was tested against standard dietary advice in a randomized controlled study in 51 newly diagnosed patients with Type 2 diabetes treated as out-patients with diet only over a 12-week study period. Outcome was assessed by dietary analysis of 3-day diet diaries, fasting blood glucose, fructosamine, total cholesterol, LDL-cholesterol, HDL-cholesterol, and triglycerides. Dietary analysis indicated that the group who received low glycaemic advice not only had a significantly lower calculated mean diet glycaemic index intake (77 ± 1.1 (SEM) vs 82 ± 1%, p < 0.01) but also had a lower fat intake (25 ± 1 vs 32 ± 2% of total energy day^?1, p < 0.001), a higher carbohydrate intake (49 ± 2% vs 44 ± 1% of total energy day^?1, p < 0.05) and non-starch polysaccharide intake (21 ± 1.5 vs 14 ± 1 g, p < 0.01). There was a significantly greater within-group fall in fructosamine (3.8 ± 0.2 to 3.2 ± 0.2 mmol^?1 vs 3.6 ± 0.2 to 3.6 ± 0.3 mmol^?1, p < 0.05) and cholesterol (6.1 ± 0.3 to 5.4 ± 0.3 mmol^?1 vs. 5.6 + 0.2 to 5.3 ± 0.1 mmol^?1, p < 0.05) in the low glycaemic index group. A significant correlation was detected between the glycaemic index of the diet and the fall in fructosamine (r = 0.54, p < 0.01) and fasting blood glucose (r = 0.41, p < 0.05) which could not be demonstrated with the changes in fat or non-starch polysaccharides content of the diet, irrespective of the original study group, suggesting an independent role of the change in glycaemic index of the carbohydrate in the diet. Subjects given advice to lower the glycaemic index of the carbohydrate in their diet achieve a lower calculated dietary glycaemic intake than those who do not. This appears to have a beneficial effect on the intake of other nutrients and results in an improvement in metabolic control.     

Calcium Metabolism in Diabetes Mellitus: Effect of Improved Blood Glucose Control

Reduced bone mass occurring with increased frequency in diabetes mellitus has been attributed to poor blood glucose control but the pathogenetic mechanisms remain unknown. To evaluate the role of calcium metabolism, 59 patients with diabetes and normal renal function (22 Type 1, 37 Type 2) were studied. In all patients plasma calcium (Ca), serum phosphate (PO₄), serum parathyroid hormone (PTH), and 24-h urinary calcium (uCa) were determined under both poor and improved control (for at least 7 days) as ascertained by four blood glucose determinations daily. Improvement of blood glucose control (p = 0.001) was associated with reduction of uCa both in Type 1 (6.9 ± 1 vs 4.9 ± 0.9 mmol day^?1, mean ± SEM, p = 0.02) and in Type 2 patients (4.2 ± 0.4 vs 3.2 ± 0.4 mmol day^?1, mean ± SEM, p = 0.002). Considerably more Type 1 patients (10 out of 22) had PTH values below the detection limit (1.5 pmol l^?1) during poor than during improved control (2 out of 22). Comparison between the two types of diabetes showed that in Type 1 under poor control, Ca and PTH were lower (p = 0.03), while uCa was higher (p = 0.003), and after improved control, only uCa continued to be higher (p = 0.035). These findings suggest that increased uCa excretion in association witih ‘functional hypoparathyroidism’ (especially in Type 1 diabetes) is observed during poor blood glucose control, and may be one of the factors leading to reduced bone mass in diabetes mellitus.     

Insulin Therapy in Type 2 Diabetic Subjects Suppresses Plasminogen Activator Inhibitor (PAI-1) Activity and Proinsulin-like Molecules Independently of Glycaemic Control

Eleven Type 2 diabetic subjects (10 male 1 female: age 56.2 ± 9.7 (SD) yr) were treated in random order either with insulin or with sulphonylureas for 8 weeks each, without attempting to alter glycaemic control between the two treatment periods. Insulin treatment was associated with suppression of endogenous insulin secretion (fasting C-peptide levels -35.0 ± 24.2%; p = 0.006), and of intact proinsulin (-43.1 ± 36.8%; p = 0.03) and 32,33 split proinsulin -20.1 ± 27.0%; p = 0.03). Activity of plasminogen activator inhibitor (PAI-1), a fast acting inhibitor of fibrinolysis, decreased significantly (-14.3% ± 27.5 %; p = 0.02) but no changes occurred in concentration of lipoproteins or apoproteins between therapies. Changes in concentrations of 32,33 split and intact proinsulin were closely and significantly related (r_s = 0.83; p < 0.001) to each other but not with changes in concentrations of C-peptide (intact proinsulin r_s = -0.41; p = 0.11) and 32,33 split proinsulin r_s = -0.27; (p = 0.21). Percentage changes in intact proinsulin concentrations were positively correlated with those in PAI-1 (r_s = 0.51; p = 0.05). There was, however a paradoxical negative relationship between changes in C-peptide concentrations and those of PAI-1 (r_s = -0.73; p = 0.006). These preliminary observations suggest that insulin treatment in Type 2 diabetic subjects without any changes in glycaemic control is associated with a reduced activity of PAI-1, but is without effect on any other cardiovascular risk factors. Concentrations of insulin precursor molecules may play a role in determining fibrinolytic activity.     

Microvascular Function in Type 2 (Non-insulin-dependent) Diabetes: Improved Vasodilation After One Year of Good Glycaemic Control

Abnormalities of microvascular function may be important in the development of diabetic microangiopathy. The major functional abnormality identified in patients with Type 2 diabetes has been a marked limitation of microvascular vasodilation, which is present from the time of diagnosis. The effects of sustained improvements in glycaemic control on vasodilator capacity in Type 2 diabetes are unknown. Twelve Type 2 diabetic patients were studied prospectively for 1 year after diagnosis. The reduced maximum hyperaemic response to local heating of the foot skin present at the time of diagnosis remained unchanged after 3 months of improved glycaemic control (1.12 ± 0.56 V at diagnosis vs 1.21 ± 0.69 V at 3 months, mean ± SD; p = 0.25), but was improved after 1 year (1.42 ± 0.91 V; p = 0.04 vs 3 months). The percentage increase in maximum hyperaemia correlated with the percentage decrease in HbA_1c (r_s = 0.53, p = 0.04). These results suggest that the early microvascular abnormalities demonstrated in Type 2 diabetes are potentially reversible and provide a further reason for striving for optimal glycaemic control in this patient group.     

Hyperglycaemic Progression in Subjects with Impaired Glucose Tolerance: Association with Decline in Beta Cell Function

Impaired glucose tolerance is associated with an increased risk of Type 2 diabetes. This prospective cohort study has examined the variables associated with hyperglycaemic progression in order to elucidate the aetiology of this deterioration. The 5 mg glucose-kg ideal body weight-min^?1 continuous infusion of glucose with model assessment (CIGMA) test was used to quantitate glucose tolerance, beta cell function, and insulin sensitivity. Twenty-two Caucasian subjects who had impaired glucose tolerance identified on two separate tests underwent repeat testing after a median period of 24 months. At follow-up, 2 of the 22 subjects (9%) had Type 2 diabetes, 18 (82%) had impaired glucose tolerance, and 2 (9%) were normoglycaemic. The fasting and achieved (60-min) glucose levels were significantly higher at follow-up (mean ± SD) (5.7 ± 0.8 vs 5.5 ± 0.5 mmol l^?1, p = 0.029 and 10.0 ± 0.9 vs 9.6 ± 0.6 mmol l^?1, p = 0.021, respectively), and beta cell function was significantly lower (median and interquartile range): 75% (50–93%) vs 90% (70–135%), p = 0.009. The changes in fasting plasma glucose were found to correlate with change in body mass index (r_s = 0.46, p = 0.03). We conclude that impaired glucose tolerance is associated with decline in beta cell function, and denotes substantial risk of hyperglycaemic progression. Randomized controlled trials are warranted to determine whether exercise programmes, dietary advice, and attentive follow-up and effective preventive strategies for subjects with impaired glucose tolerance.     

Cerebral Glucose Metabolism in Type 1 Diabetic Patients

To evaluate whether cerebral glucose metabolism is impaired in diabetes the [¹⁸F]–2–deoxy–2–fluoro-d-glucose method and positron emission tomography were used to determine the regional cerebral metabolic rate of glucose in 12 healthy subjects, 8 newly diagnosed Type 1 diabetic patients, 6 Type 1 diabetic subjects without peripheral neuropathy, and 7 Type 1 diabetic patients with symptomatic peripheral neuropathy, all of whom were men. In addition, multimodal evoked potentials were assessed. Cerebral glucose consumption was significantly reduced in the group with neuropathy as compared with the newly diagnosed diabetic patients and the healthy subjects (26.9 ± 1.0 vs 33.9 ± 1.9 and 32.5 ± 1.1 ±mol 100 g^-1 min^-1; p<0.05), while in the patients without neuropathy it was 30.2 ± 2.5 ±mol 100 g^-1 min^-1 (NS vs the remaining groups). There were no significant differences between the groups regarding brainstem auditory and visual evoked potentials. No relationship was noted between cerebral glucose metabolism and P300 latency of event-related potentials as an index of cognitive function, but there was an inverse correlation with age (r = -0.42; p < 0.05) and duration of diabetes (r = -0.67; p < 0.05). These results suggest that cerebral glucose metabolism is normal at the time of diagnosis of Type 1 diabetes, but may become altered with both increasing duration of diabetes and age in the absence of central conduction deficits or cognitive dysfunction. Diabetic neuropathy may constitute a possible additional correlate of reduced cerebral glucose consumption.     

Menstrual Irregularities are more Common in Adolescents with Type 1 Diabetes: Association with Poor Glycaemic Control and Weight Gain

Ovarian function in post-menarchal girls with Type 1 diabetes was evaluated. Menstrual histories from 24 adolescents with Type 1 diabetes were compared with those from 24 age and sex matched controls. A fasting blood sample was obtained from subjects with Type 1 diabetes for the measurement of ovarian and adrenal sex hormones, LH and FSH, glucose and insulin, insulin-like growth factor-l (IGF-I), and insulin-like growth factor binding protein-1 (IGFBP-1); and an ovarian ultrasound scan was performed. Menstrual irregularity was more prevalent in patients with Type 1 diabetes than controls (54% vs 21%, p < 0.01) and their mean body mass index (BMI) was greater (22.3 ± 0.5 (± SEM) vs 20.7 ± 0.6 kg m^?2, p < 0.05). Subjects with Type 1 diabetes with irregular menses (when compared with diabetic subjects with a regular cycle) had a significantly higher HbA_***1 (12.8 ± 0.4 vs 10.5 ± 0.5%, p < 0.01) and BMI (23.2 ± 0.6 vs 21.4 ± 0.6 kg m^?2, p < 0.05) associated with a lower sex hormone binding globulin (SHBG) (37.2 ± 4.0 vs 52.6 ± 4.0 nmol I^?1, p < 0.025) and IGF-I (1.4 ± 0.2 vs 2.2 ± 0.2 ***mUI^?1, p < 0.025) and a higher LH:FSH ratio (2.6 ± 0.5 vs 1.4 ± 0.2, p < 0.05). Polycystic ovarian changes were identified in 10/13 (77%) of these patients with an irregular cycle. Menstrual irregularity is common in post-menarchal girls with Type 1 diabetes and is associated with poor glycaemic control and weight gain. The apparent high incidence of polycystic ovarian change requires further investigation.     

The relationships of concentrations of insulin,intact proinsulin and 32–33 split proinsulin with cardiovascular risk factors in Type 2 (non-insulin-dependent) diabetic subjects

Summary Standard radioimmunoassay for insulin may substantially overestimate levels of insulin because of cross-reaction with other insulin-like molecules. We have measured concentrations of insulin, intact proinsulin and 32–33 split proinsulin using two-site monoclonal antibody based immunoradiometric assays, and of insulin by a standard radioimmunoassay (immunoreactive insulin) in 51 Type 2 (noninsulin-dependent) diabetic subjects in the fasting state. The relationships of these concentrations were sought with those of total cholesterol, high density lipoprotein cholesterol, low density lipoprotein cholesterol, triglyceride, plasminogen activator inhibitor, blood pressure, and indices of body fat distribution. Significant relationships were apparent between concentrations of immunoreactive insulin as measured by standard radioimmunoassay and triglyceride (r _s=0.42, p<0.001), total cholesterol (r _s=0.25, p=0.038), high density lipoprotein cholesterol (r _s=–0.30, p=0.018) and body mass index (r _s=0.30, p=0.017), but only the relationships with triglyceride (r _s=0.36, p=0.006) and body mass index (r _s=0.26, p=0.034) remained significant when concentrations of immunoradiometrically measured insulin were employed. Concentrations of 32—33 split proinsulin, which comprises the major insulin-like molecule in these subjects, correlated positively with triglyceride (r _s=0.33, p=0.009), total cholesterol (r _s=0.23, p=0.050), and plasminogen activator inhibitor (r _s=0.26, p=0.049), and negatively with high density lipoprotein cholesterol (r _s=–0.29, p=0.021). Concentrations of immunoreactive insulin and immunoradiometric assay insulin showed significant positive correlaion with both systolic (r _s=0.24, p=0.044 and r _s=0.29, p=0.020 respectively), and diastolic blood pressure (r _s=0.48, p<0.001 and n=0.42, p=0.001 respectively), while those of intact proinsulin and 32–33 split proinsulin correlated only with diastolic blood pressure (r _s=0.33, p=0.009 and r _s=0.31, p=0.014 respectively). Using multiple regression analysis, and including age, sex, race and body mass index in the analyses, concentrations of intact proinsulin and 32–33 split proinsulin, but not immunoradiometric assay insulin, were significantly related to diastolic blood pressure. When all three molecules were incorporated into a single model, only 32–33 split proinsulin was related to diastolic blood pressure (F-change=6.91, [5,43 degrees of freedom]; p=0.012). Thus, high concentrations of insulin-like molecules are associated with changes in recognised cardiovascular risk factor in patients with Type 2 (non-insulin-dependent) diabetes mellitus.     

Relationship of Oxidative Stress and Fibrinolysis in Diabetes Mellitus

This study attempted to verify the existence of a relationship between oxidative stress documented by malondialdehyde (MDA) and superoxide dismutase (SOD) and fibrinolysis analysed by tissue plasminogen activator (tPA) and its inhibitor (PAI-1) in diabetes mellitus. Forty-seven patients with Type 1 (n = 27) and Type 2 (n = 20) diabetes were examined together with 20 non-diabetic controls. The following were analysed: plasma MDA concentration, SOD activity in erythrocytes, tPA activity and antigen, PAI-1 activity and antigen, fasting blood glucose, fructosamine, glycated haemoglobin (HbA_lc), and urine albumin. SOD activity was decreased in patients with diabetes. This contrasted with an increased plasma MDA concentration especially in Type 2 diabetes as compared with Type 1 or healthy persons (p < 0.001). tPA activity was increased in both groups of patients with diabetes as compared to healthy persons (p < 0.001), PAI-1 activity was higher in Type 2 diabetes with vascular changes than in the remaining subgroups (p < 0.001). Multivariate analysis revealed a significant positive relationship between plasma MDA concentrations and PAI-1 antigen (r = 0.53, p < 0.001) and a negative relationship between SOD and tPA activities (r = −0.53, p < 0.01). We conclude that oxidative stress may modulate fibrinolytic properties in diabetes mellitus.     

Insulin Deficiency Rather Than Hyperinsulinaemia in Newly Diagnosed Type 2 Diabetes Mellitus

This paper reports beta cell function as assessed during OGTT using specific IRMAs for insulin, intact and 32/33 split proinsulin in subjects with newly diagnosed Type 2 diabetes matched to normal controls. The relationships between insulin and the proinsulins to risk factors for cardiovascular disease were also examined. Similar fasting insulin concentrations but lower 30-min post-glucose-load insulin concentrations were found in diabetic subjects (mean ± SEM 143 ± 12 pmol^?1 vs 304 ± 19 (p < 0.001). Subjects with diabetes had increased fasting intact (10.6 ± 1.1 pmol^?1 vs 3.3 ± 0.2, p < 0.001) and 32/33 split proinsulin concentrations (8.1 ± 0.9 pmol^?1 vs 2.2 ± 0.3, p < 0.0001). Beta cell dysfunction, as expressed by a reduction in the 30-min insulin to glucose ratio (9.4 ± 1 vs 34.8 ± 2.3, p < 0.0001) and an increase in the fasting percentage of total proinsulin-like to total insulin-like molecules (24.5 ± 9% vs 11.6 ± 5, p < 0.001), was present in subjects with diabetes. In diabetic subjects beta cell dysfunction and insulin deficiency increased relative to the degree of fasting hyperglycaemia. It seems clear that beta cell dysfunction and insulin deficiency are major features of Type 2 diabetes. Only the fasting concentration of 32/33 split proinsulin positively correlated with both the waist/hip ratio (r = 0.36, p < 0.001), diastolic blood pressure (r = 0.23, p < 0.01) in addition to plasma triglyceride concentration (r = 0.46, p < 0.001). It is questionable whether hyperinsulinaemia plays a pathogenic role in cardiovascular disease in subjects with glucose intolerance.     

Electronegative low density lipoprotein subform (LDL–) is increased in type 2 (non-insulin-dependent) microalbuminuric diabetic patients and is closely associated with LDL susceptibility to oxidation

There is increasing evidence that diabetes mellitus is characterized by an enhanced lipoprotein oxidation. We have therefore investigated whether a relationship exists between LDL oxidation and microalbuminuria, which is considered an early marker of vascular involvement in type 2 diabetic patients. We selected 12 microalbuminuric and 12 normoalbuminuric type 2 diabetic patients, and 12 control subjects comparable for age, sex and blood pressure values. Oxidatively modified plasma LDL, referred as LDL^–, were measured by ion-exchange HPLC. In vitro susceptibility to oxidation of LDL was evaluated by following the kinetics of conjugated diene formation in the presence of Cu⁺⁺ ions (lag-phase time). Microalbuminuric diabetic patients had a less satisfactory metabolic control and showed a higher plasma triglyceride concentration than both normoalbuminuric diabetic patients (2.21±1.01 vs 1.15±0.39 mmol/l, P<0.01) and controls (1.18±0.61 mmol/l, P<0.01). The percentage of LDL^– in plasma was significantly increased in microalbuminuric diabetic patients in comparison with both normoalbuminuric diabetic patients (5.24±1.67 vs 3.13±1.22%, P<0.01) and controls (2.34±1.03%, P<0.001). LDL isolated from microalbuminuric diabetic patients had a significantly shorter lag-phase time in comparison with normoalbuminuric diabetic patients (79±11 vs 97±10 min, P<0.05) and controls (120±24 min, P<0.001). In diabetic patients a significant linear correlation was observed between the percentage of LDL^– and amount of fructosamine (r=0.45, P<0.05), HbA_1c (r=0.41, P<0.05), and triglycerides (r=0.65, P<0.001). An inverse correlation was found between lag-phase time and fructosamine (r=–0.5, P<0.01) and triglycerides (r=–0.59, P<0.001). This study shows that microalbuminuric type 2 diabetic patients had evidence of increased LDL oxidation, which seems to be mainly due to a poor metabolic control and a more atherogenic lipid profile. Received: 9 March 1998 / Accepted in revised form: 24 June 1998     

In vivo insulin action and muscle glycogen synthase activity in Type 2 (non-insulin-dependent) diabetes mellitus: effects of diet treatment

Summary Insulin resistant glucose metabolism is a key element in the pathogenesis of Type 2 (non-insulin-dependent) diabetes mellitus. Insulin resistance may be of both primary (genetic) and secondary (metabolic) origin. Before and after diet-induced improvement of glycaemic control seven obese patients with newly-diagnosed Type 2 diabetes were studied with the euglycaemic clamp technique in combination with indirect calorimetry and forearm glucose balance. Muscle biopsies were obtained in the basal state and again after 3 h of hyperinsulinaemia (200 mU/l) for studies of insulin receptor and glycogen synthase activities. Similar studies were performed in seven matched control subjects. Insulin-stimulated glucose utilization improved from 110±11 to 183±23 mg·m^–2·min^–1 (p<0.03); control subjects: 219+23 mg·m^–2·min^–1 (p=NS, vs post-diet Type 2 diabetes). Nonoxidative glucose disposal increased from 74±17 to 138+19 mg·m^–2·min^–1 (p<0.03), control subjects: 159±22 mg· m^–2·m^–1 (p=NS, vs post-diet Type 2 diabetic patients). Forearm blood glucose uptake during hyperinsulinaemia increased from 1.58±0.54 to 3.35±0.23 mol·l^–1·min^–1 (p<0.05), control subjects: 2.99±0.86 mol·l^–1·min^–1 (p=NS, vs post-diet Type 2 diabetes). After diet therapy the increase in insulin sensitivity correlated with reductions in fasting plasma glucose levels (r=0.97, p<0.001), reductions in serum fructosamine (r=0.77, p<0.05), and weight loss (r=0.78, p<0.05). Values of muscle glycogen synthase sensitivity to glucose 6-phosphate (A_0.5 for glucose 6-phosphate) were similar in the basal state. However, insulin stimulation of glycogen synthase was more pronounced after diet treatment (A_0.5: 0.43±0.06 (before) vs 0.30±0.04 mmol/l (after); p<0.03; control subjects: 0.22±0.03 mmol/l). Muscle insulin receptor binding and kinase activity were similar before and after diet treatment and comparable to values in the control group. The data suggest that impaired insulin stimulation of in vivo glucose turn-over and muscle glycogen synthase activity tend to be restored during successful diet treatment of patients with Type 2 diabetes.     

Monitoring of metabolic control in patients with non-insulin-dependent diabetes mellitus on oral hypoglycaemic agents: value of evening blood glucose determination

Monitoring of metabolic control in patients with non-insulin-dependent (Type 2) diabetes (NIDDM) is usually based upon blood glucose assay in the morning (after an overnight fast) and in the postprandial state (breakfast or lunch). However, this schedule does not seek low blood glucose values, especially in the evening. We have conducted a prospective study of laboratory blood glucose profiles (8 am, 9.30 am after a 35 g carbohydrate breakfast and in the evening between 5 and 7 pm). We have included 58 consecutive NIDDM patients regularly followed in our clinic (39 men, age 60 ± 11.5 years, diabetes duration 8.6 ± 6.5 years, BMI 25.5 ± 3 kg m⁻² ), treated with the sulphonylurea gliclazide, alone (40–320 mg 24 h⁻¹ , mean 170 ± 110 mg) (group 1, n = 32) or in combination with metformin (1000–3000 mg 24 h⁻¹ , 2400 ± 620 mg) (group 2, n = 26). All patients were stable, with no change in dosage for at least 3 months. Mean glycaemic control was good (group 1 HbA_1c : 6.5 ± 1.1 %, group 2: 6.9 ± 0.7 %). Evening blood glucose values were the lowest of the day in 26 patients of group 1 (81.3 %) and in 22 of group 2 (84.6 %). Mean evening blood glucose levels were lower (p = 0.001) than 8 am values (group 1: 5.8 ± 1.4 vs 6.1 ± 1.6 mmol l⁻¹ , group 2: 6.5 ± 1.8 vs 6.9 ± 1.9) and than 9.30 am values (group 1: 7.6 ± 1.5, group 2: 12.3 ± 2.8). No blood glucose values in the hypoglycaemic range were observed. HbA_1c was strongly correlated (p = 0.002 to 0.0001) in the whole group with 8 am (r = 0.39), 9.30 am (r = 0.56), and evening blood glucose values (r = 0.42). These results indicate that, in patients treated with the sulphonylurea gliclazide, alone or in combination with metformin, the lowest blood glucose values occur in the evening more frequently (4/5) than in the morning. Therefore, evening blood glucose determination should be performed systematically in the course of the metabolic evaluation of NIDDM patients on oral hypoglycaemic agents. © 1997 John Wiley & Sons, Ltd.     

Cell membrane fatty acid composition in Type 1 (insulin-dependent) diabetic patients: relationship with sodium transport abnormalities and metabolic control

Summary We have studied the fatty acid composition of erythrocyte membrane phospholipids in nine Type 1 (insulin-dependent) diabetic patients and nine healthy control subjects. Cell membranes from the diabetic patients showed a marked decrease in the total amount of polyunsaturated fatty acids (19.0%±2.2 vs 24.6%±1.4, p<0.0001) mainly at the expense of docosahexaenoic acid C226(n3) (2.9%±1.1 vs 5.3%±1.3, p<0.001), and arachidonic acid C204 n6 (12.0%±1.6 vs 15.1%±0.6, p<0.0005). Conversely, the total amount of saturated fatty acids was significantly increased (p<0.05) and the polyunsaturated/saturated ratio was decreased in the Type 1 diabetic patients (p<0.00005). Neither the time from diagnosis, nor C-peptide levels, correlated with parameters indicating a poor metabolic control of Type 1 diabetes. However, C226(n–3) and total n–3 content significantly correlated with HbA_1c (r=–0.79 and r=–0.88, respectively, p<0.01), fructosamine (r=–0.71 and r=–0.74, respectively, p<0.05), and Na⁺-K⁺ ATPase activity (maximal rate/K_m quotient) (r=0.78 and r=0.71, respectively, p<0.05). In conclusion we have found marked alterations of cell membrane lipid composition in Type 1 diabetic patients. These cell membrane abnormalities in lipid content were related to sodium transport systems and to poor metabolic control. Either diet, or the diabetic state, might be responsible for the observed cell membrane abnormalities. A dietary intervention study might differentiate the role of diet and diabetes in the reported cell membrane alterations.     

Decreased Plasminogen Activator Inhibitor-1 Activity in Newly Diagnosed Type 2 Diabetic Patients Following Dietary Modification

Increased plasminogen activator inhibitor-1 (PAI-1) activity has been reported in Type 2 (non-insulin-dependent) diabetes and is a recognized risk factor for coronary artery disease. Fourteen newly diagnosed Type 2 diabetic patients were studied before and 3 months after standard clinical dietary modification. To assess the effect of improved metabolic control on PAI-1 activity, nine Type 2 diabetic patients established on diet therapy and with previous stable glycaemic control served as controls. In the newly diagnosed patients diet therapy resulted in a significant decrease in HbA_1c levels (8.3 ± 0.5 vs 5.2 ± 0.3 % (mean ± SEM); p < 0.001), and this was accompanied by a fall in fibrinogen (4.3 ± 0.3 vs 3.0 ± 0.2 g.1^?1; p < 0.01) concentration, and PAI-1 (18.7 ± 2.3 vs 12.2 ± 0.9 arbitrary units ml^?1; p < 0.02) and factor VIII (147 ± 17 vs 115 ± 13 %; p < 0.01) activities. PAI-1 activity was correlated with triglyceride levels at the first assessment in the newly diagnosed patients (r = 0.66; p < 0.01), and this was the only independent association by multiple regression analysis when all patients (n = 23) were considered (r = 0.62; p < 0.002). However, there was no association between the changes in PAI-1 activity and the changes in HbA_1c BMI, and serum triglyceride levels following treatment in the newly diagnosed patients. Serum triglyceride concentrations, HBA_1c, PAI-1 activity, and the coagulation factors remained unchanged in the control group over the same treatment period. In conclusion, the introduction of conventional diet therapy in newly diagnosed Type 2 diabetic patients was accompanied by a significant improvement in circulating PAI-1 activity, but this could not be related to changes in the common indices of metabolic control.     

Relationship Between Blood Pressure and Urinary Albumin Excretion Rate in Young Danish Type 1 Diabetic Patients: Comparison to Non-diabetic Children

In 1989 a nation-wide investigation of blood pressure and urinary albumin excretion rate (AER) was carried out in 506 boys and 441 girls with Type 1 diabetes (approximately 80 % of total) treated at 22 paediatric departments. In addition a reference population from 1979 consisting of 663 healthy non-diabetic children (334 boys, 329 girls) served as a control group with respect to blood pressure and body mass index. Microalbuminuria was defined as AER of 20–150 μg min^-1 in at least two out of three timed overnight urine collections and was diagnosed in 30 adolescents (16 boys, 14 girls). Five patients (3 boys, 2 girls) had overt proteinuria (AER: > 150μg min^-1). Age-related percentile charts based on one blood pressure reading were provided for normoalbuminuric diabetic patients and the healthy control group. The study revealed an increase in arterial blood pressure during the period of the pubertal growth spurt for the diabetic and non-diabetic group. The changes were most pronounced for systolic blood pressure. No statistically significant difference was observed in systolic and diastolic blood pressure between normoalbuminuric diabetic children and healthy control children. However, diabetic females aged 15–18 years had significantly higher diastolic blood pressure (75 ± 1 mmHg, n = 139, mean ± SE) than healthy control females (72± 1 mmHg, n = 155, p ± 0.01), and significantly (p ± 0.001) higher body mass index (diabetic females: 22.3± 0.2 kg m^-2 vs healthy females: 20.9± 0.2 kg m^-2, mean± SE). Boys aged from 15 to 18 years with Type 1 diabetes had significantly higher systolic blood pressure (123± 1 mmHg, n = 164) than girls (117± 1 mmHg, n = 139, p± 0.0001), while girls aged from 15 to 18 years had significantly higher diastolic blood pressure (75± 1 mmHg, n = 139) than boys (72± 1 mmHg, n = 72, p ± 0.01). Among the 30 adolescents with persistent microalbuminuria, 18 (10 boys, 8 girls) had diastolic blood pressure above the upper quartile for normoalbuminuric patients, while 2 out of 5 with macroalbuminuria had diastolic blood pressure above this limit. By multiple logistic regression the only risk determinants for elevated urinary albumin levels were age and diastolic blood pressure. These findings suggest that elevated arterial blood pressure is related to the increased prevalance of microalbuminuria observed in adolescents with Type 1 diabetes.