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     

Prevalence of diabetic peripheral neuropathy and its relation to glycaemic control and potential risk factors: the EURODIAB IDDM Complications Study

Summary The EURODIAB IDDM Complications Study involved the examination of 3250 randomly selected insulin-dependent diabetic patients, from 31 centres in 16 European countries. Part of the examination included an assessment of neurological function including neuropathic symptoms and physical signs, vibration perception threshold, tests of autonomic function and the prevalence of impotence. The prevalence of diabetic neuropathy across Europe was 28 % with no significant geographical differences. Significant correlations were observed between the presence of diabetic peripheral neuropathy with age (p < 0.05), duration of diabetes (p < 0.001), quality of metabolic control (p < 0.001), height (p < 0.01), the presence of background or proliferative diabetic retinopathy (p < 0.01), cigarette smoking (p < 0.001), high-density lipoprotein cholesterol (p < 0.001) and the presence of cardiovascular disease (p < 0.05), thus confirming previous associations. New associations have been identified from this study – namely with elevated diastolic blood pressure (p < 0.05), the presence of severe ketoacidosis (p < 0.001), an increase in the levels of fasting triglyceride (p < 0.001), and the presence of microalbuminuria (p < 0.01). All the data were adjusted for age, duration of diabetes and HbA_1c. Although alcohol intake correlated with absence of leg reflexes and autonomic dysfunction, there was no overall association of alcohol consumption and neuropathy. The reported problems of impotence were extremely variable between centres, suggesting many cultural and attitudinal differences in the collection of such information in different European countries. In conclusion, this study has identified previously known and new potential risk factors for the development of diabetic peripheral neuropathy. [Diabetologia (1996) 39: 1377–1384] Received: 14 December 1995 and in revised form: 27 June 1996     

Effects of different glycaemic index foods and dietary fibre intake on glycaemic control in Type 1 diabetic patients on intensive insulin therapy

To evaluate the influence of a low glycaemic index (GI), high GI and high fibre diet on glycaemic control and insulin requirement in Type 1 diabetic patients on intensive insulin therapy, nine well-controlled, highly-motivated Type 1 diabetic patients were put on a control diet for 12 days and then randomized in a consecutive manner to 12 days of each diet, in a crossover design. During each experimental diet, the study subjects adjusted their premeal insulin (soluble) dose to maintain their 1-h postprandial capillary glucose at or below 10 mmol l⁻¹. At the end of each experimental diet, they were submitted to a standardized breakfast of the diet under study, using the same premeal insulin dose as that required for the control diet. The control diet contained 16.0 ± 3.0 g of fibre day⁻¹ with a GI of 77.4 ± 2.7 compared to 15.3 ± 6.3 and 66.2 ± 1.2 for the low GI diet, 17.1 ± 7.2 and 92.9 ± 3.6 for the high GI diet, and 56.1 ± 3.6 (including 15 g of guar) and 73.5 ± 2.1 for the high fibre diet. Prebreakfast capillary blood glucose (6.2 ± 1.2 mmol l⁻¹) on the low GI diet and postbreakfast capillary blood glucose (8.7 ± 1.8 mmol l⁻¹) on the high fibre diet were significantly lower than the values obtained with the control diet (8.0 ± 1.8 and 10.6 ± 2.4, respectively; p <0.05). No change in premeal or basal insulin dose was required. During the standardized breakfasts, the incremental area under the curve was 1.6 ± 1.5 mmol l⁻¹ min⁻¹ for the control diet compared to 1.1 ± 1.8 for the low GI diet, 3.2 ± 1.4 for the high GI diet (p <0.05 versus low GI and high fibre; p = 0.08 versus control), and 1.0 ± 0.9 for the high fibre diet. These observations indicate that in well-controlled Type 1 diabetic subjects on intensive insulin therapy, major alterations in the GI and fibre content of meals induce small but significant changes in glucose profile. In everyday life, however, these differences are blunted, and plasma glucose remains within the target range for optimal metabolic control. © 1998 John Wiley & Sons, Ltd.     

Electronegative low-density lipoprotein subfraction from type 2 diabetic subjects is proatherogenic and unrelated to glycemic control

BACKGROUND: The physicochemical and biological characteristics of electronegative low-density lipoprotein (LDL) (LDL(-)) from type 2 diabetic patients (DM2), before and after insulin therapy, were studied. METHODS: Total LDL was subfractionated in LDL(+) (native LDL) and LDL(-) by anion-exchange chromatography. RESULTS: The proportion of LDL(-) was increased in plasma from DM2 patients compared to control subjects (13.8 +/- 4.6% versus 6.1 +/- 2.5, P < 0.05) and was not modified after glycemic optimization (14.0 +/- 5.9%). LDL(-) from DM2 patients presented similar differential characteristics versus LDL(+) than LDL(-) from controls; that is, decreased apoB and oxidizability, and increased triglyceride, nonesterified fatty acids (NEFA), apoE, apoC-III, platelet-activating factor (PAF) acetylhydrolase activity and aggregability. No difference in particle size, antioxidants, malondialdehyde (MDA), fructosamine or glycated low-density lipoprotein (gLDL) was observed between LDL subfractions. Concerning differences between LDL subfractions isolated from DM2 and from control subjects, the former showed increased MDA, fructosamine and gLDL proportion and decreased LDL size and antioxidant content. The only effect of glycemic optimization was a decrease in fructosamine and gLDL in LDL(+) from DM2 subjects. LDL(-) from DM2 patients presented low binding affinity to the low-density lipoprotein receptor (LDLr) in cultured fibroblasts compared to LDL(+) and two- to threefold increased ability to release interleukin-8 (IL-8) and monocyte chemotactic protein 1 (MCP-1) in endothelial cells. CONCLUSION: These results suggest that, although nonenzymatic glycosylation and oxidation are increased in type 2 diabetes, these features would not be directly involved in the generation of LDL(-). Moreover, LDL(-) properties suggest that the high proportion observed in plasma could promote accelerated atherosclerosis in DM2 patients through increased residence time in plasma and induction of inflammatory responses in artery wall cells.     

Effect of 14 days' subcutaneous administration of the human amylin analogue,pramlintide (AC137), on an intravenous insulin challenge and response to a standard liquid meal in patients with IDDM

Summary Individuals with insulin-dependent diabetes mellitus (IDDM or type 1 diabetes) are deficient in both insulin and amylin, peptides secreted by the beta cell. We have investigated the effects of amylin replacement therapy employing the human amylin analogue, pramlintide (25, 28, 29-pro-human amylin, previously referred to as AC137), upon the responses to a standardized insulin infusion (40 mU · kg^–1 · h^–1) for 100 min and a liquid Sustacal meal (360 kcal) in 84 healthy IDDM patients. Following baseline evaluations, patients were randomly assigned to receive subcutaneous injections of placebo, 30, 100 or 300 g pramlintide 30 min before meals for 14 days. There was no meaningful difference between adverse events reported by the 30-g pramlintide and the placebo groups, but ten subjects withdrew due to nausea, eight of these in the 300-g dose group. Peak plasma pramlintide concentrations for the 30-g group were 21±3 and 29±5 pmol/l on Days 1 and 14, respectively. These values are similar to postprandial plasma amylin concentrations in normal volunteers. The plasma glucose, free insulin, glucagon, epinephrine and norepinephrine concentrations during the insulin infusion test before and after therapy were identical in each of the groups. Prior to pramlintide therapy, Sustacal ingestion produced a 4.0–4.8 mmol/l rise in plasma glucose concentrations in each of the groups. Pramlintide therapy reduced postprandial hyperglycaemia as reflected by the 3-h incremental AUC_glucose (AUC_glucose above or below fasting glucose concentration) Day 1 vs Day 14: 30 g, 322±92 vs –38±161 mmol/l · min, p=0.010; 100 g, 317±92 vs –39±76 mmol/l · min, p=0.001; and 300 g, 268±96 vs –245±189 mmol/l · min, p=0.077. Thus, pramlintide therapy with these regimens did not appear to impair either in vivo insulin action or the counter-regulatory response to hypoglycaemia but did show a clear effect of blunting postprandial hyperglycaemia following a standardized meal.Abbreviations IDDM Insulin-dependent diabetes mellitus - AUC_glucose area under the plasma glucose concentration curve - ANOVA analysis of variance     

Autoantibodies to oxidised low density lipoproteins in IDDM are inversely related to metabolic control and microvascular complications

Summary Diabetes mellitus is associated with an increased risk of atherosclerosis. The oxidation of low-density lipoproteins (LDL) is considered a key event in the initiation of atherosclerosis. To investigate LDL oxidation in vivo we measured autoantibodies to oxidised LDL (oxLDL) in 94 patients with insulin-dependent diabetes mellitus (IDDM), compared to 27 age-matched, healthy control subjects. Patients and control subjects were screened for autoantibodies using a solid phase ELISA, comparing the binding to oxLDL with that to native LDL (nLDL). In patients with IDDM the oxLDL/nLDL antibody ratio was significantly higher than in control subjects (means ± SEM: 2.24 ± 0.26 vs 1.17 ± 0.17, p < 0.03). Antibody-negative patients had a longer diabetes duration (13.5 ± 1.3 vs 9.1 ± 1.1 years, p < 0.01) and higher actual and mean HbA_{1 c} levels compared to antibody-positive patients (8.8 ± 0.2 vs 7.9 ± 0.2 %, p < 0.005 and 8.3 ± 0.2 vs 7.7 ± 0.2 %, p < 0.03; respectively). In patients with a high microangiopathy score, the antibody ratio was lower than in patients without complications (1.04 ± 0.10 vs 2.40 ± 0.29, p < 0.01). OxLDL specific immune complexes were found exclusively in antibody-negative as compared to antibody-positive patients (18.3 vs 0 %; p < 0.01). Our data demonstrate an inverse relationship between free oxLDL antibodies and the severity of the disease. This apparent paradox can be explained in part by our demonstration of oxLDL immune complexes, masking free antibodies. [Diabetologia (1998) 41: 350–356] Received: 18 June 1997 and in final revised form: 30 September 1997     

Glycated low density lipoprotein catabolism is increased in rabbits with alloxan-induced diabetes mellitus

Summary Hyperglycaemia in diabetes mellitus is responsible for the process of non-enzymatic glycosylation of different proteins. Since we did not find elevated glycated apolipoprotein B levels in diabetic patients, an altered glycated apolipoprotein B metabolism was suspected in diabetic patients. Experiments in normal rabbits showed that non-reductive (in vitro) glycated low density lipoprotein (gly-LDL) was cleared at a slower rate than control LDL and thus stayed longer in the circulation (vascular mean residence time: 10 vs 8 h, p<0.001). The body mean residence time for gly-LDL was 22 h vs 17 h for control LDL. In diabetic animals the catabolic parameters of both LDL preparations changed towards a faster clearance, the effect being greatest for gly-LDL (total mean residence times of gly-LDL pre-diabetic: 19 h, diabetic: 16 h; control LDL pre-diabetic and diabetic: 14 h). The difference in clearance between glycated and control LDL was thus strongly reduced. Virtually no antibody complexed to gly-LDL could be measured. The results suggest an increased activity of the non-receptor mediated pathway in diabetes mellitus, possibly co-responsible for an increased atherosclerotic risk.     

Troglitazone increases the resistance of low density lipoprotein to oxidation in healthy volunteers

Summary The oxidative modification of low density lipoprotein is of importance in atherogenesis. Antioxidant supplementation has been shown, in published work, to increase low density lipoprotein resistance to oxidation in both healthy subjects and diabetic subjects; in animal studies a contemporary reduction in atherogenesis has been demonstrated. Troglitazone is a novel oral antidiabetic drug which has similarities in structure with vitamin E. The present study assessed the effect of troglitazone 400 mg twice daily for 2 weeks on the resistance of low density lipoprotein to oxidation in healthy male subjects. Ten subjects received troglitazone and ten received placebo in a randomised, placebo-controlled, parallel-group design. The lag phase (a measure of the resistance of low density lipoprotein to oxidation) was determined by measurement of fluorescence development during copper-catalysed oxidative modification of low density lipoprotein. The lag phase was increased by 27 % (p < 0.001) at week 1 and by 24 % (p < 0.001) at week 2 in the troglitazone treated group compared with the placebo group. A number of variables known to influence the resistance of low density lipoprotein to oxidation were measured. They included macronutrient consumption, plasma and lipoprotein lipid profile, alpha-tocopherol, beta-carotene levels in low density lipoprotein, low density lipoprotein particle size, mono and polyunsaturated fatty acid content of low density lipoprotein and pre-formed low density lipoprotein hydroperoxide levels in low density lipoprotein. Troglitazone was associated with a significant reduction in the amount of pre-formed low density lipoprotein lipid hydroperoxides. At weeks 1 and 2, the low density lipoprotein hydroperoxide content was 17 % (p < 0.05) and 18 % (p < 0.05) lower in the troglitazone group compared to placebo, respectively. In summary the increase in lag phase duration in the troglitazone group appeared to be due to the compound's activity as an antioxidant and to its ability to reduce the amount of pre-formed low density lipoprotein lipid hydroperoxides. This antioxidant activity could provide considerable benefit to diabetic patients where atherosclerosis accounts for the majority of total mortality. [Diabetologia (1997) 40: 1211–1218] Received: 18 February 1997 and in revised form: 6 June 1997     

Longitudinal study on glycaemic control and quality of life in patients with Type 2 diabetes mellitus referred for intensified control.

AIM: The aim of our study was to describe investigate and association between improved glycaemic control on quality of life (QoL) during 1 year of treatment in a sample of 94 Type 2 diabetic patients referred for insulin therapy to an outpatient department (OPD). Treatment was aimed at achieving acceptable glycaemic control by means of maximizing oral therapy, if necessary switching over to insulin therapy, and information and education provided by a diabetes specialist nurse and dietitian. METHODS: QoL was measured using a disease-specific (Diabetes Health Profile (DHP)) and a generic questionnaire (RAND-36). After 1 year the medical examination and QoL measurements were repeated. The association between 1-year changes in QoL and achievement of good metabolic control (final glycosylated haemoglobin (HbA1c) < or = 8%), switch to insulin therapy, and presence of hyperglycaemic complaints at baseline was analysed after adjustment for appropriate confounders. RESULTS: After 1 year, mean HbA1c was reduced from 10.4% to 7.8%. Also QoL improved in the total group. Patients who achieved good glycaemic control after 1 year (61%) improved in a similar manner as the others. Patients switched over to insulin (65%) improved in a similar manner as the others, but at the final examination they experienced more problems with social functioning and pain. Patients with hyperglycaemic complaints at baseline (49%) improved more in QoL than those without, especially in physical functioning, vitality and health change, but at the final examination still scored lower on a majority of the DHP and RAND-36 dimensions. CONCLUSION: Symptoms of hyperglycaemia predict the strength of an association between improvements of glycaemic control and QoL.     

The potential role of glucagon-like peptide-1 or its analogues in enhancing glycaemic control in critically ill adult patients

Intravenous insulin therapy is the gold standard therapy for glycaemic control in hyperglycaemic critically ill adult patients. However, hypoglycaemia remains a major concern in critically ill patients, even in some populations who are not receiving infused insulin. Furthermore, the influence of factors such as glycaemic variability and nutritional support may conceal any benefit of strict glycaemic control on morbidity and mortality in these patients. The recently revised guidelines of the American Diabetic Association/American College of Clinical Endocrinologists no longer advocate very tight glycaemic control or normalization of glucose levels in all critically ill patients. In the light of various concerns over the optimal glucose level and means to achieve such control, the use of glucagon-like peptide-1 or its analogues administered intravenously may represent an interesting therapeutic option.     

Subclinical nerve dysfunction in children and adolescents with IDDM

Summary The purpose of this study was to investigate whether young insulin-dependent diabetic patients still develop peripheral nerve dysfunction when using modern multiple insulin injection therapy and to elucidate if this correlated with various disease parameters. Seventy-five patients, 7 to 20 years old with a duration of diabetes of more than 3 years, and 128 age-matched healthy control subjects underwent bilateral studies of median, peroneal, and sural nerves. Presence of diabetes lowered motor conduction velocity (p<0.0001), sensory conduction velocity (p<0.0001) and sensory nerve action potential (p<0.05) in all examined nerves. The mean change in conduction velocity induced by diabetes was –4.8 m/s in the peroneal nerve, –3.3 m/s in the median motor nerve, –2.6 m/s in the sural nerve and –2.4 m/s in the median sensory nerve. Fifty-seven percent of the patients had abnormal conduction (values outside 95% predictive interval) which was seen most often in the motor nerves, especially in the peroneal nerve (41%) followed by the median nerve (24%). In multiple regression analysis, long-term poor metabolic control and increased body length correlated with nerve dysfunction identified in most examined parameters. Three patients had signs or symptoms suggestive of neuropathy. It is concluded that despite modern multiple insulin injection therapy, with reasonably good metabolic control, nerve dysfunction is still common in children and adolescents with insulin-dependent diabetes mellitus. Risk factors are increased height and long-term poor metabolic control.Abbreviations IDDM Insulin-dependent diabetes mellitus - MIT multiple insulin injection therapy - MCV motor nerve conduction velocity - CMAP compound muscle action potential - DML distal motor latency - SCV sensory nerve conduction velocity - SNAP sensory nerve action potential     

The effect of long-term glycaemic control on serum lipoprotein(a) levels in patients with Type 2 diabetes mellitus.

AIMS: To examine whether long-term glycaemic control affects lipoprotein(a) (Lp(a)) levels in patients with Type 2 diabetes mellitus. METHODS: Eighty-nine Type 2 diabetic patients (38 men, 51 women) were recruited from the diabetes clinic. Based on HbA1c concentrations at baseline, patients were divided into two groups: those with HbA1c < 8.0% (n =45) and those with HbA1c > or = 8.0% (n=44). Comparisons of Lp(a) levels were made between both groups. The effect of long-term glycaemic control on Lp(a) levels was investigated in a subgroup of 20 patients, selected from those with baseline HbA1c > or = 8%. All these patients were treated with a goal of HbA1c <7%. RESULTS: Lp(a) levels were not significantly different between those with HbA1c< 8.0% and those with HbA1c, > or = 8.0%. No correlation between Lp(a) and HbA1c or fasting blood glucose levels was noted in diabetic patients as a whole. After 2 years of intensive glycaemic control, all patients exhibited remarkable improvement of therapy: their average HbA1c levels were 6.5 +/- 0.7%, being < 7% in 70% of patients. However, no change in Lp(a) levels were observed after 2 years (19.5 +/- 14.8-21.4 +/- 13.4 mg/dl, P = 0.390). CONCLUSION: These results indicate that improvement of glycaemic control does not affect serum Lp(a) levels in patients with Type 2 diabetes mellitus.     

E-Selectin plasma concentration is influenced by glycaemic control in NIDDM patients: possible role of oxidative stress

Summary Although elevated levels of soluble E-selectin and intercellular cell adhesion molecules-1 (ICAM-1) have been reported in non-insulin-dependent diabetes mellitus (NIDDM), it is not clear by what mechanism this elevation occurs and whether or not it is related to glycaemic control. In this study we analyse: 1) the relation of glycaemic control with the concentrations of E-selectin, vascular cell adhesion molecules-1 (VCAM-1) and ICAM-1 in NIDDM patients; 2) whether metabolic control can affect the oxidative stress (as measured by plasma hydroperoxide concentration and susceptibility of LDL to in vitro oxidation) and hence the adhesion molecule plasma concentrations. Thirty-four (19 males and 15 females) poorly controlled NIDDM patients were studied. All parameters were evaluated at the beginning of the study and after 90 days of dietary and pharmacological treatment. The treatment decreased HbA_1C (p < 0.001), E-selectin (p < 0.001), plasma hydroperoxides (p < 0.003) and the susceptibility of LDL to in vitro oxidation (lag phase) (p < 0.0001). Before treatment HbA_1C, lag phase and lipid hydroperoxides correlated with E-selectin plasma concentration (r = 0.51, –0.57 and 0.54, respectively, p < 0.01). There was also a correlation between HbA _1C and lag phase (p < 0.01) and between HbA _1C and lipid hydroperoxides (p < 0.01). In addition, the variations of HbA _1C, lag phase and lipid hydroperoxide values correlated with those for E-selectin concentration after 90 days' treatment (r = 0.54, –0.64 and 0.61, respectively, p < 0.01). In multiple linear correlation analysis, however, the partial correlation coefficients of HbA _1C (basal and variations) with E-selectin concentration (basal and variations) fell to non-significant values (r = 0.12 and 0.25, respectively) when LDL lag phase and plasma hydroperoxides were kept constant. The results indicate that the improvement of metabolic control in NIDDM patients is associated with a decrease of E-selectin plasma levels; they also suggest that glycaemic control per se is not directly implicated in determining E-selectin plasma concentration; glycaemic control could affect E-selectin concentration through its effect on oxidative stress. [Diabetologia (1997) 40: 584–589] Received: 31 October 1996 and in revised form 23 January 1997     

Intramuscular triglyceride content is increased in IDDM

Summary Increased lipid oxidation is related to insulin resistance. Some of the enhanced lipid utilization may be derived from intramuscular sources. We studied muscle triglyceride (mTG) concentration and its relationship to insulin sensitivity in 10 healthy men (age 29 ± 2 years, BMI 23.3 ± 0.6 kg/m²) and 17 men with insulin-dependent diabetes mellitus (IDDM) (age 30 ± 2 years, BMI 22.8 ± 0.5 kg/m², diabetes duration 14 ± 2 years, HbA_{1 c} 7.7 ± 0.3 %, insulin dose 48 ± 3 U/day). Insulin sensitivity was measured with a 4 h euglycaemic (5 mmol/l) hyperinsulinaemic (1.5 mU or 9 pmol · kg^–1· min^–1) clamp accompanied by indirect calorimetry before and at the end of the insulin infusion. A percutaneous biopsy was performed from m. vastus lateralis for the determination of mTG. At baseline the IDDM patients had higher glucose (10.2 ± 0.9 vs 5.6 ± 0.1 mmol/l, p < 0.001), insulin (40.3 ± 3.2 vs 23.2 ± 4.2 pmol/l, p < 0.01), HDL cholesterol (1.28 ± 0.06 vs 1.04 ± 0.03 mmol/l, p < 0.01) and mTG (32.9 ± 4.6 vs 13.6 ± 2.7 mmol/kg dry weight, p < 0.01) concentrations than the healthy men, respectively. The IDDM patients had lower insulin stimulated whole body total (–25 %, p < 0.001), oxidative (–18 %, p < 0.01) and non-oxidative glucose disposal rates (–43 %, p < 0.001), whereas lipid oxidation rate was higher in the basal state ( + 44 %, p < 0.01) and during hyperinsulinaemia ( + 283 %, p < 0.05). mTG concentrations did not change significantly during the clamp or correlate with insulin stimulated glucose disposal. In healthy men mTG correlated positively with lipid oxidation rate at the end of hyperinsulinaemia (r = 0.75, p < 0.05). In conclusion: 1) IDDM is associated with increased intramuscular TG content. 2) mTG content does not correlate with insulin sensitivity in healthy subjects or patients with IDDM. [Diabetologia (1998) 41: 111–115] Received: 12 June 1997 and in revised form: 8 September 1997     

The predictive capability of the glycaemic response to spaghetti in non-insulin dependent (NIDDM) and insulin dependent (IDDM) diabetic subjects

To evaluate the predictive capability of the postprandial blood glucose response after consumption of a starch-rich meal, we compared the glycaemic effects of spaghetti (60 g) taken alone and with bolognese sauce (167 g). The study was carried out in both NIDDM (n = 6) and IDDM (n = 6) subjects. The latter had achieved normoglycaemia 120 min prior to the test meal by means of an artificial pancreas (Biostator) which provided constant insulinaemia during the observation period of 4 h. We found that the areas of blood glucose (above basal) were identical irrespective of whether spaghetti was taken alone or as part of a mixed meal in both NIDDM (484 +/- 154 mmol l-1 240 min-1 vs. 393 +/- 126 mmol l-1 240 min-1) and IDDM subjects (610 +/- 143 mmol l-1 240 min-1 vs. 770 +/- 135 mmol l-1 240 min-1). The insulin levels were identical in the IDDM diabetics. By contrast, the mixed meal caused a more marked insulinaemic response than spaghetti per se in the NIDDM subjects (3187 +/- 637 mU l-1 240 min-1 vs. 1940 +/- 235 mU l-1 240 min-1; P less than 0.05). In conclusion, the predictive capability of the glycaemic response to spaghetti was good in both IDDM and NIDDM diabetic subjects, at least under the conditions of the present study.     

Efficacy of two telemonitoring systems to improve glycaemic control during basal insulin initiation in patients with type 2 diabetes: The TeleDiab-2 randomized controlled trial

TeleDiab-2 was a 13-month randomized controlled trial evaluating the efficacy and safety of two telemonitoring systems to optimize basal insulin (BI) initiation in subjects with inadequately controlled type 2 diabetes (HbA1c, 7.5%-10%). A total of 191 participants (mean age 58.7 years, mean HbA1c 8.9%) were randomized into three groups: group 1(G1, standard care, n = 63), group 2 (G2, interactive voice response system, n = 64) and group 3 (G3, Diabeo-BI app software, n = 64). The two telemonitoring systems proposed daily adjustments of BI doses, in order to facilitate the achievement of fasting blood glucose (FBG) values targeted at ~100 mg/dL. At 4 months follow-up, HbA1c reduction was significantly higher in the telemonitoring groups (G2: −1.44% and G3: −1.48% vs. G1: −0.92%; P < 0.002). Moreover, target FBG was reached by twice as many patients in the telemonitoring groups as in the control group, and insulin doses were also titrated to higher levels. No severe hypoglycaemia was observed in the telemonitoring groups and mild hypoglycaemia frequency was similar in all groups. In conclusion, both telemonitoring systems improved glycaemic control to a similar extent, without increasing hypoglycaemic episodes.     

Effect of pioglitazone in combination with insulin therapy on glycaemic control, insulin dose requirement and lipid profile in patients with type 2 diabetes previously poorly controlled with combination therapy

AIM: The aim of this randomized placebo-controlled study was to evaluate the safety and efficacy of pioglitazone administered alone or in combination with metformin in reducing insulin dosage requirements for improved glycaemic control in patients with type 2 diabetes previously poorly controlled with combination therapy. METHODS: In this multicentre, double-blind study, 222 patients with haemoglobin A1c (HbA(1c))>8.0% at screening treated with combination therapy initially were given titrated insulin therapy (to fasting plasma glucose <140 mg/dl) and then were randomly assigned to 20-week treatment with pioglitazone or placebo in combination with insulin, with or without concurrent metformin therapy. More than 98% of patients were taking metformin prior to and during the study. RESULTS: Pioglitazone significantly reduced (p < 0.05) insulin dose requirements 2 weeks after treatment initiation. At study end relative to baseline, pioglitazone reduced daily insulin dosages by 12.0 units (p < 0.001), a 21.5% (12.0/55.8 units at baseline) group mean average reduction. Relative to placebo, pioglitazone reduced daily insulin dosages by 12.7 units [95% confidence interval [CI]: -17.5, -8.0], while improving mean HbA(1c) levels [adjusted mean HbA(1c) change: pioglitazone, -1.6% vs. placebo, -1.4% (not statistically different)]. Pioglitazone also significantly increased high-density lipoprotein cholesterol levels [adjusted mean difference: +4.5 (95% CI: 2.6-6.5) mg/dl], decreased triglyceride levels [-43.9 (-69.2, -18.6) mg/dl], shifted low-density lipoprotein (LDL) particle concentrations from small [pattern B, -13.6% (-17.7%, -9.5%)] to large [pattern A, +15.1% (10.8%, 19.5%)] and increased mean LDL particle size [+3.8 (2.6, 4.9) A]. More pioglitazone-treated patients experienced oedema (9.0 vs. 4.5%) and weight gain (9.1 vs. 2.7%) than placebo patients. CONCLUSIONS: Pioglitazone in combination with insulin therapy improved glycaemic control, reduced insulin dose requirements and improved lipid profiles in patients with type 2 diabetes previously poorly controlled with combination therapy.     

Very low density lipoprotein subfraction abnormalities in IDDM patients: any effect of blood glucose control?

Summary Normolipidaemic insulin-dependent diabetic (IDDM) patients are characterized by an increase in the smaller VLDL particles, considered to be the most atherogenic. Since blood glucose control is one of the main regulators of lipid metabolism in diabetic patients, it could influence the shift in the distribution of VLDL subfractions towards smaller particles. To evaluate this possibility, VLDL subfractions, post-heparin lipoprotein lipase and hepatic lipase activities have been evaluated in male IDDM patients with either unsatisfactory blood glucose control (group 1, HbA_1c>8%, n=18) or good blood glucose control (group 2, HbA_1c<8%, n=16) and in 16 normoglycaemic individuals. The three groups were comparable for sex, age, body mass index, and plasma lipid levels. Three VLDL subfractions (large, Svedberg flotation unit (Sf) 175–400; intermediate, Sf 100–175; small, Sf 20–100) were separated by density gradient ultracentrifugation and analysed for cholesterol, triglyceride, and phospholipid levels. When compared to control subjects both groups of IDDM patients showed a clear shift in VLDL subfraction distribution with a significant increase in the proportion of small VLDL (group 1; 49±2%; p<0.005; group 2: 51±3%, p<0.01; control subjects 40±2%) (mean ± SEM) in relation to total VLDL. By contrast, the absolute lipid concentration of small VLDL was higher only in group 1, compared to control subjects (35±4 vs 27±3 mg/dl, p=0.05). Post-heparin hepatic lipase activity was significantly reduced in both IDDM groups (group 1: 254±19 mU/ ml, p<0.05; group 2: 202±19 mU/ml, p<0.005; control subjects 317±31 mU/ml). In conclusion, normolipidaemic IDDM patients show an increase in the smallest VLDL, whatever their degree of blood glucose control. However, this abnormality may be clinically relevant only in patients with unsatisfactory blood glucose control, since absolute lipid concentration of these potentially atherogenic particles is only increased in this group.Abbreviations IDDM Insulin-dependent diabetes mellitus - VLDL very low density lipoprotein - LPL lipoprotein lipase - HL hepatic lipase     

High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria

Summary Life expectancy is shorter in the subset of insulin-dependent diabetic (IDDM) patients who are susceptible to kidney disease. Familial factors may be important. In this study the prevalence of cardiovascular disease mortality and morbidity and of risk factors for cardiovascular disease was compared in the parents of 31 IDDM patients with elevated albumin excretion rate (AER > 45 μg/min; group A) with that of parents of 31 insulin-dependent diabetic patients with normoalbuminuria (AER < 20 μg/min; group B). The two diabetic patient groups were matched for age and duration of disease. Information on deceased parents was obtained from death certificates and clinical records and morbidity for cardiovascular disease was ascertained using the World Health Organization questionnaire and Minnesota coded ECG. Hyperlipidaemia was defined as serum cholesterol higher than 6 mmol/l and/or plasma triglycerides higher than 2.3 mmol/l and/or lipid lowering therapy; arterial hypertension as systolic blood pressure higher than 140 mmHg and/or diastolic blood pressure higher than 90 mmHg and/or antihypertensive treatment. The percentage of dead parents was similar in the two groups (26 vs 20 % for parents of group A vs group B, respectively), but the parents of the diabetic patients with elevated AER had died at a younger age (58 ± 10 vs 70 ± 14 years; p < 0.05). Parents of diabetic patients with nephropathy had a more than three times greater frequency of combined mortality and morbidity for cardiovascular disease than that of the parents of diabetic patients without nephropathy (26 vs 8 %; odds ratio 3.96, 95 % CI 1.3 to 12.2; p < 0.02). Living parents of group A had a higher prevalence of arterial hypertension (42 vs 14 % p < 0.01) and hyperlipidaemia (49 vs 26 % p < 0.05) as well as higher levels of lipoprotein (a) [median (range) 27.2 (1–107) vs 15.6 (0.2–98) mg/dl; p < 0.05]. They also had reduced insulin sensitivity [insulin tolerance test: median (range) K_itt index: 3.7 (0.7–6.2) vs 4.8 (0.7–6.7)% per min; p < 0.05]. In the families of IDDM patients with elevated AER there was a higher frequency of risk factors for cardiovascular disease as well as a predisposition to cardiovascular disease events. This may help explain, in part, the high prevalence of cardiovascular disease mortality and morbidity in those IDDM patients who develop nephropathy. [Diabetologia (1997) 40: 1191–1196] Received: 4 March 1997 and in revised form: 9 May 1997